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  • 101. Miller, Webb
    et al.
    Drautz, Daniela I
    Ratan, Aakrosh
    Pusey, Barbara
    Qi, Ji
    Lesk, Arthur M
    Tomsho, Lynn P
    Packard, Michael D
    Zhao, Fangqing
    Sher, Andrei
    Tikhonov, Alexei
    Raney, Brian
    Patterson, Nick
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lander, Eric S
    Knight, James R
    Irzyk, Gerard P
    Fredrikson, Karin M
    Harkins, Timothy T
    Sheridan, Sharon
    Pringle, Tom
    Schuster, Stephan C
    Sequencing the nuclear genome of the extinct woolly mammoth.2008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 456, no 7220, p. 387-390Article in journal (Refereed)
    Abstract [en]

    In 1994, two independent groups extracted DNA from several Pleistocene epoch mammoths and noted differences among individual specimens. Subsequently, DNA sequences have been published for a number of extinct species. However, such ancient DNA is often fragmented and damaged, and studies to date have typically focused on short mitochondrial sequences, never yielding more than a fraction of a per cent of any nuclear genome. Here we describe 4.17 billion bases (Gb) of sequence from several mammoth specimens, 3.3 billion (80%) of which are from the woolly mammoth (Mammuthus primigenius) genome and thus comprise an extensive set of genome-wide sequence from an extinct species. Our data support earlier reports that elephantid genomes exceed 4 Gb. The estimated divergence rate between mammoth and African elephant is half of that between human and chimpanzee. The observed number of nucleotide differences between two particular mammoths was approximately one-eighth of that between one of them and the African elephant, corresponding to a separation between the mammoths of 1.5-2.0 Myr. The estimated probability that orthologous elephant and mammoth amino acids differ is 0.002, corresponding to about one residue per protein. Differences were discovered between mammoth and African elephant in amino-acid positions that are otherwise invariant over several billion years of combined mammalian evolution. This study shows that nuclear genome sequencing of extinct species can reveal population differences not evident from the fossil record, and perhaps even discover genetic factors that affect extinction.

  • 102. Miller, Webb
    et al.
    Rosenbloom, Kate
    Hardison, Ross C
    Hou, Minmei
    Taylor, James
    Raney, Brian
    Burhans, Richard
    King, David C
    Baertsch, Robert
    Blankenberg, Daniel
    Kosakovsky Pond, Sergei L
    Nekrutenko, Anton
    Giardine, Belinda
    Harris, Robert S
    Tyekucheva, Svitlana
    Diekhans, Mark
    Pringle, Thomas H
    Murphy, William J
    Lesk, Arthur
    Weinstock, George M
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gibbs, Richard A
    Lander, Eric S
    Siepel, Adam
    Haussler, David
    Kent, W James
    28-Way vertebrate alignment and conservation track in the UCSC Genome Browser2007In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 17, no 12, p. 1797-1808Article in journal (Refereed)
    Abstract [en]

    This article describes a set of alignments of 28 vertebrate genome sequences that is provided by the UCSC Genome Browser. The alignments can be viewed on the Human Genome Browser (March 2006 assembly) at http://genome.ucsc.edu, downloaded in bulk by anonymous FTP from http://hgdownload.cse.ucsc.edu/goldenPath/hg18/multiz28way, or analyzed with the Galaxy server at http://g2.bx.psu.edu. This article illustrates the power of this resource for exploring vertebrate and mammalian evolution, using three examples. First, we present several vignettes involving insertions and deletions within protein-coding regions, including a look at some human-specific indels. Then we study the extent to which start codons and stop codons in the human sequence are conserved in other species, showing that start codons are in general more poorly conserved than stop codons. Finally, an investigation of the phylogenetic depth of conservation for several classes of functional elements in the human genome reveals striking differences in the rates and modes of decay in alignability. Each functional class has a distinctive period of stringent constraint, followed by decays that allow (for the case of regulatory regions) or reject (for coding regions and ultraconserved elements) insertions and deletions.

  • 103.
    Molin, Anna-Maja
    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.
    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.
    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.
    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.
    Genome-wide copy number variant discovery in dogs using the CanineHD genotyping array2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 210-Article in journal (Refereed)
    Abstract [en]

    Background: Substantial contribution to phenotypic diversity is accounted for by copy number variants (CNV). In human, as well as other species, the effect of CNVs range from benign to directly disease-causing which motivates the continued investigations of CNVs. Previous canine genome-wide screenings for CNVs have been performed using high-resolution comparative genomic hybridisation arrays which have contributed with a detailed catalogue of CNVs. Here, we present the first CNV investigation in dogs based on the recently reported CanineHD 170 K genotyping array. The hitherto largest dataset in canine CNV discovery was assessed, 351 dogs from 30 different breeds, enabling identification of novel CNVs and a thorough characterisation of breed-specific CNVs. Results: A stringent procedure identified 72 CNV regions with the smallest size of 38 kb and of the 72 CNV regions, 38 overlapped 148 annotated genes. A total of 29 novel CNV regions were found containing 44 genes. Furthermore, 15 breed specific CNV regions were identified of which 14 were novel and some of them overlapped putative disease susceptibility genes. In addition, the human ortholog of 23 canine copy number variable genes identified herein has been previously suggested to be dosage-sensitive in human. Conclusions: The present study evaluated the performance of the CanineHD in detecting CNVs and extends the current catalogue of canine CNV regions with several dozens of novel CNV regions. These novel CNV regions, which harbour candidate genes that possibly contribute to phenotypic variation in dogs or to disease-susceptibility, are a rich resource for future investigations.

  • 104.
    Noh, Hyun Ji
    et al.
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    Tang, Ruqi
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA.;MIT, McGovern Inst Brain Res, Dept Brain & Cognit Sci, 43 Vassar St, Cambridge, MA 02139 USA.;Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, 145 Shandong Middle Rd, Shanghai 200001, Peoples R China..
    Flannick, Jason
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    O'Dushlaine, Colm
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    Swofford, Ross
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    Howrigan, Daniel
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    Genereux, Diane P.
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    Johnson, Jeremy
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    van Grootheest, Gerard
    Vrije Univ Amsterdam, Med Ctr, GGZ inGeest, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands..
    Grunblatt, Edna
    Univ Zurich, Univ Hosp Psychiat Zurich, Dept Child & Adolescent Psychiat & Psychotherapy, Neumunsterallee 9, CH-8032 Zurich, Switzerland.;Univ Zurich, Neurosci Ctr Zurich, Winterthurer Str 190, CH-8057 Zurich, Switzerland.;Swiss Fed Inst Technol, Winterthurer Str 190, CH-8057 Zurich, Switzerland.;Univ Zurich, Zurich Ctr Integrat Human Physiol, Winterthurer Str 190, CH-8057 Zurich, Switzerland..
    Andersson, Erik
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Tomtebodavagen 18A, S-17177 Stockholm, Sweden..
    Djurfeldt, Diana R.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Tomtebodavagen 18A, S-17177 Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, S-14186 Stockholm, Sweden..
    Patel, Paresh D.
    Univ Michigan, Dept Psychiat, 4250 Plymouth Rd, Ann Arbor, MI 48109 USA..
    Koltookian, Michele
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    Hultman, Christina M.
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden..
    Pato, Michele T.
    USC, Dept Psychiat & Behav Sci, 2250 Alcazar St, Los Angeles, CA 90033 USA..
    Pato, Carlos N.
    USC, Dept Psychiat & Behav Sci, 2250 Alcazar St, Los Angeles, CA 90033 USA..
    Rasmussen, Steven A.
    Brown Med Sch, Dept Psychiat & Human Behav, 345 Blackstone Blvd,Box G-BH, Providence, RI 02906 USA..
    Jenike, Michael A.
    Harvard Med Sch, Dept Psychiat, 401 Pk Dr, Boston, MA 02215 USA..
    Hanna, Gregory L.
    Univ Michigan, Dept Psychiat, 4250 Plymouth Rd, Ann Arbor, MI 48109 USA..
    Stewart, S. Evelyn
    Univ British Columbia, BC Mental Hlth & Addict Res Inst, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada..
    Knowles, James A.
    USC, Dept Psychiat & Behav Sci, 2250 Alcazar St, Los Angeles, CA 90033 USA..
    Ruhrmann, Stephan
    Univ Cologne, Dept Psychiat & Psychotherapy, Kerpener St 62, D-50937 Cologne, Germany..
    Grabe, Hans-Joergen
    Univ Med Greifswald, Dept Psychiat & Psychotherapy, Fleischmannstr 8, D-17475 Greifswald, Germany..
    Wagner, Michael
    Univ Bonn, Dept Psychiat & Psychotherapy, Regina Pacis Weg 3, D-53113 Bonn, Germany.;German Ctr Neurodegenerat Dis, Sigmund Freud Str 27, D-53127 Bonn, Germany..
    Ruck, Christian
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Tomtebodavagen 18A, S-17177 Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, S-14186 Stockholm, Sweden..
    Mathews, Carol A.
    Univ Florida, Dept Psychiat & Genet, 1149 Newell Dr, Gainesville, FL 32610 USA..
    Walitza, Susanne
    Univ Zurich, Univ Hosp Psychiat Zurich, Dept Child & Adolescent Psychiat & Psychotherapy, Neumunsterallee 9, CH-8032 Zurich, Switzerland.;Univ Zurich, Neurosci Ctr Zurich, Winterthurer Str 190, CH-8057 Zurich, Switzerland.;Swiss Fed Inst Technol, Winterthurer Str 190, CH-8057 Zurich, Switzerland.;Univ Zurich, Zurich Ctr Integrat Human Physiol, Winterthurer Str 190, CH-8057 Zurich, Switzerland..
    Cath, Danielle C.
    Univ Utrecht, Dept Clin & Hlth Psychol, Heidelberglaan 1, NL-3584 CS Utrecht, Netherlands..
    Feng, Guoping
    MIT, McGovern Inst Brain Res, Dept Brain & Cognit Sci, 43 Vassar St, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, 415 Main St, Cambridge, MA 02142 USA..
    Karlsson, Elinor K.
    Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA.;Univ Massachusetts, Med Sch, Program Bioinformat & Integrat Biol, Sherman Ctr, 368 Plantat St, Worcester, MA 01605 USA..
    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 Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    Integrating evolutionary and regulatory information with multispecies approach implicates genes and pathways in obsessive-compulsive disorder2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 774Article in journal (Refereed)
    Abstract [en]

    Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 x 10(-11)) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited.

