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  • 1.
    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.

  • 2.
    Axelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Quantification of Adaptive Evolution of Genes Expressed in Avian Brain and the Population Size Effect on the Efficacy of Selection2009In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 26, no 5, p. 1073-1079Article in journal (Refereed)
    Abstract [en]

    Whether protein evolution is mainly due to fixation of beneficial alleles by positive selection or to random genetic drift has remained a contentious issue over the years. Here, we use two genomewide polymorphism data sets collected from chicken populations, together with divergence data from >5,000 chicken-zebra finch gene orthologs expressed in brain, to assess the amount of adaptive evolution in protein-coding genes of birds. First, we show that estimates of the fixation index (FI, the ratio of fixed nonsynonymous-to-synonymous changes over the ratio of the corresponding polymorphisms) are highly dependent on the character of the underlying data sets. Second, by using polymorphism data from high-frequency alleles, to avoid the confounding effect of slightly deleterious mutations segregating at low frequency, we estimate that about 20% of amino acid changes have been brought to fixation through positive selection during avian evolution. This estimate is intermediate to that obtained in humans (lower) and flies as well as bacteria (higher), and is consistent with population genetics theory that stipulates a positive relationship between the efficiency of selection and the effective population size. Further, by comparing the FIs for common and all alleles, we estimate that approximate to 20% of nonsynonymous variation segregating in chicken populations represent slightly deleterious mutations, which is less than in Drosophila. Overall, these results highlight the link between the effective population size and positive as well as negative selection.

  • 3.
    Axelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Hultin-Rosenberg, Lina
    Brandström, Mikael
    Zwalen, Martin
    Clayton, David F.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Natural selection in protein-coding genes expressed in avian brain2008In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 17, no 12, p. 3008-3017Article in journal (Refereed)
    Abstract [en]

    The evolution of birds from theropod dinosaurs took place approximately 150 million years ago, and was associated with a number of specific adaptations that are still evident among extant birds, including feathers, song and extravagant secondary sexual characteristics. Knowledge about the molecular evolutionary background to such adaptations is lacking. Here, we analyse the evolution of > 5000 protein-coding gene sequences expressed in zebra finch brain by comparison to orthologous sequences in chicken. Mean d(N)/d(S) is 0.085 and genes with their maximal expression in the eye and central nervous system have the lowest mean d(N)/d(S) value, while those expressed in digestive and reproductive tissues exhibit the highest. We find that fast-evolving genes (those which have higher than expected rate of nonsynonymous substitution, indicative of adaptive evolution) are enriched for biological functions such as fertilization, muscle contraction, defence response, response to stress, wounding and endogenous stimulus, and cell death. After alignment to mammalian orthologues, we identify a catalogue of 228 genes that show a significantly higher rate of protein evolution in the two bird lineages than in mammals. These accelerated bird genes, representing candidates for avian-specific adaptations, include genes implicated in vocal learning and other cognitive processes. Moreover, colouration genes evolve faster in birds than in mammals, which may have been driven by sexual selection for extravagant plumage characteristics.

  • 4.
    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.

  • 5.
    Axelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Smith, Nick G.C.
    Sundström, Hannah
    Berlin, Sofia
    Ellegren, Hans
    Male-biased mutation rate and divergence in autosomal, Z-linked and W-linked introns of chicken and turkey2004In: Mol. Biol. Evol., ISSN 0737-4038, Vol. 21, no 8, p. 1538−1547-Article in journal (Refereed)
  • 6. Axelsson, Erik
    et al.
    Webster, Matthew
    Base Composition Patterns2011In: Encyclopedia of Life Sciences, ISSN 1561592617 9781561592616Article, book review (Refereed)
  • 7.
    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.

