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  • 1. Andersson, Lisa S.
    et al.
    Larhammar, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Memic, Fatima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wootz, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Schwochow, Doreen
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Patra, Kalicharan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Arnason, Thorvaldur
    Wellbring, Lisbeth
    Hjälm, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Imsland, Freyja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Petersen, Jessica L.
    McCue, Molly E.
    Mickelson, James R.
    Cothran, Gus
    Ahituv, Nadav
    Roepstorff, Lars
    Mikko, Sofia
    Vallstedt, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lindgren, Gabriella
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 488, no 7413, p. 642-646Article in journal (Refereed)
    Abstract [en]

    Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

  • 2.
    Andrade, Pedro
    et al.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Pinho, Catarina
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Perez i de lanuza, Guillem
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Afonso, Sandra
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Brejcha, Jindrich
    Charles Univ Prague, Fac Sci, Dept Philosophy & Hist Sci, Prague 12800 2, Czech Republic;Natl Museum, Dept Zool, Prague 19300, Czech Republic;Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pereira, Paulo
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Sabatino, Stephen J.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Bellati, Adriana
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Pellitteri-Rosa, Daniele
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Bosakova, Zuzana
    Charles Univ Prague, Fac Sci, Dept Analyt Chem, Prague 12843 2, Czech Republic.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Carretero, Miguel A.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Feiner, Nathalie
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Marsik, Petr
    Czech Univ Life Sci Prague, Fac Agrobiol Food & Nat Resources, Dept Food Sci, Prague 16521 6, Czech Republic.
    Pauperio, Francisco
    Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Salvi, Daniele
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Aquila, Dept Hlth Life & Environm Sci, I-67100 Laquila, Italy.
    Soler, Lucile
    Natl Bioinformat Infrastruct Sweden, Sci Life Lab, S-75123 Uppsala, Sweden.
    While, Geoffrey M.
    Univ Tasmania, Sch ol Biol Sci, Hobart, Tas 7005, Australia;Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
    Uller, Tobias
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Font, Enrique
    Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Carneiro, Miguel
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Regulatory changes in pterin and carotenoid genes underlie balanced color polymorphisms in the wall lizard2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 12, p. 5633-5642Article in journal (Refereed)
    Abstract [en]

    Reptiles use pterin and carotenoid pigments to produce yellow, orange, and red colors. These conspicuous colors serve a diversity of signaling functions, but their molecular basis remains unresolved. Here, we show that the genomes of sympatric color morphs of the European common wall lizard (Podarcis muralis), which differ in orange and yellow pigmentation and in their ecology and behavior, are virtually undifferentiated. Genetic differences are restricted to two small regulatory regions near genes associated with pterin [sepiapterin reductase (SPR)] and carotenoid [beta-carotene oxygenase 2 (BCO2)] metabolism, demonstrating that a core gene in the housekeeping pathway of pterin biosynthesis has been coopted for bright coloration in reptiles and indicating that these loci exert pleiotropic effects on other aspects of physiology. Pigmentation differences are explained by extremely divergent alleles, and haplotype analysis revealed abundant transspecific allele sharing with other lacertids exhibiting color polymorphisms. The evolution of these conspicuous color ornaments is the result of ancient genetic variation and cross-species hybridization.

  • 3.
    Ayllon, Fernando
    et al.
    Inst Marine Res, N-5024 Bergen, Norway..
    Kjaerner-Semb, Erik
    Inst Marine Res, N-5024 Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Furmanek, Tomasz
    Inst Marine Res, N-5024 Bergen, Norway..
    Wennevik, Vidar
    Inst Marine Res, N-5024 Bergen, Norway..
    Solberg, Monica F.
    Inst Marine Res, N-5024 Bergen, Norway..
    Dahle, Geir
    Inst Marine Res, N-5024 Bergen, Norway..
    Taranger, Geir Lasse
    Inst Marine Res, N-5024 Bergen, Norway..
    Glover, Kevin A.
    Inst Marine Res, N-5024 Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Edvardsen, Rolf B.
    Inst Marine Res, N-5024 Bergen, Norway..
    Wargelius, Anna
    Inst Marine Res, N-5024 Bergen, Norway..
    The vgll3 Locus Controls Age at Maturity in Wild and Domesticated Atlantic Salmon (Salmo salar L.) Males2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11, article id e1005628Article in journal (Refereed)
    Abstract [en]

    Wild and domesticated Atlantic salmon males display large variation for sea age at sexual maturation, which varies between 1-5 years. Previous studies have uncovered a genetic predisposition for variation of age at maturity with moderate heritability, thus suggesting a polygenic or complex nature of this trait. The aim of this study was to identify associated genetic loci, genes and ultimately specific sequence variants conferring sea age at maturity in salmon. We performed a genome wide association study (GWAS) using a pool sequencing approach (20 individuals per river and phenotype) of male salmon returning to rivers as sexually mature either after one sea winter (2009) or three sea winters (2011) in six rivers in Norway. The study revealed one major selective sweep, which covered 76 significant SNPs in which 74 were found in a 370 kb region of chromosome 25. Genotyping other smolt year classes of wild and domesticated salmon confirmed this finding. Genotyping domesticated fish narrowed the haplotype region to four SNPs covering 2386 bp, containing the vgll3 gene, including two missense mutations explaining 33-36% phenotypic variation. A single locus was found to have a highly significant role in governing sea age at maturation in this species. The SNPs identified may be both used as markers to guide breeding for late maturity in salmon aquaculture and in monitoring programs of wild salmon. Interestingly, a SNP in proximity of the VGLL3 gene in humans (Homo sapiens), has previously been linked to age at puberty suggesting a conserved mechanism for timing of puberty in vertebrates.

  • 4.
    Brusini, Irene
    et al.
    KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, Huddinge, Sweden.
    Carneiro, Miguel
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, Vairao, Portugal; Univ Porto, Dept Biol, Fac Ciencias, Porto, Portugal.
    Wang, Chunliang
    KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, Huddinge, Sweden.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ring, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Afonso, Sandra
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, Vairao, Portugal.
    Blanco-Aguiar, José A.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, Vairao, Portugal; CSIC, Inst Invest Recursos Cineget IREC, Ciudad Real, Spain; UCLM, CSIC, Ciudad Real, Spain.
    Ferrand, Nuno
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, Vairao, Portugal; Univ Porto, Dept Biol, Fac Ciencias, Porto, Portugal; Univ Johannesburg, Dept Zool, Johannesburg, South Africa.
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Villafuerte, Rafael
    CSIC, IESA, Cordoba, Spain.
    Smedby, Örjan
    KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, Huddinge, Sweden.
    Damberg, Peter
    Karolinska Univ Hosp, Karolinska Expt Res & Imaging Ctr, Solna, Sweden.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Fredriksson, M
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX USA; Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Changes in brain architecture are consistent with altered fear processing in domestic rabbits2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 28, p. 7380-7385Article in journal (Refereed)
    Abstract [en]

    The most characteristic feature of domestic animals is their change in behavior associated with selection for tameness. Here we show, using high-resolution brain magnetic resonance imaging in wild and domestic rabbits, that domestication reduced amygdala volume and enlarged medial prefrontal cortex volume, supporting that areas driving fear have lost volume while areas modulating negative affect have gained volume during domestication. In contrast to the localized gray matter alterations, white matter anisotropy was reduced in the corona radiata, corpus callosum, and the subcortical white matter. This suggests a compromised white matter structural integrity in projection and association fibers affecting both afferent and efferent neural flow, consistent with reduced neural processing. We propose that compared with their wild ancestors, domestic rabbits are less fearful and have an attenuated flight response because of these changes in brain architecture.

  • 5.
    Carneiro, Miguel
    et al.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.;Univ Porto, Fac Ciencias, Dept Biol, P-4169007 Oporto, Portugal..
    Hu, Dou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Archer, John
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal..
    Feng, Chungang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Afonso, Sandra
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal..
    Chen, Congying
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Jiangxi Agr Univ, State Key Lab Pig Genet Improvement & Prod Techno, Nanchang 330045, Jiangxi, Peoples R China..
    Blanco-Aguiar, Jose A.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.;Inst Invest Recursos Cineget IREC CSIC UCLM JCCM, Ciudad Real 13071, Spain..
    Garreau, Herve
    Univ Toulouse, INRA, Genet Physiol & Syst Elevage UMR1388, F-31326 Castanet Tolosan, France..
    Boucher, Samuel
    FFC, F-75009 Paris, France..
    Ferreira, Paula G.
    Univ Porto, ICBAS, Dept Anat, P-4050343 Oporto, Portugal.;Univ Porto, UMIB, P-4050343 Oporto, Portugal..
    Ferrand, Nuno
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.;Univ Porto, Fac Ciencias, Dept Biol, P-4169007 Oporto, Portugal.;Univ Johannesburg, Fac Sci, Dept Zool, ZA-2006 Auckland Pk, South Africa..
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden.;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. ETH, Inst Anim Sci, CH-8092 Zurich, Switzerland..
    Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus2017In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 205, no 2, p. 955-965Article in journal (Refereed)
    Abstract [en]

    The dwarf phenotype characterizes the smallest of rabbit breeds and is governed largely by the effects of a single dwarfing allele with an incompletely dominant effect on growth. Dwarf rabbits typically weigh under 1 kg and have altered craniofacial morphology. The dwarf allele is recessive lethal and dwarf homozygotes die within a few days of birth. The dwarf phenotype is expressed in heterozygous individuals and rabbits from dwarf breeds homozygous for the wild-type allele are normal, although smaller when compared to other breeds. Here, we show that the dwarf allele constitutes a similar to 12.1 kb deletion overlapping the promoter region and first three exons of the HMGA2 gene leading to inactivation of this gene. HMGA2 has been frequently associated with variation in body size across species. Homozygotes for null alleles are viable in mice but not in rabbits and probably not in humans. RNA-sequencing analysis of rabbit embryos showed that very few genes (4-29 genes) were differentially expressed among the three HMGA2/dwarf genotypes, suggesting that dwarfism and inviability in rabbits are caused by modest changes in gene expression. Our results show that HMGA2 is critical for normal expression of IGF2BP2, which encodes an RNA-binding protein. Finally, we report a catalog of regions of elevated genetic differentiation between dwarf and normal-size rabbits, including LCORL-NCAPG, STC2, HOXD cluster, and IGF2BP2. Levels and patterns of genetic diversity at the LCORL-NCAPG locus further suggest that small size in dwarf breeds was enhanced by crosses with wild rabbits. Overall, our results imply that small size in dwarf rabbits results from a large effect, loss-of-function (LOF) mutation in HMGA2 combined with polygenic selection.

  • 6. Carneiro, Miguel
    et al.
    Piorno, Vicente
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alves, Joel M.
    Ferrand, Nuno
    Alves, Paulo C.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Candidate genes underlying heritable differences in reproductive seasonality between wild and domestic rabbits2015In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 46, no 4, p. 418-425Article in journal (Refereed)
    Abstract [en]

    Reproductive seasonality is a trait that often differs between domestic animals and their wild ancestors, with domestic animals showing prolonged or even continuous breeding seasons. However, the genetic basis underlying this trait is still poorly understood for most species, and because environmental factors and resource availability are known to play an important role in determining breeding seasons, it is also not clear in most cases to what extent this phenotypic shift is determined by the more lenient captive conditions or by genetic factors. Here, using animals resulting from an initial cross between wild and domestic rabbits followed by two consecutive backcrosses (BC1 and BC2) to wild rabbits, we evaluated the yearly distribution of births for the different generations. Similar to domestic rabbits, F1 animals could be bred all year round but BC1 and BC2 animals showed a progressive and significant reduction in the span of the breeding season, providing experimental evidence that reduced seasonal breeding in domestic rabbits has a clear genetic component and is not a simple by-product of rearing conditions. We then took advantage of a recently published genome-wide scan of selection in the domesticated lineage and searched for candidate genes potentially associated with this phenotypic shift. Candidate genes located within regions targeted by selection include well-known examples of genes controlling clock functions (CRY1 and NR3C1) and reproduction (PRLR).