  • 105.
    Olsson, M.
    et al.
    Karolinska Inst, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Kierczak, Marcin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Karlsson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jablonska, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leegwater, P.
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands..
    Koltookian, M.
    Broad Inst MIT & Harvard, Boston, MA USA..
    Abadie, J.
    LUNAM Univ, Oniris, AMaROC Unit, F-44307 Nantes, France..
    De Citres, C. Dufaure
    ANTAGENE Anim Genet Lab, Lyon 69, France..
    Thomas, A.
    ANTAGENE Anim Genet Lab, Lyon 69, France..
    Hedhammar, A.
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Tintle, L.
    Wurtsboro Vet Clin, Wurtsboro, NY USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Boston, MA USA..
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Absolute quantification reveals the stable transmission of a high copy number variant linked to autoinflammatory disease2016In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, article id 299Article in journal (Refereed)
    Abstract [en]

    Background: Dissecting the role copy number variants (CNVs) play in disease pathogenesis is directly reliant on accurate methods for quantification. The Shar-Pei dog breed is predisposed to a complex autoinflammatory disease with numerous clinical manifestations. One such sign, recurrent fever, was previously shown to be significantly associated with a novel, but unstable CNV (CNV_16.1). Droplet digital PCR (ddPCR) offers a new mechanism for CNV detection via absolute quantification with the promise of added precision and reliability. The aim of this study was to evaluate ddPCR in relation to quantitative PCR (qPCR) and to assess the suitability of the favoured method as a genetic test for Shar-Pei Autoinflammatory Disease (SPAID). Results: One hundred and ninety-six individuals were assayed using both PCR methods at two CNV positions (CNV_14.3 and CNV_16.1). The digital method revealed a striking result. The CNVs did not follow a continuum of alleles as previously reported, rather the alleles were stable and pedigree analysis showed they adhered to Mendelian segregation. Subsequent analysis of ddPCR case/control data confirmed that both CNVs remained significantly associated with the subphenotype of fever, but also to the encompassing SPAID complex (p < 0.001). In addition, harbouring CNV_16.1 allele five (CNV_16.1 vertical bar 5) resulted in a four-fold increase in the odds for SPAID (p < 0.001). The inclusion of a genetic marker for CNV_16.1 in a genome-wide association test revealed that this variant explained 9.7 % of genetic variance and 25.8 % of the additive genetic heritability of this autoinflammatory disease. Conclusions: This data shows the utility of the ddPCR method to resolve cryptic copy number inheritance patterns and so open avenues of genetic testing. In its current form, the ddPCR test presented here could be used in canine breeding to reduce the number of homozygote CNV_16.1 broken vertical bar 5 individuals and thereby to reduce the prevalence of disease in this breed.

  • 106.
    Olsson, Mia
    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.
    Frankowiack, Marcel
    Tengvall, Katarina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Roosje, Petra
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ivansson, Emma
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergvall, Kerstin
    Hansson-Hamlin, Helene
    Sundberg, Katarina
    Hedhammar, Ake
    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.
    Hammarstrom, Lennart
    The dog as a genetic model for immunoglobulin A (IgA) deficiency: Identification of several breeds with low serum IgA concentrations2014In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 60, no 3-4, p. 255-259Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin A (IgA) serves as the basis of the secretory immune system by protecting the lining of mucosal sites from pathogens. In both humans and dogs, IgA deficiency (IgAD) is associated with recurrent infections of mucosal sites and immune-mediated diseases. Low concentrations of serum IgA have previously been reported to occur in a number of dog breeds but no generally accepted cut-off value has been established for canine IgAD. The current study represents the largest screening to date of IgA in dogs in terms of both number of dogs (n = 1267) and number of breeds studied (n = 22). Serum IgA concentrations were quantified by using capture ELISA and were found to vary widely between breeds. We also found IgA to be positively correlated with age (p < 0.0001). Apart from the two breeds previously reported as predisposed to low IgA (Shar-Pei and German shepherd), we identified six additional breeds in which > 10% of all tested dogs had very low (<0.07 g/l) IgA concentrations (Hovawart, Norwegian elkhound, Nova Scotia duck tolling retriever, Bullterrier, Golden retriever and Labrador retriever). In addition, we discovered low IgA concentrations to be significantly associated with canine atopic dermatitis (CAD, p < 0.0001) and pancreatic acinar atrophy (PAA, p = 0.04) in German shepherds.

  • 107.
    Olsson, Mia
    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.
    Meadows, Jennifer R. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Truve, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli Rosengren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Puppo, Francesca
    Mauceli, Evan
    Quilez, Javier
    Tonomura, Noriko
    Zanna, Giordana
    Jose Docampo, Maria
    Bassols, Anna
    Avery, Anne C.
    Karlsson, Elinor K.
    Thomas, Anne
    Kastner, Daniel L.
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    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.
    Sanchez, Armand
    Hedhammar, Åke
    Remmers, Elaine F.
    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.
    Ferrer, Lluis
    Tintle, Linda
    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.
    A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 3, p. e1001332-Article in journal (Refereed)
    Abstract [en]

    Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 x 10(-6), p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p, < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

  • 108. Olsson, Mia
    et al.
    Tengvall, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Frankowiack, Marcel
    Kierczak, Marcin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergvall, Kerstin
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tintle, Linda
    Marti, Eliane
    Roosje, Petra
    Leeb, Tosso
    Hedhammar, Åke
    Hammarström, Lennart
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133844Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development.

  • 109.
    Olsson, Mia
    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.
    Tintle, Linda
    Wurtsboro Veterinary Clinic, Wurtsboro, NY, United States of America.
    Kierczak, Marcin
    Computational Genetics Group, Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Perloski, Michele
    Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA, United States of America.
    Tonomura, Noriko
    Lindquist, Andrew
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fels, Max
    Tengvall, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Dufaure de Citres, Caroline
    ANTAGENE Animal Genetics Laboratory, La Tour de Salvagny (69 Lyon), France..
    Dorso, Laetitia
    LUNAM University, Oniris, AMaROC Unit, Nantes, F-44307, France.
    Abadie, Jérôme
    LUNAM University, Oniris, AMaROC Unit, Nantes, F-44307, France.
    Hanson, Jeanette
    Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden. .
    Thomas, Anne
    Leegwater, Peter
    Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, The Netherlands..
    Hedhammar, Åke
    Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden..
    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.
    Meadows, Jennifer R. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Thorough investigation of a canine autoinflammatory disease (AID) syndrome confirms one main risk factor and suggests a modifier locus for amyloidosis2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, p. e75242-Article in journal (Refereed)
    Abstract [en]

    Autoinflammatory disease (AID) manifests from the dysregulation of the innate immune system and is characterised by systemic and persistent inflammation. Clinical heterogeneity leads to patients presenting with one or a spectrum of phenotypic signs, leading to difficult diagnoses in the absence of a clear genetic cause. We used separate genome-wide SNP analyses to investigate five signs of AID (recurrent fever, arthritis, breed specific secondary dermatitis, otitis and systemic reactive amyloidosis) in a canine comparative model, the pure bred Chinese Shar-Pei. Analysis of 255 DNA samples revealed a shared locus on chromosome 13 spanning two peaks of association. A three-marker haplotype based on the most significant SNP (p<2.6x10(-8)) from each analysis showed that one haplotypic pair (H13-11) was present in the majority of AID individuals, implicating this as a shared risk factor for all phenotypes. We also noted that a genetic signature (F-ST) distinguishing the phenotypic extremes of the breed specific Chinese Shar-Pei thick and wrinkled skin, flanked the chromosome 13 AID locus; suggesting that breed development and differentiation has played a parallel role in the genetics of breed fitness. Intriguingly, a potential modifier locus for amyloidosis was revealed on chromosome 14, and an investigation of candidate genes from both this and the chromosome 13 regions revealed significant (p<0.05) renal differential expression in four genes previously implicated in kidney or immune health (AOAH, ELMO1, HAS2 and IL6). These results illustrate that phenotypic heterogeneity need not be a reflection of genetic heterogeneity, and that genetic modifiers of disease could be masked if syndromes were not first considered as individual clinical signs and then as a sum of their component parts.

  • 110. Owczarek-Lipska, Marta
    et al.
    Lauber, Béatrice
    Molitor, Vivianne
    Meury, Sabrina
    Kierczak, Marcin
    Tengvall, Katarina
    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 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.
    Jagannathan, Vidhya
    Schlotter, Yvette
    Willemse, Ton
    Hendricks, Anke
    Bergvall, Kerstin
    Hedhammar, Åke
    Andersson, Göran
    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.
    Favrot, Claude
    Roosje, Petra
    Marti, Eliane
    Leeb, Tosso
    Two Loci on Chromosome 5 Are Associated with Serum IgE Levels in Labrador Retrievers2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e39176-Article in journal (Refereed)
    Abstract [en]

    Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response.

