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  • 1. Agler, Caryline
    et al.
    Nielsen, Dahlia M.
    Urkasemsin, Ganokon
    Singleton, Andrew
    Tonomura, Noriko
    Sigurdsson, Snaevar
    Tang, Ruqi
    Linder, Keith
    Arepalli, Sampath
    Hernandez, Dena
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van de Leemput, Joyce
    Motsinger-Reif, Alison
    O'Brien, Dennis P.
    Bell, Jerold
    Harris, Tonya
    Steinberg, Steven
    Olby, Natasha J.
    Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB242014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 2, p. e1003991-Article in journal (Refereed)
    Abstract [en]

    Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia. Author Summary Neurodegenerative diseases are one of the most important causes of decline in an aging population. An important subset of these diseases are known as the hereditary ataxias, familial neurodegenerative diseases that affect the cerebellum causing progressive gait disturbance in both humans and dogs. We identified a mutation in RAB24, a gene associated with autophagy, in Old English Sheepdogs and Gordon Setters with hereditary ataxia. Autophagy is a process by which cell proteins and organelles are removed and recycled and its critical role in maintenance of the continued health of cells is becoming clear. We evaluated the brains of affected dogs and identified accumulations of autophagosomes within the cerebellum, suggesting a defect in the autophagy pathway. Our results suggest that a defect in the autophagy pathway results in neuronal death in a naturally occurring disease in dogs. The autophagy pathway should be investigated in human hereditary ataxia and may represent a therapeutic target in neurodegenerative diseases.

  • 2.
    Ahlgren, Kerstin M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    Sundberg, Katarina
    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.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedhammar, Åke
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lernmark, Åke
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e105473-Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

    METHODS:

    Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

    RESULTS:

    None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

    CONCLUSIONS/INTERPRETATIONS:

    Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

  • 3. Alfoeldi, Jessica
    et al.
    Di Palma, Federica
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Williams, Christina
    Kong, Lesheng
    Mauceli, Evan
    Russell, Pamela
    Lowe, Craig B.
    Glor, Richard E.
    Jaffe, Jacob D.
    Ray, David A.
    Boissinot, Stephane
    Shedlock, Andrew M.
    Botka, Christopher
    Castoe, Todd A.
    Colbourne, John K.
    Fujita, Matthew K.
    Moreno, Ricardo Godinez
    ten Hallers, Boudewijn F.
    Haussler, David
    Heger, Andreas
    Heiman, David
    Janes, Daniel E.
    Johnson, Jeremy
    de Jong, Pieter J.
    Koriabine, Maxim Y.
    Lara, Marcia
    Novick, Peter A.
    Organ, Chris L.
    Peach, Sally E.
    Poe, Steven
    Pollock, David D.
    de Queiroz, Kevin
    Sanger, Thomas
    Searle, Steve
    Smith, Jeremy D.
    Smith, Zachary
    Swofford, Ross
    Turner-Maier, Jason
    Wade, Juli
    Young, Sarah
    Zadissa, Amonida
    Edwards, Scott V.
    Glenn, Travis C.
    Schneider, Christopher J.
    Losos, Jonathan B.
    Lander, Eric S.
    Breen, Matthew
    Ponting, Chris P.
    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.
    The genome of the green anole lizard and a comparative analysis with birds and mammals2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 477, no 7366, p. 587-591Article in journal (Refereed)
    Abstract [en]

    The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments(1). Among amniotes, genome sequences are available for mammals and birds(2-4), but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes(2). Also, A. carolinensis mobile elements are very young and diverse-more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds(5). We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.

  • 4. Alfoeldi, Jessica
    et al.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Comparative genomics as a tool to understand evolution and disease2013In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 23, no 7, p. 1063-1068Article in journal (Refereed)
    Abstract [en]

    When the human genome project started, the major challenge was how to sequence a 3 billion letter code in an organized and cost-effective manner. When completed, the project had laid the foundation for a huge variety of biomedical fields through the production of a complete human genome sequence, but also had driven the development of laboratory and analytical methods that could produce large amounts of sequencing data cheaply. These technological developments made possible the sequencing of many more vertebrate genomes, which have been necessary for the interpretation of the human genome. They have also enabled large-scale studies of vertebrate genome evolution, as well as comparative and human medicine. In this review, we give examples of evolutionary analysis using a wide variety of time frames-from the comparison of populations within a species to the comparison of species separated by at least 300 million years. Furthermore, we anticipate discoveries related to evolutionary mechanisms, adaptation, and disease to quickly accelerate in the coming years.

  • 5. Amemiya, Chris T.
    et al.
    Alfoeldi, Jessica
    Lee, Alison P.
    Fan, Shaohua
    Philippe, Herve
    MacCallum, Iain
    Braasch, Ingo
    Manousaki, Tereza
    Schneider, Igor
    Rohner, Nicolas
    Organ, Chris
    Chalopin, Domitille
    Smith, Jeramiah J.
    Robinson, Mark
    Dorrington, Rosemary A.
    Gerdol, Marco
    Aken, Bronwen
    Biscotti, Maria Assunta
    Barucca, Marco
    Baurain, Denis
    Berlin, Aaron M.
    Blatch, Gregory L.
    Buonocore, Francesco
    Burmester, Thorsten
    Campbell, Michael S.
    Canapa, Adriana
    Cannon, John P.
    Christoffels, Alan
    De Moro, Gianluca
    Edkins, Adrienne L.
    Fan, Lin
    Fausto, Anna Maria
    Feiner, Nathalie
    Forconi, Mariko
    Gamieldien, Junaid
    Gnerre, Sante
    Gnirke, Andreas
    Goldstone, Jared V.
    Haerty, Wilfried
    Hahn, Mark E.
    Hesse, Uljana
    Hoffmann, Steve
    Johnson, Jeremy
    Karchner, Sibel I.
    Kuraku, Shigehiro
    Lara, Marcia
    Levin, Joshua Z.
    Litman, Gary W.
    Mauceli, Evan
    Miyake, Tsutomu
    Mueller, M. Gail
    Nelson, David R.
    Nitsche, Anne
    Olmo, Ettore
    Ota, Tatsuya
    Pallavicini, Alberto
    Panji, Sumir
    Picone, Barbara
    Ponting, Chris P.
    Prohaska, Sonja J.
    Przybylski, Dariusz
    Saha, Nil Ratan
    Ravi, Vydianathan
    Ribeiro, Filipe J.
    Sauka-Spengler, Tatjana
    Scapigliati, Giuseppe
    Searle, Stephen M. J.
    Sharpe, Ted
    Simakov, Oleg
    Stadler, Peter F.
    Stegeman, John J.
    Sumiyama, Kenta
    Tabbaa, Diana
    Tafer, Hakim
    Turner-Maier, Jason
    van Heusden, Peter
    White, Simon
    Williams, Louise
    Yandell, Mark
    Brinkmann, Henner
    Volff, Jean-Nicolas
    Tabin, Clifford J.
    Shubin, Neil
    Schartl, Manfred
    Jaffe, David B.
    Postlethwait, John H.
    Venkatesh, Byrappa
    Di Palma, Federica
    Lander, Eric S.
    Meyer, Axel
    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.
    The African coelacanth genome provides insights into tetrapod evolution2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 496, no 7445, p. 311-316Article in journal (Refereed)
    Abstract [en]

    The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.

  • 6.
    Andersson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hjälm, Göran
    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.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindroth, Anders M
    Markljung, Ellen
    Nyström, Anna-Maja
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundström, Elisabeth
    ZBED6: the birth of a new transcription factor in the common ancestor of placental mammals2010In: Transcription, ISSN 2154-1272, Vol. 1, no 3, p. 144-148Article in journal (Refereed)
    Abstract [en]

    A DNA transposon integrated into -the genome of a primitive mammal some 200 million years ago and, millions of years later, it evolved an essential function in the common ancestor of all placental mammals. This protein, now named ZBED6, was recently discovered because a mutation disrupting one of its binding sites, in an intron of the IGF2 gene, makes pigs grow more muscle. These findings have revealed a new mechanism for regulating muscle growth as well as a novel transcription factor that appears to be of major importance for transcriptional regulation in placental mammals.

  • 7.
    Ardesjö-Lundgren, Brita
    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. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Box 7023, SE-75007 Uppsala, Sweden..
    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. Karolinska Inst, Neuroimmunol Unit, Centrum Mol Med, Dept Clin Neurosci, S-17176 Stockholm, Sweden..
    Bergvall, Kerstin
    Swedish Univ Agr Sci, Dept Clin Sci, Box 7054, SE-75007 Uppsala, Sweden..
    Farias, Fabiana H. G.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wang, Liya
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Box 7011, S-75007 Uppsala, Sweden..
    Hedhammar, Åke
    Swedish Univ Agr Sci, Dept Clin Sci, Box 7054, SE-75007 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 MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA..
    Andersson, Göran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Box 7023, SE-75007 Uppsala, Sweden..
    Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs2017In: Veterinary dermatology (Print), ISSN 0959-4493, E-ISSN 1365-3164, Vol. 28, no 4, p. 377-e88Article in journal (Refereed)
    Abstract [en]

    Background - Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome-wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin-2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities.

    Objectives - The main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD-affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location.

    Animals/Methods - Skin biopsies were collected from nine CAD-affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology.

    Results - We observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed.

    Conclusion - Plakophilin-2 protein in dog skin is expressed in both epithelial and immune cells; based on Its sub cellular location its functional role is implicated in both nuclear and structural processes.

  • 8.
    Arendt, Maja
    et al.
    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.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    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.
    Axelsson, Erik
    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.
    Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes2014In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 45, no 5, p. 716-722Article in journal (Refereed)
    Abstract [en]

    High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.

  • 9.
    Arendt, Maja Louise
    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. Univ Cambridge, Dept Vet Med, Cambridge, England..
    Melin, Malin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tonomura, Noriko
    Broad Inst MIT & Harvard, Cambridge, MA USA.;Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA..
    Koltookian, Michele
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    Courtay-Cahen, Celine
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Flindall, Netty
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Bass, Joyce
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Boerkamp, Kim
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands..
    Megquir, Katherine
    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.;Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA..
    Youell, Lisa
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Murphy, Sue
    Anim Hlth Trust, Newmarket, Suffolk, England..
    McCarthy, Colleen
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    London, Cheryl
    Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA..
    Rutteman, Gerard R.
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands.;Vet Specialist Ctr De Wagenrenk, Wageningen, Netherlands..
    Starkey, Mike
    Anim Hlth Trust, Newmarket, Suffolk, 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 MIT & Harvard, Cambridge, MA USA..
    Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11, article id e1005647Article in journal (Refereed)
    Abstract [en]

    Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10(-16)), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

  • 10. Astrof, Sophie
    et al.
    Kirby, Andrew
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Daly, Mark
    Hynes, Richard O
    Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four2007In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 124, no 7-8, p. 551-558Article in journal (Refereed)
    Abstract [en]

    Absence of the fibronectin (FN) gene leads to early embryonic lethality in both 129S4 and C57BL/6J strains due to severe cardiovascular defects. However, heart development is arrested at different stages in these embryos depending on the genetic background. In the majority of 129S4 FN-null embryos, heart progenitors remain at their anterior bilateral positions and fail to fuse at the midline to form a heart tube. However, on the C57BL/6J genetic background, cardiac development progresses further and results in a centrally positioned and looped heart. To find factor(s) involved in embryonic heart formation and governing the extent of heart development in FN-null embryos in 129S4 and C57BL/6J strains, we performed genetic mapping and haplotype analyses. These analyses lead to identification of a significant linkage to a 1-Mbp interval on chromosome four. Microarray analysis and sequencing identified 21 genes in this region, including five that are differentially expressed between the strains, as potential modifiers. Since none of these genes was previously known to play a role in heart development, one or more of them is likely to be a novel modifier affecting cardiac development. Identification of the modifier would significantly enhance our understanding of the molecular underpinning of heart development and disease.