  • 7. Carneiro, Miguel
    et al.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Di Palma, Federica
    Albert, Frank W.
    Alfoeldi, Jessica
    Barrio, Alvaro Martinez
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rafati, Nima
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sayyab, Shumaila
    Turner-Maier, Jason
    Younis, Shady
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Afonso, Sandra
    Aken, Bronwen
    Alves, Joel M.
    Barrell, Daniel
    Bolet, Gerard
    Boucher, Samuel
    Burbano, Hernan A.
    Campos, Rita
    Chang, Jean L.
    Duranthon, Veronique
    Fontanesi, Luca
    Garreau, Herve
    Heiman, David
    Johnson, Jeremy
    Mage, Rose G.
    Peng, Ze
    Queney, Guillaume
    Rogel-Gaillard, Claire
    Ruffier, Magali
    Searle, Steve
    Villafuerte, Rafael
    Xiong, Anqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Sarah
    Forsberg-Nilsson, Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Good, Jeffrey M.
    Lander, Eric S.
    Ferrand, Nuno
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication2014In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 345, no 6200, p. 1074-1079Article in journal (Refereed)
    Abstract [en]

    The genetic changes underlying the initial steps of animal domestication are still poorly understood. We generated a high-quality reference genome for the rabbit and compared it to resequencing data from populations of wild and domestic rabbits. We identified more than 100 selective sweeps specific to domestic rabbits but only a relatively small number of fixed (or nearly fixed) single-nucleotide polymorphisms (SNPs) for derived alleles. SNPs with marked allele frequency differences between wild and domestic rabbits were enriched for conserved noncoding sites. Enrichment analyses suggest that genes affecting brain and neuronal development have often been targeted during domestication. We propose that because of a truly complex genetic background, tame behavior in rabbits and other domestic animals evolved by shifts in allele frequencies at many loci, rather than by critical changes at only a few domestication loci.

  • 8.
    Dorshorst, Ben
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Harun-Or-Rashid, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bagherpoor, Alireza Jian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ashwell, Chris
    Gourichon, David
    Tixier-Boichard, Michèle
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A Genomic Duplication is Associated with Ectopic Eomesodermin Expression in the Embryonic Chicken Comb and Two Duplex-comb Phenotypes2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 3, article id e1004947Article in journal (Refereed)
    Abstract [en]

    Duplex-comb (D) is one of three major loci affecting comb morphology in the domestic chicken. Here we show that the two Duplex-comb alleles, V-shaped (D*V) and Buttercup (D*C), are both associated with a 20 Kb tandem duplication containing several conserved putative regulatory elements located 200 Kb upstream of the eomesodermin gene (EOMES). EOMES is a T-box transcription factor that is involved in mesoderm specification during gastrulation. In D*V and D*C chicken embryos we find that EOMES is ectopically expressed in the ectoderm of the comb-developing region as compared to wild-type embryos. The confinement of the ectopic expression of EOMES to the ectoderm is in stark contrast to the causal mechanisms underlying the two other major comb loci in the chicken (Rose-comb and Pea-comb) in which the transcription factors MNR2 and SOX5 are ectopically expressed strictly in the mesenchyme. Interestingly, the causal mutations of all three major comb loci in the chicken are now known to be composed of large-scale structural genomic variants that each result in ectopic expression of transcription factors. The Duplex-comb locus also illustrates the evolution of alleles in domestic animals, which means that alleles evolve by the accumulation of two or more consecutive mutations affecting the phenotype. We do not yet know whether the V-shaped or Buttercup allele correspond to the second mutation that occurred on the haplotype of the original duplication event.

  • 9.
    Dorshorst, Ben
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Henegar, Corneliu
    Liao, Xiaoping
    Almén, Markus Sällman
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ito, Shosuke
    Wakamatsu, Kazumasa
    Stothard, Paul
    Van Doormaal, Brian
    Plastow, Graham
    Barsh, Gregory S.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dominant Red Coat Color in Holstein Cattle Is Associated with a Missense Mutation in the Coatomer Protein Complex, Subunit Alpha (COPA) Gene2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0128969Article in journal (Refereed)
    Abstract [en]

    Coat color in Holstein dairy cattle is primarily controlled by the melanocortin 1 receptor (MC1R) gene, a central determinant of black (eumelanin) vs. red/brown pheomelanin synthesis across animal species. The major MC1R alleles in Holsteins are Dominant Black (MC1R(D)) and Recessive Red (MC1R(e)). A novel form of dominant red coat color was first observed in an animal born in 1980. The mutation underlying this phenotype was named Dominant Red and is epistatic to the constitutively activated MC1R(D). Here we show that a missense mutation in the coatomer protein complex, subunit alpha (COPA), a gene with previously no known role in pigmentation synthesis, is completely associated with Dominant Red in Holstein dairy cattle. The mutation results in an arginine to cysteine substitution at an amino acid residue completely conserved across eukaryotes. Despite this high level of conservation we show that both heterozygotes and homozygotes are healthy and viable. Analysis of hair pigment composition shows that the Dominant Red phenotype is similar to the MC1R Recessive Red phenotype, although less effective at reducing eumelanin synthesis. RNA-seq data similarly show that Dominant Red animals achieve predominantly pheomelanin synthesis by down regulating genes normally required for eumelanin synthesis. COPA is a component of the coat protein I seven subunit complex that is involved with retrograde and cis-Golgi intracellular coated vesicle transport of both protein and RNA cargo. This suggests that Dominant Red may be caused by aberrant MC1R protein or mRNA trafficking within the highly compartmentalized melanocyte, mimicking the effect of the Recessive Red loss of function MC1R allele.

  • 10.
    Dorshorst, Ben
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Molin, Anna-Maja
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Anna M.
    Stromstedt, Lina
    Pham, Manh-Hung
    Chen, Chih-Feng
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Ashwell, Chris
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A Complex Genomic Rearrangement Involving the Endothelin 3 Locus Causes Dermal Hyperpigmentation in the Chicken2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 12, p. e1002412-Article in journal (Refereed)
    Abstract [en]

    Dermal hyperpigmentation or Fibromelanosis (FM) is one of the few examples of skin pigmentation phenotypes in the chicken, where most other pigmentation variants influence feather color and patterning. The Silkie chicken is the most widespread and well-studied breed displaying this phenotype. The presence of the dominant FM allele results in extensive pigmentation of the dermal layer of skin and the majority of internal connective tissue. Here we identify the causal mutation of FM as an inverted duplication and junction of two genomic regions separated by more than 400 kb in wild-type individuals. One of these duplicated regions contains endothelin 3 (EDN3), a gene with a known role in promoting melanoblast proliferation. We show that EDN3 expression is increased in the developing Silkie embryo during the time in which melanoblasts are migrating, and elevated levels of expression are maintained in the adult skin tissue. We have examined four different chicken breeds from both Asia and Europe displaying dermal hyperpigmentation and conclude that the same structural variant underlies this phenotype in all chicken breeds. This complex genomic rearrangement causing a specific monogenic trait in the chicken illustrates how novel mutations with major phenotypic effects have been reused during breed formation in domestic animals.

  • 11.
    Felkel, S.
    et al.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria.;Vienna Grad Sch Populat Genet, Vienna, Austria..
    Vogl, C.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria..
    Rigler, D.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria..
    Jagannathan, V.
    Univ Bern, Inst Genet, Vetsuisse Fac, Bern, Switzerland..
    Leeb, T.
    Univ Bern, Inst Genet, Vetsuisse Fac, Bern, Switzerland..
    Fries, R.
    Tech Univ Munich, Lehrstuhl Tierzucht, Freising Weihenstephan, Germany..
    Neuditschko, M.
    Agroscope, Swiss Natl Stud Farm, Avenches, Switzerland..
    Rieder, S.
    Agroscope, Swiss Natl Stud Farm, Avenches, Switzerland..
    Velie, B.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Lindgren, G.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schlötterer, C.
    Univ Vet Med Vienna, Inst Populat Genet, Vienna, Austria..
    Rattei, T.
    Univ Vienna, Dept Microbiol & Ecosyst Sci, Div Computat Syst Biol, Vienna, Austria..
    Brem, G.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria..
    Wallner, B.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria..
    Asian horses deepen the MSY phylogeny2018In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 49, no 1, p. 90-93Article in journal (Refereed)
    Abstract [en]

    Humans have shaped the population history of the horse ever since domestication about 5500years ago. Comparative analyses of the Y chromosome can illuminate the paternal origin of modern horse breeds. This may also reveal different breeding strategies that led to the formation of extant breeds. Recently, a horse Y-chromosomal phylogeny of modern horses based on 1.46Mb of the male-specific Y (MSY) was generated. We extended this dataset with 52 samples from five European, two American and seven Asian breeds. As in the previous study, almost all modern European horses fall into a crown group, connected via a few autochthonous Northern European lineages to the outgroup, the Przewalski's Horse. In total, we now distinguish 42 MSY haplotypes determined by 158 variants within domestic horses. Asian horses show much higher diversity than previously found in European breeds. The Asian breeds also introduce a deep split to the phylogeny, preliminarily dated to 5527 +/- 872years. We conclude that the deep splitting Asian Y haplotypes are remnants of a far more diverse ancient horse population, whose haplotypes were lost in other lineages.