  • 111.
    Palkopoulou, Eleftheria
    et al.
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Lipson, Mark
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA..
    Mallick, Swapan
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Nielsen, Svend
    Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark..
    Rohland, Nadin
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA..
    Baleka, Sina
    Univ Potsdam, Unit Gen Zool Evolutionary Adapt Genom, Inst Biochem & Biol, Fac Math & Life Sci, D-14476 Potsdam, Germany..
    Karpinski, Emil
    McMaster Univ, McMaster Ancient DNA Ctr, Dept Anthropol, Hamilton, ON L8S 4L9, Canada.;McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada.;McMaster Univ, Dept Biochem, Hamilton, ON L8S 4L8, Canada.;McMaster Univ, Michael G DeGroote Inst Infect Dis Res, Hamilton, ON L8S 4L8, Canada..
    Ivancevici, Atma M.
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    To, Thu-Hien
    Kortschak, Daniel
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    Raison, Joy M.
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    Qu, Zhipeng
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    Chin, Tat-Jun
    Univ Adelaide, Sch Comp Sci, Adelaide, SA 5005, Australia..
    Alt, Kurt W.
    Danube Private Univ, Ctr Nat & Cultural Human Hist, A-3500 Krems, Austria.;Univ Basel, Univ Basel Hosp, Dept Biomed Engn, CH-4123 Basel, Switzerland.;Univ Basel, Integrat Prehist & Archaeol Sci, CH-4051 Basel, Switzerland..
    Claesson, Stefan
    Inst Maritime Hist, Tall Timbers, MD 20690 USA..
    Dalen, Love
    Swedish Museum Nat Hist, Dept Bioinformat & Genet, SE-10405 Stockholm, Sweden..
    MacPhee, Ross D. E.
    Amer Museum Nat Hist, Div Vertebrate Zool Mammal, New York, NY 10024 USA..
    Meller, Harald
    State Off Heritage Management & Archaeol, D-06114 Halle, Saale, Germany..
    Rocar, Alfred L.
    Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA.;Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA..
    Ryder, Oliver A.
    San Diego Zoo, Inst Conservat Res, Escondido, CA 92027 USA..
    Heiman, David
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Young, Sarah
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Breen, Matthew
    North Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27607 USA..
    Williams, Christina
    North Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27607 USA..
    Aken, Bronwen L.
    European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Sanger Inst, Cambridge CB10 1SD, England..
    Ruffier, Magali
    European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Sanger Inst, Cambridge CB10 1SD, England..
    Karlsson, Elinor
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.;Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01655 USA..
    Johnson, Jeremy
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Di Palma, Federica
    Earlham Inst, Norwich NR4 7UZ, Norfolk, England..
    Alfoldi, Jessica
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Adelsoni, David L.
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    Mailund, Thomas
    Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark..
    Munch, Kasper
    Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark..
    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 Inst MIT & Harvard, Cambridge, MA 02142 USA.
    Hofreiter, Michael
    Univ Potsdam, Unit Gen Zool Evolutionary Adapt Genom, Inst Biochem & Biol, Fac Math & Life Sci, D-14476 Potsdam, Germany..
    Poinar, Hendrik
    McMaster Univ, McMaster Ancient DNA Ctr, Dept Anthropol, Hamilton, ON L8S 4L9, Canada.;McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada.;McMaster Univ, Dept Biochem, Hamilton, ON L8S 4L8, Canada.;McMaster Univ, Michael G DeGroote Inst Infect Dis Res, Hamilton, ON L8S 4L8, Canada..
    Reich, David
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.;Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA..
    A comprehensive genomic history of extinct and living elephants2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 11, p. E2566-E2574Article in journal (Refereed)
    Abstract [en]

    Elephantids are the world's most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an similar to 120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant's ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for similar to 500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species.

  • 112. Parra, Zuly E
    et al.
    Baker, Michelle L
    Schwarz, Ryan S
    Deakin, Janine E
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Miller, Robert D
    A unique T cell receptor discovered in marsupials2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 23, p. 9776-9781Article in journal (Refereed)
    Abstract [en]

    T cells recognize antigens by using T cell receptors (TCRs) encoded by gene segments, called variable (V), diversity (D), and joining (J), that undergo somatic recombination to create diverse binding specificities. Four TCR chains (alpha, beta, gamma, and delta) have been identified to date, and, as T cells develop in the thymus, they express exclusively either an alphabetaTCR or a gammadeltaTCR heterodimer. Here, we show that marsupials have an additional TCR (TCRmu) that has V, D, and J that are either somatically recombined, as in conventional TCRs, or are already prejoined in the germ-line DNA in a manner consistent with their creation by retrotransposition. TCRmu does not have a known homolog in eutherian mammals but has features analogous to a recently described TCRdelta isoform in sharks. TCRmu is expressed in at least two mRNA isoforms that appear capable of encoding a full-length protein, both of which are transcribed in the thymus and spleen. One contains two variable domains: a somatically recombined V and a prejoined V. This appears to be the dominant isoform in peripheral lymphoid tissue. The other isoform contains only the prejoined V and is structurally more similar to conventional TCR chains, however invariant. Unlike other TCRs, TCRmu uses prejoined gene segments and is likely present in all marsupials. Its similarity to a TCR isoform in sharks suggests that it, or something similar, may be present in other vertebrate lineages and, therefore, may represent an ancient receptor system.

  • 113. Peng, Xinxia
    et al.
    Alfoeldi, Jessica
    Gori, Kevin
    Eisfeld, Amie J.
    Tyler, Scott R.
    Tisoncik-Go, Jennifer
    Brawand, David
    Law, G. Lynn
    Skunca, Nives
    Hatta, Masato
    Gasper, David J.
    Kelly, Sara M.
    Chang, Jean
    Thomas, Matthew J.
    Johnson, Jeremy
    Berlin, Aaron M.
    Lara, Marcia
    Russell, Pamela
    Swofford, Ross
    Turner-Maier, Jason
    Young, Sarah
    Hourlier, Thibaut
    Aken, Bronwen
    Searle, Steve
    Sun, Xingshen
    Yi, Yaling
    Suresh, M.
    Tumpey, Terrence M.
    Siepel, Adam
    Wisely, Samantha M.
    Dessimoz, Christophe
    Kawaoka, Yoshihiro
    Birren, Bruce W.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Di Palma, Federica
    Engelhardt, John F.
    Palermo, Robert E.
    Katze, Michael G.
    The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease2014In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 32, no 12, p. 1250-U114Article in journal (Refereed)
    Abstract [en]

    The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the 'gold standard' for modeling human influenza virus infection and transmission(1-)4. Here we describe the 2.41 Gb draft genome assembly of the domestic ferret, constituting 2.28 Gb of sequence plus gaps. We annotated 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues. We characterized the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time-course data and showed distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis disease progression, we showed that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with cystic fibrosis disease.

  • 114.
    Penso-Dolfin, Luca
    et al.
    Genome Anal Ctr, Vertebrate & Hlth Genom, Norwich, Norfolk, England..
    Swofford, Ross
    Broad Inst MIT & Harvard, Vertebrate Genome Biol, Cambridge, MA USA..
    Johnson, Jeremy
    Broad Inst MIT & Harvard, Vertebrate Genome Biol, Cambridge, MA USA..
    Alfoldi, Jessica
    Broad Inst MIT & Harvard, Vertebrate Genome Biol, Cambridge, MA USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Vertebrate Genome Biol, Cambridge, MA USA..
    Swarbreck, David
    Genome Anal Ctr, Regulatory Genom, Norwich, Norfolk, England..
    Moxon, Simon
    Genome Anal Ctr, Regulatory Genom, Norwich, Norfolk, England..
    Di Palma, Federica
    Genome Anal Ctr, Vertebrate & Hlth Genom, Norwich, Norfolk, England..
    An Improved microRNA Annotation of the Canine Genome2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153453Article in journal (Refereed)
    Abstract [en]

    The domestic dog, Canis familiaris, is a valuable model for studying human diseases. The publication of the latest Canine genome build and annotation, CanFam3.1 provides an opportunity to enhance our understanding of gene regulation across tissues in the dog model system. In this study, we used the latest dog genome assembly and small RNA sequencing data from 9 different dog tissues to predict novel miRNAs in the dog genome, as well as to annotate conserved miRNAs from the miRBase database that were missing from the current dog annotation. We used both miRCat and miRDeep2 algorithms to computationally predict miRNA loci. The resulting, putative hairpin sequences were analysed in order to discard false positives, based on predicted secondary structures and patterns of small RNA read alignments. Results were further divided into high and low confidence miRNAs, using the same criteria. We generated tissue specific expression profiles for the resulting set of 811 loci: 720 conserved miRNAs, (207 of which had not been previously annotated in the dog genome) and 91 novel miRNA loci. Comparative analyses revealed 8 putative homologues of some novel miRNA in ferret, and one in microbat. All miRNAs were also classified into the genic and intergenic categories, based on the Ensembl RefSeq gene annotation for CanFam3.1. This additionally allowed us to identify four previously undescribed MiRtrons among our total set of miRNAs. We additionally annotated piRNAs, using proTRAC on the same input data. We thus identified 263 putative clusters, most of which (211 clusters) were found to be expressed in testis. Our results represent an important improvement of the dog genome annotation, paving the way to further research on the evolution of gene regulation, as well as on the contribution of post-transcriptional regulation to pathological conditions.

  • 115.
    Pielberg, Gerli Rosengren
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Golovko, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundström, Elisabeth
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-751 24 Uppsala, Sweden.
    Curik, Ino
    Animal Science Department, Faculty of Agriculture, University of Zagreb, HR-10000 Zagreb, Croatia.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Seltenhammer, Monika H.
    Department of Clinical Surgery and Ophthalmology, University of Veterinary Medicine, A-1200 Vienna, Austria.
    Druml, Thomas
    Department of Sustainable Agricultural Systems, University of Natural Resources and Applied Life Sciences, Vienna, A-1180 Vienna, Austria.
    Binns, Matthew
    Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
    Fitzsimmons, Carolyn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindgren, Gabriella
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-751 24 Uppsala, Sweden.
    Sandberg, Kaj
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-751 24 Uppsala, Sweden.
    Baumung, Roswitha
    Department of Sustainable Agricultural Systems, University of Natural Resources and Applied Life Sciences, Vienna, A-1180 Vienna, Austria.
    Vetterlein, Monika
    Centre for Anatomy and Cell Biology, Department of Cell Biology and Ultrastructure Research, Medical University of Vienna, A-1080 Vienna, Austria.
    Strömberg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grabherr, Manfred
    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
    Wade, Claire
    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Sölkner, Johann
    Department of Sustainable Agricultural Systems, University of Natural Resources and Applied Life Sciences, Vienna, A-1180 Vienna, Austria.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse2008In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 40, no 8, p. 1004-1009Article in journal (Refereed)
    Abstract [en]

    In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.