  • 8.
    Axelsson, Erik
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Webster, Matthew T
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Smith, Nick G C
    Burt, David W
    Ellegren, Hans
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Comparison of the chicken and turkey genomes reveals a higher rate of nucleotide divergence on microchromosomes than macrochromosomes.2005In: Genome Res, ISSN 1088-9051, Vol. 15, no 1, p. 120-5Article in journal (Refereed)
    Abstract [en]

    A distinctive feature of the avian genome is the large heterogeneity in the size of chromosomes, which are usually classified into a small number of macrochromosomes and numerous microchromosomes. These chromosome classes show characteristic differences in a number of interrelated features that could potentially affect the rate of sequence evolution, such as GC content, gene density, and recombination rate. We studied the effects of these factors by analyzing patterns of nucleotide substitution in two sets of chicken-turkey sequence alignments. First, in a set of 67 orthologous introns, divergence was significantly higher in microchromosomes (chromosomes 11-38; 11.7% divergence) than in both macrochromosomes (chromosomes 1-5; 9.9% divergence; P = 0.016) and intermediate-sized chromosomes (chromosomes 6-10; 9.5% divergence; P = 0.026). At least part of this difference was due to the higher incidence of CpG sites on microchromosomes. Second, using 155 orthologous coding sequences we noted a similar pattern, in which synonymous substitution rates on microchromosomes (13.1%) were significantly higher than were rates on macrochromosomes (10.3%; P = 0.024). Broadly assuming neutrality of introns and synonymous sites, or constraints on such sequences do not differ between chromosomal classes, these observations imply that microchromosomal genes are exposed to more germ line mutations than those on other chromosomes. We also find that dN/dS ratios for genes located on microchromosomes (average, 0.094) are significantly lower than those of macrochromosomes (average, 0.185; P = 0.025), suggesting that the proteins of genes on microchromosomes are under greater evolutionary constraint.

  • 9.
    Axelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Webster, Matthew T.
    Smith, Nick G.C.
    Burt, David W.
    Ellegren, Hans
    Comparison of the chicken and turkey genomes reveals a higher rate of nucleotide divergence on microchromosmes then on macrochromosomes2005In: Genome Res., ISSN 1088-9051, Vol. 15, p. 120-125Article in journal (Refereed)
  • 10. Axelsson, Erik
    et al.
    Willerslev, Eske
    Gilbert, M Thomas P
    Nielsen, Rasmus
    The effect of ancient DNA damage on inferences of demographic histories.2008In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 25, no 10, p. 2181-7Article in journal (Refereed)
    Abstract [en]

    The field of ancient DNA (aDNA) is casting new light on many evolutionary questions. However, problems associated with the postmortem instability of DNA may complicate the interpretation of aDNA data. For example, in population genetic studies, the inclusion of damaged DNA may inflate estimates of diversity. In this paper, we examine the effect of DNA damage on population genetic estimates of ancestral population size. We simulate data using standard coalescent simulations that include postmortem damage and show that estimates of effective population sizes are inflated around, or right after, the sampling time of the ancestral DNA sequences. This bias leads to estimates of increasing, and then decreasing, population sizes, as observed in several recently published studies. We reanalyze a recently published data set of DNA sequences from the Bison (Bison bison/Bison priscus) and show that the signal for a change in effective population size in this data set vanishes once the effects of putative damage are removed. Our results suggest that population genetic analyses of aDNA sequences, which do not accurately account for damage, should be interpreted with great caution.

  • 11.
    Berlin, Sofia
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Evolutionsbiologi.
    Brandström, Mikael
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Evolutionsbiologi.
    Backström, Niclas
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Evolutionsbiologi.
    Axelsson, Erik
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Evolutionsbiologi.
    Smith, Nick G C
    Ellegren, Hans
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Evolutionsbiologi.
    Substitution rate heterogeneity and the male mutation bias.2006In: Journal of Molecular Evolution, ISSN 0022-2844, Vol. 62, no 2, p. 226-33Article in journal (Refereed)
  • 12. Campos, Paula F
    et al.
    Willerslev, Eske
    Sher, Andrei
    Orlando, Ludovic
    Axelsson, Erik
    Tikhonov, Alexei
    Aaris-Sørensen, Kim
    Greenwood, Alex D
    Kahlke, Ralf-Dietrich
    Kosintsev, Pavel
    Krakhmalnaya, Tatiana
    Kuznetsova, Tatyana
    Lemey, Philippe
    MacPhee, Ross
    Norris, Christopher A
    Shepherd, Kieran
    Suchard, Marc A
    Zazula, Grant D
    Shapiro, Beth
    Gilbert, M Thomas P
    Ancient DNA analyses exclude humans as the driving force behind late Pleistocene musk ox (Ovibos moschatus) population dynamics2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 12, p. 5675-5680Article in journal (Refereed)
    Abstract [en]