  • 11. Awano, Tomoyuki
    et al.
    Johnson, Gary S.
    Wade, Claire M.
    Katz, Martin L.
    Johnson, Gayle C.
    Taylor, Jeremy F.
    Perloski, Michele
    Biagi, Tara
    Baranowska, Izabella
    Long, Sam
    March, Philip A.
    Olby, Natasha J.
    Shelton, G. Diane
    Khan, Shahnawaz
    O'Brien, Dennis P.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Coates, Joan R.
    Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 8, p. 2794-2799Article in journal (Refereed)
    Abstract [en]

    Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.

  • 12.
    Axelsson, Erik
    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.
    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.
    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.
    Maqbool, Khurram
    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.
    Perloski, Michele
    Liberg, Olof
    Arnemo, Jon M.
    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.
    The genomic signature of dog domestication reveals adaptation to a starch-rich diet2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 495, no 7441, p. 360-364Article in journal (Refereed)
    Abstract [en]

    The domestication of dogs. was an important episode in the development of human civilization. The precise timing and location of this event is debated(1-5) and little is known about the genetic changes that accompanied the transformation of ancient wolves into domestic dogs. Here we conduct whole-genome resequencimg of dogs and wolves to identify 3.8 million genetic variants used to identify 36 genomic regions that probably represent targets for selection during dog domestication. Nineteen of these regions contain genes important in brain function, eight of which belong to nervous system development pathways and potentially underlie behavioural changes central to dog domestication(6). Ten genes with key roles in starch digestion and fat metabolism also show signals of selection. We identify candidate mutations in key genes and provide functional support for an increased starch digestion in dogs relative to wolves. Our results indicate that novel adaptations allowing the early ancestors of modern dogs to thrive on a diet rich in starch, relative to the carnivorous diet of wolves, constituted a crucial step in the early domestication of dogs.

  • 13.
    Axelsson, Erik
    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.
    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.
    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.
    Ponting, Chris P.
    Univ Oxford, MRC Funct Genom Unit, Dept Physiol Anat & Genet, Oxford OX1 3QX, 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 Massachusetts Inst Technol & Harvard, Cambridge, MA 02139 USA.
    Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome2011In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 22, no 1, p. 51-63Article in journal (Refereed)
    Abstract [en]

    Analysis of diverse eukaryotes has revealed that recombination events cluster in discrete genomic locations known as hotspots. In humans, a zinc-finger protein, PRDM9, is believed to initiate recombination in >40% of hotspots by binding to a specific DNA sequence motif. However, the PRDM9 coding sequence is disrupted in the dog genome assembly, raising questions regarding the nature and control of recombination in dogs. By analyzing the sequences of PRDM9 orthologs in a number of dog breeds and several carnivores, we show here that this gene was inactivated early in canid evolution. We next use patterns of linkage disequilibrium using more than 170,000 SNP markers typed in almost 500 dogs to estimate the recombination rates in the dog genome using a coalescent-based approach. Broad-scale recombination rates show good correspondence with an existing linkage-based map. Significant variation in recombination rate is observed on the fine scale, and we are able to detect over 4000 recombination hotspots with high confidence. In contrast to human hotspots, 40% of canine hotspots are characterized by a distinct peak in GC content. A comparative genomic analysis indicates that these peaks are present also as weaker peaks in the panda, suggesting that the hotspots have been continually reinforced by accelerated and strongly GC biased nucleotide substitutions, consistent with the long-term action of biased gene conversion on the dog lineage. These results are consistent with the loss of PRDM9 in canids, resulting in a greater evolutionary stability of recombination hotspots. The genetic determinants of recombination hotspots in the dog genome may thus reflect a fundamental process of relevance to diverse animal species.

  • 14. Baker, Michelle L
    et al.
    Indiviglio, Sandra
    Nyberg, April M
    Rosenberg, George H
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Miller, Robert D
    Papenfuss, Anthony T
    Analysis of a set of Australian northern brown bandicoot expressed sequence tags with comparison to the genome sequence of the South American grey short tailed opossum2007In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, p. 50-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Expressed sequence tags (ESTs) have been used for rapid gene discovery in a variety of organisms and provide a valuable resource for whole genome annotation. Although the genome of one marsupial, the opossum Monodelphis domestica, has now been sequenced, no EST datasets have been reported from any marsupial species. In this study we describe an EST dataset from the bandicoot, Isoodon macrourus, providing information on the transcriptional profile of the bandicoot thymus and the opportunity for a genome wide comparison between the bandicoot and opossum, two distantly related marsupial species. RESULTS: A set of 1319 ESTs was generated from sequencing randomly chosen clones from a bandicoot thymus cDNA library. The nucleic acid and deduced amino acid sequences were compared with sequences both in GenBank and the recently completed whole genome sequence of M. domestica. This study provides information on the transcriptional profile of the bandicoot thymus with the identification of genes involved in a broad range of activities including protein metabolism (24%), transcription and/or nucleic acid metabolism (10%), metabolism/energy pathways (9%), immunity (5%), signal transduction (5%), cell growth and maintenance (3%), transport (3%), cell cycle (0.7%) and apoptosis (0.5%) and a proportion of genes whose function is unknown (5.8%). Thirty four percent of the bandicoot ESTs found no match with annotated sequences in any of the public databases. Clustering and assembly of the 1319 bandicoot ESTs resulted in a set of 949 unique sequences of which 375 were unannotated ESTs. Of these, seventy one unannotated ESTs aligned to non-coding regions in the opossum, human, or both genomes, and were identified as strong non-coding RNA candidates. Eighty-four percent of the 949 assembled ESTs aligned with the M. domestica genome sequence indicating a high level of conservation between these two distantly related marsupials. CONCLUSION: This study is among the first reported marsupial EST datasets with a significant inter-species genome comparison between marsupials, providing a valuable resource for transcriptional analyses in marsupials and for future annotation of marsupial whole genome sequences.

  • 15. Bannasch, Danika
    et al.
    Young, Amy
    Myers, Jeffrey
    Truvé, Katarina
    Dickinson, Peter
    Gregg, Jeffrey
    Davis, Ryan
    Bongcam-Rudloff, Eric
    Webster, Matthew T.
    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.
    Pedersen, Niels
    Localization of canine brachycephaly using an across breed mapping approach2010In: PLoS ONE, ISSN 1932-6203, Vol. 5, no 3, p. e9632-Article in journal (Refereed)
    Abstract [en]

    The domestic dog, Canis familiaris, exhibits profound phenotypic diversity and is an ideal model organism for the genetic dissection of simple and complex traits. However, some of the most interesting phenotypes are fixed in particular breeds and are therefore less tractable to genetic analysis using classical segregation-based mapping approaches. We implemented an across breed mapping approach using a moderately dense SNP array, a low number of animals and breeds carefully selected for the phenotypes of interest to identify genetic variants responsible for breed-defining characteristics. Using a modest number of affected (10-30) and control (20-60) samples from multiple breeds, the correct chromosomal assignment was identified in a proof of concept experiment using three previously defined loci; hyperuricosuria, white spotting and chondrodysplasia. Genome-wide association was performed in a similar manner for one of the most striking morphological traits in dogs: brachycephalic head type. Although candidate gene approaches based on comparable phenotypes in mice and humans have been utilized for this trait, the causative gene has remained elusive using this method. Samples from nine affected breeds and thirteen control breeds identified strong genome-wide associations for brachycephalic head type on Cfa 1. Two independent datasets identified the same genomic region. Levels of relative heterozygosity in the associated region indicate that it has been subjected to a selective sweep, consistent with it being a breed defining morphological characteristic. Genotyping additional dogs in the region confirmed the association. To date, the genetic structure of dog breeds has primarily been exploited for genome wide association for segregating traits. These results demonstrate that non-segregating traits under strong selection are equally tractable to genetic analysis using small sample numbers.

  • 16. Baranowska Korberg, Izabella
    et al.
    Sundström, Elisabeth
    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. 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 Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli Rosengren
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafson, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hedhammar, Ake
    Karlsson, Elinor K.
    Seddon, Jennifer
    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.
    Soderberg, Arne
    Vila, Carles
    Zhang, Xiaolan
    Akesson, Mikael
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Goran
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A Simple Repeat Polymorphism in the MITF-M Promoter Is a Key Regulator of White Spotting in Dogs2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e104363-Article in journal (Refereed)
    Abstract [en]

    The white spotting locus (S) in dogs is colocalized with the MITF (microphtalmia-associated transcription factor) gene. The phenotypic effects of the four S alleles range from solid colour (S) to extreme white spotting (s(w)). We have investigated four candidate mutations associated with the s(w) allele, a SINE insertion, a SNP at a conserved site and a simple repeat polymorphism all associated with the MITF-M promoter as well as a 12 base pair deletion in exon 1B. The variants associated with white spotting at all four loci were also found among wolves and we conclude that none of these could be a sole causal mutation, at least not for extreme white spotting. We propose that the three canine white spotting alleles are not caused by three independent mutations but represent haplotype effects due to different combinations of causal polymorphisms. The simple repeat polymorphism showed extensive diversity both in dogs and wolves, and allele-sharing was common between wolves and white spotted dogs but was non-existent between solid and spotted dogs as well as between wolves and solid dogs. This finding was unexpected as Solid is assumed to be the wild-type allele. The data indicate that the simple repeat polymorphism has been a target for selection during dog domestication and breed formation. We also evaluated the significance of the three MITF-M associated polymorphisms with a Luciferase assay, and found conclusive evidence that the simple repeat polymorphism affects promoter activity. Three alleles associated with white spotting gave consistently lower promoter activity compared with the allele associated with solid colour. We propose that the simple repeat polymorphism affects cooperativity between transcription factors binding on either flanking sides of the repeat. Thus, both genetic and functional evidence show that the simple repeat polymorphism is a key regulator of white spotting in dogs.

  • 17. Bellone, Rebecca R
    et al.
    Forsyth, George
    Leeb, Tosso
    Archer, Sheila
    Sigurdsson, Snaevar
    Imsland, Freyja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mauceli, Evan
    Engensteiner, Martina
    Bailey, Ernest
    Sandmeyer, Lynne
    Grahn, Bruce
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wade, Claire M
    Fine-mapping and mutation analysis of TRPM1: a candidate gene for leopard complex (LP) spotting and congenital stationary night blindness in horses2010In: Briefings in Functional Genomics & Proteomics, ISSN 1473-9550, E-ISSN 1477-4062, Vol. 9, no 3, p. 193-207Article in journal (Refereed)
    Abstract [en]

    Leopard Complex spotting occurs in several breeds of horses and is caused by an incompletely dominant allele (LP). Homozygosity for LP is also associated with congenital stationary night blindness (CSNB) in Appaloosa horses. Previously, LP was mapped to a 6 cm region on ECA1 containing the candidate gene TRPM1 (Transient Receptor Potential Cation Channel, Subfamily M, Member 1) and decreased expression of this gene, measured by qRT-PCR, was identified as the likely cause of both spotting and ocular phenotypes. This study describes investigations for a mutation causing or associated with the Leopard Complex and CSNB phenotype in horses. Re-sequencing of the gene and associated splice sites within the 105 624 bp genomic region of TRPM1 led to the discovery of 18 SNPs. Most of the SNPs did not have a predictive value for the presence of LP. However, one SNP (ECA1:108,249,293 C>T) found within intron 11 had a strong (P < 0.0005), but not complete, association with LP and CSNB and thus is a good marker but unlikely to be causative. To further localize the association, 70 SNPs spanning over two Mb including the TRPM1 gene were genotyped in 192 horses from three different breeds segregating for LP. A single 173 kb haplotype associated with LP and CSNB (ECA1: 108,197,355- 108,370,150) was identified. Illumina sequencing of 300 kb surrounding this haplotype revealed 57 SNP variants. Based on their localization within expressed sequences or regions of high sequence conservation across mammals, six of these SNPs were considered to be the most likely candidate mutations. While the precise function of TRPM1 remains to be elucidated, this work solidifies its functional role in both pigmentation and night vision. Further, this work has identified several potential regulatory elements of the TRPM1 gene that should be investigated further in this and other species.