  • 116. Pontius, Joan U
    et al.
    Mullikin, James C
    Smith, Douglas R
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gnerre, Sante
    Clamp, Michele
    Chang, Jean
    Stephens, Robert
    Neelam, Beena
    Volfovsky, Natalia
    Schäffer, Alejandro A
    Agarwala, Richa
    Narfström, Kristina
    Murphy, William J
    Giger, Urs
    Roca, Alfred L
    Antunes, Agostinho
    Menotti-Raymond, Marilyn
    Yuhki, Naoya
    Pecon-Slattery, Jill
    Johnson, Warren E
    Bourque, Guillaume
    Tesler, Glenn
    O'Brien, Stephen J
    Initial sequence and comparative analysis of the cat genome2007In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 17, no 11, p. 1675-1689Article in journal (Refereed)
    Abstract [en]

    The genome sequence (1.9-fold coverage) of an inbred Abyssinian domestic cat was assembled, mapped, and annotated with a comparative approach that involved cross-reference to annotated genome assemblies of six mammals (human, chimpanzee, mouse, rat, dog, and cow). The results resolved chromosomal positions for 663,480 contigs, 20,285 putative feline gene orthologs, and 133,499 conserved sequence blocks (CSBs). Additional annotated features include repetitive elements, endogenous retroviral sequences, nuclear mitochondrial (numt) sequences, micro-RNAs, and evolutionary breakpoints that suggest historic balancing of translocation and inversion incidences in distinct mammalian lineages. Large numbers of single nucleotide polymorphisms (SNPs), deletion insertion polymorphisms (DIPs), and short tandem repeats (STRs), suitable for linkage or association studies were characterized in the context of long stretches of chromosome homozygosity. In spite of the light coverage capturing approximately 65% of euchromatin sequence from the cat genome, these comparative insights shed new light on the tempo and mode of gene/genome evolution in mammals, promise several research applications for the cat, and also illustrate that a comparative approach using more deeply covered mammals provides an informative, preliminary annotation of a light (1.9-fold) coverage mammal genome sequence.

  • 117.
    Raffan, Eleanor
    et al.
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    Dennis, Rowena J.
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    O'Donovan, Conor J.
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    Becker, Julia M.
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    Scott, Robert A.
    Univ Cambridge, WT MRC Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Smith, Stephen P.
    Univ Cambridge, Sch Clin Med, Cambridge CB2 0SP, England..
    Withers, David J.
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    Wood, Claire J.
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    Conci, Elena
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    Clements, Dylan N.
    Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland.;Univ Edinburgh, Royal Dick Sch Vet Studies, Easter Bush EH25 9RG, Midlothian, Scotland..
    Summers, Kim M.
    Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland..
    German, Alexander J.
    Univ Liverpool, Inst Ageing & Chron Dis, Neston CH64 7TE, Cheshire, England..
    Mellersh, Cathryn S.
    Anim Hlth Trust, Dept Canine Genet, Newmarket CB8 7UU, Suffolk, England..
    Arendt, Maja L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Iyemere, Valentine P.
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    Withers, Elaine
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    Soder, Josefin
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, S-75007 Uppsala, Sweden..
    Wernersson, Sara
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, S-75007 Uppsala, Sweden..
    Andersson, Goran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & MIT, Cambridge, MA 02142 USA..
    Yeo, Giles S. H.
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    O'Rahilly, Stephen
    Univ Cambridge, WT MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England..
    A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs2016In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 23, no 5, p. 893-900Article in journal (Refereed)
    Abstract [en]

    Sequencing of candidate genes for obesity in Labrador retriever dogs identified a 14 bp deletion in pro-opiomelanocortin (POMC) with an allele frequency of 12%. The deletion disrupts the b-MSH and beta-endorphin coding sequences and is associated with body weight (per allele effect of 0.33 SD), adiposity, and greater food motivation. Among other dog breeds, the deletion was only found in the closely related flat-coat retriever (FCR), where it is similarly associated with body weight and food motivation. The mutation is significantly more common in Labrador retrievers selected to become assistance dogs than pets. In conclusion, the deletion in POMC is a significant modifier of weight and appetite in Labrador retrievers and FCRs and may influence other behavioral traits.

  • 118. Rincon, Gonzalo
    et al.
    Tengvall, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Belanger, Janelle M
    Lagoutte, Laetitia
    Medrano, Juan F
    André, Catherine
    Thomas, Anne
    Lawley, Cynthia Taylor
    Hansen, Mark St
    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.
    Oberbauer, Anita M
    Comparison of buccal and blood-derived canine DNA, either native or whole genome amplified, for array-based genome-wide association studies2011In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 4, p. 226-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The availability of array-based genotyping platforms for single nucleotide polymorphisms (SNPs) for the canine genome has expanded the opportunities to undertake genome-wide association (GWA) studies to identify the genetic basis for Mendelian and complex traits. Whole blood as the source of high quality DNA is undisputed but often proves impractical for collection of the large numbers of samples necessary to discover the loci underlying complex traits. Further, many countries prohibit the collection of blood from dogs unless medically necessary thereby restricting access to critical control samples from healthy dogs. Alternate sources of DNA, typically from buccal cytobrush extractions, while convenient, have been suggested to have low yield and perform poorly in GWA. Yet buccal cytobrushes provide a cost-effective means of collecting DNA, are readily accepted by dog owners, and represent a large resource base in many canine genetics laboratories. To increase the DNA quantities, whole genome amplification (WGA) can be performed. Thus, the present study assessed the utility of buccal-derived DNA as well as whole genome amplification in comparison to blood samples for use on the most recent iteration of the canine HD SNP array (Illumina).

    FINDINGS:

    In both buccal and blood samples, whether whole genome amplified or not, 97% of the samples had SNP call rates in excess of 80% indicating that the vast majority of the SNPs would be suitable to perform association studies regardless of the DNA source. Similarly, there were no significant differences in marker intensity measurements between buccal and blood samples for copy number variations (CNV) analysis.

    CONCLUSIONS:

    All DNA samples assayed, buccal or blood, native or whole genome amplified, are appropriate for use in array-based genome-wide association studies. The concordance between subsets of dogs for which both buccal and blood samples, or those samples whole genome amplified, was shown to average >99%. Thus, the two DNA sources were comparable in the generation of SNP genotypes and intensity values to estimate structural variation indicating the utility for the use of buccal cytobrush samples and the reliability of whole genome amplification for genome-wide association and CNV studies.

  • 119. Rivera, Patricio
    et al.
    Melin, Malin
    Biagi, Tara
    Fall, Tove
    Häggström, Jens
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    von Euler, Henrik
    Mammary tumor development in dogs is associated with BRCA1 and BRCA22009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 22, p. 8770-8774Article in journal (Refereed)
    Abstract [en]

    Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of approximately 4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer.

  • 120.
    Rohdin, C.
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, S-75007 Uppsala, Sweden;Albano Small Anim Hosp, Anicura, Rinkebyvagen 21, S-18236 Danderyd, Sweden.
    Haggstrom, J.
    Swedish Univ Agr Sci, Dept Clin Sci, S-75007 Uppsala, Sweden.
    Ljungvall, I.
    Swedish Univ Agr Sci, Dept Clin Sci, S-75007 Uppsala, Sweden.
    Lee, H. Nyman
    Bagarmossen Small Anim Hosp, Anicura, Ljusnevagen 17, S-12848 Bagarmossen, Sweden.
    De Decker, S.
    Univ London, Royal Vet Coll, Clin Sci & Serv, Hawkshead Lane, N Mymms AL9 7TA, England.
    Bertram, S.
    Univ London, Royal Vet Coll, Clin Sci & Serv, Hawkshead Lane, N Mymms AL9 7TA, England.
    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 Inst Harvard & MIT, Cambridge, MA USA.
    Jaderlund, K. Hultin
    Norwegian Univ Life Sci, Dept Compan Anim Clin Sci, N-0033 Oslo, Norway.
    Presence of thoracic and lumbar vertebral malformations in pugs with and without chronic neurological deficits2018In: The Veterinary Journal, ISSN 1090-0233, E-ISSN 1532-2971, Vol. 241, p. 24-30Article in journal (Refereed)
    Abstract [en]

    Congenital vertebral malformations (CVMs) are common in brachycephalic dogs such as the pug, and are often considered incidental findings. However, specific CVMs have been suggested to be associated with neurological deficits in pugs. The objective of this study was to investigate the clinical importance of CVMs in the pug by comparing computed tomography studies of the thoracolumbar spine from pugs without neurological deficits with those from pugs with a confirmed T3-L3 spinal cord lesion and neurological deficits consistent with a chronic T3-L3 myelopathy. A total of 57 pugs were recruited into the study from Sweden (n=33), United Kingdom (n=21) and Norway (n = 3); 30 with neurological deficits and 27 without. Focal T3-L3 pathology was confirmed in all pugs with neurological deficits by magnetic resonance imaging (n = 29) and/or pathology (n = 15). Computed tomography studies of the thoracolumbar spine from pugs with and without neurological deficits were compared to investigate possible associations between presentation of neurological deficits consistent with chronic T3-L3 pathology and signalment variables, presence of CVMs and type of CVMs. Congenital vertebral malformations were as common in pugs with, as in pugs without, neurological deficits. Regardless of neurological status, the majority of pugs (96%) presented with one or more CVM. An association between presence, or type of CVM in the T1-L3 vertebral column, and neurological deficits consistent with T3-L3 pathology could not be confirmed.