  • 12.
    Felkel, Sabine
    et al.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria;Vienna Grad Sch Populat Genet, Vienna, Austria.
    Vogl, Claus
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    Rigler, Doris
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    Dobretsberger, Viktoria
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    Chowdhary, Bhanu P.
    United Arab Emirates Univ, Al Ain 15551, U Arab Emirates.
    Distl, Ottmar
    Univ Vet Med Hannover, Inst Anim Breeding & Genet, D-30559 Hannover, Germany.
    Fries, Ruedi
    Tech Univ Muenchen, Lehrstuhl Tierzucht, D-85354 Freising Weihenstephan, Germany.
    Jagannathan, Vidhya
    Univ Bern, Vetsuisse Fac, Inst Genet, CH-3001 Bern, Switzerland.
    Janecka, Jan E.
    Duquesne Univ, Dept Biol Sci, Pittsburgh, PA 15282 USA.
    Leeb, Tosso
    Univ Bern, Vetsuisse Fac, Inst Genet, CH-3001 Bern, Switzerland.
    Lindgren, Gabriella
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Katholieke Univ Leuven, Dept Biosyst, B-3001 Leuven, Belgium.
    McCue, Molly
    Univ Minnesota, Vet Populat Med Dept, St Paul, MN 55108 USA.
    Metzger, Julia
    Univ Vet Med Hannover, Inst Anim Breeding & Genet, D-30559 Hannover, Germany.
    Neuditschko, Markus
    Agroscope, Swiss Natl Stud Farm, CH-1580 Avenches, Switzerland.
    Rattei, Thomas
    Univ Vienna, Dept Microbiol & Ecosyst Sci, Div Computat Syst Biol, Althanstr 14, A-1090 Vienna, Austria.
    Raudsepp, Terje
    Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Rieder, Stefan
    Agroscope, Swiss Natl Stud Farm, CH-1580 Avenches, Switzerland.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schaefer, Robert
    Agroscope, Swiss Natl Stud Farm, CH-1580 Avenches, Switzerland.
    Schloetterer, Christian
    Univ Vet Med Vienna, Inst Populat Genet, A-1210 Vienna, Austria.
    Thaller, Georg
    Univ Kiel, Inst Anim Breeding & Husb, D-24098 Kiel, Germany.
    Tetens, Jens
    Univ Kiel, Inst Anim Breeding & Husb, D-24098 Kiel, Germany;Georg August Univ Gottingen, Dept Anim Sci, Funct Breeding Grp, D-37077 Gottingen, Germany.
    Velie, Brandon
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Univ Sydney, Sch Life & Environm Sci, Sydney, NSW 2006, Australia.
    Brem, Gottfried
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    Wallner, Barbara
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    The horse Y chromosome as an informative marker for tracing sire lines2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6095Article in journal (Refereed)
    Abstract [en]

    Analysis of the Y chromosome is the best-established way to reconstruct paternal family history in humans. Here, we applied fine-scaled Y-chromosomal haplotyping in horses with biallelic markers and demonstrate the potential of our approach to address the ancestry of sire lines. We de novo assembled a draft reference of the male-specific region of the Y chromosome from Illumina short reads and then screened 5.8 million basepairs for variants in 130 specimens from intensively selected and rural breeds and nine Przewalski's horses. Among domestic horses we confirmed the predominance of a young'crown haplogroup' in Central European and North American breeds. Within the crown, we distinguished 58 haplotypes based on 211 variants, forming three major haplogroups. In addition to two previously characterised haplogroups, one observed in Arabian/Coldblooded and the other in Turkoman/Thoroughbred horses, we uncovered a third haplogroup containing Iberian lines and a North African Barb Horse. In a genealogical showcase, we distinguished the patrilines of the three English Thoroughbred founder stallions and resolved a historic controversy over the parentage of the horse 'Galopin', born in 1872. We observed two nearly instantaneous radiations in the history of Central and Northern European Y-chromosomal lineages that both occurred after domestication 5,500 years ago.

  • 13. Feng, Chungang
    et al.
    Gao, Yu
    Dorshorst, Ben
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Song, Chi
    Gu, Xiaorong
    Li, Qingyuan
    Li, Jinxiu
    Liu, Tongxin
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhao, Yiqiang
    Wang, Yanqiang
    Fei, Jing
    Li, Huifang
    Chen, Kuanwei
    Qu, Hao
    Shu, Dingming
    Ashwell, Chris
    Da, Yang
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hu, Xiaoxiang
    Li, Ning
    A cis-Regulatory Mutation of PDSS2 Causes Silky-Feather in Chickens2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 8, p. e1004576-Article in journal (Refereed)
    Abstract [en]

    Silky-feather has been selected and fixed in some breeds due to its unique appearance. This phenotype is caused by a single recessive gene (hookless, h). Here we map the silky-feather locus to chromosome 3 by linkage analysis and subsequently fine-map it to an 18.9 kb interval using the identical by descent (IBD) method. Further analysis reveals that a C to G transversion located upstream of the prenyl (decaprenyl) diphosphate synthase, subunit 2 (PDSS2) gene is causing silky-feather. All silky-feather birds are homozygous for the G allele. The silky-feather mutation significantly decreases the expression of PDSS2 during feather development in vivo. Consistent with the regulatory effect, the C to G transversion is shown to remarkably reduce PDSS2 promoter activity in vitro. We report a new example of feather structure variation associated with a spontaneous mutation and provide new insight into the PDSS2 function.

  • 14.
    Feng, Chungang
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pettersson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lamichhaney, Sangeet
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rafati, Nima
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Casini, Michele
    Swedish Univ Agr Sci, Dept Aquat Resources, Inst Marine Res, Lysekil, Sweden..
    Folkvord, Arild
    Univ Bergen, Dept Biol, Bergen, Norway.;Hjort Ctr Marine Ecosyst Dynam, Bergen, Norway.;Inst Marine Res, Bergen, Norway..
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    Moderate nucleotide diversity in the Atlantic herring is associated with a low mutation rate2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23907Article in journal (Refereed)
    Abstract [en]

    The Atlantic herring is one of the most abundant vertebrates on earth but its nucleotide diversity is moderate (pi = 0.3%), only three-fold higher than in human. Here, we present a pedigree-based estimation of the mutation rate in this species. Based on whole-genome sequencing of four parents and 12 offspring, the estimated mutation rate is 2.0 x 10(-9) per base per generation. We observed a high degree of parental mosaicism indicating that a large fraction of these de novo mutations occurred during early germ cell development. The estimated mutation rate the lowest among vertebrates analyzed to date - partially explains the discrepancy between the rather low nucleotide diversity in herring and its huge census population size. But a species like the herring will never reach its expected nucleotide diversity because of fluctuations in population size over the millions of years it takes to build up high nucleotide diversity.

  • 15.
    Herrmann, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Larsson, Viviana Cavaglia
    Klinisk virologi.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Sund, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Eriksson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Arvidson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Yun, Zhibing
    Bondeson, Kåre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Comparison of a duplex quantitative real-time PCR assay and the COBAS Amplicor CMV Monitor test for detection of cytomegalovirus2004In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 42, no 5, p. 1909-14Article in journal (Refereed)
    Abstract [en]

    A duplex quantitative real-time PCR (qPCR) assay was designed to detect both the polymerase gene (pol) and the glycoprotein gene (gB) of cytomegalovirus (CMV). The detection limit of the qPCR was determined to be 1 to 3 copies/reaction and the linear measure interval was 10(3) to 10(8) copies/ml. The qPCR system was compared to the COBAS Amplicor CMV Monitor test (COBAS) by an analysis of 138 plasma samples. Both systems detected CMV in 71 cases and had negative results for 33 samples. In addition, 34 samples were positive by qPCR and negative by the COBAS assay, but in no case was the COBAS result positive and the qPCR result negative. Thus, qPCR detected 48% more positive cases than the COBAS method. For samples with > or = 10(5) copies/ml by qPCR, a saturation effect was seen in the COBAS assay and quantification required dilution. Copy numbers for pol and gB by qPCR generally agreed. However, the reproducibility of qPCR assays and the need for an international standard are discussed. Discrepant copy numbers for pol and gB by qPCR were found for samples from two patients, and sequence analysis revealed that the corresponding CMV strains were mismatched at four nucleotide positions compared with the gB fragment primer sequences. In conclusion, a duplex qPCR assay in a real-time format facilitates quantitative measurements and minimizes the risk of false-negative results.

  • 16.
    Herrmann, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Stolt, Pelle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Abdeldaim, Guma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Kirsebom, Leif A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Thollesson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Differentiation and Phylogenetic Relationships in Mycobacterium spp with Special Reference to the RNase P RNA Gene rnpB2014In: Current Microbiology, ISSN 0343-8651, E-ISSN 1432-0991, Vol. 69, no 5, p. 634-639Article in journal (Refereed)
    Abstract [en]

    The rnpB gene encodes for the RNA subunit of the catalytic ribonuclease RNase P and is present in all bacteria and has both conserved and highly variable sequence regions. Determination of rnpB in 35 Mycobacterium spp. showed species specific sequences for all species except the Mycobacterium tuberculosis complex (four species). High sequence variation was seen in the P3, P15 and P19 regions of suggested secondary structures of the corresponding RNase P RNA molecules. Phylogenetic analysis showed that rnpB gave similar tree topologies as 16S rRNA and hsp65 genes. A combined analysis of the three genes increased the number of nodes with significant support from 10 to 19. The results indicate that rnpB is useful for phylogenetic studies and is a possible target for identification and detection of Mycobacterium spp.

  • 17.
    Imsland, Freyja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Feng, Chungang
    Boije, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bed'hom, Bertrand
    Fillon, Valerie
    Dorshorst, Ben
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Liu, Ranran
    Gao, Yu
    Gu, Xiaorong
    Wang, Yanqiang
    Gourichon, David
    Zody, Michael C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zecchin, William
    Vieaud, Agathe
    Tixier-Boichard, Michele
    Hu, Xiaoxiang
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Li, Ning
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The Rose-comb Mutation in Chickens Constitutes a Structural Rearrangement Causing Both Altered Comb Morphology and Defective Sperm Motility2012In: PLOS Genetics, ISSN 1553-7404, Vol. 8, no 6, p. e1002775-Article in journal (Refereed)
    Abstract [en]

    Rose-comb, a classical monogenic trait of chickens, is characterized by a drastically altered comb morphology compared to the single-combed wild-type. Here we show that Rose-comb is caused by a 7.4 Mb inversion on chromosome 7 and that a second Rose-comb allele arose by unequal crossing over between a Rose-comb and wild-type chromosome. The comb phenotype is caused by the relocalization of the MNR2 homeodomain protein gene leading to transient ectopic expression of MNR2 during comb development. We also provide a molecular explanation for the first example of epistatic interaction reported by Bateson and Punnett 104 years ago, namely that walnut-comb is caused by the combined effects of the Rose-comb and Pea-comb alleles. Transient ectopic expression of MNR2 and SOX5 (causing the Pea-comb phenotype) occurs in the same population of mesenchymal cells and with at least partially overlapping expression in individual cells in the comb primordium. Rose-comb has pleiotropic effects, as homozygosity in males has been associated with poor sperm motility. We postulate that this is caused by the disruption of the CCDC108 gene located at one of the inversion breakpoints. CCDC108 is a poorly characterized protein, but it contains a MSP (major sperm protein) domain and is expressed in testis. The study illustrates several characteristic features of the genetic diversity present in domestic animals, including the evolution of alleles by two or more consecutive mutations and the fact that structural changes have contributed to fast phenotypic evolution.

  • 18.
    Imsland, Freyja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    McGowan, Kelly
    HudsonAlpha Institute for Biotechnology / Department of Genetics, Stanford University School of Medicine.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Henegar, Corneliu
    Department of Genetics, Stanford University School of Medicine.
    Sundström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schwochow, Doreen
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences / INRA - AgroParisTech.
    Gustafson, Ulla
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Imsland, Páll
    Menntaskólinn við Hamrahlíð.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of Harvard and MIT.
    Lindgren, Gabriella
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Mikko, Sofia
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Millon, Lee
    Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis.
    Wade, Claire
    Broad Institute of Harvard and MIT.
    Schubert, Mikkel
    Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen.
    Orlando, Ludovic
    Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen.
    Penedo, Maria Cecilia T.
    Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis.
    Barsh, Gregory S.
    HudsonAlpha Institute for Biotechnology / Department of Genetics, Stanford University School of Medicine.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Texas A&M University.
    Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation underlying Dun camouflage colour in horses2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 2, p. 152-158Article in journal (Refereed)
    Abstract [en]

    Dun is a wild-type coat color in horses characterized by pigment dilution with a striking pattern of dark areas termed primitive markings. Here we show that pigment dilution in Dun horses is due to radially asymmetric deposition of pigment in the growing hair caused by localized expression of the T-box 3 (TBX3) transcription factor in hair follicles, which in turn determines the distribution of hair follicle melanocytes. Most domestic horses are non-dun, a more intensely pigmented phenotype caused by regulatory mutations impairing TBX3 expression in the hair follicle, resulting in a more circumferential distribution of melanocytes and pigment granules in individual hairs. We identified two different alleles (non-dun1 and non-dun2) causing non-dun color. non-dun2 is a recently derived allele, whereas the Dun and non-dun1 alleles are found in ancient horse DNA, demonstrating that this polymorphism predates horse domestication. These findings uncover a new developmental role for T-box genes and new aspects of hair follicle biology and pigmentation.