  • 18.
    Berglund, Jonas
    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.
    Nevalainen, Elisa M
    Molin, Anna-Maja
    Perloski, Michele
    André, Catherine
    Zody, Michael C
    Sharpe, Ted
    Hitte, Christophe
    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.
    Lohi, Hannes
    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.
    Novel origins of copy number variation in the dog genome2012In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, no 8, p. R73-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution.

  • 19. Birney, Ewan
    et al.
    Stamatoyannopoulos, John A.
    Dutta, Anindya
    Guigó, Roderic
    Gingeras, Thomas R.
    Margulies, Elliott H.
    Weng, Zhiping
    Snyder, Michael
    Dermitzakis, Emmanouil T.
    Thurman, Robert E.
    Kuehn, Michael S.
    Taylor, Christopher M.
    Neph, Shane
    Koch, Christoph M.
    Asthana, Saurabh
    Malhotra, Ankit
    Adzhubei, Ivan
    Greenbaum, Jason A.
    Andrews, Robert M.
    Flicek, Paul
    Boyle, Patrick J.
    Cao, Hua
    Carter, Nigel P.
    Clelland, Gayle K.
    Davis, Sean
    Day, Nathan
    Dhami, Pawandeep
    Dillon, Shane C.
    Dorschner, Michael O.
    Fiegler, Heike
    Giresi, Paul G.
    Goldy, Jeff
    Hawrylycz, Michael
    Haydock, Andrew
    Humbert, Richard
    James, Keith D.
    Johnson, Brett E.
    Johnson, Ericka M.
    Frum, Tristan T.
    Rosenzweig, Elizabeth R.
    Karnani, Neerja
    Lee, Kirsten
    Lefebvre, Gregory C.
    Navas, Patrick A.
    Neri, Fidencio
    Parker, Stephen C.
    Sabo, Peter J.
    Sandstrom, Richard
    Shafer, Anthony
    Vetrie, David
    Weaver, Molly
    Wilcox, Sarah
    Yu, Man
    Collins, Francis S.
    Dekker, Job
    Lieb, Jason D.
    Tullius, Thomas D.
    Crawford, Gregory E.
    Sunyaev, Shamil
    Noble, William S.
    Dunham, Ian
    Denoeud, France
    Reymond, Alexandre
    Kapranov, Philipp
    Rozowsky, Joel
    Zheng, Deyou
    Castelo, Robert
    Frankish, Adam
    Harrow, Jennifer
    Ghosh, Srinka
    Sandelin, Albin
    Hofacker, Ivo L.
    Baertsch, Robert
    Keefe, Damian
    Dike, Sujit
    Cheng, Jill
    Hirsch, Heather A.
    Sekinger, Edward A.
    Lagarde, Julien
    Abril, Josep F.
    Shahab, Atif
    Flamm, Christoph
    Fried, Claudia
    Hackermüller, Jörg
    Hertel, Jana
    Lindemeyer, Manja
    Missal, Kristin
    Tanzer, Andrea
    Washietl, Stefan
    Korbel, Jan
    Emanuelsson, Olof
    Pedersen, Jakob S.
    Holroyd, Nancy
    Taylor, Ruth
    Swarbreck, David
    Matthews, Nicholas
    Dickson, Mark C.
    Thomas, Daryl J.
    Weirauch, Matthew T.
    Gilbert, James
    Drenkow, Jorg
    Bell, Ian
    Zhao, XiaoDong
    Srinivasan, K. G.
    Sung, Wing-Kin
    Ooi, Hong Sain
    Chiu, Kuo Ping
    Foissac, Sylvain
    Alioto, Tyler
    Brent, Michael
    Pachter, Lior
    Tress, Michael L.
    Valencia, Alfonso
    Choo, Siew Woh
    Choo, Chiou Yu
    Ucla, Catherine
    Manzano, Caroline
    Wyss, Carine
    Cheung, Evelyn
    Clark, Taane G.
    Brown, James B.
    Ganesh, Madhavan
    Patel, Sandeep
    Tammana, Hari
    Chrast, Jacqueline
    Henrichsen, Charlotte N.
    Kai, Chikatoshi
    Kawai, Jun
    Nagalakshmi, Ugrappa
    Wu, Jiaqian
    Lian, Zheng
    Lian, Jin
    Newburger, Peter
    Zhang, Xueqing
    Bickel, Peter
    Mattick, John S.
    Carninci, Piero
    Hayashizaki, Yoshihide
    Weissman, Sherman
    Hubbard, Tim
    Myers, Richard M.
    Rogers, Jane
    Stadler, Peter F.
    Lowe, Todd M.
    Wei, Chia-Lin
    Ruan, Yijun
    Struhl, Kevin
    Gerstein, Mark
    Antonarakis, Stylianos E.
    Fu, Yutao
    Green, Eric D.
    Karaöz, U.
    Siepel, Adam
    Taylor, James
    Liefer, Laura A
    Wetterstrand, Kris A.
    Good, Peter J.
    Feingold, Elise A.
    Guyer, Mark S.
    Cooper, Gregory M.
    Asimenos, George
    Dewey, Colin N.
    Hou, Minmei
    Nikolaev, Sergey
    Montoya-Burgos, Juan I.
    Löytynoja, Ari
    Whelan, Simon
    Pardi, Fabio
    Massingham, Tim
    Huang, Haiyan
    Zhang, Nancy R.
    Holmes, Ian
    Mullikin, James C.
    Ureta-Vidal, Abel
    Paten, Benedict
    Seringhaus, Michael
    Church, Deanna
    Rosenbloom, Kate
    Kent, W. James
    Stone, Eric A.
    Batzoglou, Serafim
    Goldman, Nick
    Hardison, Ross C.
    Haussler, David
    Miller, Webb
    Sidow, Arend
    Trinklein, Nathan D.
    Zhang, Zhengdong D.
    Barrera, Leah
    Stuart, Rhona
    King, David C.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bieda, Mark C.
    Kim, Jonghwan
    Bhinge, Akshay A.
    Jiang, Nan
    Liu, Jun
    Yao, Fei
    Vega, Vinsensius B.
    Lee, Charlie W.
    Ng, Patrick
    Shahab, Atif
    Yang, Annie
    Moqtaderi, Zarmik
    Zhu, Zhou
    Xu, Xiaoqin
    Squazzo, Sharon
    Oberley, Matthew J.
    Inman, David
    Singer, Michael A.
    Richmond, Todd A.
    Munn, Kyle J.
    Rada-Iglesias, Alvaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Fowler, Joanna C.
    Couttet, Phillippe
    Bruce, Alexander W.
    Dovey, Oliver M.
    Ellis, Peter D.
    Langford, Cordelia F.
    Nix, David A.
    Euskirchen, Ghia
    Hartman, Stephen
    Urban, Alexander E.
    Kraus, Peter
    Van Calcar, Sara
    Heintzman, Nate
    Kim, Tae Hoon
    Wang, Kun
    Qu, Chunxu
    Hon, Gary
    Luna, Rosa
    Glass, Christopher K.
    Rosenfeld, M. Geoff
    Aldred, Shelley Force
    Cooper, Sara J.
    Halees, Anason
    Lin, Jane M.
    Shulha, Hennady P.
    Zhang, Xiaoling
    Xu, Mousheng
    Haidar, Jaafar N.
    Yu, Yong
    Ruan, Yijun
    Iyer, Vishwanath R.
    Green, Roland D.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Farnham, Peggy J.
    Ren, Bing
    Harte, Rachel A.
    Hinrichs, Angie S.
    Trumbower, Heather
    Clawson, Hiram
    Hillman-Jackson, Jennifer
    Zweig, Ann S.
    Smith, Kayla
    Thakkapallayil, Archana
    Barber, Galt
    Kuhn, Robert M.
    Karolchik, Donna
    Armengol, Lluis
    Bird, Christine P.
    de Bakker, Paul I.
    Kern, Andrew D.
    Lopez-Bigas, Nuria
    Martin, Joel D.
    Stranger, Barbara E.
    Woodroffe, Abigail
    Davydov, Eugene
    Dimas, Antigone
    Eyras, Eduardo
    Hallgrí­msdóttir, Ingileif B.
    Huppert, Julian
    Zody, Michael C.
    Abecasis, G. R.
    Estivill, Xavier
    Bouffard, Gerard G.
    Guan, Xiaobin
    Hansen, Nancy F.
    Idol, Jacquelyn R.
    Maduro, Valerie V.
    Maskeri, Baishali
    McDowell, Jennifer C.
    Park, Morgan
    Thomas, Pamela J.
    Young, Alice C.
    Blakesley, Robert W.
    Muzny, Donna M.
    Sodergren, Erica
    Wheeler, David A.
    Worley, Kim C.
    Jiang, Huaiyang
    Weinstock, George M.
    Gibbs, Richard A.
    Graves, Tina
    Fulton, Robert
    Mardis, Elaine R.
    Wilson, Richard K.
    Clamp, Michele
    Cuff, James
    Gnerre, Sante
    Jaffe, David B.
    Chang, Jean L.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lander, Eric S.
    Koriabine, Maxim
    Nefedov, Mikhail
    Osoegawa, Kazutoyo
    Yoshinaga, Yuko
    Zhu, Baoli
    de Jong, Pieter J.
    Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 447, no 7146, p. 799-816Article in journal (Refereed)
    Abstract [en]

    We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

  • 20. Borgatti, Antonella
    et al.
    Koopmeiners, Joseph S
    Sarver, Aaron L
    Winter, Amber L
    Stuebner, Kathleen
    Todhunter, Deborah
    Rizzardi, Anthony E
    Henricksen, Jonathan C
    Schmechel, Stephen
    Forster, Colleen L
    Kim, Jong-Hyuk
    Froelich, Jerry
    Walz, Jillian
    Henson, Michael S
    Breen, Matthew
    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.
    Oh, Felix
    Pilbeam, Kristy
    Modiano, Jaime F
    Vallera, Daniel A
    Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR.2017In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 16, no 5, p. 956-965, article id molcanther.0637.2016Article in journal (Refereed)
    Abstract [en]

    Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to epidermal growth factor (EGF) and the amino terminal fragment (ATF) of urokinase. Here, we study the drug in an in vivo "ontarget" companion dog trial since eBAT effectively kills canine hemangiosarcoma (HSA) and human sarcoma cells in vitro. We reasoned the model has value due to the common occurrence of spontaneous sarcomas in dogs and a limited lifespan allowing for rapid accrual and data collection. Splenectomized dogs with minimal residual disease were given one cycle of eBAT followed by adjuvant doxorubicin in an adaptive dose-finding, phase I-II study of 23 dogs with spontaneous, stage I-II, splenic HSA. eBAT improved 6-month survival from <40% in a comparison population to ~70% in dogs treated at a biologically active dose (50 µg/kg). Six dogs were long-term survivors, living >450 days. eBAT abated expected toxicity associated with EGFR-targeting, a finding supported by mouse studies. Urokinase plasminogen activator receptor (uPAR) and EGFR are targets for human sarcomas, so thorough evaluation is crucial for validation of the dog model. Thus, we validated these markers for human sarcoma targeting in the study of 212 human and 97 canine sarcoma samples. Our results support further translation of eBAT for human patients with sarcomas and perhaps other EGFR-expressing malignancies.