  • 121.
    Rohdin, Cecilia
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden.;Albano Anim Hosp, Anicura, Danderyd, Sweden..
    Jäderlund, Karin Hultin
    Norwegian Univ Life Sci, Dept Compan Anim Clin Sci, Oslo, Norway..
    Ljungvall, Ingrid
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & Massachusetts, Inst Technol, Cambridge, MA USA..
    Häggstrom, Jens
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    High prevalence of gait abnormalities in pugs2018In: The Veterinary Record, ISSN 0042-4900, E-ISSN 2042-7670, Vol. 182, no 6, article id 167Article in journal (Refereed)
    Abstract [en]

    The objective of this prospective study was to determine the prevalence of gait abnormalities in a cohort of Swedish pugs by using an owner-based questionnaire targeting signs of gait abnormality and video footage showing the dog's gait. This study also evaluated associated conditions of abnormal gait, including other health disorders prevalent in the breed. Five hundred and fifty (550) pugs registered in the Swedish Kennel Club, of one, five and eight years of age, in 2015 and 2016, were included in the study. Gait abnormalities were reported in 30.7 per cent of the responses. In the majority of cases, the character of the described gait indicated a neurological cause for the gait abnormality. An association was observed between abnormal gait and age, with gait abnormalities being significantly more common in older pugs (P=0.004). An association was also found between abnormal gait and dyspnoea, with dyspnoea being significantly more common in pugs with gait abnormalities (P<0.0001). This study demonstrated that the prevalence of gait abnormalities was high in the Swedish pug breed and increased with age. Future studies on the mechanisms behind these gait abnormalities are warranted.

  • 122.
    Rubin, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zody, Michael C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sherwood, Ellen
    Karolinska Institutet, Department of cell and Molecular Biology.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jiang, Lin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ingman, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sharpe, Ted
    Broad Institute.
    Besnier, Francois
    Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics.
    Ka, Sojeong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics.
    Bed'hom, Bertrand
    INRA, AgroParisTech, Animal Genetics and Integrative Biology.
    Tixier-Boichard, Michèle
    INRA, AgroParisTech, Animal Genetics and Integrative Biology.
    Jensen, Per
    Linköping University, IFM Biology.
    Siegel, Paul
    Virginia Polytechnic Institute and State University, Department of Animal and Poultry Sciences.
    Lindblad-Toh, Kerstin
    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.
    Whole genome resequencing reveals loci under selection during chicken domestication2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, no 7288, p. 587-591Article in journal (Refereed)
    Abstract [en]

    Domestic animals are excellent models for genetic studies of phenotypic evolution. They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.

  • 123.
    Sakthikumar, Sharadha
    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. Broad Inst, Cambridge, MA USA.
    Elvers, Ingegerd
    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 Inst, Cambridge, MA USA.
    Kim, Jaegil
    Broad Inst, Cambridge, MA USA.
    Arendt, Maja Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg D, Denmark.
    Thomas, Rachael
    North Carolina State Univ, Comparat Med Inst, Raleigh, NC USA;North Carolina State Univ, Coll Vet Med, Raleigh, NC USA.
    Turner-Maier, Jason
    Broad Inst, Cambridge, MA USA.
    Swofford, Ross
    Broad Inst, Cambridge, MA USA.
    Johnson, Jeremy
    Broad Inst, Cambridge, MA USA.
    Schumacher, Steven E.
    Broad Inst, Cambridge, MA USA.
    Alfoldi, Jessica
    Broad Inst, Cambridge, MA USA.
    Axelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Couto, C. Guillermo
    Ohio State Univ, Ctr Vet Med, Columbus, OH 43210 USA;Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA;Couto Vet Consultants, Hilliard, OH USA.
    Kisseberth, William C.
    Ohio State Univ, Ctr Vet Med, Columbus, OH 43210 USA;Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA.
    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.
    Getz, Gad
    Harvard Med Sch, Boston, MA USA;Broad Inst, Cambridge, MA USA;Massachusetts Gen Hosp, Boston, MA 02114 USA.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Modiano, Jaime F.
    Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA;Univ Minnesota, Stem Cell Inst, Minneapolis, MN USA;Univ Minnesota, Inst Engn & Med, Minneapolis, MN USA;Univ Minnesota, Ctr Immunol, Minneapolis, MN USA;Coll Vet Med, Dept Vet Clin Sci, St Paul, MN USA;Coll Vet Med, Anim Canc Care & Res Program, St Paul, MN USA.
    Breen, Matthew
    North Carolina State Univ, Comparat Med Inst, Raleigh, NC USA;North Carolina State Univ, Coll Vet Med, Raleigh, NC USA.
    Kierczak, Marcin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg-Nilsson, Karin
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden.
    Marinescu, Voichita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    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 Inst, Cambridge, MA USA.
    SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13, p. 3421-3431Article in journal (Refereed)
    Abstract [en]

    Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease.

  • 124.
    Sakthikumar, Sharadha
    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.
    Roy, Ananya
    Broad Institute, Cambridge, Massachusetts, USA..
    Haseeb, Lulu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    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.
    Marinescu, Voichita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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, Cambridge, Massachusetts, USA..
    Forsberg Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Whole Genome Sequencing of Glioblastoma Reveals Enrichment of Non-Coding Constraint Mutations in Known and Novel GenesManuscript (preprint) (Other academic)
  • 125.
    Salmon Hillbertz, Nicolette H. C.
    et al.
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Karlsson, Elinor K.
    Hellmén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pielberg, Gerli Rosengren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Savolainen, Peter
    Wade, Claire M.
    von Euler, Henrik
    Gustafson, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hedhammar, Åke
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lindblad-Toh, Kerstin
    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.
    Andersson, Göran
    Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs2007In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 39, no 11, p. 1318-1320Article in journal (Refereed)
    Abstract [en]

    The dorsal hair ridge in Rhodesian and Thai Ridgeback dogs is caused by a dominant mutation that also predisposes to the congenital developmental disorder dermoid sinus. Here we show that the causative mutation is a 133-kb duplication involving three fibroblast growth factor (FGF) genes. FGFs play a crucial role in development, suggesting that the ridge and dermoid sinus are caused by dysregulation of one or more of the three FGF genes during development.

  • 126. Seelig, Davis M
    et al.
    Ito, Daisuke
    Forster, Colleen L
    Yoon, Una A
    Breen, Matthew
    Burns, Linda J
    Bachanova, Veronika
    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 MIT and Harvard, Cambridge, MA, USA.
    O'Brien, Timothy D
    Schmechel, Stephen C
    Rizzardi, Anthony E
    Modiano, Jaime F
    Linden, Michael A
    Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 7, p. 1702-1710Article in journal (Refereed)
    Abstract [en]

    Activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a common molecular event observed in both human and canine diffuse large B-cell lymphoma (DLBCL). Although the oncogenic potential of the alternative NFκB pathway (ANFκBP) has also been recently identified in DLBCL, its precise role in tumor pathogenesis and potential as a treatment target is understudied. We hypothesized that up-regulation of the ANFκBP plays an important role in the proliferation and survival of canine DLBCL cells, and we demonstrate that the ANFκBP is constitutively active in primary canine DLBCL samples and a cell line (CLBL1). We further demonstrate that a small interfering RNA inhibits the activation of the NFκB pathway and induces apoptosis in canine DLBCL cells. In conclusion, the ANFκBP facilitates survival of canine DLBCL cells, and thus, dogs with spontaneous DLBCL can provide a useful large animal model to study therapies targeting the ANFκBP.

  • 127. Seppala, Eija H.
    et al.
    Jokinen, Tarja S.
    Fukata, Masaki
    Fukata, Yuko
    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.
    Karlsson, Elinor K.
    Kilpinen, Sami K.
    Steffen, Frank
    Dietschi, Elisabeth
    Leeb, Tosso
    Eklund, Ranja
    Zhao, Xiaochu
    Rilstone, Jennifer J.
    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.
    Minassian, Berge A.
    Lohi, Hannes
    LGI2 Truncation Causes a Remitting Focal Epilepsy in Dogs2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 7, p. e1002194-Article in journal (Refereed)
    Abstract [en]

    One quadrillion synapses are laid in the first two years of postnatal construction of the human brain, which are then pruned until age 10 to 500 trillion synapses composing the final network. Genetic epilepsies are the most common neurological diseases with onset during pruning, affecting 0.5% of 2-10-year-old children, and these epilepsies are often characterized by spontaneous remission. We previously described a remitting epilepsy in the Lagotto romagnolo canine breed. Here, we identify the gene defect and affected neurochemical pathway. We reconstructed a large Lagotto pedigree of around 34 affected animals. Using genome-wide association in 11 discordant sib-pairs from this pedigree, we mapped the disease locus to a 1.7 Mb region of homozygosity in chromosome 3 where we identified a protein-truncating mutation in the Lgi2 gene, a homologue of the human epilepsy gene LGI1. We show that LGI2, like LGI1, is neuronally secreted and acts on metalloproteinase-lacking members of the ADAM family of neuronal receptors, which function in synapse remodeling, and that LGI2 truncation, like LGI1 truncations, prevents secretion and ADAM interaction. The resulting epilepsy onsets at around seven weeks (equivalent to human two years), and remits by four months (human eight years), versus onset after age eight in the majority of human patients with LGI1 mutations. Finally, we show that Lgi2 is expressed highly in the immediate post-natal period until halfway through pruning, unlike Lgi1, which is expressed in the latter part of pruning and beyond. LGI2 acts at least in part through the same ADAM receptors as LGI1, but earlier, ensuring electrical stability (absence of epilepsy) during pruning years, preceding this same function performed by LGI1 in later years. LGI2 should be considered a candidate gene for common remitting childhood epilepsies, and LGI2-to-LGI1 transition for mechanisms of childhood epilepsy remission.