    The causes of the late Pleistocene megafaunal extinctions are poorly understood. Different lines of evidence point to climate change, the arrival of humans, or a combination of these events as the trigger. Although many species went extinct, others, such as caribou and bison, survived to the present. The musk ox has an intermediate story: relatively abundant during the Pleistocene, it is now restricted to Greenland and the Arctic Archipelago. In this study, we use ancient DNA sequences, temporally unbiased summary statistics, and Bayesian analytical techniques to infer musk ox population dynamics throughout the late Pleistocene and Holocene. Our results reveal that musk ox genetic diversity was much higher during the Pleistocene than at present, and has undergone several expansions and contractions over the past 60,000 years. Northeast Siberia was of key importance, as it was the geographic origin of all samples studied and held a large diverse population until local extinction at approximately 45,000 radiocarbon years before present ((14)C YBP). Subsequently, musk ox genetic diversity reincreased at ca. 30,000 (14)C YBP, recontracted at ca. 18,000 (14)C YBP, and finally recovered in the middle Holocene. The arrival of humans into relevant areas of the musk ox range did not affect their mitochondrial diversity, and both musk ox and humans expanded into Greenland concomitantly. Thus, their population dynamics are better explained by a nonanthropogenic cause (for example, environmental change), a hypothesis supported by historic observations on the sensitivity of the species to both climatic warming and fluctuations.

  • 13. Gilbert, M. Thomas P.
    et al.
    Kivisild, Toomas
    Gronnow, Bjarne
    Andersen, Pernille K.
    Metspalu, Ene
    Reidla, Maere
    Tamm, Erika
    Axelsson, Erik
    Götherström, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Campos, Paula F.
    Rasmussen, Morten
    Metspalu, Mait
    Higham, Thomas F. G.
    Schwenninger, Jean-Luc
    Nathan, Roger
    De Hoog, Cees-Jan
    Koch, Anders
    Möller, Lone Nukaaraq
    Andreasen, Claus
    Meldgaard, Morten
    Villems, Richard
    Bendixen, Christian
    Willerslev, Eske
    Paleo-Eskimo mtDNA genome reveals matrilineal discontinuity in Greenland2008In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 320, no 5884, p. 1787-1789Article in journal (Refereed)
    Abstract [en]

    The Paleo- Eskimo Saqqaq and Independence I cultures, documented from archaeological remains in Northern Canada and Greenland, represent the earliest human expansion into the New World's northern extremes. However, their origin and genetic relationship to later cultures are unknown. We sequenced a mitochondrial genome from a Paleo- Eskimo human by using 3400- to 4500- year- old frozen hair excavated from an early Greenlandic Saqqaq settlement. The sample is distinct from modern Native Americans and Neo- Eskimos, falling within haplogroup D2a1, a group previously observed among modern Aleuts and Siberian Sireniki Yuit. This result suggests that the earliest migrants into the New World's northern extremes derived from populations in the Bering Sea area and were not directly related to Native Americans or the later Neo- Eskimos that replaced them.