  • 19.
    Jiang, Lin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gilbert, Elizabeth
    Virginia Polytechnic Institute and State University, Department of Animal and Poultry Sciences.
    Sundström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ghazal, Awaisa
    Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics.
    Zhang, Xiaolan
    Broad Institute.
    Wang, Li
    Broad Institute.
    Mikkelsen, Tarjei
    Harvard University, Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology.
    Andersson, Göran
    Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The role of ZBED6 in transcriptional regulation studied by transcriptome  analysis after RNAi in mouse myoblastsArticle, review/survey (Other academic)
    Abstract [en]

    ZBED6 is a recently discovered transcription factor that has evolved from a domesticated DNA transposon and is unique to placental mammals. Here we further characterize the functional significance of ZBED6 based on transcriptome analysis of mouse myoblasts after Zbed6-silencing. ZBED6 appears as an important transcriptional regulator since differential expression of more than 700 genes was observed after Zbed6-silencing. The most significantly enriched GO term was muscle protein and contractile fiber, which is consistent with increased myotube formation. Twenty small nucleolar RNAs showed differential expression and all increased in expression after Zbed6-silencing. This is particularly interesting because ZBED6 localization is strongly enriched in the nucleolus. There was an overrepresentation of genes with ZBED6 binding sites among the differentially expressed genes after silencing, suggesting that ZBED6 acts as a transcriptional regulator at many loci. Many genes showed significant down-regulation after Zbed6-silencing, which begs the question of whether ZBED6 acts as an activator at some of these loci or if the decreased mRNA levels of these genes all represent secondary effects. The co-localization of histone marks and ZBED6 binding sites and the effect of ZBED6-silencing on distribution of histone marks was evaluated by ChIP-seq. There was a strong association between ZBED6 binding sites and the H3K4me3, H3K4me2 and H3K27ac modifications, which are usually found at active promoters, but no association with the repressive marks H3K27me3. We propose that ZBED6 preferentially binds to active promoters and modulates transcriptional activity by a novel mechanism rather than by recruiting repressive histone modifications.  

  • 20.
    Jiang, Lin
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gilbert, Elizabeth R.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundström, Elisabeth
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ghazal, Awaisa
    Zhang, Xiaolan
    Wang, Li
    Mikkelsen, Tarjei S.
    Andersson, Goran
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    ZBED6 Modulates the Transcription of Myogenic Genes in Mouse Myoblast Cells2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e94187-Article in journal (Refereed)
    Abstract [en]

    ZBED6 is a recently discovered transcription factor, unique to placental mammals, that has evolved from a domesticated DNA transposon. It acts as a repressor at the IGF2 locus. Here we show that ZBED6 acts as a transcriptional modulator in mouse myoblast cells, where more than 700 genes were differentially expressed after Zbed6-silencing. The most significantly enriched GO term was muscle protein and contractile fiber, which was consistent with increased myotube formation. Twenty small nucleolar RNAs all showed increased expression after Zbed6-silencing. The co-localization of histone marks and ZBED6 binding sites and the effect of Zbed6-silencing on distribution of histone marks was evaluated by ChIP-seq analysis. There was a strong association between ZBED6 binding sites and the H3K4me3, H3K4me2 and H3K27ac modifications, which are usually found at active promoters, but no association with the repressive mark H3K27me3. Zbed6-silencing led to increased enrichment of active marks at myogenic genes, in agreement with the RNA-seq findings. We propose that ZBED6 preferentially binds to active promoters and modulates transcriptional activity without recruiting repressive histone modifications.

  • 21. Johnsson, M.
    et al.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Hoglund, A.
    Sahlqvist, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Jensen, P.
    Wright, D.
    The role of pleiotropy and linkage in genes affecting a sexual ornament and bone allocation in the chicken2014In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 23, no 9, p. 2275-2286Article in journal (Refereed)
    Abstract [en]

    Sexual selection and the ornaments that inform such choices have been extensively studied, particularly from a phenotypic perspective. Although more is being revealed about the genetic architecture of sexual ornaments, much still remains to be discovered. The comb of the chicken is one of the most widely recognized sexual ornaments, which has been shown to be correlated with both fecundity and bone allocation. In this study, we use a combination of multiple intercrosses between White Leghorn populations and wild-derived Red Junglefowl to, first, map quantitative trait loci (QTL) for bone allocation and, second, to identify expression QTL that correlate and colocalize with comb mass. These candidate quantitative genes were then assessed for potential pleiotropic effects on bone tissue and fecundity traits. We identify genes that correlate with both relative comb mass and bone traits suggesting a combination of both pleiotropy and linkage mediates gene regulatory variation in these traits.

  • 22. Johnsson, Martin
    et al.
    Gustafson, Ida
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sahlqvist, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Jonsson, Kenneth B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jensen, Per
    Wright, Dominic
    A Sexual Ornament in Chickens Is Affected by Pleiotropic Alleles at HAO1 and BMP2, Selected during Domestication2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 8, p. e1002914-Article in journal (Refereed)
    Abstract [en]

    Domestication is one of the strongest forms of short-term, directional selection. Although selection is typically only exerted on one or a few target traits, domestication can lead to numerous changes in many seemingly unrelated phenotypes. It is unknown whether such correlated responses are due to pleiotropy or linkage between separate genetic architectures. Using three separate intercrosses between wild and domestic chickens, a locus affecting comb mass (a sexual ornament in the chicken) and several fitness traits (primarily medullary bone allocation and fecundity) was identified. This locus contains two tightly-linked genes, BMP2 and HAO1, which together produce the range of pleiotropic effects seen. This study demonstrates the importance of pleiotropy (or extremely close linkage) in domestication. The nature of this pleiotropy also provides insights into how this sexual ornament could be maintained in wild populations.

  • 23.
    Kjaerner-Semb, Erik
    et al.
    Inst Marine Res, Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Ayllon, Fernando
    Inst Marine Res, Bergen, Norway..
    Furmanek, Tomasz
    Inst Marine Res, Bergen, Norway..
    Wennevik, Vidar
    Inst Marine Res, Bergen, Norway..
    Dahle, Geir
    Inst Marine Res, Bergen, Norway..
    Niemela, Eero
    Nat Resources Inst Finland, Helsinki, Finland..
    Ozerov, Mikhail
    Univ Turku, Kevo Subarctic Res Inst, Turku, Finland..
    Vaha, Juha-Pekka
    Univ Turku, Kevo Subarctic Res Inst, Turku, Finland.;Assoc Water & Environm Western Uusimaa, Uusimaa, Finland..
    Glover, Kevin A.
    Inst Marine Res, Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wargelius, Anna
    Inst Marine Res, Bergen, Norway..
    Edvardsen, Rolf B.
    Inst Marine Res, Bergen, Norway..
    Atlantic salmon populations reveal adaptive divergence of immune related genes - a duplicated genome under selection2016In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, article id 610Article in journal (Refereed)
    Abstract [en]

    Background: Populations of Atlantic salmon display highly significant genetic differences with unresolved molecular basis. These differences may result from separate postglacial colonization patterns, diversifying natural selection and adaptation, or a combination. Adaptation could be influenced or even facilitated by the recent whole genome duplication in the salmonid lineage which resulted in a partly tetraploid species with duplicated genes and regions. Results: In order to elucidate the genes and genomic regions underlying the genetic differences, we conducted a genome wide association study using whole genome resequencing data from eight populations from Northern and Southern Norway. From a total of similar to 4.5 million sequencing-derived SNPs, more than 10 % showed significant differentiation between populations from these two regions and ten selective sweeps on chromosomes 5, 10, 11, 13-15, 21, 24 and 25 were identified. These comprised 59 genes, of which 15 had one or more differentiated missense mutation. Our analysis showed that most sweeps have paralogous regions in the partially tetraploid genome, each lacking the high number of significant SNPs found in the sweeps. The most significant sweep was found on Chr 25 and carried several missense mutations in the antiviral mx genes, suggesting that these populations have experienced differing viral pressures. Interestingly the second most significant sweep, found on Chr 5, contains two genes involved in the NF-KB pathway (nkap and nkrf), which is also a known pathogen target that controls a large number of processes in animals. Conclusion: Our results show that natural selection acting on immune related genes has contributed to genetic divergence between salmon populations in Norway. The differences between populations may have been facilitated by the plasticity of the salmon genome. The observed signatures of selection in duplicated genomic regions suggest that the recently duplicated genome has provided raw material for evolutionary adaptation.

  • 24.
    Lamichhaney, Sangeet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Barrio, Alvaro Martinez
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gilbert, Elizabeth R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wetterbom, Anna
    Laikre, Linda
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ryman, Nils
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Population-scale sequencing reveals genetic differentiation due to local adaptation in Atlantic herring2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 47, p. 19345-19350Article in journal (Refereed)
    Abstract [en]

    The Atlantic herring (Clupea harengus), one of the most abundant marine fishes in the world, has historically been a critical food source in Northern Europe. It is one of the few marine species that can reproduce throughout the brackish salinity gradient of the Baltic Sea. Previous studies based on few genetic markers have revealed a conspicuous lack of genetic differentiation between geographic regions, consistent with huge population sizes and minute genetic drift. Here, we present a cost-effective genome-wide study in a species that lacks a genome sequence. We first assembled amuscle transcriptome and then aligned genomic reads to the transcripts, creating an "exome assembly," capturing both exons and flanking sequences. We then resequenced pools of fish from a wide geographic range, including the Northeast Atlantic, as well as different regions in the Baltic Sea, aligned the reads to the exome assembly, and identified 440,817 SNPs. The great majority of SNPs showed no appreciable differences in allele frequency among populations; however, several thousand SNPs showed striking differences, some approaching fixation for different alleles. The contrast between low genetic differentiation at most loci and striking differences at others implies that the latter category primarily reflects natural selection. A simulation study confirmed that the distribution of the fixation index F-ST deviated significantly from expectation for selectively neutral loci. This study provides insights concerning the population structure of an important marine fish and establishes the Atlantic herring as a model for population genetic studies of adaptation and natural selection.

  • 25.
    Lamichhaney, Sangeet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Almen, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Maqbool, Khurram
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Martinez-Barrio, Alvaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Promerova, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zamani, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grant, B. Rosemary
    Grant, Peter R.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evolution of Darwin's finches and their beaks revealed by genome sequencing2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7539Article in journal (Refereed)
    Abstract [en]

    Darwin's finches, inhabiting the Galapagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin's finch species and two close relatives' Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial. development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis) a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin's finches and thereby, to an expanded utilization of food resources.

  • 26.
    Laxman, Navya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Grundberg, Elin
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Global miRNA expression and correlation with mRNA levels in primary human bone cells2015In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 21, no 8, p. 1433-1443Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, alpha 1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.