  • 128. Shirak, Andrey
    et al.
    Grabherr, Manfred
    Di Palma, Federica
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hulata, Gideon
    Ron, Micha
    Kocher, Tom D
    Seroussi, Eyal
    Identification of Repetitive Elements in the Genome of Oreochromis niloticus: Tilapia Repeat Masker2009In: Marine Biotechnology, ISSN 1436-2228, E-ISSN 1436-2236, Vol. 12, no 2, p. 121-125Article in journal (Refereed)
    Abstract [en]

    The large-scale bacterial artificial chromosome-end sequencing project of Nile tilapia (Oreochromis niloticus) has generated extensive sequence data that allowed the examination of the repeat content in this fish genome and building of a repeat library specific for this species. This library was established based on Tilapiini repeat sequences from GenBank, sequences orthologous to the repeat library of zebrafish in Repbase, and novel repeats detected by genome analysis using MIRA assembler. We estimate that repeats constitute about 14% of the tilapia genome and also give estimates for the occurrence of the different repeats based on the Basic Local Alignment Search Tool searches within the database of known tilapia sequences. The frequent occurrence of novel repeats in the tilapia genome indicates the importance of using the species-specific repeat masker prior to sequence analyses. A web tool based on the RepeatMasker software was designed to assist tilapia genomics.

  • 129. Sjoestrand, K.
    et al.
    Wess, G.
    Ljungvall, I.
    Haggstrom, J.
    Merveille, A-C
    Wiberg, M.
    Gouni, V.
    Willesen, J. Lundgren
    Hanas, S.
    Lequarre, A-S
    Sorensen, L. Mejer
    Wolf, J.
    Tiret, L.
    Kierczak, M.
    Forsberg, S.
    McEntee, K.
    Battaille, G.
    Seppala, E.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Georges, M.
    Lohi, Hannes
    Chetboul, V.
    Fredholm, M.
    Hoglund, K.
    Breed Differences in Natriuretic Peptides in Healthy Dogs2014In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 28, no 2, p. 451-457Article in journal (Refereed)
    Abstract [en]

    Background Measurement of plasma concentration of natriuretic peptides (NPs) is suggested to be of value in diagnosis of cardiac disease in dogs, but many factors other than cardiac status may influence their concentrations. Dog breed potentially is 1 such factor. Objective To investigate breed variation in plasma concentrations of pro-atrial natriuretic peptide 31-67 (proANP 31-67) and N-terminal B-type natriuretic peptide (NT-proBNP) in healthy dogs. Animals 535 healthy, privately owned dogs of 9 breeds were examined at 5 centers as part of the European Union (EU) LUPA project. Methods Absence of cardiovascular disease or other clinically relevant organ-related or systemic disease was ensured by thorough clinical investigation. Plasma concentrations of proANP 31-67 and NT-proBNP were measured by commercially available ELISA assays. Results Overall significant breed differences were found in proANP 31-67 (P<.0001) and NT-proBNP (P<.0001) concentrations. Pair-wise comparisons between breeds differed in approximately 50% of comparisons for proANP 31-67 as well as NT-proBNP concentrations, both when including all centers and within each center. Interquartile range was large for many breeds, especially for NT-proBNP. Among included breeds, Labrador Retrievers and Newfoundlands had highest median NT-proBNP concentrations with concentrations 3 times as high as those of Dachshunds. German Shepherds and Cavalier King Charles Spaniels had the highest median proANP 31-67 concentrations, twice the median concentration in Doberman Pinschers. Conclusions and Clinical Importance Considerable interbreed variation in plasma NP concentrations was found in healthy dogs. Intrabreed variation was large in several breeds, especially for NT-proBNP. Additional studies are needed to establish breed-specific reference ranges.

  • 130.
    Soda, Takahiro
    et al.
    Univ N Carolina, Chapel Hill, NC USA..
    Crowley, James
    Univ N Carolina, Chapel Hill, NC USA..
    Breen, Gerome
    King Coll London, London, England..
    Bulik, Cynthia
    Univ N Carolina, Chapel Hill, NC USA..
    Collier, Sarah
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Denny, Joshua
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Howell, Kayla
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sullivan, Patrick
    Univ N Carolina, Chapel Hill, NC USA..
    Biovupsych: Electronic Medical Record-Based Identification of Dna Samples for Disorders Under-Represented n The'Pgc2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, p. S243-S243Article in journal (Other academic)
  • 131. Soler, Lucile
    et al.
    Conte, Matthew A
    Katagiri, Takayuki
    Howe, Aimee E
    Lee, Bo-Young
    Amemiya, Chris
    Stuart, Andrew
    Dossat, Carole
    Poulain, Julie
    Johnson, Jeremy
    Di Palma, Federica
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Baroiller, Jean-Francois
    D'Cotta, Helena
    Ozouf-Costaz, Catherine
    Kocher, Thomas D
    Comparative physical maps derived from BAC end sequences of tilapia (Oreochromis niloticus).2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, p. 636-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The Nile tilapia is the second most important fish in aquaculture. It is an excellent laboratory model, and is closely related to the African lake cichlids famous for their rapid rates of speciation. A suite of genomic resources has been developed for this species, including genetic maps and ESTs. Here we analyze BAC end-sequences to develop comparative physical maps, and estimate the number of genome rearrangements, between tilapia and other model fish species.

    RESULTS:

    We obtained sequence from one or both ends of 106,259 tilapia BACs. BLAST analysis against the genome assemblies of stickleback, medaka and pufferfish allowed identification of homologies for approximately 25,000 BACs for each species. We calculate that rearrangement breakpoints between tilapia and these species occur about every 3 Mb across the genome. Analysis of 35,000 clones previously assembled into contigs by restriction fingerprints allowed identification of longer-range syntenies.

    CONCLUSIONS:

    Our data suggest that chromosomal evolution in recent teleosts is dominated by alternate loss of gene duplicates, and by intra-chromosomal rearrangements (~one per million years). These physical maps are a useful resource for comparative positional cloning of traits in cichlid fishes. The paired BAC end sequences from these clones will be an important resource for scaffolding forthcoming shotgun sequence assemblies of the tilapia genome.

  • 132.
    Sundström, Elisabeth
    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.
    Imsland, Freyja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mikko, Sofia
    Wade, Claire
    Sigurdsson, Snaevar
    Pielberg, Gerli 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.
    Golovko, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Curik, Ino
    Seltenhammer, Monika H.
    Soelkner, Johann
    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, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 365-Article in journal (Refereed)
    Abstract [en]

    Background: Greying with age in horses is an autosomal dominant trait, associated with loss of hair pigmentation, melanoma and vitiligo-like depigmentation. We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype. The aims of this study were to investigate if the duplication in Grey horses shows copy number variation and to exclude that any other polymorphism is uniquely associated with the Grey mutation.

    Results: We found little evidence for copy number expansion of the duplicated sequence in blood DNA from Grey horses. In contrast, clear evidence for copy number expansions was indicated in five out of eight tested melanoma tissues or melanoma cell lines. A tendency of a higher copy number in aggressive tumours was also found. Massively parallel resequencing of the similar to 350 kb Grey haplotype did not reveal any additional mutations perfectly associated with the phenotype, confirming the duplication as the true causative mutation. We identified three SNP alleles that were present in a subset of Grey haplotypes within the 350 kb region that shows complete linkage disequilibrium with the causative mutation. Thus, these three nucleotide substitutions must have occurred subsequent to the duplication, consistent with our interpretation that the Grey mutation arose more than 2,000 years before present.

    Conclusions: These results suggest that the mutation acts as a melanoma-driving regulatory element. The elucidation of the mechanistic features of the duplication will be of considerable interest for the characterization of these horse melanomas as well as for the field of human melanoma research.

  • 133.
    Sundström, Elisabeth
    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.
    Imsland, Freyja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mikko, Sofia
    Wade, Claire
    Sigurdsson, Snaevar
    Pielberg, Gerli 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.
    Golovko, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Curik, Ino
    Seltenhammer, Monika H.
    Soelkner, Johann
    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, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 365-Article in journal (Refereed)
    Abstract [en]

    Background: Greying with age in horses is an autosomal dominant trait, associated with loss of hair pigmentation, melanoma and vitiligo-like depigmentation. We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype. The aims of this study were to investigate if the duplication in Grey horses shows copy number variation and to exclude that any other polymorphism is uniquely associated with the Grey mutation.

    Results: We found little evidence for copy number expansion of the duplicated sequence in blood DNA from Grey horses. In contrast, clear evidence for copy number expansions was indicated in five out of eight tested melanoma tissues or melanoma cell lines. A tendency of a higher copy number in aggressive tumours was also found. Massively parallel resequencing of the similar to 350 kb Grey haplotype did not reveal any additional mutations perfectly associated with the phenotype, confirming the duplication as the true causative mutation. We identified three SNP alleles that were present in a subset of Grey haplotypes within the 350 kb region that shows complete linkage disequilibrium with the causative mutation. Thus, these three nucleotide substitutions must have occurred subsequent to the duplication, consistent with our interpretation that the Grey mutation arose more than 2,000 years before present.

    Conclusions: These results suggest that the mutation acts as a melanoma-driving regulatory element. The elucidation of the mechanistic features of the duplication will be of considerable interest for the characterization of these horse melanomas as well as for the field of human melanoma research.

  • 134. Tang, Ruqi
    et al.
    Noh, Hyun Ji
    Wang, Dongqing
    Sigurdsson, Snaevar
    Swofford, Ross
    Perloski, Michele
    Duxbury, Margaret
    Patterson, Edward E.
    Albright, Julie
    Castelhano, Marta
    Auton, Adam
    Boyko, Adam R.
    Feng, Guoping
    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.
    Karlsson, Elinor K.
    Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder2014In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, no 3, p. R25-Article in journal (Refereed)
    Abstract [en]

    Background: Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier. Results: We use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding. Conclusions: The limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.