  • 21. Borge, Kaja Sverdrup
    et al.
    Melin, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rivera, Patricio
    Thoresen, Stein Istre
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    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.
    Lingaas, Frode
    The ESR1 gene is associated with risk for canine mammary tumours2013In: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, p. 69-Article in journal (Refereed)
    Abstract [en]

    Background: The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. Results: We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best P-Bonf = 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best P-Bonf = 8.8E-32, best P-BPerm = 0.076). Conclusions: The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research.

  • 22.
    Braasch, Ingo
    et al.
    Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA.;Michigan State Univ, Dept Integrat Biol, E Lansing, MI 48824 USA..
    Gehrke, Andrew R.
    Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA..
    Smith, Jeramiah J.
    Univ Kentucky, Dept Biol, Lexington, KY USA..
    Kawasaki, Kazuhiko
    Penn State Univ, Dept Anthropol, University Pk, PA 16802 USA..
    Manousaki, Tereza
    Hellen Ctr Marine Res, Inst Marine Biol Biotechnol & Aquaculture, Iraklion, Greece..
    Pasquier, Jeremy
    INRA, LPGP, UR1037, Campus Beaulieu, F-35042 Rennes, France..
    Amores, Angel
    Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA..
    Desvignes, Thomas
    Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA..
    Batzel, Peter
    Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA..
    Catchen, Julian
    Univ Illinois, Dept Anim Biol, Urbana, IL 61801 USA..
    Berlin, Aaron M.
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard, Cambridge, MA USA..
    Campbell, Michael S.
    Univ Utah, Eccles Inst Human Genet, Salt Lake City, UT USA.;Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA..
    Barrell, Daniel
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England.;European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Hinxton, England..
    Martin, Kyle J.
    Univ Oxford, Dept Zool, Oxford, England.;Univ Sheffield, Dept Anim & Plant Sci, Sheffield S10 2TN, S Yorkshire, England..
    Mulley, John F.
    Bangor Univ, Sch Biol Sci, Bangor, Gwynedd, Wales..
    Ravi, Vydianathan
    ASTAR, Inst Mol & Cell Biol, Comparat Genom Lab, Singapore, Singapore..
    Lee, Alison P.
    ASTAR, Inst Mol & Cell Biol, Comparat Genom Lab, Singapore, Singapore..
    Nakamura, Tetsuya
    Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA..
    Chalopin, Domitille
    Ecole Normale Super Lyon, Inst Genom Fonct Lyon, F-69364 Lyon, France.;Univ Georgia, Dept Genet, Athens, GA 30602 USA..
    Fan, Shaohua
    Univ Konstanz, Dept Biol, Constance, Germany.;Univ Penn, Dept Genet, Philadelphia, PA 19104 USA..
    Wcisel, Dustin
    N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USA.;N Carolina State Univ, Ctr Comparat Med & Translat Res, Raleigh, NC 27695 USA..
    Canestro, Cristian
    Univ Barcelona, Dept Genet, Barcelona, Spain.;Univ Barcelona, Inst Recerca Biodiversitat, Barcelona, Spain..
    Sydes, Jason
    Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA..
    Beaudry, Felix E. G.
    Univ Victoria, Dept Biol, POB 1700, Victoria, BC V8W 2Y2, Canada..
    Sun, Yi
    Soochow Univ, Ctr Circadian Clocks, Suzhou, Peoples R China.;Soochow Univ, Coll Med, Sch Biol & Basic Med Sci, Suzhou, Peoples R China..
    Hertel, Jana
    Univ Leipzig, Dept Comp Sci, Bioinformat Grp, D-04109 Leipzig, Germany.;UFZ Helmholtz Ctr Environm Res, Young Investigators Grp Bioinformat & Transcript, Leipzig, Germany..
    Beam, Michael J.
    Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA..
    Fasold, Mario
    Univ Leipzig, Dept Comp Sci, Bioinformat Grp, D-04109 Leipzig, Germany.;ecSeq Bioinformat, Leipzig, Germany..
    Ishiyama, Mikio
    Nippon Dent Univ Coll Niigata, Dept Dent Hyg, Niigata, Japan..
    Johnson, Jeremy
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard, Cambridge, MA USA..
    Kehr, Steffi
    Univ Leipzig, Dept Comp Sci, Bioinformat Grp, D-04109 Leipzig, Germany..
    Lara, Marcia
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard, Cambridge, MA USA..
    Letaw, John H.
    Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA..
    Litman, Gary W.
    Univ S Florida, Morsani Coll Med, Dept Pediat, St Petersburg, FL 33701 USA..
    Litman, Ronda T.
    Univ S Florida, Morsani Coll Med, Dept Pediat, St Petersburg, FL 33701 USA..
    Mikami, Masato
    Nippon Dent Univ, Sch Life Dent Niigata, Dept Microbiol, Niigata, Japan..
    Ota, Tatsuya
    SOKENDAI Grad Univ Adv Studies, Dept Evolutionary Studies Biosyst, Hayama, Japan..
    Saha, Nil Ratan
    Benaroya Res Inst, Mol Genet Program, Seattle, WA USA..
    Williams, Louise
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard, Cambridge, MA USA..
    Stadler, Peter F.
    Univ Leipzig, Dept Comp Sci, Bioinformat Grp, D-04109 Leipzig, Germany..
    Wang, Han
    Soochow Univ, Ctr Circadian Clocks, Suzhou, Peoples R China.;Soochow Univ, Coll Med, Sch Biol & Basic Med Sci, Suzhou, Peoples R China..
    Taylor, John S.
    Univ Victoria, Dept Biol, POB 1700, Victoria, BC V8W 2Y2, Canada..
    Fontenot, Quenton
    Nicholls State Univ, Dept Biol Sci, Thibodaux, LA 70310 USA..
    Ferrara, Allyse
    Nicholls State Univ, Dept Biol Sci, Thibodaux, LA 70310 USA..
    Searle, Stephen M. J.
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England..
    Aken, Bronwen
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England.;European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Hinxton, England..
    Yandell, Mark
    Univ Utah, Eccles Inst Human Genet, Salt Lake City, UT USA..
    Schneider, Igor
    Fed Univ Para, Inst Ciencias Biol, BR-66059 Belem, Para, Brazil..
    Yoder, Jeffrey A.
    N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USA.;N Carolina State Univ, Ctr Comparat Med & Translat Res, Raleigh, NC 27695 USA..
    Volff, Jean-Nicolas
    Ecole Normale Super Lyon, Inst Genom Fonct Lyon, F-69364 Lyon, France..
    Meyer, Axel
    Univ Konstanz, Dept Biol, Constance, Germany.;Univ Konstanz, Int Max Planck Res Sch Organismal Biol, Constance, Germany..
    Amemiya, Chris T.
    Benaroya Res Inst, Mol Genet Program, Seattle, WA USA..
    Venkatesh, Byrappa
    ASTAR, Inst Mol & Cell Biol, Comparat Genom Lab, Singapore, Singapore..
    Holland, Peter W. H.
    Univ Oxford, Dept Zool, Oxford, England..
    Guiguen, Yann
    INRA, LPGP, UR1037, Campus Beaulieu, F-35042 Rennes, France..
    Bobe, Julien
    INRA, LPGP, UR1037, Campus Beaulieu, F-35042 Rennes, France..
    Shubin, Neil H.
    Univ Chicago, Dept Organismal Biol & Anat, 1025 E 57Th St, Chicago, IL 60637 USA..
    Di Palma, Federica
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard, Cambridge, MA USA.;Genome Anal Ctr, Vertebrate & Hlth Genom, Norwich, Norfolk, England..
    Alfoeldi, Jessica
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard, Cambridge, MA 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. MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard, Cambridge, MA USA.;Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, Uppsala, Sweden..
    Postlethwait, John H.
    Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA..
    The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 4, p. 427-437Article in journal (Refereed)
    Abstract [en]

    To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before teleost genome duplication (TGD). The slowly evolving gar genome has conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization and development (mediated, for example, by Hox, ParaHox and microRNA genes). Numerous conserved noncoding elements (CNEs; often cis regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles for such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses showed that the sums of expression domains and expression levels for duplicated teleost genes often approximate the patterns and levels of expression for gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes and the function of human regulatory sequences.

  • 23. Brawand, David
    et al.
    Wagner, Catherine E.
    Li, Yang I.
    Malinsky, Milan
    Keller, Irene
    Fan, Shaohua
    Simakov, Oleg
    Ng, Alvin Y.
    Lim, Zhi Wei
    Bezault, Etienne
    Turner-Maier, Jason
    Johnson, Jeremy
    Alcazar, Rosa
    Noh, Hyun Ji
    Russell, Pamela
    Aken, Bronwen
    Alfoeldi, Jessica
    Amemiya, Chris
    Azzouzi, Naoual
    Baroiller, Jean-Francois
    Barloy-Hubler, Frederique
    Berlin, Aaron
    Bloomquist, Ryan
    Carleton, Karen L.
    Conte, Matthew A.
    D'Cotta, Helena
    Eshel, Orly
    Gaffney, Leslie
    Galibert, Francis
    Gante, Hugo F.
    Gnerre, Sante
    Greuter, Lucie
    Guyon, Richard
    Haddad, Natalie S.
    Haerty, Wilfried
    Harris, Rayna M.
    Hofmann, Hans A.
    Hourlier, Thibaut
    Hulata, Gideon
    Jaffe, David B.
    Lara, Marcia
    Lee, Alison P.
    MacCallum, Iain
    Mwaiko, Salome
    Nikaido, Masato
    Nishihara, Hidenori
    Ozouf-Costaz, Catherine
    Penman, David J.
    Przybylski, Dariusz
    Rakotomanga, Michaelle
    Renn, Suzy C. P.
    Ribeiro, Filipe J.
    Ron, Micha
    Salzburger, Walter
    Sanchez-Pulido, Luis
    Santos, M. Emilia
    Searle, Steve
    Sharpe, Ted
    Swofford, Ross
    Tan, Frederick J.
    Williams, Louise
    Young, Sarah
    Yin, Shuangye
    Okada, Norihiro
    Kocher, Thomas D.
    Miska, Eric A.
    Lander, Eric S.
    Venkatesh, Byrappa
    Fernald, Russell D.
    Meyer, Axel
    Ponting, Chris P.
    Streelman, J. Todd
    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.
    Seehausen, Ole
    Di Palma, Federica
    The genomic substrate for adaptive radiation in African cichlid fish2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 513, no 7518, p. 375-381Article in journal (Refereed)
    Abstract [en]

    Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand themolecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.