  • 27.
    Laxman, Navya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Second generation sequencing of microRNA in Human Bone Cells treated with Parathyroid Hormone or Dexamethasone2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 84, p. 181-188Article in journal (Refereed)
    Abstract [en]

    We investigated the impact of treatment with parathyroid hormone (PTH) and dexamethasone (DEX) for 2 and 24 h by RNA sequencing of miRNAs in primary human bone (HOB) cells. A total of 207 million reads were obtained, and normalized absolute expression retrieved for 373 most abundant miRNAs. In naive control cells, 7 miRNAs were differentially expressed (FDR < 0.05) between the two time points. Ten miRNAs exhibited differential expression (FDR < 0.05) across two time points and treatments after adjusting for expression in controls and were selected for downstream analyses. Results show significant effects on miRNA expression when comparing PTH with DEX at 2 h with even more pronounced effects at 24 h. Interestingly, several miRNAs exhibiting differences in expression are predicted to target genes involved in bone metabolism e.g. miR-30c2, miR-203 and miR-205 targeting RUNX2, and miR-320 targeting beta-catenin (CTNNB1) mRNA expression. CTNNB1 and RUNX2 levels were decreased after DEX treatment and increased after PTH treatment. Our analysis also identified 2 putative novel miRNAs in PTH and DEX treated cells at 24 h. RNA sequencing showed that PTH and DEX treatment affect miRNA expression in HOB cells and that regulated miRNAs in turn are correlated with expression levels of key genes involved in bone metabolism.

  • 28.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Astrom, Eva
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grigelioniene, Giedre
    Malmgren, Barbro
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 8, p. 1042-1050Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on 4100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the alpha 1-and alpha 2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the alpha 1-chain were associated with blue sclera (P = 0.0110). Comparing glycine with serine substitutions, alpha 1-alterations were associated with more severe phenotype (P = 0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P < 0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in > 95% of an entire OI population.

  • 29.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Laxman, Navya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Åström, Eva
    Karolinska Institutet.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels: a Novel Therapeutic Approach in Osteogenesis Imperfecta2013In: International Journal of Medical Sciences, ISSN 1449-1907, E-ISSN 1449-1907, Vol. 10, no 10, p. 1333-1343Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta, also known as "brittle bone disease", is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis imperfecta.

  • 30.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Malmgren, B.
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Stockholm, Sweden..
    Grigelioniene, G.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp Stockholm, Dept Clin Genet, Stockholm, Sweden..
    Soderhall, S.
    Karolinska Univ Hosp, Neuropediat Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Åstrom, E.
    Karolinska Univ Hosp, Neuropediat Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 87, p. 11-18Article in journal (Refereed)
    Abstract [en]

    Background: Osteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe 01; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated.

    Materials and methods: COL1A1 and COL1A2 were analyzed in 79 children with OI (type I n = 33, type III n = 25 and type IV n = 21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non vertebral and vertebral fractures were collected prior to, and at several time points during treatment.

    Results: An increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to A LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p < 0.0003, < 0.0001 and 0.0003 for all 01 types 1, III and IV respectively). The reduced fracture rate was maintained for types I and IV, while an additional decrease was observed over time for type III. The fracture rate was reduced also in individuals with continued low BMD after >4 yrs Pamidronate. Twice as many boys as girls with 01 type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p = 0.0236). Greater Delta LS BMD, but smaller Delta fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11 years of age at treatment initiation. (p < 0.0001).

    Conclusion: Pamidronate treatment in children with all types of 01 increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type.

  • 31.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Astrom, E.
    Malmgren, B.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Genotype-phenotype correlations and pharmacogenetic studies in 140 Swedish families with osteogenesis imperfecta2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, p. S109-S109Article in journal (Other academic)
    Abstract [en]

    Objective: Osteogenesis imperfecta (OI) is a rare heterogeneous disease of connective tissue leading to varying degrees of bone fragility. The worst form (type II) is peri-natally lethal whereas the mildest form (type I) is compatible with a normal life span. Over 1000 mutations causing OI have been described in the genes encoding collagen type I. As COL1A1 and COL1A2 are large genes, there are still many codon positions where no mutations have been reported and only a fraction of theoretically possible glycine substitutions have been described. In this study the spectrum of mutations causing OI in Sweden will be investigated and genotype–phenotype correlations as well as pharmacogenetics will be studied.

    Method: All patients with OI cared for at the Uppsala Osteoporosis Unit (Uppsala University Hospital) or Astrid Lindgren's Paediatric Hospital (Karolinska Institutet, Stockholm) were offered to enter the study. Patients from 140 unrelated families with OI accepted participation; 77 type I, 34 type IV, 20 type III, 5 without previous diagnosis and 4 with unclear OI type. Extensive clinical data is currently being collected on enrolled patients. Exons and flanking intron sequences of COL1A1 and COL1A2 are being sequenced in these families.

    Results: So far 133/140 families have been completely analyzed and in 27 no mutation was found. A total of 120 mutations have been detected, of which 104 are of a typical OI-type. In COL1A1 73 mutations were found and in COL1A2 31 mutations were noted. In 7 families 2 mutations were present, but only one of these was a typical OI-causing mutation. To date 16 amino acid changing mutations that were not of a typical OI-causing type have been noted and the majority of these have an unclear significance. Calculations of delta BMD Z-score response to bisphosphonate treatment did not show a difference in treatment response between groups with different types of OI or between patients with OI type I due to a qualitative vs. a quantitative collagen type I defect.

    Conclusion: The spectrum of mutations causing OI described in this Swedish cohort is of the expected type, with the exception of the amino acid changing mutations. It is notable that in seven families two separate mutations were identified. Calculations do not support a mutation dependent response to bisphosphonate treatment.

  • 32.
    Ljunggren, Östen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Allele-Specific Gene Silencing in Osteogenesis Imperfecta2011In: Cartilage and Bone Development and Its Disorders / [ed] C. Camacho-Hübner, O. Nilsson, L. Sävendahl, 2011, p. 85-90Conference paper (Refereed)
    Abstract [en]

    OI is caused by mutations in the genes encoding for collagen type I COL1A1 and COL1A2, respectively. The patients suffer from bone fragility, and the severity can range from mild, with fractures in the youth, to lethal forms. Today, there is no effective treatment for the disorder. OI is caused by dominant negative mutations. A tempting approach to treat the disease would be to silence the allele carrying the mutation. This could in theory be done with siRNAs. Today, more than 800 various mutations are reported, and to create siRNA against a specific mutation is difficult. Instead, by developing siRNA against common polymorphic variations, it would be possible to silence the mutation by a standardized method regardless where the mutation is located on the allele. If the concept of allele-specific gene silencing by inhibitory RNA directed towards dominant negative mutations could be proven, this might be a novel approach to gene therapy in OI.

  • 33.
    Lysén, Maria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Osterlund, Anders
    Rubin, Carl-Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Persson, Tina
    Persson, Ingrid
    Herrmann, Björn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Characterization of ompA genotypes by sequence analysis of DNA from all detected cases of Chlamydia trachomatis infections during 1 year of contact tracing in a Swedish County.2004In: J Clin Microbiol, ISSN 0095-1137, Vol. 42, no 4, p. 1641-7Article in journal (Refereed)
  • 34.
    Makino, Takashi
    et al.
    Department of Ecology and Evolutionary Biology, Graduate School of Life Sciences, Tohoku University, 6 - 3, Aramaki Aza Aoba, Aoba - ku, Sendai 980 - 8578, Japan.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carneiro, Miguel
    CIBIO/InBIO, Centro de Investiga ção em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485 - 661, Vairão, Portugal.
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew Thomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elevated proportions of deleterious genetic variation in domestic animals and plants2018In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 10, no 1, p. 276-290Article in journal (Refereed)
    Abstract [en]

    A fraction of genetic variants segregating in any population are deleterious, which negatively impacts individual fitness. The domestication of animals and plants is associated with population bottlenecks and artificial selection, which are predicted to increase the proportion of deleterious variants. However, the extent to which this is a general feature of domestic species is unclear. Here we examine the effects of domestication on the prevalence of deleterious variation using pooled whole-genome resequencing data from five domestic animal species (dog, pig, rabbit, chicken and silkworm) and two domestic plant species (rice and soybean) compared to their wild ancestors. We find significantly reduced genetic variation and increased proportion of nonsynonymous amino acid changes in all but one of the domestic species. These differences are observable across a range of allele frequencies, both common and rare. We find proportionally more SNPs in highly conserved elements in domestic species and a tendency for domestic species to harbour a higher proportion of changes classified as damaging. Our findings most likely reflect an increased incidence of deleterious variants in domestic species, which is most likely attributable to population bottlenecks that lead to a reduction in the efficacy of selection. An exception to this pattern is displayed by European domestic pigs, which do not show traces of a strong population bottleneck and probably continued to exchange genes with wild boar populations after domestication. The results presented here indicate that an elevated proportion of deleterious variants is a common, but not ubiquitous, feature of domestic species.

  • 35.
    Martínez Barrio, Álvaro
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lamichhaney, Sangeet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fan, Guangyi
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; BGI-Shenzhen, Shenzen, China; 5 College of Physics, Qingdao University, Qingdao, China .
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, He
    BGI-Shenzhen, Shenzen, China; College of Physics, Qingdao University, Qingdao, China.
    Dainat, Jacques
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University.
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, Marcel
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liu, Xin
    BGI-Shenzhen, Shenzen, China.
    Chen, Wenbin
    BGI-Shenzhen, Shenzhen, China.
    Liang, Xinming
    BGI-Shenzhen, Shenzhen, China.
    Shi, Chengcheng
    BGI-Shenzhen, Shenzhen, China.
    Fu, Yuanyuan
    BGI-Shenzhen, Shenzhen, China.
    Ma, Kailong
    BGI-Shenzhen, Shenzhen, China.
    Zhan, Xiao
    BGI-Shenzhen, Shenzhen, China.
    Feng, Chungang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafson, Ulla
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Blass, Martina
    Department of Aquatic Resources, Institute of Coastal Research, Swedish University of Agricultural Sciences, Öregrund, Sweden.
    Casini, Michele
    Swedish University of Agricultural Sciences, Department of Aquatic Resources, Institute of Marine Research.
    Folkvord, Arild
    Department of Biology, University of Bergen, Bergen, Norway; Hjort Center of Marine Ecosystem Dynamics, Bergen, Norway; Institute of Marine Research, Bergen, Norway .
    Laikre, Linda
    Department of Zoology, Stockholm University.
    Ryman, Nils
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Lee, Simon Ming-Yuen Lee
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao.
    Xu, Xun
    BGI-Shenzhen, Shenzhen, China.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden; Department of Veterinary Integrative Biosciences, Texas A&M University, Texas, United States.
    The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e12081Article in journal (Refereed)
    Abstract [en]

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation.