  • 135.
    Tengvall, Katarina
    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.
    Kierczak, Marcin
    Bergvall, Kerstin
    Olsson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frankowiack, Marcel
    Farias, Fabiana H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Leeb, Tosso
    Andersson, Göran
    Hammarström, Lennart
    Hedhammar, Åke
    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 MIT and Harvard, Cambridge, Massachusetts, USA.
    Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 5, p. e1003475-Article in journal (Refereed)
    Abstract [en]

    Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

  • 136.
    Tengvall, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kozyrev, Sergey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kierczak, Marcin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergvall, Kerstin
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Farias, Fabiana H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ardesjö-Lundgren, Brita
    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..
    Olsson, Mia
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, Uppsala, Sweden..
    Hagman, Ragnvi
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Leeb, Tosso
    Univ Bern, Inst Genet, Bern, Switzerland..
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hedhammar, Åke
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Andersson, Göran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs2016In: BMC Genetics, ISSN 1471-2156, E-ISSN 1471-2156, Vol. 17, article id 97Article in journal (Refereed)
    Abstract [en]

    Background: Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a similar to 1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2. Results: Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27: 19,086,778 (p = 1.4 x 10(-7)) and a rare similar to 48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the similar to 48 kb risk haplotype) that spanned similar to 280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 x 10(-5)), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27: 19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (p(difference) = 0.003), and also mapped close (similar to 3 kb) to an ENCODE skin-specific enhancer region. Conclusions: Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.

  • 137. Thomas, R
    et al.
    Duke, S E
    Karlsson, E K
    Evans, A
    Ellis, P
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Langford, C F
    Breen, M
    A genome assembly-integrated dog 1 Mb BAC microarray: a cytogenetic resource for canine cancer studies and comparative genomic analysis.2008In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 122, no 2, p. 110-121Article in journal (Refereed)
    Abstract [en]

    Molecular cytogenetic studies have been instrumental in defining the nature of numerical and structural chromosome changes in human cancers, but their significance remains to be fully understood. The emergence of high quality genome assemblies for several model organisms provides exciting opportunities to develop novel genome-integrated molecular cytogenetic resources that now permit a comparative approach to evaluating the relevance of tumor-associated chromosome aberrations, both within and between species. We have used the dog genome sequence assembly to identify a framework panel of 2,097 bacterial artificial chromosome (BAC) clones, selected at intervals of approximately one megabase. Each clone has been evaluated by multicolor fluorescence in situ hybridization (FISH) to confirm its unique cytogenetic location in concordance with its reported position in the genome assembly, providing new information on the organization of the dog genome. This panel of BAC clones also represents a powerful cytogenetic resource with numerous potential applications. We have used the clone set to develop a genome-wide microarray for comparative genomic hybridization (aCGH) analysis, and demonstrate its application in detection of tumor-associated DNA copy number aberrations (CNAs) including single copy deletions and amplifications, regional aneuploidy and whole chromosome aneuploidy. We also show how individual clones selected from the BAC panel can be used as FISH probes in direct evaluation of tumor karyotypes, to verify and explore CNAs detected using aCGH analysis. This cytogenetically validated, genome integrated BAC clone panel has enormous potential for aiding gene discovery through a comparative approach to molecular oncology.

  • 138. Thomas, Rachael
    et al.
    Borst, Luke
    Rotroff, Daniel
    Motsinger-Reif, Alison
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Modiano, Jaime F.
    Breen, Matthew
    Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma2014In: Chromosome Research, ISSN 0967-3849, E-ISSN 1573-6849, Vol. 22, no 3, p. 305-319Article in journal (Refereed)
    Abstract [en]

    Canine hemangiosarcoma is a highly aggressive vascular neoplasm associated with extensive clinical and anatomical heterogeneity and a grave prognosis. Comprehensive molecular characterization of hemangiosarcoma may identify novel therapeutic targets and advanced clinical management strategies, but there are no published reports of tumor-associated genome instability and disrupted gene dosage in this cancer. We performed genome-wide microarray-based somatic DNA copy number profiling of 75 primary intra-abdominal hemangiosarcomas from five popular dog breeds that are highly predisposed to this disease. The cohort exhibited limited global genomic instability, compared to other canine sarcomas studied to date, and DNA copy number aberrations (CNAs) were predominantly of low amplitude. Recurrent imbalances of several key cancer-associated genes were evident; however, the global penetrance of any single CNA was low and no distinct hallmark aberrations were evident. Copy number gains of dog chromosomes 13, 24, and 31, and loss of chromosome 16, were the most recurrent CNAs involving large chromosome regions, but their relative distribution within and between cases suggests they most likely represent passenger aberrations. CNAs involving CDKN2A, VEGFA, and the SKI oncogene were identified as potential driver aberrations of hemangiosarcoma development, highlighting potential targets for therapeutic modulation. CNA profiles were broadly conserved between the five breeds, although subregional variation was evident, including a near twofold lower incidence of VEGFA gain in Golden Retrievers versus other breeds (22 versus 40 %). These observations support prior transcriptional studies suggesting that the clinical heterogeneity of this cancer may reflect the existence of multiple, molecularly distinct subtypes of canine hemangiosarcoma.

  • 139. Thomas, Rachael
    et al.
    Valli, Victor E
    Ellis, Peter
    Bell, Jerold
    Karlsson, Elinor K
    Cullen, John
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Langford, Cordelia F
    Breen, Matthew
    Microarray-based cytogenetic profiling reveals recurrent and subtype-associated genomic copy number aberrations in feline sarcomas2009In: Chromosome Research, ISSN 0967-3849, E-ISSN 1573-6849, Vol. 17, no 8, p. 987-1000Article in journal (Refereed)
    Abstract [en]

    Injection-site-associated sarcomas (ISAS), commonly arising at the site of routine vaccine administration, afflict as many as 22,000 domestic cats annually in the USA. These tumors are typically more aggressive and prone to recurrence than spontaneous sarcomas (non-ISAS), generally receiving a poorer long-term prognosis and warranting a more aggressive therapeutic approach. Although certain clinical and histological factors are highly suggestive of ISAS, timely diagnosis and optimal clinical management may be hindered by the absence of definitive markers that can distinguish between tumors with underlying injection-related etiology and their spontaneous counterpart. Specific nonrandom chromosome copy number aberrations (CNAs) have been associated with the clinical behavior of a vast spectrum of human tumors, providing an extensive resource of potential diagnostic and prognostic biomarkers. Although similar principles are now being applied with great success in other species, their relevance to feline molecular oncology has not yet been investigated in any detail. We report the construction of a genomic microarray platform for detection of recurrent CNAs in feline tumors through cytogenetic assignment of 210 large-insert DNA clones selected at intervals of approximately 15 Mb from the feline genome sequence assembly. Microarray-based profiling of 19 ISAS and 27 non-ISAS cases identified an extensive range of genomic imbalances that were highly recurrent throughout the combined panel of 46 sarcomas. Deletions of two specific regions were significantly associated with the non-ISAS phenotype. Further characterization of these regions may ultimately permit molecular distinction between ISAS and non-ISAS, as a tool for predicting tumor behavior and prognosis, as well as refining means for therapeutic intervention.

  • 140.
    Thorlacius, Gudny Ella
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Theander, Elke
    Skane Univ Hosp, Dept Rheumatol, Malmo, Sweden.
    Kvarnstrom, Marika
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Forsblad-d'Elia, Helena
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Bucher, Sara Magnusson
    Orebro Univ, Fac Med & Hlth, Dept Rheumatol, Orebro, Sweden.
    Norheim, Katrine Braekke
    Stavanger Univ Hosp, Dept Internal Med, Stavanger, Norway.
    Johnsen, Svein Joar
    Stavanger Univ Hosp, Dept Internal Med, Stavanger, Norway.
    Hammenfors, Daniel
    Haukeland Hosp, Dept Rheumatol, Bergen, Norway.
    Skarstein, Kathrine
    Haukeland Hosp, Dept Pathol, Bergen, Norway.
    Jonsson, Malin V.
    Univ Bergen, Dept Clin Dent, Bergen, Norway.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mandl, Thomas
    Skane Univ Hosp, Dept Rheumatol, Malmo, Sweden.
    Eriksson, Per
    Linkoping Univ, Dept Clin Expt Med, Linkoping, Sweden.
    Omdal, Roald
    Stavanger Univ Hosp, Dept Internal Med, Stavanger, Norway.
    Jonsson, Roland
    Univ Bergen, Broegelmann Res Lab, Bergen, Norway.
    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 Inst MIT & Harvard, Cambridge, MA USA.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wahren-Herlenius, Marie
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic basis and clinical evidence for two variants of primary Sjögren's syndrome with distinct outcomes2018In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 36, no 3, p. S246-S247Article in journal (Other academic)
  • 141.
    Truve, Katarina
    et al.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Bioinformat Core Facil, Gothenburg, Sweden..
    Dickinson, Peter
    Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, Davis, CA 95616 USA..
    Xiong, Anqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    York, Daniel
    Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, Davis, CA 95616 USA..
    Jayashankar, Kartika
    Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA..
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Koltookian, Michele
    Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA..
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fuxelius, Hans-Henrik
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Andersson, Göran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Hedhammar, Ake
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Bongcam-Rudloff, Erik
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bannasch, Danika
    Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA..
    Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 5, article id e1006000Article in journal (Refereed)
    Abstract [en]

    Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10(-8)). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.