  • 14. Hillier, Ladeana W
    et al.
    Miller, Webb
    Birney, Ewan
    Warren, Wesley
    Hardison, Ross C
    Ponting, Chris P
    Bork, Peer
    Burt, David W
    Groenen, Martien A M
    Delany, Mary E
    Dodgson, Jerry B
    Chinwalla, Asif T
    Cliften, Paul F
    Clifton, Sandra W
    Delehaunty, Kimberly D
    Fronick, Catrina
    Fulton, Robert S
    Graves, Tina A
    Kremitzki, Colin
    Layman, Dan
    Magrini, Vincent
    McPherson, John D
    Miner, Tracie L
    Minx, Patrick
    Nash, William E
    Nhan, Michael N
    Nelson, Joanne O
    Oddy, Lachlan G
    Pohl, Craig S
    Randall-Maher, Jennifer
    Smith, Scott M
    Wallis, John W
    Yang, Shiaw-Pyng
    Romanov, Michael N
    Rondelli, Catherine M
    Paton, Bob
    Smith, Jacqueline
    Morrice, David
    Daniels, Laura
    Tempest, Helen G
    Robertson, Lindsay
    Masabanda, Julio S
    Griffin, Darren K
    Vignal, Alain
    Fillon, Valerie
    Jacobbson, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Crooijmans, Richard P M
    Aerts, Jan
    van der Poel, Jan J
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Caldwell, Randolph B
    Hubbard, Simon J
    Grafham, Darren V
    Kierzek, Andrzej M
    McLaren, Stuart R
    Overton, Ian M
    Arakawa, Hiroshi
    Beattie, Kevin J
    Bezzubov, Yuri
    Boardman, Paul E
    Bonfield, James K
    Croning, Michael D R
    Davies, Robert M
    Francis, Matthew D
    Humphray, Sean J
    Scott, Carol E
    Taylor, Ruth G
    Tickle, Cheryll
    Brown, William R A
    Rogers, Jane
    Buerstedde, Jean-Marie
    Wilson, Stuart A
    Stubbs, Lisa
    Ovcharenko, Ivan
    Gordon, Laurie
    Lucas, Susan
    Miller, Marcia M
    Inoko, Hidetoshi
    Shiina, Takashi
    Kaufman, Jim
    Salomonsen, Jan
    Skjoedt, Karsten
    Wong, Gane Ka-Shu
    Wang, Jun
    Liu, Bin
    Wang, Jian
    Yu, Jun
    Yang, Huanming
    Nefedov, Mikhail
    Koriabine, Maxim
    Dejong, Pieter J
    Goodstadt, Leo
    Webber, Caleb
    Dickens, Nicholas J
    Letunic, Ivica
    Suyama, Mikita
    Torrents, David
    von Mering, Christian
    Zdobnov, Evgeny M
    Makova, Kateryna
    Nekrutenko, Anton
    Elnitski, Laura
    Eswara, Pallavi
    King, David C
    Yang, Shan
    Tyekucheva, Svitlana
    Radakrishnan, Anusha
    Harris, Robert S
    Chiaromonte, Francesca
    Taylor, James
    He, Jianbin
    Rijnkels, Monique
    Griffiths-Jones, Sam
    Ureta-Vidal, Abel
    Hoffman, Michael M
    Severin, Jessica
    Searle, Stephen M J
    Law, Andy S
    Speed, David
    Waddington, Dave
    Cheng, Ze
    Tuzun, Eray
    Eichler, Evan
    Bao, Zhirong
    Flicek, Paul
    Shteynberg, David D
    Brent, Michael R
    Bye, Jacqueline M
    Huckle, Elizabeth J
    Chatterji, Sourav
    Dewey, Colin
    Pachter, Lior
    Kouranov, Andrei
    Mourelatos, Zissimos
    Hatzigeorgiou, Artemis G
    Paterson, Andrew H
    Ivarie, Robert
    Brandström, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Axelsson, Erik
    Backström, Niclas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Berlin, Sofia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Pourquie, Olivier
    Reymond, Alexandre
    Ucla, Catherine
    Antonarakis, Stylianos E
    Long, Manyuan
    Emerson, J J
    Betrán, Esther
    Dupanloup, Isabelle
    Kaessmann, Henrik
    Hinrichs, Angie S
    Bejerano, Gill
    Furey, Terrence S
    Harte, Rachel A
    Raney, Brian
    Siepel, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kent, W James
    Haussler, David
    Eyras, Eduardo
    Castelo, Robert
    Abril, Josep F
    Castellano, Sergi
    Camara, Francisco
    Parra, Genis
    Guigo, Roderic
    Bourque, Guillaume
    Tesler, Glenn
    Pevzner, Pavel A
    Smit, Arian
    Fulton, Lucinda A
    Mardis, Elaine R
    Wilson, Richard K
    Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution2004In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 432, no 7018, p. 695-716Article in journal (Refereed)
    Abstract [en]