  • 36.
    McCoy, Annette M.
    et al.
    Univ Illinois, Dept Vet Clin Med, Urbana, IL 61801 USA.
    Beeson, Samantha K.
    Univ Minnesota, Vet Populat Med Dept, St Paul, MN 55108 USA.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA.
    Caputo, Paul
    Paul Caputo, DVM, Pompano Beach, FL USA.
    Lykkjen, Sigrid
    Norwegian Univ Life Sci, Fac Vet Med, Oslo, Norway.
    Moore, Alison
    Moore Equine Serv, Cambridge, ON, Canada.
    Piercy, Richard J.
    Royal Vet Coll, Dept Clin Sci & Serv, London, England.
    Mickelson, James R.
    Univ Minnesota, Vet & Biomed Sci Dept, St Paul, MN 55108 USA.
    McCue, Molly E.
    Univ Minnesota, Vet Populat Med Dept, St Paul, MN 55108 USA.
    Identification and validation of genetic variants predictive of gait in standardbred horses2019In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 5, article id e1008146Article in journal (Refereed)
    Abstract [en]

    Several horse breeds have been specifically selected for the ability to exhibit alternative patterns of locomotion, or gaits. A premature stop codon in the gene DMRT3 is permissive for gaitedness across breeds. However, this mutation is nearly fixed in both American Standardbred trotters and pacers, which perform a diagonal and lateral gait, respectively, during harness racing. This suggests that modifying alleles must influence the preferred gait at racing speeds in these populations. A genome-wide association analysis for the ability to pace was performed in 542 Standardbred horses (n = 176 pacers, n = 366 trotters) with genotype data imputed to similar to 74,000 single nucleotide polymorphisms (SNPs). Nineteen SNPs on nine chromosomes (ECA1, 2, 6, 9, 17, 19, 23, 25, 31) reached genome-wide significance (p < 1.44 x 10(-6)). Variant discovery in regions of interest was carried out via whole-genome sequencing. A set of 303 variants from 22 chromosomes with putative modifying effects on gait was genotyped in 659 Standardbreds (n = 231 pacers, n = 428 trotters) using a high-throughput assay. Random forest classification analysis resulted in an out-of-box error rate of 0.61%. A conditional inference tree algorithm containing seven SNPs predicted status as a pacer or trotter with 99.1% accuracy and subsequently performed with 99.4% accuracy in an independently sampled population of 166 Standardbreds (n = 83 pacers, n = 83 trotters). This highly accurate algorithm could be used by owners/trainers to identify Standardbred horses with the potential to race as pacers or as trotters, according to the genotype identified, prior to initiating training and would enable fine-tuning of breeding programs with designed matings. Additional work is needed to determine both the algorithm's utility in other gaited breeds and whether any of the predictive SNPs play a physiologically functional role in the tendency to pace or tag true functional alleles.

  • 37. Natt, Daniel
    et al.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wright, Dominic
    Johnsson, Martin
    Belteky, Johan
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jensen, Per
    Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 59-Article in journal (Refereed)
    Abstract [en]

    Background: Variations in gene expression, mediated by epigenetic mechanisms, may cause broad phenotypic effects in animals. However, it has been debated to what extent expression variation and epigenetic modifications, such as patterns of DNA methylation, are transferred across generations, and therefore it is uncertain what role epigenetic variation may play in adaptation. Results: In Red Junglefowl, ancestor of domestic chickens, gene expression and methylation profiles in thalamus/hypothalamus differed substantially from that of a domesticated egg laying breed. Expression as well as methylation differences were largely maintained in the offspring, demonstrating reliable inheritance of epigenetic variation. Some of the inherited methylation differences were tissue-specific, and the differential methylation at specific loci were little changed after eight generations of intercrossing between Red Junglefowl and domesticated laying hens. There was an over-representation of differentially expressed and methylated genes in selective sweep regions associated with chicken domestication. Conclusions: Our results show that epigenetic variation is inherited in chickens, and we suggest that selection of favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation states which are inherited independently of sequence differences, may have been an important aspect of chicken domestication.

  • 38. Orlando, Ludovic
    et al.
    Ginolhac, Aurelien
    Zhang, Guojie
    Froese, Duane
    Albrechtsen, Anders
    Stiller, Mathias
    Schubert, Mikkel
    Cappellini, Enrico
    Petersen, Bent
    Moltke, Ida
    Johnson, Philip L. F.
    Fumagalli, Matteo
    Vilstrup, Julia T.
    Raghavan, Maanasa
    Korneliussen, Thorfinn
    Malaspinas, Anna-Sapfo
    Vogt, Josef
    Szklarczyk, Damian
    Kelstrup, Christian D.
    Vinther, Jakob
    Dolocan, Andrei
    Stenderup, Jesper
    Velazquez, Amhed M. V.
    Cahill, James
    Rasmussen, Morten
    Wang, Xiaoli
    Min, Jiumeng
    Zazula, Grant D.
    Seguin-Orlando, Andaine
    Mortensen, Cecilie
    Magnussen, Kim
    Thompson, John F.
    Weinstock, Jacobo
    Gregersen, Kristian
    Roed, Knut H.
    Eisenmann, Vera
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Miller, Donald C.
    Antczak, Douglas F.
    Bertelsen, Mads F.
    Brunak, Soren
    Al-Rasheid, Khaled A. S.
    Ryder, Oliver
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mundy, John
    Krogh, Anders
    Gilbert, M. Thomas P.
    Kjaer, Kurt
    Sicheritz-Ponten, Thomas
    Jensen, Lars Juhl
    Olsen, Jesper V.
    Hofreiter, Michael
    Nielsen, Rasmus
    Shapiro, Beth
    Wang, Jun
    Willerslev, Eske
    Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 499, no 7456, p. 74-+Article in journal (Refereed)
    Abstract [en]

    The rich fossil record of equids has made them a model for evolutionary processes(1). Here we present a 1.12-times coverage draft genome from a horse bone recovered from permafrost dated to approximately 560-780 thousand years before present (kyr BP)(2,3). Our data represent the oldest full genome sequence determined so far by almost an order of magnitude. For comparison, we sequenced the genome of a Late Pleistocene horse (43 kyr BP), and modern genomes of five domestic horse breeds (Equus ferus caballus), a Przewalski's horse (E. f. prze-walskii) and a donkey (E. asinus). Our analyses suggest that the Equus lineage giving rise to all contemporary horses, zebras and donkeys originated 4.0-4.5 million years before present (Myr BP), twice the conventionally accepted time to the most recent common ancestor of the genus Equus(4,5). We also find that horse population size fluctuated multiple times over the past 2 Myr, particularly during periods of severe climatic changes. We estimate that the Przewalski's and domestic horse populations diverged 38-72 kyr BP, and find no evidence of recent admixture between the domestic horse breeds and the Przewalski's horse investigated. This supports the contention that Przewalski's horses represent the last surviving wild horse population(6). We find similar levels of genetic variation among Przewalski's and domestic populations, indicating that the former are genetically viable and worthy of conservation efforts. We also find evidence for continuous selection on the immune system and olfaction throughout horse evolution. Finally, we identify 29 genomic regions among horse breeds that deviate from neutrality and show low levels of genetic variation compared to the Przewalski's horse. Such regions could correspond to loci selected early during domestication.

  • 39.
    Qanbari, Saber
    et al.
    Univ Gottingen, Dept Anim Sci, Anim Breeding & Genet Grp, Gottingen, Germany;AREEO, ABRII, Dept Anim Biotechnol, Karaj, Iran.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maqbool, Khurram
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Weigend, Steffen
    Friedrich Loeffler Inst, Neustadt, Germany;Univ Gottingen, Ctr Integrated Breeding Res, Gottingen, Germany.
    Weigend, Annett
    Friedrich Loeffler Inst, Neustadt, Germany.
    Geibel, Johannes
    Univ Gottingen, Dept Anim Sci, Anim Breeding & Genet Grp, Gottingen, Germany;Univ Gottingen, Ctr Integrated Breeding Res, Gottingen, Germany.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wurmser, Christine
    Tech Univ Munich, Chair Anim Breeding, Freising Weihenstephan, Germany.
    Peterson, Andrew Townsend
    Univ Kansas, Biodivers Inst, Lawrence, KS 66045 USA.
    Brisbi, I. Lehr, Jr.
    Univ Georgia, Savannah River Ecol Lab, Odum Sch Ecol, Aiken, SC USA.
    Preisinger, Ruedi
    Lohmann Tierzucht GmbH, Cuxhaven, Germany.
    Fries, Ruedi
    Tech Univ Munich, Chair Anim Breeding, Freising Weihenstephan, Germany.
    Simianer, Henner
    Univ Gottingen, Dept Anim Sci, Anim Breeding & Genet Grp, Gottingen, Germany;Univ Gottingen, Ctr Integrated Breeding Res, Gottingen, Germany.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA.
    Genetics of adaptation in modern chicken2019In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 4, article id e1007989Article in journal (Refereed)
    Abstract [en]

    We carried out whole genome resequencing of 127 chicken including red jungle fowl and multiple populations of commercial broilers and layers to perform a systematic screening of adaptive changes in modern chicken (Gallus gallus domesticus). We uncovered >21 million high quality SNPs of which 34% are newly detected variants. This panel comprises >115,000 predicted amino-acid altering substitutions as well as 1,100 SNPs predicted to be stop-gain or -loss, several of which reach high frequencies. Signatures of selection were investigated both through analyses of fixation and differentiation to reveal selective sweeps that may have had prominent roles during domestication and breed development. Contrasting wild and domestic chicken we confirmed selection at the BCO2 and TSHR loci and identified 34 putative sweeps co-localized with ALX1, KITLG, EPGR, IGF1, DLK1, JPT2, CRAMP1, and GLI3, among others. Analysis of enrichment between groups of wild vs. commercials and broilers vs. layers revealed a further panel of candidate genes including CORIN, SKIV2L2 implicated in pigmentation and LEPR, MEGF10 and SPEF2, suggestive of production-oriented selection. SNPs with marked allele frequency differences between wild and domestic chicken showed a highly significant deficiency in the proportion of amino-acid altering mutations (P<2.5x10(-6)). The results contribute to the understanding of major genetic changes that took place during the evolution of modern chickens and in poultry breeding. Author summary Domestic chickens (Gallus gallus domesticus) provide a critical resource for animal proteins for human nutrition worldwide. Chickens were primarily domesticated from the red jungle fowl (Gallus gallus gallus), a bird that still runs wild in most of Southeast Asia. Human driven selection during domestication and subsequent specialization into meat type (broilers) and egg layer (layers) birds has left detectable signatures of selection within the genome of modern chicken. In this study, we performed whole genome sequencing of 127 chicken including the red jungle fowl and multiple populations of commercial broilers and layers to perform a systematic screening of adaptive changes in modern chicken. Analysis of selection provided a comprehensive list of several tens of independent loci that are likely to have contributed to domestication or improving production. SNP by SNP comparison of allele frequency between groups of wild and domestic chicken showed a highly significant deficiency of the proportion of amino acid altering mutations. This implies that commercial birds have undergone purifying selection reducing the frequency of deleterious variants.

  • 40.
    Rafati, Nima
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Lisa S.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Mikko, Sofia
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Feng, Chungang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Raudsepp, Terje
    Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77845 USA..
    Pettersson, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Janecka, Jan
    Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77845 USA..
    Wattle, Ove
    Swedish Univ Agr Sci, Dept Clin Sci, S-75007 Uppsala, Sweden..
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Thyreen, Gunilla
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Eberth, John
    Univ Kentucky, Gluck Equine Res Ctr, Dept Vet Sci, Lexington, KY 40546 USA..
    Huddleston, John
    Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98105 USA.;Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA..
    Malig, Maika
    Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA..
    Bailey, Ernest
    Univ Kentucky, Gluck Equine Res Ctr, Dept Vet Sci, Lexington, KY 40546 USA..
    Eichler, Evan E.
    Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA..
    Dalin, Goran
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, S-75007 Uppsala, Sweden..
    Chowdary, Bhanu
    Qatar Univ, New Res Complex, Doha 2713, Qatar..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77845 USA..
    Lindgren, Gabriella
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Large Deletions at the SHOX Locus in the Pseudoautosomal Region Are Associated with Skeletal Atavism in Shetland Ponies2016In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 6, no 7, p. 2213-2223Article in journal (Refereed)
    Abstract [en]

    Skeletal atavism in Shetland ponies is a heritable disorder characterized by abnormal growth of the ulna and fibula that extend the carpal and tarsal joints, respectively. This causes abnormal skeletal structure and impaired movements, and affected foals are usually killed. In order to identify the causal mutation we subjected six confirmed Swedish cases and a DNA pool consisting of 21 control individuals to whole genome resequencing. We screened for polymorphisms where the cases and the control pool were fixed for opposite alleles and observed this signature for only 25 SNPs, most of which were scattered on genome assembly unassigned scaffolds. Read depth analysis at these loci revealed homozygosity or compound heterozygosity for two partially overlapping large deletions in the pseudoautosomal region (PAR) of chromosome X/Y in cases but not in the control pool. One of these deletions removes the entire coding region of the SHOX gene and both deletions remove parts of the CRLF2 gene located downstream of SHOX. The horse reference assembly of the PAR is highly fragmented, and in order to characterize this region we sequenced bacterial artificial chromosome (BAC) clones by single-molecule real-time (SMRT) sequencing technology. This considerably improved the assembly and enabled size estimations of the two deletions to 1602180 kb and 60280 kb, respectively. Complete association between the presence of these deletions and disease status was verified in eight other affected horses. The result of the present study is consistent with previous studies in humans showing crucial importance of SHOX for normal skeletal development.