  • 24.
    Bremer, Hanna D.
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Landegren, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden..
    Sjöberg, Ronald
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, SE-17121 Solna, Sweden..
    Hallgren, Åsa
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, CMM, L8 01, SE-17176 Stockholm, Sweden..
    Renneker, Stefanie
    Euroimmun AG, D-23560 Lubeck, Germany..
    Lattwein, Erik
    Euroimmun AG, D-23560 Lubeck, Germany..
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    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.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, SE-17121 Solna, Sweden..
    Andersson, Goran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Lilliehöök, Inger
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 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. Broad Inst Harvard & MIT, Cambridge, USA..
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, CMM, L8 01, SE-17176 Stockholm, Sweden.; Univ Bergen, Dept Clin Sci, N-5021 Bergen, Norway.;Univ Bergen, KG Jebsen Ctr Autoimmune Disorders, N-5021 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Hansson-Hamlin, Helene
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4852Article in journal (Refereed)
    Abstract [en]

    Dogs can spontaneously develop complex systemic autoimmune disorders, with similarities to human autoimmune disease. Autoantibodies directed at self-antigens are a key feature of these autoimmune diseases. Here we report the identification of interleukin enhancer-binding factors 2 and 3 (ILF2 and ILF3) as autoantigens in canine immune-mediated rheumatic disease. The ILF2 autoantibodies were discovered in a small, selected canine cohort through the use of human protein arrays; a method not previously described in dogs. Subsequently, ILF3 autoantibodies were also identified in the same cohort. The results were validated with an independent method in a larger cohort of dogs. ILF2 and ILF3 autoantibodies were found exclusively, and at a high frequency, in dogs that showed a speckled pattern of antinuclear antibodies on immunofluorescence. ILF2 and ILF3 autoantibodies were also found at low frequency in human patients with SLE and Sjogren's syndrome. These autoantibodies have the potential to be used as diagnostic biomarkers for canine, and possibly also human, autoimmune disease.

  • 25.
    Broeckx, Bart J. G.
    et al.
    Univ Ghent, Lab Anim Genet, Fac Vet Med, Merelbeke, Belgium..
    Derrien, Thomas
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    Mottier, Stephanie
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    Wucher, Valentin
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    Cadieu, Edouard
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    Hedan, Benoit
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    Le Beguec, Celine
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    Botherel, Nadine
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    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.
    Saunders, Jimmy H.
    Univ Ghent, Dept Med Imaging & Orthoped, Fac Vet Med, Merelbeke, Belgium..
    Deforce, Dieter
    Univ Ghent, Fac Pharmaceut Sci, Lab Pharmaceut Biotechnol, Ghent, Belgium..
    Andre, Catherine
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    Peelman, Luc
    Univ Ghent, Lab Anim Genet, Fac Vet Med, Merelbeke, Belgium..
    Hitte, Christophe
    Univ Rennes 1, CNRS URM6290, Inst Genet & Dev Rennes, Rennes, France..
    An exome sequencing based approach for genome-wide association studies in the dog2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15680Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. However, a disadvantage of GWAS is that it always requires subsequent fine-mapping or sequencing to pinpoint causal mutations. Here, we performed whole exome sequencing (WES) and canine high-density (cHD) SNP genotyping of 28 dogs from 3 breeds to compare the SNP and linkage disequilibrium characteristics together with the power and mapping precision of exome-guided GWAS (EG-GWAS) versus cHD-based GWAS. Using simulated phenotypes, we showed that EG-GWAS has a higher power than cHD to detect associations within target regions and less power outside target regions, with power being influenced further by sample size and SNP density. We analyzed two real phenotypes (hair length and furnishing), that are fixed in certain breeds to characterize mapping precision of the known causal mutations. EG-GWAS identified the associated exonic and 3'UTR variants within the FGF5 and RSPO2 genes, respectively, with only a few samples per breed. In conclusion, we demonstrated that EG-GWAS can identify loci associated with Mendelian phenotypes both within and across breeds.

  • 26. Broeckx, Bart J. G.
    et al.
    Hitte, Christophe
    Coopman, Frank
    Verhoeven, Geert E. C.
    De Keulenaer, Sarah
    De Meester, Ellen
    Derrien, Thomas
    Alfoldi, Jessica
    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.
    Bosmans, Tim
    Gielen, Ingrid
    Van Bree, Henri
    Van Ryssen, Bernadette
    Saunders, Jimmy H.
    Van Nieuwerburgh, Filip
    Deforce, Dieter
    Improved canine exome designs, featuring ncRNAs and increased coverage of protein coding genes2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 12810Article in journal (Refereed)
    Abstract [en]

    By limiting sequencing to those sequences transcribed as mRNA, whole exome sequencing is a cost-efficient technique often used in disease-association studies. We developed two target enrichment designs based on the recently released annotation of the canine genome: the exome-plus design and the exome-CDS design. The exome-plus design combines the exons of the CanFam 3.1 Ensembl annotation, more recently discovered protein-coding exons and a variety of non-coding RNA regions (microRNAs, long non-coding RNAs and antisense transcripts), leading to a total size of approximate to 152 Mb. The exome-CDS was designed as a subset of the exome-plus by omitting all 3' and 5' untranslated regions. This reduced the size of the exome-CDS to approximate to 71 Mb. To test the capturing performance, four exome-plus captures were sequenced on a NextSeq 500 with each capture containing four pre-capture pooled, barcoded samples. At an average sequencing depth of 68.3x, 80% of the regions and well over 90% of the targeted base pairs were completely covered at least 5 times with high reproducibility. Based on the performance of the exome-plus, we estimated the performance of the exome-CDS. Overall, these designs provide flexible solutions for a variety of research questions and are likely to be reliable tools in disease studies.

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

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

  • 28.
    Cavalli, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Arzt, Emelie Wallén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci, Huddinge, Sweden..
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Toh, Kerstin Lindblad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression2016In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 135, no 5, p. 485-497Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.

  • 29. Ching, Yung-Hao
    et al.
    Munroe, Robert J.
    Moran, Jennifer L.
    Barker, Anna K.
    Mauceli, Evan
    Fennell, Tim
    diPalma, Frederica
    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.
    Abcunas, Lindsay M.
    Gilmour, Joyanna F.
    Harris, Tanya P.
    Kloet, Susan L.
    Luo, Yunhai
    McElwee, John L.
    Mu, Weipeng
    Park, Hyo K.
    Rogal, David L.
    Schimenti, Kerry J.
    Shen, Lishuang
    Shindo, Mami
    Shou, James Y.
    Stenson, Erin K.
    Stover, Patrick J.
    Schimenti, John C.
    High resolution mapping and positional cloning of ENU-induced mutations in the Rw region of mouse chromosome 52010In: BMC Genetics, ISSN 1471-2156, E-ISSN 1471-2156, Vol. 11, p. 106-Article in journal (Refereed)
    Abstract [en]

    Background: Forward genetic screens in mice provide an unbiased means to identify genes and other functional genetic elements in the genome. Previously, a large scale ENU mutagenesis screen was conducted to query the functional content of a similar to 50 Mb region of the mouse genome on proximal Chr 5. The majority of phenotypic mutants recovered were embryonic lethals. Results: We report the high resolution genetic mapping, complementation analyses, and positional cloning of mutations in the target region. The collection of identified alleles include several with known or presumed functions for which no mutant models have been reported (Tbc1d14, Nol14, Tyms, Cad, Fbxl5, Haus3), and mutations in genes we or others previously reported (Tapt1, Rest, Ugdh, Paxip1, Hmx1, Otoe, Nsun7). We also confirmed the causative nature of a homeotic mutation with a targeted allele, mapped a lethal mutation to a large gene desert, and localized a spermiogenesis mutation to a region in which no annotated genes have coding mutations. The mutation in Tbc1d14 provides the first implication of a critical developmental role for RAB-GAP-mediated protein transport in early embryogenesis. Conclusion: This collection of alleles contributes to the goal of assigning biological functions to all known genes, as well as identifying novel functional elements that would be missed by reverse genetic approaches.

  • 30. Church, Deanna M
    et al.
    Goodstadt, Leo
    Hillier, Ladeana W
    Zody, Michael C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Goldstein, Steve
    She, Xinwe
    Bult, Carol J
    Agarwala, Richa
    Cherry, Joshua L
    DiCuccio, Michael
    Hlavina, Wratko
    Kapustin, Yuri
    Meric, Peter
    Maglott, Donna
    Birtle, Zoë
    Marques, Ana C
    Graves, Tina
    Zhou, Shiguo
    Teague, Brian
    Potamousis, Konstantinos
    Churas, Christopher
    Place, Michael
    Herschleb, Jill
    Runnheim, Ron
    Forrest, Daniel
    Amos-Landgraf, James
    Schwartz, David C
    Cheng, Ze
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eichler, Evan E
    Ponting, Chris P
    Lineage-specific biology revealed by a finished genome assembly of the mouse2009In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 7, no 5, p. e1000112-Article in journal (Refereed)
    Abstract [en]

    The mouse (Mus musculus) is the premier animal model for understanding human disease and development. Here we show that a comprehensive understanding of mouse biology is only possible with the availability of a finished, high-quality genome assembly. The finished clone-based assembly of the mouse strain C57BL/6J reported here has over 175,000 fewer gaps and over 139 Mb more of novel sequence, compared with the earlier MGSCv3 draft genome assembly. In a comprehensive analysis of this revised genome sequence, we are now able to define 20,210 protein-coding genes, over a thousand more than predicted in the human genome (19,042 genes). In addition, we identified 439 long, non-protein-coding RNAs with evidence for transcribed orthologs in human. We analyzed the complex and repetitive landscape of 267 Mb of sequence that was missing or misassembled in the previously published assembly, and we provide insights into the reasons for its resistance to sequencing and assembly by whole-genome shotgun approaches. Duplicated regions within newly assembled sequence tend to be of more recent ancestry than duplicates in the published draft, correcting our initial understanding of recent evolution on the mouse lineage. These duplicates appear to be largely composed of sequence regions containing transposable elements and duplicated protein-coding genes; of these, some may be fixed in the mouse population, but at least 40% of segmentally duplicated sequences are copy number variable even among laboratory mouse strains. Mouse lineage-specific regions contain 3,767 genes drawn mainly from rapidly-changing gene families associated with reproductive functions. The finished mouse genome assembly, therefore, greatly improves our understanding of rodent-specific biology and allows the delineation of ancestral biological functions that are shared with human from derived functions that are not.

  • 31. Clamp, Michele
    et al.
    Fry, Ben
    Kamal, Mike
    Xie, Xiaohui
    Cuff, James
    Lin, Michael F
    Kellis, Manolis
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lander, Eric S
    Distinguishing protein-coding and noncoding genes in the human genome2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 49, p. 19428-19433Article in journal (Refereed)
    Abstract [en]

    Although the Human Genome Project was completed 4 years ago, the catalog of human protein-coding genes remains a matter of controversy. Current catalogs list a total of ≈24,500 putative protein-coding genes. It is broadly suspected that a large fraction of these entries are functionally meaningless ORFs present by chance in RNA transcripts, because they show no evidence of evolutionary conservation with mouse or dog. However, there is currently no scientific justification for excluding ORFs simply because they fail to show evolutionary conservation: the alternative hypothesis is that most of these ORFs are actually valid human genes that reflect gene innovation in the primate lineage or gene loss in the other lineages. Here, we reject this hypothesis by carefully analyzing the nonconserved ORFs—specifically, their properties in other primates. We show that the vast majority of these ORFs are random occurrences. The analysis yields, as a by-product, a major revision of the current human catalogs, cutting the number of protein-coding genes to ≈20,500. Specifically, it suggests that nonconserved ORFs should be added to the human gene catalog only if there is clear evidence of an encoded protein. It also provides a principled methodology for evaluating future proposed additions to the human gene catalog. Finally, the results indicate that there has been relatively little true innovation in mammalian protein-coding genes.