    We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

  • 15.
    Makino, Takashi
    et al.
    Department of Ecology and Evolutionary Biology, Graduate School of Life Sciences, Tohoku University, 6 - 3, Aramaki Aza Aoba, Aoba - ku, Sendai 980 - 8578, Japan.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carneiro, Miguel
    CIBIO/InBIO, Centro de Investiga ção em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485 - 661, Vairão, Portugal.
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew Thomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elevated proportions of deleterious genetic variation in domestic animals and plants2018In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 10, no 1, p. 276-290Article in journal (Refereed)
    Abstract [en]

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

  • 16.
    Mank, Judith E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Fast-X on the Z: Rapid evolution of sex-linked genes in birds2007In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 17, no 5, p. 618-624Article in journal (Refereed)
    Abstract [en]

    Theoretical work predicts natural selection to be more efficient in the fixation of beneficial mutations in X-linked genes than in autosomal genes. This “fast-X effect” should be evident by an increased ratio of nonsynonymous to synonymous substitutions (dN/dS) for sex-linked genes; however, recent studies have produced mixed support for this expectation. To make an independent test of the idea of fast-X evolution, we focused on birds, which have female heterogamety (males ZZ, females ZW), where analogous arguments would predict a fast-Z effect. We aligned 2.8 Mb of orthologous protein-coding sequence of zebra finch and chicken from 172 Z-linked and 4848 autosomal genes. Zebra finch data were in the form of EST sequences from brain cDNA libraries, while chicken genes were from the draft genome sequence. The dN/dS ratio was significantly higher for Z-linked (0.110) than for all autosomal genes (0.085; P = 0.002), as well as for genes linked to similarly sized autosomes 1–10 (0.0948; P = 0.04). This pattern of fast-Z was evident even after we accounted for the nonrandom distribution of male-biased genes. We also examined the nature of standing variation in the chicken protein-coding regions. The ratio of nonsynonymous to synonymous polymorphism (pN/pS) did not differ significantly between genes on the Z chromosome (0.104) and on the autosomes (0.0908). In conjunction, these results suggest that evolution proceeds more quickly on the Z chromosome, where hemizygous exposure of beneficial nondominant mutations increases the rate of fixation.

  • 17.
    Mank, Judith E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Rapid evolution of female-biased, but not male-biased, genes expressed in the avian brain2007In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 24, no 12, p. 2698-2706Article in journal (Refereed)
    Abstract [en]

    The powerful pressures of sexual and natural selection associated with species recognition and reproduction are thought to manifest in a faster rate of evolution in sex-biased genes, an effect that has been documented particularly for male-biased genes expressed in the reproductive tract. However, little is known about the rate of evolution for genes involved in sexually dimorphic behaviors, which often form the neurological basis of intrasexual competition and mate choice. We used microarray data, designed to uncover sex-biased expression patterns in embryonic chicken brain, in conjunction with data on the rate of sequence evolution for >4,000 coding regions aligned between chicken and zebra finch in order to study the role of selection in governing the molecular evolution for sex-biased and unbiased genes. Surprisingly, we found that female-biased genes, defined across a range of cutoff values, show a higher rate of functional evolution than both male-biased and unbiased genes. Autosomal male-biased genes evolve at a similar rate as unbiased genes. Sex-specific genomic properties, such as heterogeneity in genomic distribution and GC content, and codon usage bias for sex-biased classes fail to explain this surprising result, suggesting that selective pressures may be acting differently on the male and female brain.