  • 142. van den Berg, L
    et al.
    Vos-Loohuis, M
    Schilder, M B H
    van Oost, B A
    Hazewinkel, H A W
    Wade, C M
    Karlsson, E K
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Liinamo, A E
    Leegwater, P A J
    Evaluation of the serotonergic genes htr1A, htr1B, htr2A, and slc6A4 in aggressive behavior of golden retriever dogs2008In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 38, no 1, p. 55-66Article in journal (Refereed)
    Abstract [en]

    Aggressive behavior displays a high heritability in our study group of Golden Retriever dogs. Alterations in brain serotonin metabolism have been described in aggressive dogs before. Here, we evaluate whether four genes of the canine serotonergic system, coding for the serotonin receptors 1A, 1B, and 2A, and the serotonin transporter, could play a major role in aggression in Golden Retrievers. We performed mutation screens, linkage analysis, an association study, and a quantitative genetic analysis. There was no systematic difference between the coding DNA sequence of the candidate genes in aggressive and non-aggressive Golden Retrievers. An affecteds-only parametric linkage analysis revealed no strong major locus effect on human-directed aggression related to the candidate genes. An analysis of 41 single nucleotide polymorphisms (SNPs) in the 1 Mb regions flanking the genes in 49 unrelated human-directed aggressive and 49 unrelated non-aggressive dogs did not show association of SNP alleles, genotypes, or haplotypes with aggression at the candidate loci. We completed our analyses with a study of the effect of variation in the candidate genes on a collection of aggression-related phenotypic measures. The effects of the candidate gene haplotypes were estimated using the Restricted Maximum Likelihood method, with the haplotypes included as fixed effects in a linear animal model. We observed no effect of the candidate gene haplotypes on a range of aggression-related phenotypes, thus extending our conclusions to several types of aggressive behavior. We conclude that it is unlikely that these genes play a major role in the variation in aggression in the Golden Retrievers that we studied. Smaller phenotypic effects of these loci could not be ruled out with our sample size.

  • 143. Vaysse, Amaury
    et al.
    Ratnakumar, Abhirami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Derrien, Thomas
    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.
    Rosengren 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.
    Sigurdsson, Snaevar
    Fall, Tove
    Seppälä, Eija H
    Hansen, Mark S T
    Lawley, Cindy T
    Karlsson, Elinor K
    Bannasch, Danika
    Vilà, Carles
    Lohi, Hannes
    Galibert, Francis
    Fredholm, Merete
    Häggström, Jens
    Hedhammar, Ake
    André, Catherine
    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.
    Hitte, Christophe
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping2011In: PLoS Genetics, ISSN 1553-7404, Vol. 7, no 10, p. e1002316-Article in journal (Refereed)
    Abstract [en]

    The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

  • 144.
    Vieira, Natassia M.
    et al.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Elvers, Ingegerd
    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 Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA..
    Alexander, Matthew S.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA..
    Moreira, Yuri B.
    Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, Brazil..
    Eran, Alal
    Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA..
    Gomes, Juliana P.
    Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Marshall, Jamie L.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA..
    Karlsson, Elinor K.
    Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.;Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01605 USA..
    Verjovski-Almeida, Sergio
    Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, Brazil.;Inst Butantan, BR-05508050 Sao Paulo, Brazil..
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA..
    Kunkel, Louis M.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA..
    Zatz, Mayana
    Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 163, no 5, p. 1204-1213Article in journal (Refereed)
    Abstract [en]

    Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner.

  • 145. Våge, J.
    et al.
    Wade, C.
    Biagi, T.
    Fatjó, J.
    Amat, M.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lingaas, F.
    Association of dopamine- and serotonin-related genes with canine aggression2010In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 9, no 4, p. 372-378Article in journal (Refereed)
    Abstract [en]

    Human-directed canine aggression was studied using 50 aggressive and 81 non-aggressive dogs. We examined 62 single nucleotide polymorphisms (SNPs) occurring in or in the close vicinity of 16 neurotransmitter-related genes. Allelic associations with aggression were identified for DRD1, HTR1D, HTR2C and SLC6A1. Risk or protective haplotypes for aggressive behaviour based on 2-5 SNPs were identified. The frequency of aggressive dogs varied significantly between the haplotypes within loci and the odds ratios of aggression in dogs with risk haplotypes compared with protective haplotypes varied from 4.4 (HTR2C) to 9.0 (SLC6A1). A risk haplotype across the neurotransmitter receptor gene HTR1D harboured a non-synonymous SNP with a potential effect on protein function. We identified no haplotypes in complete association with the recorded phenotypes, supporting a complex inheritance of aggression.

  • 146. Wade, C. M.
    et al.
    Giulotto, E.
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zoli, M.
    Gnerre, S.
    Imsland, Freyja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lear, T. L.
    Adelson, D. L.
    Bailey, E.
    Bellone, R. R.
    Bloecker, H.
    Distl, O.
    Edgar, R. C.
    Garber, M.
    Leeb, T.
    Mauceli, E.
    MacLeod, J. N.
    Penedo, M. C. T.
    Raison, J. M.
    Sharpe, T.
    Vogel, J.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antczak, D. F.
    Biagi, T.
    Binns, M. M.
    Chowdhary, B. P.
    Coleman, S. J.
    Della Valle, G.
    Fryc, S.
    Guerin, G.
    Hasegawa, T.
    Hill, E. W.
    Jurka, J.
    Kiialainen, A.
    Lindgren, G.
    Liu, J.
    Magnani, E.
    Mickelson, J. R.
    Murray, J.
    Nergadze, S. G.
    Onofrio, R.
    Pedroni, S.
    Piras, M. F.
    Raudsepp, T.
    Rocchi, M.
    Roed, K. H.
    Ryder, O. A.
    Searle, S.
    Skow, L.
    Swinburne, J. E.
    Syvänen, A. C.
    Tozaki, T.
    Valberg, S. J.
    Vaudin, M.
    White, J. R.
    Zody, Michael C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lander, E. S.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Genome Sequence, Comparative Analysis, and Population Genetics of the Domestic Horse2009In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 326, no 5954, p. 865-867Article in journal (Refereed)
    Abstract [en]

    We report a high-quality draft sequence of the genome of the horse ( Equus caballus). The genome is relatively repetitive but has little segmental duplication. Chromosomes appear to have undergone few historical rearrangements: 53% of equine chromosomes show conserved synteny to a single human chromosome. Equine chromosome 11 is shown to have an evolutionary new centromere devoid of centromeric satellite DNA, suggesting that centromeric function may arise before satellite repeat accumulation. Linkage disequilibrium, showing the influences of early domestication of large herds of female horses, is intermediate in length between dog and human, and there is long-range haplotype sharing among breeds.

  • 147.
    Webster, Matthew T.
    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.
    Kamgari, Nona
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Perloski, Michele
    Höppner, Marc P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Axelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hedhammar, Ake
    Pielberg, Gerli
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 474Article in journal (Refereed)
    Abstract [en]

    Background: The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants. Results: We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves. Conclusions: We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals.

  • 148. Wiik, A. C.
    et al.
    Thoresen, S. I.
    Wade, C
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lingaas, F
    A population study of a mutation allele associated with cone-rod dystrophy in the standard wire-haired dachshund2009In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 40, no 4, p. 572-574Article in journal (Refereed)
    Abstract [en]

    Cone-rod dystrophy in the standard wire-haired dachshund (SWHD) is inherited as a simple autosomal recessive trait and the recently discovered mutation is widespread within the SWHD population in Norway and other Scandinavian countries. The gene frequency was estimated to be 4.8%. On the basis of the assumption that the size of the ancestral haplotype around a mutation is inversely correlated with the number of generations since the mutation arose, we have found that the mutation is of a relatively recent origin. The conserved haplotype was found to be 8 Mb in size and therefore we estimate that the mutation arose roughly eight generations (approximately 37 years) ago. This indicates that the mutation arose after breed separation.

  • 149. Wiik, Anne Caroline
    et al.
    Wade, Claire
    Biagi, Tara
    Ropstad, Ernst-Otto
    Bjerkås, Ellen
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lingaas, Frode
    A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone-rod dystrophy in standard wire-haired dachshund2008In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 18, no 9, p. 1415-21Article in journal (Refereed)
    Abstract [en]

    Cone-rod dystrophy is a retinal degenerative disorder occurring naturally in man and dog. Here we identify a novel gene for early-onset cone-rod dystrophy in the wire-haired dachshund. For the first time, we use genome-wide association-based Sibling Transmission Disequilibrium Test (sibTDT) analysis of only 13 discordant sib-pairs to identify a single significantly associated 6.5-Mb region (PrawTDT = 4.8 x 10(-5), PgenomeTDT = 6 x 10(-4)) on canine chromosome 5, containing more than 70 genes. Segregation studies using microsatellites in the candidate region including additional meiosis supported the sibTDT analysis but could not further reduce the area. Candidate gene resequencing identified a 180-bp deletion in exon/intron 5 of NPHP4 (nephronophthisis 4, also known as nephroretinin). RT-PCR analysis of NPHP4 in cases and controls showed exon skipping of exon 5, resulting in a truncated protein that retains the binding domain interacting with nephronophthisis 1 (also known as nephrocystin-1) in the kidney but lacks the domain interacting with RPGRIP1 in retina. We suggest that this deletion in the canine NPHP4 gene is the cause of cone-rod dystrophy in the standard wire-haired dachshund. In humans, mutations in NPHP4 have been associated with simultaneous eye and kidney disease. Here we describe the first naturally occurring mutation in NPHP4 without additional kidney disease. Further studies will permit elucidation of the complex molecular mechanism of this retinopathy and the development of potential therapies.

  • 150. Wilbe, Maria
    et al.
    Jokinen, Päivi
    Truvé, Katarina
    Seppala, Eija H
    Karlsson, Elinor K
    Biagi, Tara
    Hughes, Angela
    Bannasch, Danika
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lohi, Hannes
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex.2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 3, p. 250-254Article in journal (Refereed)
    Abstract [en]

    The unique canine breed structure makes dogs an excellent model for studying genetic diseases. Within a dog breed, linkage disequilibrium is extensive, enabling genome-wide association (GWA) with only around 15,000 SNPs and fewer individuals than in human studies. Incidences of specific diseases are elevated in different breeds, indicating that a few genetic risk factors might have accumulated through drift or selective breeding. In this study, a GWA study with 81 affected dogs (cases) and 57 controls from the Nova Scotia duck tolling retriever breed identified five loci associated with a canine systemic lupus erythematosus (SLE)-related disease complex that includes both antinuclear antibody (ANA)-positive immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). Fine mapping with twice as many dogs validated these loci. Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases.

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