  • 41.
    Rafati, Nima
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Blanco-Aguiar, Jose A.
    CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sayyab, Shumaila
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden;Natl Univ Sci & Technol, Res Ctr Modeling & Simulat, Islamabad, Pakistan.
    Sabatino, Stephen
    CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.
    Afonso, Sandra
    CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.
    Feng, Chungang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alves, Paulo Celio
    CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.
    Villafuerte, Rafael
    6Instituto de Estudios Sociales Avanzados, (IESA-CSIC) Campo Santo de los Mártires 7, Córdoba Spain.
    Ferrand, Nuno
    CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden;Texas A&M Univ, Dept Vet Integrat Biosci, Coll Vet Med & Biomed Sci, College Stn, TX USA.
    Carneiro, Miguel
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Vairao, Portugal:Univ Porto, Dept Biol, Fac Ciencias, Porto, Portugal.
    A genomic map of clinal variation across the European rabbit hybrid zone2018In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 27, no 6, p. 1457-1478Article in journal (Refereed)
    Abstract [en]

    Speciation is a process proceeding from weak to complete reproductive isolation. In this continuum, naturally hybridizing taxa provide a promising avenue for revealing the genetic changes associated with the incipient stages of speciation. To identify such changes between two subspecies of rabbits that display partial reproductive isolation, we studied patterns of allele frequency change across their hybrid zone using whole-genome sequencing. To connect levels and patterns of genetic differentiation with phenotypic manifestations of subfertility in hybrid rabbits, we further investigated patterns of gene expression in testis. Geographic cline analysis revealed 253 regions characterized by steep changes in allele frequency across their natural region of contact. This catalog of regions is likely to be enriched for loci implicated in reproductive barriers and yielded several insights into the evolution of hybrid dysfunction in rabbits: (i) incomplete reproductive isolation is likely governed by the effects of many loci, (ii) protein-protein interaction analysis suggest that genes within these loci interact more than expected by chance, (iii) regulatory variation is likely the primary driver of incompatibilities, and (iv) large chromosomal rearrangements appear not to be a major mechanism underlying incompatibilities or promoting isolation in the face of gene flow. We detected extensive misregulation of gene expression in testis of hybrid males, but not a statistical overrepresentation of differentially expressed genes in candidate regions. Our results also did not support an X chromosome-wide disruption of expression as observed in mice and cats, suggesting variation in the mechanistic basis of hybrid male reduced fertility among mammals.

  • 42.
    Reimer, C.
    et al.
    Univ Goettingen, Dept Anim Sci, Anim Breeding & Genet Grp, Albrecht Thaer Weg 3, D-37075 Gottingen, Germany;Univ Goettingen, Ctr Integrated Breeding Res, Albrecht Thaer Weg 3, D-37075 Gottingen, Germany.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sharifi, A. R.
    Univ Goettingen, Dept Anim Sci, Anim Breeding & Genet Grp, Albrecht Thaer Weg 3, D-37075 Gottingen, Germany;Univ Goettingen, Ctr Integrated Breeding Res, Albrecht Thaer Weg 3, D-37075 Gottingen, Germany.
    Ha, N. -T
    Weigend, S.
    Friedrich Loeffler Inst, Inst Farm Anim Genet, Holtystr 10, D-31535 Neustadt, Germany;Univ Goettingen, Ctr Integrated Breeding Res, Albrecht Thaer Weg 3, D-37075 Gottingen, Germany.
    Waldmann, K. -H
    Distl, O.
    Univ Vet Med Fdn, Inst Anim Breeding & Genet, Bunteweg 17p, D-30559 Hannover, Germany.
    Pant, S. D.
    Charles Sturt Univ, Sch Anim & Vet Sci, Graham Ctr Agr Innovat, Locked Bag 588,Boorooma St, Wagga Wagga, NSW, Australia.
    Fredholm, M.
    Univ Copenhagen, Dept Vet & Anim Sci, Gronnegardsvej 3, DK-1870 Frederiksberg C, Denmark.
    Schlather, M.
    Univ Mannheim, Sch Business Informat & Math, A5 6, D-68131 Mannheim, Germany;Univ Goettingen, Ctr Integrated Breeding Res, Albrecht Thaer Weg 3, D-37075 Gottingen, Germany.
    Simianer, H.
    Univ Goettingen, Dept Anim Sci, Anim Breeding & Genet Grp, Albrecht Thaer Weg 3, D-37075 Gottingen, Germany;Univ Goettingen, Ctr Integrated Breeding Res, Albrecht Thaer Weg 3, D-37075 Gottingen, Germany.
    Analysis of porcine body size variation using re-sequencing data of miniature and large pigs2018In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 19, article id 687Article in journal (Refereed)
    Abstract [en]

    Background: Domestication has led to substantial phenotypic and genetic variation in domestic animals. In pigs, the size of so called minipigs differs by one order of magnitude compared to breeds of large body size. We used biallelic SNPs identified from re-sequencing data to compare various publicly available wild and domestic populations against two minipig breeds to gain better understanding of the genetic background of the extensive body size variation. We combined two complementary measures, expected heterozygosity and the composite likelihood ratio test implemented in "SweepFinder", to identify signatures of selection in Minipigs. We intersected these sweep regions with a measure of differentiation, namely F-ST, to remove regions of low variation across pigs. An extraordinary large sweep between 52 and 61 Mb on chromosome X was separately analyzed based on SNP-array data of F-2 individuals from a cross of Goettingen Minipigs and large pigs. Results: Selective sweep analysis identified putative sweep regions for growth and subsequent gene annotation provided a comprehensive set of putative candidate genes. A long swept haplotype on chromosome X, descending from the Goettingen Minipig founders was associated with a reduction of adult body length by 3% in F-2 cross-breds. Conclusion: The resulting set of genes in putative sweep regions implies that the genetic background of body size variation in pigs is polygenic rather than mono-or oligogenic. Identified genes suggest alterations in metabolic functions and a possible insulin resistance to contribute to miniaturization. A size QTL located within the sweep on chromosome X, with an estimated effect of 3% on body length, is comparable to the largest known in pigs or other species. The androgen receptor AR, previously known to influence pig performance and carcass traits, is the most obvious potential candidate gene within this region.

  • 43.
    Rivas-Carrillo, Salvador Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Whole-genome comparison of endogenous retrovirus segregation across wild and domestic host species populations2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 43, p. 11012-11017, article id 201815056Article in journal (Refereed)
    Abstract [en]

    Although recent advances in sequencing and computational analyses have facilitated use of endogenous retroviruses (ERVs) for deciphering coevolution among retroviruses and their hosts, sampling effects from different host populations present major challenges. Here we utilize available whole-genome data from wild and domesticated European rabbit (Oryctolagus cuniculus sp.) populations, sequenced as DNA pools by paired-end Illumina technology, for identifying segregating reference as well as nonreference ERV loci, to reveal their variation along the host phylogeny and domestication history. To produce new viruses, retroviruses must insert a proviral DNA copy into the host nuclear DNA. Occasional proviral insertions into the host germline have been passed down through generations as inherited ERVs during millions of years. These ERVs represent retroviruses that were active at the time of infection and thus present a remarkable record of historical virus–host associations. To examine segregating ERVs in host populations, we apply a reference library search strategy for anchoring ERV-associated short-sequence read pairs from pooled whole-genome sequences to reference genome assembly positions. We show that most ERVs segregate along host phylogeny but also uncover radiation of some ERVs, identified as segregating loci among wild and domestic rabbits. The study targets pertinent issues regarding genome sampling when examining virus–host evolution from the genomic ERV record and offers improved scope regarding common strategies for single-nucleotide variant analyses in host population comparative genomics.

  • 44.
    Rubin, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wright, Dominic
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gunnarsson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schütz, Karin
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Jensen, Per
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ohlsson, Claes
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Quantitative Trait Loci for BMD and Bone Strength in an Intercross Between Domestic and Wildtype Chickens2007In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 22, no 3, p. 375-384Article in journal (Refereed)
    Abstract [en]

    With chicken used as a model species, we used QTL analysis to examine the genetic contribution to bone traits. We report the identification of four QTLs for femoral traits: one for bone strength, one for endosteal circumference, and two affecting mineral density of noncortical bone. Introduction: BMD is a highly heritable phenotype, governed by elements at numerous loci. In studies examining the genetic contribution to bone traits, many loci have been identified in humans and in other species. The goal of this study was to identify quantitative trait loci (QTLs) controlling BMD and bone strength in an intercross between wildtype and domestic chickens. Materials and Methods: A set of 164 markers, covering 30 chromosomes (chr.), were used to genotype 337 F 2-individuals from an intercross of domesticated white Leghorn and wildtype red junglefowl chicken. DXA and pQCT were used to measure BMD and bone structure. Three-point bending tests and torsional strength tests were performed to determine the biomechanical strength of the bone. QTLs were mapped using forward selection for loci with significant marginal effects. Results: Four QTLs for femoral bone traits were identified in QTL analysis with body weight included as a covariate. A QTL on chr. 1 affected female noncortical BMD (LOD 4.6) and is syntenic to human 12q21-12q23. Also located on chr. 1, a locus with synteny to human 12q 13-1.4 affected endosteal circumference (LOD 4.6). On chr. 2, a QTL corresponding to human 5p13-p15, 7p12, 18q12, 18q21, and 9q22-9q31 affected BMD in females; noncortical (LOD 4.0) and metaphyseal (LOD 7.0) BMD by pQCT and BMD by DXA (LOD 5.9). A QTL located on chr. 20 (LOD 5.2) affected bone biomechanical strength and had sex-dependent effects. In addition to the significant QTLs, 10 further loci with suggestive linkage to bone traits were identified. Conclusions: Four QTLs were identified: two for noncortical BMD, one for endosteal circumference, and one affecting bone biomechanical strength. The future identification of genes responsible for these QTLs will increase the understanding of vertebrate skeletal biology.