  • 18.
    Ollivier, Morgane
    et al.
    Ecole Normale Super Lyon, PALGENE, French Natl Platform Paleogenet, CNRS ENS Lyon, 46 Allee Italie, F-69364 Lyon 07, France.;Univ Grenoble Alpes, Lab Ecol Alpine LECA, F-38000 Grenoble, France..
    Tresset, Anne
    CNRS MNHN SUs UMR 7209, Archeozool Archeobot Soc Prat & Environm, 55 Rue Buffon, F-75005 Paris, France..
    Bastian, Fabiola
    Ecole Normale Super Lyon, PALGENE, French Natl Platform Paleogenet, CNRS ENS Lyon, 46 Allee Italie, F-69364 Lyon 07, France.;Univ Grenoble Alpes, Lab Ecol Alpine LECA, F-38000 Grenoble, France..
    Lagoutte, Laetitia
    Univ Rennes 1, CNRS UMR6290, Inst Genet & Dev Rennes, F-35000 Rennes, France..
    Axelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Arendt, Maja Louise
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Balasescu, Adrian
    Natl Museum Romanian Hist, 12 Calea Victoriei, Bucharest 030026, Romania..
    Marshour, Marjan
    CNRS MNHN SUs UMR 7209, Archeozool Archeobot Soc Prat & Environm, 55 Rue Buffon, F-75005 Paris, France..
    Sablin, Mikhail V.
    Russian Acad Sci, Inst Zool, St Petersburg, Russia..
    Salanova, Laure
    CNRS ENS, Aoroc, 45 Rue Ulm, F-75005 Paris, France..
    Vigne, Jean-Denis
    Hitte, Christophe
    Univ Rennes 1, CNRS UMR6290, Inst Genet & Dev Rennes, F-35000 Rennes, France..
    Hanni, Catherine
    Ecole Normale Super Lyon, PALGENE, French Natl Platform Paleogenet, CNRS ENS Lyon, 46 Allee Italie, F-69364 Lyon 07, France.;Univ Grenoble Alpes, Lab Ecol Alpine LECA, F-38000 Grenoble, France..
    Amy2B copy number variation reveals starch diet adaptations in ancient European dogs2016In: Royal Society Open Science, E-ISSN 2054-5703, Vol. 3, no 11, article id 160449Article in journal (Refereed)
    Abstract [en]

    Extant dog and wolf DNA indicates that dog domestication was accompanied by the selection of a series of duplications on the Amy2B gene coding for pancreatic amylase. In this study, we used a palaeogenetic approach to investigate the timing and expansion of the Amy2B gene in the ancient dog populations of Western and Eastern Europe and Southwest Asia. Quantitative polymerase chain reaction was used to estimate the copy numbers of this gene for 13 ancient dog samples, dated to between 15 000 and 4000 years before present (cal. BP). This evidenced an increase of Amy2B copies in ancient dogs from as early as the 7th millennium cal. BP in Southeastern Europe. We found that the gene expansion was not fixed across all dogs within this early farming context, with ancient dogs bearing between 2 and 20 diploid copies of the gene. The results also suggested that selection for the increased Amy2B copy number started 7000 years cal. BP, at the latest. This expansion reflects a local adaptation that allowed dogs to thrive on a starch rich diet, especially within early farming societies, and suggests a biocultural coevolution of dog genes and human culture.