  • 32. Clark, Andrew G.
    et al.
    Eisen, Michael B.
    Smith, Douglas R.
    Bergman, Casey M.
    Oliver, Brian
    Markow, Therese A.
    Kaufman, Thomas C.
    Kellis, Manolis
    Gelbart, William
    Iyer, Venky N.
    Pollard, Daniel A.
    Sackton, Timothy B.
    Larracuente, Amanda M.
    Singh, Nadia D.
    Abad, Jose P.
    Abt, Dawn N.
    Adryan, Boris
    Aguade, Montserrat
    Akashi, Hiroshi
    Anderson, Wyatt W.
    Aquadro, Charles F.
    Ardell, David H.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Arguello, Roman
    Artieri, Carlo G.
    Barbash, Daniel A.
    Barker, Daniel
    Barsanti, Paolo
    Batterham, Phil
    Batzoglou, Serafim
    Begun, Dave
    Bhutkar, Arjun
    Blanco, Enrico
    Bosak, Stephanie A.
    Bradley, Robert K.
    Brand, Adrianne D.
    Brent, Michael R.
    Brooks, Angela N.
    Brown, Randall H.
    Butlin, Roger K.
    Caggese, Corrado
    Calvi, Brian R.
    de Carvalho, A. Bernardo
    Caspi, Anat
    Castrezana, Sergio
    Celniker, Susan E.
    Chang, Jean L.
    Chapple, Charles
    Chatterji, Sourav
    Chinwalla, Asif
    Civetta, Alberto
    Clifton, Sandra W.
    Comeron, Josep M.
    Costello, James C.
    Coyne, Jerry A.
    Daub, Jennifer
    David, Robert G.
    Delcher, Arthur L.
    Delehaunty, Kim
    Do, Chuong B.
    Ebling, Heather
    Edwards, Kevin
    Eickbush, Thomas
    Evans, Jay D.
    Filipski, Alan
    Findeiss, Sven
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Fulton, Lucinda
    Fulton, Robert
    Garcia, Ana C. L.
    Gardiner, Anastasia
    Garfield, David A.
    Garvin, Barry E.
    Gibson, Greg
    Gilbert, Don
    Gnerre, Sante
    Godfrey, Jennifer
    Good, Robert
    Gotea, Valer
    Gravely, Brenton
    Greenberg, Anthony J.
    Griffiths-Jones, Sam
    Gross, Samuel
    Guigo, Roderic
    Gustafson, Erik A.
    Haerty, Wilfried
    Hahn, Matthew W.
    Halligan, Daniel L.
    Halpern, Aaron L.
    Halter, Gillian M.
    Han, Mira V.
    Heger, Andreas
    Hillier, LaDeana
    Hinrichs, Angie S.
    Holmes, Ian
    Hoskins, Roger A.
    Hubisz, Melissa J.
    Hultmark, Dan
    Huntley, Melanie A.
    Jaffe, David B.
    Jagadeeshan, Santosh
    Jeck, William R.
    Johnson, Justin
    Jones, Corbin D.
    Jordan, William C.
    Karpen, Gary H.
    Kataoka, Eiko
    Keightley, Peter D.
    Kheradpour, Pouya
    Kirkness, Ewen F.
    Koerich, Leonardo B.
    Kristiansen, Karsten
    Kudrna, Dave
    Kulathinal, Rob J.
    Kumar, Sudhir
    Kwok, Roberta
    Lander, Eric
    Langley, Charles H.
    Lapoint, Richard
    Lazzaro, Brian P.
    Lee, So-Jeong
    Levesque, Lisa
    Li, Ruiqiang
    Lin, Chiao-Feng
    Lin, Michael F.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Llopart, Ana
    Long, Manyuan
    Low, Lloyd
    Lozovsky, Elena
    Lu, Jian
    Luo, Meizhong
    Machado, Carlos A.
    Makalowski, Wojciech
    Marzo, Mar
    Matsuda, Muneo
    Matzkin, Luciano
    McAllister, Bryant
    McBride, Carolyn S.
    McKernan, Brendan
    McKernan, Kevin
    Mendez-Lago, Maria
    Minx, Patrick
    Mollenhauer, Michael U.
    Montooth, Kristi
    Mount, Stephen M.
    Mu, Xu
    Myers, Eugene
    Negre, Barbara
    Newfeld, Stuart
    Nielsen, Rasmus
    Noor, Mohamed A. F.
    O'Grady, Patrick
    Pachter, Lior
    Papaceit, Montserrat
    Parisi, Matthew J.
    Parisi, Michael
    Parts, Leopold
    Pedersen, Jakob S.
    Pesole, Graziano
    Phillippy, Adam M.
    Ponting, Chris P.
    Pop, Mihai
    Porcelli, Damiano
    Powell, Jeffrey R.
    Prohaska, Sonja
    Pruitt, Kim
    Puig, Marta
    Quesneville, Hadi
    Ram, Kristipati Ravi
    Rand, David
    Rasmussen, Matthew D.
    Reed, Laura K.
    Reenan, Robert
    Reily, Amy
    Remington, Karin A.
    Rieger, Tania T.
    Ritchie, Michael G.
    Robin, Charles
    Rogers, Yu-Hui
    Rohde, Claudia
    Rozas, Julio
    Rubenfield, Marc J.
    Ruiz, Alfredo
    Russo, Susan
    Salzberg, Steven L.
    Sanchez-Gracia, Alejandro
    Saranga, David J.
    Sato, Hajime
    Schaeffer, Stephen W.
    Schatz, Michael C.
    Schlenke, Todd
    Schwartz, Russell
    Segarra, Carmen
    Singh, Rama S.
    Sirot, Laura
    Sirota, Marina
    Sisneros, Nicholas B.
    Smith, Chris D.
    Smith, Temple F.
    Spieth, John
    Stage, Deborah E.
    Stark, Alexander
    Stephan, Wolfgang
    Strausberg, Robert L.
    Strempel, Sebastian
    Sturgill, David
    Sutton, Granger
    Sutton, Granger G.
    Tao, Wei
    Teichmann, Sarah
    Tobari, Yoshiko N.
    Tomimura, Yoshihiko
    Tsolas, Jason M.
    Valente, Vera L. S.
    Venter, Eli
    Venter, J. Craig
    Vicario, Saverio
    Vieira, Filipe G.
    Vilella, Albert J.
    Villasante, Alfredo
    Walenz, Brian
    Wang, Jun
    Wasserman, Marvin
    Watts, Thomas
    Wilson, Derek
    Wilson, Richard K.
    Wing, Rod A.
    Wolfner, Mariana F.
    Wong, Alex
    Wong, Gane Ka-Shu
    Wu, Chung-I
    Wu, Gabriel
    Yamamoto, Daisuke
    Yang, Hsiao-Pei
    Yang, Shiaw-Pyng
    Yorke, James A.
    Yoshida, Kiyohito
    Zdobnov, Evgeny
    Zhang, Peili
    Zhang, Yu
    Zimin, Aleksey V.
    Baldwin, Jennifer
    Abdouelleil, Amr
    Abdulkadir, Jamal
    Abebe, Adal
    Abera, Brikti
    Abreu, Justin
    Acer, St Christophe
    Aftuck, Lynne
    Alexander, Allen
    An, Peter
    Anderson, Erica
    Anderson, Scott
    Arachi, Harindra
    Azer, Marc
    Bachantsang, Pasang
    Barry, Andrew
    Bayul, Tashi
    Berlin, Aaron
    Bessette, Daniel
    Bloom, Toby
    Blye, Jason
    Boguslavskiy, Leonid
    Bonnet, Claude
    Boukhgalter, Boris
    Bourzgui, Imane
    Brown, Adam
    Cahill, Patrick
    Channer, Sheridon
    Cheshatsang, Yama
    Chuda, Lisa
    Citroen, Mieke
    Collymore, Alville
    Cooke, Patrick
    Costello, Maura
    D'Aco, Katie
    Daza, Riza
    De Haan, Georgius
    DeGray, Stuart
    DeMaso, Christina
    Dhargay, Norbu
    Dooley, Kimberly
    Dooley, Erin
    Doricent, Missole
    Dorje, Passang
    Dorjee, Kunsang
    Dupes, Alan
    Elong, Richard
    Falk, Jill
    Farina, Abderrahim
    Faro, Susan
    Ferguson, Diallo
    Fisher, Sheila
    Foley, Chelsea D.
    Franke, Alicia
    Friedrich, Dennis
    Gadbois, Loryn
    Gearin, Gary
    Gearin, Christina R.
    Giannoukos, Georgia
    Goode, Tina
    Graham, Joseph
    Grandbois, Edward
    Grewal, Sharleen
    Gyaltsen, Kunsang
    Hafez, Nabil
    Hagos, Birhane
    Hall, Jennifer
    Henson, Charlotte
    Hollinger, Andrew
    Honan, Tracey
    Huard, Monika D.
    Hughes, Leanne
    Hurhula, Brian
    Husby, M. Erii
    Kamat, Asha
    Kanga, Ben
    Kashin, Seva
    Khazanovich, Dmitry
    Kisner, Peter
    Lance, Krista
    Lara, Marcia
    Lee, William
    Lennon, Niall
    Letendre, Frances
    LeVine, Rosie
    Lipovsky, Alex
    Liu, Xiaohong
    Liu, Jinlei
    Liu, Shangtao
    Lokyitsang, Tashi
    Lokyitsang, Yeshi
    Lubonja, Rakela
    Lui, Annie
    MacDonald, Pen
    Magnisalis, Vasilia
    Maru, Kebede
    Matthews, Charles
    McCusker, William
    McDonough, Susan
    Mehta, Teena
    Meldrim, James
    Meneus, Louis
    Mihai, Oana
    Mihalev, Atanas
    Mihova, Tanya
    Mittelman, Rachel
    Mlenga, Valentine
    Montmayeur, Anna
    Mulrain, Leonidas
    Navidi, Adam
    Naylor, Jerome
    Negash, Tamrat
    Nguyen, Thu
    Nguyen, Nga
    Nicol, Robert
    Norbu, Choe
    Norbu, Nyima
    Novod, Nathaniel
    O'Neill, Barry
    Osman, Sahal
    Markiewicz, Eva
    Oyono, Otero L.
    Patti, Christopher
    Phunkhang, Pema
    Pierre, Fritz
    Priest, Margaret
    Raghuraman, Sujaa
    Rege, Filip
    Reyes, Rebecca
    Rise, Cecil
    Rogov, Peter
    Ross, Keenan
    Ryan, Elizabeth
    Settipalli, Sampath
    Shea, Terry
    Sherpa, Ngawang
    Shi, Lu
    Shih, Diana
    Sparrow, Todd
    Spaulding, Jessica
    Stalker, John
    Stange-Thomann, Nicole
    Stavropoulos, Sharon
    Stone, Catherine
    Strader, Christopher
    Tesfaye, Senait
    Thomson, Talene
    Thoulutsang, Yama
    Thoulutsang, Dawa
    Topham, Kerri
    Topping, Ira
    Tsamla, Tsamla
    Vassiliev, Helen
    Vo, Andy
    Wangchuk, Tsering
    Wangdi, Tsering
    Weiand, Michael
    Wilkinson, Jane
    Wilson, Adam
    Yadav, Shailendra
    Young, Geneva
    Yu, Qing
    Zembek, Lisa
    Zhong, Danni
    Zimmer, Andrew
    Zwirko, Zac
    Alvarez, Pablo
    Brockman, Will
    Butler, Jonathan
    Chin, CheeWhye
    Grabherr, Manfred
    Kleber, Michael
    Mauceli, Evan
    MacCallum, Iain
    Evolution of genes and genomes on the Drosophila phylogeny.2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 450, no 7167, p. 203-218Article in journal (Refereed)
    Abstract [en]

    Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

  • 33. Das, Radhika
    et al.
    Anderson, Nathan
    Koran, MaryEllen I.
    Weidman, Jennifer R.
    Mikkelsen, Tarjei S.
    Kamal, Michael
    Murphy, Susan K.
    Linblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Greally, John M.
    Jirtle, Randy L.
    Convergent and divergent evolution of genomic imprinting in the marsupial Monodelphis domestica2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 394-Article in journal (Refereed)
    Abstract [en]

    Background: Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin specific monoallelic gene expression. It is postulated to have evolved in placental mammals to modulate intrauterine resource allocation to the offspring. In this study, we determined the imprint status of metatherian orthologues of eutherian imprinted genes. Results: L3MBTL and HTR2A were shown to be imprinted in Monodelphis domestica (the gray short-tailed opossum). MEST expressed a monoallelic and a biallelic transcript, as in eutherians. In contrast, IMPACT, COPG2, and PLAGL1 were not imprinted in the opossum. Differentially methylated regions (DMRs) involved in regulating imprinting in eutherians were not found at any of the new imprinted loci in the opossum. Interestingly, a novel DMR was identified in intron 11 of the imprinted IGF2R gene, but this was not conserved in eutherians. The promoter regions of the imprinted genes in the opossum were enriched for the activating histone modification H3 Lysine 4 dimethylation. Conclusions: The phenomenon of genomic imprinting is conserved in Therians, but the marked difference in the number and location of imprinted genes and DMRs between metatherians and eutherians indicates that imprinting is not fully conserved between the two Therian infra-classes. The identification of a novel DMR at a non-conserved location as well as the first demonstration of histone modifications at imprinted loci in the opossum suggest that genomic imprinting may have evolved in a common ancestor of these two Therian infra-classes with subsequent divergence of regulatory mechanisms in the two lineages.

  • 34. Dodman, N. H.
    et al.
    Karlsson, E. K.
    Moon-Fanelli, A.
    Galdzicka, M.
    Perloski, M.
    Shuster, L.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ginns, E. I.
    A canine chromosome 7 locus confers compulsive disorder susceptibility2010In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 15, no 1, p. 8-10Article in journal (Refereed)
  • 35. Droegemueller, Cord
    et al.
    Tetens, Jens
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gentile, Arcangelo
    Testoni, Stefania
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leeb, Tosso
    Identification of the Bovine Arachnomelia Mutation by Massively Parallel Sequencing Implicates Sulfite Oxidase (SUOX) in Bone Development2010In: PLoS Genetics, ISSN 1553-7390, Vol. 6, no 8, p. e1001079-Article in journal (Refereed)
    Abstract [en]

    Arachnomelia is a monogenic recessive defect of skeletal development in cattle. The causative mutation was previously mapped to a similar to 7 Mb interval on chromosome 5. Here we show that array-based sequence capture and massively parallel sequencing technology, combined with the typical family structure in livestock populations, facilitates the identification of the causative mutation. We re-sequenced the entire critical interval in a healthy partially inbred cow carrying one copy of the critical chromosome segment in its ancestral state and one copy of the same segment with the arachnomelia mutation, and we detected a single heterozygous position. The genetic makeup of several partially inbred cattle provides extremely strong support for the causality of this mutation. The mutation represents a single base insertion leading to a premature stop codon in the coding sequence of the SUOX gene and is perfectly associated with the arachnomelia phenotype. Our findings suggest an important role for sulfite oxidase in bone development.

  • 36. Drögemüller, Cord
    et al.
    Becker, Doreen
    Brunner, Adrian
    Haase, Bianca
    Kircher, Patrick
    Seeliger, Frank
    Fehr, Michael
    Baumann, Ulrich
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leeb, Tosso
    A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta2009In: PLoS genetics, ISSN 1553-7404, Vol. 5, no 7, p. e1000579-Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene.

  • 37. Drögemüller, Cord
    et al.
    Becker, Doreen
    Kessler, Barbara
    Kemter, Elisabeth
    Tetens, Jens
    Jurina, Konrad
    Jäderlund, Karin Hultin
    Flagstad, Annette
    Perloski, Michele
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Matiasek, Kaspar
    A deletion in the N-myc downstream regulated gene 1 (NDRG1) gene in Greyhounds with polyneuropathy2010In: PloS one, ISSN 1932-6203, Vol. 5, no 6, p. e11258-Article in journal (Refereed)
    Abstract [en]

    The polyneuropathy of juvenile Greyhound show dogs shows clinical similarities to the genetically heterogeneous Charcot-Marie-Tooth (CMT) disease in humans. The pedigrees containing affected dogs suggest monogenic autosomal recessive inheritance and all affected dogs trace back to a single male. Here, we studied the neuropathology of this disease and identified a candidate causative mutation. Peripheral nerve biopsies from affected dogs were examined using semi-thin histology, nerve fibre teasing and electron microscopy. A severe chronic progressive mixed polyneuropathy was observed. Seven affected and 17 related control dogs were genotyped on the 50k canine SNP chip. This allowed us to localize the causative mutation to a 19.5 Mb interval on chromosome 13 by homozygosity mapping. The NDRG1 gene is located within this interval and NDRG1 mutations have been shown to cause hereditary motor and sensory neuropathy-Lom in humans (CMT4D). Therefore, we considered NDRG1 a positional and functional candidate gene and performed mutation analysis in affected and control Greyhounds. A 10 bp deletion in canine NDRG1 exon 15 (c.1080_1089delTCGCCTGGAC) was perfectly associated with the polyneuropathy phenotype of Greyhound show dogs. The deletion causes a frame shift (p.Arg361SerfsX60) which alters several amino acids before a stop codon is encountered. A reduced level of NDRG1 transcript could be detected by RT-PCR. Western blot analysis demonstrated an absence of NDRG1 protein in peripheral nerve biopsy of an affected Greyhound. We thus have identified a candidate causative mutation for polyneuropathy in Greyhounds and identified the first genetically characterized canine CMT model which offers an opportunity to gain further insights into the pathobiology and therapy of human NDRG1 associated CMT disease. Selection against this mutation can now be used to eliminate polyneuropathy from Greyhound show dogs.

  • 38. Drögemüller, Cord
    et al.
    Karlsson, Elinor K
    Hytönen, Marjo K
    Perloski, Michele
    Dolf, Gaudenz
    Sainio, Kirsi
    Lohi, Hannes
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leeb, Tosso
    A mutation in hairless dogs implicates FOXI3 in ectodermal development2008In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 321, no 5895, p. 1462-Article in journal (Refereed)
    Abstract [en]

    Mexican and Peruvian hairless dogs and Chinese crested dogs are characterized by missing hair and teeth, a phenotype termed canine ectodermal dysplasia (CED). CED is inherited as a monogenic autosomal semidominant trait. With genomewide association analysis we mapped the CED mutation to a 102-kilo-base pair interval on chromosome 17. The associated interval contains a previously uncharacterized member of the forkhead box transcription factor family (FOXI3), which is specifically expressed in developing hair and teeth. Mutation analysis revealed a frameshift mutation within the FOXI3 coding sequence in hairless dogs. Thus, we have identified FOXI3 as a regulator of ectodermal development.

  • 39. Duke, S E
    et al.
    Samollow, P B
    Mauceli, E
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Breen, M
    Integrated cytogenetic BAC map of the genome of the gray, short-tailed opossum, Monodelphis domestica2007In: Chromosome Research, ISSN 0967-3849, E-ISSN 1573-6849, Vol. 15, no 3, p. 361-370Article in journal (Refereed)
    Abstract [en]

    The generation of high-quality genome assemblies for numerous species is advancing at a rapid pace. As the number of genome assemblies increases, so does our ability to investigate genome relationships and their contributions to unraveling complex biological, evolutionary, and biomedical processes. A key process in the generation of a genome assembly is to determine and verify the precise physical location and order of the large sequence blocks (scaffolds) that result from the assembly. For organisms of relatively recent common ancestry this process may be achieved largely through comparative sequence alignment. However, as the evolutionary distance between species lengthens, the use of comparative sequence alignment becomes increasingly less reliable. Simultaneous cytogenetic mapping, using multicolor fluorescence in-situ hybridization (FISH) analysis, offers an alternative means to define the cytogenetic location and relative order of DNA sequences, thereby anchoring the genome sequence to the karyotype. In this article we report the molecular cytogenetic locations of 415 bacterial artificial chromosome (BAC) clones that served to anchor sequence scaffolds of the gray, short-tailed opossum (Monodelphis domestica) to its karyotype, which enabled accurate integration of these regions into the genome assembly.

  • 40. Eckalbar, Walter L.
    et al.
    Hutchins, Elizabeth D.
    Markov, Glenn J.
    Allen, April N.
    Corneveaux, Jason 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.
    Di Palma, Federica
    Alfoeldi, Jessica
    Huentelman, Matthew J.
    Kusumi, Kenro
    Genome reannotation of the lizard Anolis carolinensis based on 14 adult and embryonic deep transcriptomes2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 49-Article in journal (Refereed)
    Abstract [en]

    Background: The green anole lizard, Anolis carolinensis, is a key species for both laboratory and field-based studies of evolutionary genetics, development, neurobiology, physiology, behavior, and ecology. As the first non-avian reptilian genome sequenced, A. carolinesis is also a prime reptilian model for comparison with other vertebrate genomes. The public databases of Ensembl and NCBI have provided a first generation gene annotation of the anole genome that relies primarily on sequence conservation with related species. A second generation annotation based on tissue-specific transcriptomes would provide a valuable resource for molecular studies. Results: Here we provide an annotation of the A. carolinensis genome based on de novo assembly of deep transcriptomes of 14 adult and embryonic tissues. This revised annotation describes 59,373 transcripts, compared to 16,533 and 18,939 currently for Ensembl and NCBI, and 22,962 predicted protein-coding genes. A key improvement in this revised annotation is coverage of untranslated region (UTR) sequences, with 79% and 59% of transcripts containing 5' and 3' UTRs, respectively. Gaps in genome sequence from the current A. carolinensis build (Anocar2.0) are highlighted by our identification of 16,542 unmapped transcripts, representing 6,695 orthologues, with less than 70% genomic coverage. Conclusions: Incorporation of tissue-specific transcriptome sequence into the A. carolinensis genome annotation has markedly improved its utility for comparative and functional studies. Increased UTR coverage allows for more accurate predicted protein sequence and regulatory analysis. This revised annotation also provides an atlas of gene expression specific to adult and embryonic tissues.