  • 45.
    Rubin, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindberg, Johan
    Fitzsimmons, Carolyn
    Savolainen, Peter
    Jensen, Per
    Lundeberg, Joakim
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Differential gene expression in femoral bone from red junglefowl and domestic chicken, differing for bone phenotypic traits2007In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, p. 208-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Osteoporosis is frequently observed among aging hens from egg-producing strains (layers) of domestic chicken. White Leghorn (WL) has been intensively selected for egg production and it manifests striking phenotypic differences for a number of traits including several bone phenotypes in comparison with the wild ancestor of chicken, the red junglefowl (RJ). Previously, we have identified four Quantitative Trait Loci (QTL) affecting bone mineral density and bone strength in an intercross between RJ and WL. With the aim of further elucidating the genetic basis of bone traits in chicken, we have now utilized cDNA-microarray technology in order to compare global RNA-expression in femoral bone from adult RJ and WL (five of each sex and population). RESULTS: When contrasting microarray data for all WL-individuals to that of all RJ-individuals we observed differential expression (False discovery rate adjusted p-values < 0.015) for 604 microarray probes. In corresponding male and female contrasts, differential expression was observed for 410 and 270 probes, respectively. Altogether, the three contrasts between WL and RJ revealed differential expression of 779 unique transcripts, 57 of which are located to previously identified QTL-regions for bone traits. Some differentially expressed genes have previously been attributed roles in bone metabolism and these were: WNT inhibitory factor 1 (WIF1), WD repeat-containing protein 5 (WDR5) and Syndecan 3 (SDC3). Among differentially expressed transcripts, those encoding structural ribosomal proteins were highly enriched and all 15 had lower expression in WL. CONCLUSION: We report the identification of 779 differentially expressed transcripts, several residing within QTL-regions for bone traits. Among differentially expressed transcripts, those encoding structural ribosomal proteins were highly enriched and all had lower expression levels in WL. In addition, transcripts encoding four translation initiation and translation elongation factor proteins also had lower expression levels in WL, possibly indicating perturbation of protein biosynthesis pathways between the two populations. Information derived from this study could be relevant to the bone research field and may also aid in further inference of genetic changes accompanying animal domestication.

  • 46.
    Rubin, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Megens, H. -J
    Barrio, Alvaro Martinez
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maqbool, K.
    Sayyab, S.
    Schwochow, D.
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlborg, Örjan
    SLU.
    Jørgensen, C. B.
    Archibald, A. L.
    Fredholm, M.
    Groenen, M. A. M.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strong signatures of selection in the domestic pig genome2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 48, p. 19529-19536Article in journal (Refereed)
    Abstract [en]

    Domestication of wild boar (Sus scrofa) and subsequent selection have resulted in dramatic phenotypic changes in domestic pigs for a number of traits, including behavior, body composition, reproduction, and coat color. Here we have used whole-genome resequencing to reveal some of the loci that underlie phenotypic evolution in European domestic pigs. Selective sweep analyses revealed strong signatures of selection at three loci harboring quantitative trait loci that explain a considerable part of one of the most characteristic morphological changes in the domestic pig - the elongation of the back and an increased number of vertebrae. The three loci were associated with the NR6A1, PLAG1, and LCORL genes. The latter two have repeatedly been associated with loci controlling stature in other domestic animals and in humans. Most European domestic pigs are homozygous for the same haplotype at these three loci. We found an excess of derived nonsynonymous substitutions in domestic pigs, most likely reflecting both positive selection and relaxed purifying selection after domestication. Our analysis of structural variation revealed four duplications at the KIT locus that were exclusively present in white or white-spotted pigs, carrying the Dominant white, Patch, or Belt alleles. This discovery illustrates how structural changes have contributed to rapid phenotypic evolution in domestic animals and how alleles in domestic animals may evolve by the accumulation of multiple causative mutations as a response to strong directional selection.

  • 47.
    Rubin, Carl-Johan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Thollesson, Mikael
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics.
    Kirsebom, Leif A
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Herrmann, Björn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Phylogenetic relationships and species differentiation of 39 Legionella species by sequence determination of the RNase P RNA gene rnpB2005In: Int J Syst Evol Microbiol, ISSN 1466-5026, Vol. 55, no Pt 5, p. 2039-49Article in journal (Refereed)
  • 48. Schubert, Mikkel
    et al.
    Jonsson, Hakon
    Chang, Dan
    Sarkissian, Clio Der
    Ermini, Luca
    Ginolhac, Aurelien
    Albrechtsen, Anders
    Dupanloup, Isabelle
    Foucal, Adrien
    Petersen, Bent
    Fumagalli, Matteo
    Raghavan, Maanasa
    Seguin-Orlando, Andaine
    Korneliussen, Thorfinn S.
    Velazquez, Amhed M. V.
    Stenderup, Jesper
    Hoover, Cindi A.
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alfarhan, Ahmed H.
    Alquraishi, Saleh A.
    Al-Rasheid, Khaled A. S.
    MacHugh, David E.
    Kalbfleisch, Ted
    MacLeod, James N.
    Rubin, Edward M.
    Sicheritz-Ponten, Thomas
    Andersson, Leif
    Hofreiter, Michael
    Marques-Bonet, Tomas
    Gilbert, M. Thomas P.
    Nielsen, Rasmus
    Excoffier, Laurent
    Willerslev, Eske
    Shapiro, Beth
    Orlando, Ludovic
    Prehistoric genomes reveal the genetic foundation and cost of horse domestication2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 52, p. E5661-E5669Article in journal (Refereed)
    Abstract [en]

    The domestication of the horse similar to 5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse domestication are difficult to reconstruct, given the near extinction of wild horses. We therefore sequenced two ancient horse genomes from Taymyr, Russia (at 7.4- and 24.3-fold coverage), both predating the earliest archeological evidence of domestication. We compared these genomes with genomes of domesticated horses and the wild Przewalski's horse and found genetic structure within Eurasia in the Late Pleistocene, with the ancient population contributing significantly to the genetic variation of domesticated breeds. We furthermore identified a conservative set of 125 potential domestication targets using four complementary scans for genes that have undergone positive selection. One group of genes is involved in muscular and limb development, articular junctions, and the cardiac system, and may represent physiological adaptations to human utilization. A second group consists of genes with cognitive functions, including social behavior, learning capabilities, fear response, and agreeableness, which may have been key for taming horses. We also found that domestication is associated with inbreeding and an excess of deleterious mutations. This genetic load is in line with the "cost of domestication" hypothesis also reported for rice, tomatoes, and dogs, and it is generally attributed to the relaxation of purifying selection resulting from the strong demographic bottlenecks accompanying domestication. Our work demonstrates the power of ancient genomes to reconstruct the complex genetic changes that transformed wild animals into their domesticated forms, and the population context in which this process took place.

  • 49.
    Staiger, E. A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Cornell Univ, Dept Anim Sci, Ithaca, NY 14853 USA..
    Almén, M. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Promerova, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Max Planck Inst Sci Human Hist, Dept Archaeogenet, D-07745 Jena, Germany..
    Brooks, S.
    Univ Florida, Dept Anim Sci, Gainesville, FL 32611 USA..
    Cothran, E. G.
    Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    Imsland, F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fegraeus, K. Jaderkvist
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Lindgren, G.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Yeganeh, H. Mehrabani
    Univ Tehran, Dept Anim Sci, Tehran 54500, Iran..
    Mikko, S.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Vega-Pla, J. L.
    Cria Caballar Fuerzas Armadas, Lab Invest Aplicada, Cordoba 14080, Spain..
    Tozaki, T.
    Lab Racing Chem, Genet Anal Dept, Utsunomiya, Tochigi 3200851, Japan..
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.;Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    The evolutionary history of the DMRT3 'Gait keeper' haplotype2017In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 48, no 5, p. 551-559Article in journal (Refereed)
    Abstract [en]

    A previous study revealed a strong association between the DMRT3:Ser301STOP mutation in horses and alternate gaits as well as performance in harness racing. Several follow-up studies have confirmed a high frequency of the mutation in gaited horse breeds and an effect on gait quality. The aim of this study was to determine when and where the mutation arose, to identify additional potential causal mutations and to determine the coalescence time for contemporary haplotypes carrying the stop mutation. We utilized sequences from 89 horses representing 26 breeds to identify 102 SNPs encompassing the DMRT3 gene that are in strong linkage disequilibrium with the stop mutation. These 102 SNPs were genotyped in an additional 382 horses representing 72 breeds, and we identified 14 unique haplotypes. The results provided conclusive evidence that DMRT3: Ser301STOP is causal, as no other sequence polymorphisms showed an equally strong association to locomotion traits. The low sequence diversity among mutant chromosomes demonstrated that they must have diverged from a common ancestral sequence within the last 10 000 years. Thus, the mutation occurred either just before domestication or more likely some time after domestication and then spread across the world as a result of selection on locomotion traits.

  • 50.
    Wallner, Barbara
    et al.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria..
    Palmieri, Nicola
    Univ Vet Med Vienna, Inst Populat Genet, A-1210 Vienna, Austria.;Univ Vet Med Vienna, Inst Parasitol, A-1210 Vienna, Austria..
    Vogl, Claus
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria..
    Rigler, Doris
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria..
    Bozlak, Elif
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria..
    Druml, Thomas
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria..
    Jagannathan, Vidhya
    Univ Bern, Vetsuisse Fac, Inst Genet, CH-3001 Bern, Switzerland..
    Leeb, Tosso
    Univ Bern, Vetsuisse Fac, Inst Genet, CH-3001 Bern, Switzerland..
    Fries, Ruedi
    Tech Univ Munich, Lehrstuhl Tierzucht, D-85354 Freising Weihenstephan, Germany..
    Tetens, Jens
    Univ Kiel, Inst Anim Breeding & Husb, D-24098 Kiel, Germany.;Georg August Univ Gottingen, Dept Anim Sci, Funct Breeding Grp, D-37077 Gottingen, Germany..
    Thaller, Georg
    Univ Kiel, Inst Anim Breeding & Husb, D-24098 Kiel, Germany..
    Metzger, Julia
    Univ Vet Med Hannover, Inst Anim Breeding & Genet, D-30559 Hannover, Germany..
    Distl, Ottmar
    Univ Vet Med Hannover, Inst Anim Breeding & Genet, D-30559 Hannover, Germany..
    Lindgren, Gabriella
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden.;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    Schaefer, Robert
    Univ Minnesota, Vet Populat Med Dept, St Paul, MN 55108 USA..
    McCue, Molly
    Univ Minnesota, Vet Populat Med Dept, St Paul, MN 55108 USA..
    Neuditschko, Markus
    Agroscope, Swiss Natl Stud Farm, CH-1580 Avenches, Switzerland..
    Rieder, Stefan
    Agroscope, Swiss Natl Stud Farm, CH-1580 Avenches, Switzerland..
    Schloetterer, Christian
    Univ Vet Med Vienna, Inst Populat Genet, A-1210 Vienna, Austria..
    Brem, Gottfried
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria..
    Y Chromosome Uncovers the Recent Oriental Origin of Modern Stallions2017In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 27, no 13, p. 2029-2035Article in journal (Refereed)
    Abstract [en]

    The Y chromosome directly reflects male genealogies, but the extremely low Y chromosome sequence diversity in horses has prevented the reconstruction of stallion genealogies [1, 2]. Here, weresolve the first Y chromosomegenealogy of modern horses by screening 1.46 Mb of the male-specific region of the Y chromosome (MSY) in 52 horses from 21 breeds. Based on highly accurate pedigree data, we estimated the de novo mutation rate of the horse MSY and showed that various modern horse Y chromosome lineages split much later than the domestication of the species. Apart from few private northern European haplotypes, all modern horse breeds clustered together in a roughly 700-year-old haplogroup that was transmitted to Europe by the import of Oriental stallions. The Oriental horse group consisted of two major subclades: the Original Arabian lineage and the Turkoman horse lineage. We show that the English Thoroughbred MSY was derived from the Turkoman lineage and that English Thoroughbred sires are largely responsible for the predominance of this haplotype in modern horses.

12 1 - 50 of 51
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