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

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

  • 20.
    Sakthikumar, Sharadha
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst, Cambridge, MA USA.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst, Cambridge, MA USA.
    Kim, Jaegil
    Broad Inst, Cambridge, MA USA.
    Arendt, Maja Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg D, Denmark.
    Thomas, Rachael
    North Carolina State Univ, Comparat Med Inst, Raleigh, NC USA;North Carolina State Univ, Coll Vet Med, Raleigh, NC USA.
    Turner-Maier, Jason
    Broad Inst, Cambridge, MA USA.
    Swofford, Ross
    Broad Inst, Cambridge, MA USA.
    Johnson, Jeremy
    Broad Inst, Cambridge, MA USA.
    Schumacher, Steven E.
    Broad Inst, Cambridge, MA USA.
    Alfoldi, Jessica
    Broad Inst, Cambridge, MA USA.
    Axelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Couto, C. Guillermo
    Ohio State Univ, Ctr Vet Med, Columbus, OH 43210 USA;Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA;Couto Vet Consultants, Hilliard, OH USA.
    Kisseberth, William C.
    Ohio State Univ, Ctr Vet Med, Columbus, OH 43210 USA;Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Getz, Gad
    Harvard Med Sch, Boston, MA USA;Broad Inst, Cambridge, MA USA;Massachusetts Gen Hosp, Boston, MA 02114 USA.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Modiano, Jaime F.
    Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA;Univ Minnesota, Stem Cell Inst, Minneapolis, MN USA;Univ Minnesota, Inst Engn & Med, Minneapolis, MN USA;Univ Minnesota, Ctr Immunol, Minneapolis, MN USA;Coll Vet Med, Dept Vet Clin Sci, St Paul, MN USA;Coll Vet Med, Anim Canc Care & Res Program, St Paul, MN USA.
    Breen, Matthew
    North Carolina State Univ, Comparat Med Inst, Raleigh, NC USA;North Carolina State Univ, Coll Vet Med, Raleigh, NC USA.
    Kierczak, Marcin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg-Nilsson, Karin
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden.
    Marinescu, Voichita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst, Cambridge, MA USA.
    SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13, p. 3421-3431Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 22. Webster, Matthew T.
    et al.
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Ellegren, Hans
    Strong regional biases in nucleotide substitution in the chicken genome2006In: Mol. Biol. Evol., ISSN 0737-4038, Vol. 23, no 6, p. 1203-1216Article in journal (Refereed)
  • 23.
    Webster, Matthew T
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Axelsson, Erik
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Ellegren, Hans
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Strong regional biases in nucleotide substitution in the chicken genome.2006In: Mol Biol Evol, ISSN 0737-4038, Vol. 23, no 6, p. 1203-16Article in journal (Refereed)
    Abstract [en]

    Department of Evolution, Genomics and Systematics, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden. websterm@tcd.ie

    Interspersed repeats have emerged as a valuable tool for studying neutral patterns of molecular evolution. Here we analyze variation in the rate and pattern of nucleotide substitution across all autosomes in the chicken genome by comparing the present-day CR1 repeat sequences with their ancestral copies and reconstructing nucleotide substitutions with a maximum likelihood model. The results shed light on the origin and evolution of large-scale heterogeneity in GC content found in the genomes of birds and mammals--the isochore structure. In contrast to mammals, where GC content is becoming homogenized, heterogeneity in GC content is being reinforced in the chicken genome. This is also supported by patterns of substitution inferred from alignments of introns in chicken, turkey, and quail. Analysis of individual substitution frequencies is consistent with the biased gene conversion (BGC) model of isochore evolution, and it is likely that patterns of evolution in the chicken genome closely resemble those in the ancestral amniote genome, when it is inferred that isochores originated. Microchromosomes and distal regions of macrochromosomes are found to have elevated substitution rates and a more GC-biased pattern of nucleotide substitution. This can largely be accounted for by a strong correlation between GC content and the rate and pattern of substitution. The results suggest that an interaction between increased mutability at CpG motifs and fixation biases due to BGC could explain increased levels of divergence in GC-rich regions.

  • 24.
    Webster, Matthew T.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kamgari, Nona
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Perloski, Michele
    Höppner, Marc P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Axelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hedhammar, Ake
    Pielberg, Gerli
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 474Article in journal (Refereed)
    Abstract [en]

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

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