  • 41.
    Elvers, Ingegerd
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst, Cambridge, MA 02142 USA..
    Turner-Maier, Jason
    Broad Inst, Cambridge, MA 02142 USA..
    Swofford, Ross
    Broad Inst, Cambridge, MA 02142 USA..
    Koltookian, Michele
    Broad Inst, Cambridge, MA 02142 USA..
    Johnson, Jeremy
    Broad Inst, Cambridge, MA 02142 USA..
    Stewart, Chip
    Broad Inst, Cambridge, MA 02142 USA..
    Zhang, Cheng-Zhong
    Broad Inst, Cambridge, MA 02142 USA.;Dana Farber Canc Inst, Boston, MA 02215 USA..
    Schumacher, Steven E.
    Broad Inst, Cambridge, MA 02142 USA.;Dana Farber Canc Inst, Boston, MA 02215 USA..
    Beroukhim, Rameen
    Broad Inst, Cambridge, MA 02142 USA.;Dana Farber Canc Inst, Boston, MA 02215 USA..
    Rosenberg, Mara
    Broad Inst, Cambridge, MA 02142 USA..
    Thomas, Rachael
    N Carolina State Univ, Raleigh, NC 27695 USA..
    Mauceli, Evan
    Broad Inst, Cambridge, MA 02142 USA..
    Getz, Gad
    Broad Inst, Cambridge, MA 02142 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Di Palma, Federica
    Broad Inst, Cambridge, MA 02142 USA..
    Modiano, Jaime F.
    Univ Minnesota, Coll Vet Med, Anim Canc Care & Res Program, Minneapolis, MN 55455 USA.;Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA..
    Breen, Matthew
    N Carolina State Univ, Raleigh, NC 27695 USA.;Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst, Cambridge, MA 02142 USA..
    Alfoeldi, Jessica
    Broad Inst, Cambridge, MA 02142 USA..
    Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background2015In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 25, no 11, p. 1634-1645Article in journal (Refereed)
    Abstract [en]

    Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B- and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B- and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options.

  • 42.
    Eriksson, D.
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Nordin, Jessika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Mathioudaki, Argyri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, G. N.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zetterqvist, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Farias, F. 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.
    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.
    Ahlgren, Kerstin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, G.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, S. R.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Soderkvist, P.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    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.
    Hulting, A. -L
    Wahlberg, J.
    Linkoping Univ, Dept Endocrinol, Dept Med & Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden..
    Ekwall, O.
    Univ Gothenburg, Sahlgrenska Acad, Dept Pediat, Inst Clin Sci, Gothenburg, Sweden.;Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Dahlqvist, P.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    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.
    Bensing, S.
    Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, 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. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Pielberg, Gerli R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 595-608Article in journal (Refereed)
    Abstract [en]

    BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

  • 43.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Skov, Jakob
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mathioudaki, Argyri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordin, Jessika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Andersson, Goran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, Solbritt Rantapaa
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Soderkvist, Peter
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    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.
    Hulting, Anna-Lena
    Wahlberg, Jeanette
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Linkoping Univ, Dept Endocrinol, Linkoping, Sweden;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden.
    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.
    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.
    Bensing, Sophie
    Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    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.
    Kampe, Olle
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;KG Jebsen Ctr Autoimmune Dis, Bergen, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed)
    Abstract [en]

    Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

  • 44.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Dalin, Frida
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Eriksson, Gabriel Nordling
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Landegren, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Wahlberg, Jeanette
    Linköping Univ, Dept Endocrinol, Linköping, Sweden; Linköping Univ, Dept Med & Hlth Sci, Linköping, Sweden; Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Dept Pediat, Inst Clin Sci, Sahlgrenska Acad, Gothenburg, Sweden; Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.
    Winqvist, Ola
    Karolinska Inst, Dept Med Solna, Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hulting, Anna-Lena
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alimohammad, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Husebye, Eystein S
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Univ Bergen, Dept Clin Sci, Bergen, Norway; Univ Bergen, Dept Med, Bergen, Norway; KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.
    Knappskog, Per Morten
    Univ Bergen, Dept Clin Sci, Bergen, Norway; Haukeland Hosp, Ctr Med Genet & Mol Med, Bergen, Norway.
    Pielberg, Gerli Rosengren
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bensing, Sophie
    Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden; Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden .
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden; KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.
    Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS12018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 1, p. 179-186Article in journal (Refereed)
    Abstract [en]

    Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

    Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.

    Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.

    Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.

    Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

  • 45. Fairfield, Heather
    et al.
    Gilbert, Griffith J
    Barter, Mary
    Corrigan, Rebecca R
    Curtain, Michelle
    Ding, Yueming
    D'Ascenzo, Mark
    Gerhardt, Daniel J
    He, Chao
    Huang, Wenhui
    Richmond, Todd
    Rowe, Lucy
    Probst, Frank J
    Bergström, David E
    Murray, Stephen A
    Bult, Carol
    Richardson, Joel
    Kile, Benjamin T
    Gut, Ivo
    Hager, Jorg
    Sigurdsson, Snaevar
    Mauceli, Evan
    Di Palma, Federica
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cunningham, Michael L
    Cox, Timothy C
    Justice, Monica J
    Spector, Mona S
    Lowe, Scott W
    Albert, Thomas
    Donahue, Leah Rae
    Jeddeloh, Jeffrey
    Shendure, Jay
    Reinholdt, Laura G
    Mutation discovery in mice by whole exome sequencing2011In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, no 9, p. R86-Article in journal (Refereed)
    Abstract [en]

    We report the development and optimization of reagents for in-solution, hybridization-based capture of the mouse exome. By validating this approach in a multiple inbred strains and in novel mutant strains, we show that whole exome sequencing is a robust approach for discovery of putative mutations, irrespective of strain background. We found strong candidate mutations for the majority of mutant exomes sequenced, including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis.

  • 46. Fall, T
    et al.
    Hedhammar, A
    Wallberg, A
    Fall, N
    Ahlgren, Kerstin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hamlin, H. H.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, G.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Diabetes Mellitus in Elkhounds Is Associated with Diestrus and Pregnancy2010In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 24, no 6, p. 1322-1328Article in journal (Refereed)
    Abstract [en]

    Background: Female Elkhounds are shown to be at increased risk for diabetes mellitus, and occurrence of diabetes during pregnancy has been described in several cases. Hypothesis: Onset of diabetes mellitus in Elkhounds is associated with diestrus. Animals: Sixty-three Elkhounds with diabetes mellitus and 26 healthy controls. Methods: Medical records from 63 Elkhounds with diabetes were reviewed and owners were contacted for follow-up information. Blood samples from the day of diagnosis were available for 26 dogs. Glucose, fructosamine, C-peptide, growth hormone (GH), insulin-like growth factor-1, progesterone, and glutamate decarboxylase isoform 65-autoantibodies were analyzed and compared with 26 healthy dogs. Logistic models were used to evaluate the association of clinical variables with the probability of diabetes and with permanent diabetes mellitus after ovariohysterectomy (OHE). Results: All dogs in the study were intact females and 7 dogs (11%) were pregnant at diagnosis. The 1st clinical signs of diabetes mellitus occurred at a median of 30 days (interquartile range [IQR], 3-45) after estrus, and diagnosis was made at a median of 46 days (IQR, 27-62) after estrus. Diabetes was associated with higher concentrations of GH and lower concentrations of progesterone compared with controls matched for time after estrus. Forty-six percent of dogs that underwent OHE recovered from diabetes with a lower probability of remission in dogs with higher glucose concentrations (odds ratio [OR], 1.2; P = .03) at diagnosis and longer time (weeks) from diagnosis to surgery (OR, 1.5; P = .05). Conclusions: Diabetes mellitus in Elkhounds develops mainly during diestrus and pregnancy. Immediate OHE improves the prognosis for remission of diabetes.

  • 47. Farias, Fabiana H. G.
    et al.
    Zeng, Rong
    Johnson, Gary S.
    Wininger, Fred A.
    Taylor, Jeremy F.
    Schnabel, Robert D.
    McKay, Stephanie D.
    Sanders, Douglas N.
    Lohi, Hannes
    Seppälä, Eija H.
    Wade, Claire M.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    O'Brien, Dennis P.
    Katz, Martin L.
    A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers2011In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 42, no 3, p. 468-474Article in journal (Refereed)
    Abstract [en]

    A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide association study restricted this NCL locus to a 1.3 Mb region of canine chromosome 2 which contains canine ATP13A2. NCL-affected dogs were homozygous for a single-base deletion in ATP13A2, predicted to produce a frameshift and premature termination codon. Homozygous truncating mutations in human ATP13A2 have been shown by others to cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease. These findings suggest that KRS is also an NCL, although analysis of KRS brain tissue will be needed to confirm this prediction. Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with ATP13A2 mutations: however, other clinical features differ between the species. For example, Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. To see if ATP13A2 mutations could be responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced ATP13A2 from 28 Kufs disease patients. None of these patients had ATP13A2 sequence variants likely to be causal for their disease, suggesting that mutations in this gene are not common causes of Kufs disease.

  • 48.
    Farias, Fabiana
    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.
    Wilbe, Maria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Dahlqvist, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leonard, Dag
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kozyrev, Sergey
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eloranta, Maija-Leena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    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.
    High-Throughput Sequencing of 219 Candidate Genes for Identification of SLE-Associated Risk Variants2014In: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, no S10, p. S1170-S1170, article id 2673Article in journal (Other academic)
  • 49.
    Foote, Andrew D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Liu, Yue
    Thomas, Gregg W. C.
    Vinar, Tomas
    Alfoeldi, Jessica
    Deng, Jixin
    Dugan, Shannon
    van Elk, Cornelis E.
    Hunter, Margaret E.
    Joshi, Vandita
    Khan, Ziad
    Kovar, Christie
    Lee, Sandra L.
    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.
    Mancia, Annalaura
    Nielsen, Rasmus
    Qin, Xiang
    Qu, Jiaxin
    Raney, Brian J.
    Vijay, Nagarjun
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Wolf, Jochen B. W.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Hahn, Matthew W.
    Muzny, Donna M.
    Worley, Kim C.
    Gilbert, M. Thomas P.
    Gibbs, Richard A.
    Convergent evolution of the genomes of marine mammals2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 3, p. 272-275Article in journal (Refereed)
    Abstract [en]

    Marine mammals from different mammalian orders share several phenotypic traits adapted to the aquatic environment and therefore represent a classic example of convergent evolution. To investigate convergent evolution at the genomic level, we sequenced and performed de novo assembly of the genomes of three species of marine mammals (the killer whale, walrus and manatee) from three mammalian orders that share independently evolved phenotypic adaptations to a marine existence. Our comparative genomic analyses found that convergent amino acid substitutions were widespread throughout the genome and that a subset of these substitutions were in genes evolving under positive selection and putatively associated with a marine phenotype. However, we found higher levels of convergent amino acid substitutions in a control set of terrestrial sister taxa to the marine mammals. Our results suggest that, whereas convergent molecular evolution is relatively common, adaptive molecular convergence linked to phenotypic convergence is comparatively rare.

  • 50. Forsberg, Simon K. G.
    et al.
    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.
    Ljungvall, Ingrid
    Merveille, Anne-Christine
    Gouni, Vassiliki
    Wiberg, Maria
    Willesen, Jakob Lundgren
    Hanas, Sofia
    Lequarre, Anne-Sophie
    Sorensen, Louise Mejer
    Tiret, Laurent
    McEntee, Kathleen
    Seppala, Eija
    Koch, Jorgen
    Battaille, Geraldine
    Lohi, Hannes
    Fredholm, Merete
    Chetboul, Valerie
    Haggstrom, Jens
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, 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.
    Hoglund, Katja
    The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0123173Article in journal (Refereed)
    Abstract [en]

    Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (rho(corrected) approximate to 1:68 x 10(-6)) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (rho = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

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