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Rabbit Genome Analysis Reveals a Polygenic Basis for Phenotypic Change During Domestication

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Rabbit Genome Analysis Reveals a Polygenic Basis for Phenotypic Change During Domestication Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Carneiro, M., C.-J. Rubin, F. Di Palma, F. W. Albert, J. Alfoldi, A. M. Barrio, G. Pielberg, et al. “Rabbit Genome Analysis Reveals a Polygenic Basis for Phenotypic Change During Domestication.” Science 345, no. 6200 (August 28, 2014): 1074–1079. As Published http://dx.doi.org/10.1126/science.1253714 Publisher American Association for the Advancement of Science (AAAS) Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/98345 Terms of Use Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication Miguel Carneiro1,*, Carl-Johan Rubin2,*, Federica Di Palma3,4,*, Frank W. Albert5,24, Jessica Alföldi3, Alvaro Martinez Barrio2, Gerli Pielberg2, Nima Rafati2, Shumaila Sayyab6, Jason Turner-Maier3, Shady Younis2,7, Sandra Afonso1, Bronwen Aken8,18, Joel M. Alves1,9, Daniel Barrell8,18, Gerard Bolet10, Samuel Boucher11, Hernán A. Burbano5,25, Rita Campos1, Jean L. Chang3, Veronique Duranthon12, Luca Fontanesi13, Hervé Garreau10, David Heiman3, Jeremy Johnson3, Rose G. Mage14, Ze Peng15, Guillaume Queney16, Claire Rogel-Gaillard17, Magali Ruffier8,18, Steve Searle8, Rafael Villafuerte19, Anqi Xiong20, Sarah Young3, Karin Forsberg-Nilsson20, Jeffrey M. Good5,21, Eric S. Lander3, Nuno Ferrand1,22,*, Kerstin Lindblad-Toh2,3,*, Leif Andersson2,6,23,* 1CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal. 2Science of Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. 3Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. 4Vertebrate and Health Genomics, The Genome Analysis Center, Norwich, UK. 5Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. 6Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden. 7Department of Animal Production, Ain Shams University, Shoubra El-Kheima, Cairo, Egypt. 8Wellcome Trust Sanger Institute, Hinxton, UK. 9Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK. 1 10INRA, UMR1388 Génétique, Physiologie et Systèmes d’Elevage, F-31326 Castanet-Tolosan, France. 11Labovet Conseil, Les Herbiers Cedex, France. 12INRA, UMR1198 Biologie du Développement et Reproduction, F-78350 Jouy-en-Josas, France. 13Department of Agricultural and Food Sciences, Division of Animal Sciences, University of Bologna, 40127 Bologna Italy. 14Laboratory of Immunology, NIAID, NIH, Bethesda, MD, 20892, USA. 15DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, 2800 Mitchell Drive, Walnut Creek, CA 94598. 16ANTAGENE, Animal Genomics Laboratory, Lyon, France. 17INRA, UMR1313 Génétique Animale et Biologie Intégrative, F- 78350, Jouy-en-Josas, France. 18European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. 19Instituto de Estudios Sociales Avanzados, (IESA-CSIC) Campo Santo de los Mártires 7, Córdoba Spain. 20Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 21Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA. 22Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s⁄n. 4169-007 Porto, Portugal 23Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, USA. *contributed equally within group Correspondence should be addressed to: [email protected] and [email protected]. Present addresses: 24Department of Human Genetics, University of California, Los Angeles, Gonda Center, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA. 2 25Department of Molecular Biology, Max Planck Institute for Developmental Biology, Tübingen, Germany. 3 Abstract The genetic changes underlying the initial steps of animal domestication are still poorly understood. We generated a high-quality reference genome for rabbit and compared it to resequencing data from populations of wild and domestic rabbits. We identified over 100 selective sweeps specific to domestic rabbits, but only a relatively small number of fixed (or nearly fixed) SNPs for derived alleles. SNPs with marked allele frequency differences between wild and domestic rabbits were enriched for conserved non-coding sites. Enrichment analyses suggest that genes affecting brain and neuronal development have often been targeted during domestication. We propose that due to 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’. Introduction Domestication of animals - the evolution of wild species into tame forms – has resulted in striking changes in behavior, morphology, physiology and reproduction (1). However, the genetic underpinnings of the initial steps of animal domestication are poorly understood but likely involved changes in behavior that allowed the animals to survive and reproduce under conditions that might be too stressful for wild animals. Given the differences in behavior between wild and domesticated animals, we investigated to what extent this process involved fixation of new mutations with large phenotypic effects as opposed to selection on standing variation. Such studies are hampered in most domestic animals due to ancient domestication events, extinct wild ancestors, or geographically widespread wild ancestors. Rabbit domestication was initiated in monasteries in Southern France as recent as ~1,400 years ago (2). At this time, wild rabbits were mostly restricted to the Iberian Peninsula, where two subspecies occurred (Oryctolagus cuniculus cuniculus and O. c. algirus), and to France, colonized by O. c. cuniculus (Fig. 1). Additionally, the area of origin of domestic rabbit is still populated with wild rabbits related to 4 the ancestors of the domestic rabbit (3). This recent and well-defined origin provides a major advantage for inferring genetic changes underlying domestication. A female rabbit genome was Sanger sequenced and assembled (4). The draft OryCun2.0 assembly size is 2.66 Gb with a contig N50 size of 64.7 kb and a scaffold N50 size of 35.9 Mb (Tables S1-S2). The genome assembly was annotated using the Ensembl gene annotation pipeline (Ensembl release 73, Sept. 2013) and with both rabbit RNA-seq data and the annotation of human orthologs (4) (Table S3). Our analysis of rabbit domestication used Ensembl annotations as well as a custom pipeline for annotation of UTRs (168,286 unique features), non-coding RNA (n=9,666) and non-coding conserved elements (2,518,476 unique features). To identify genomic regions under selection during domestication we performed whole genome resequencing (10X coverage) of pooled samples (Table S4) of six different breeds of domestic rabbits (Fig. 1A), three pools of wild rabbits from Southern France, and 11 pools of wild rabbits from the Iberian Peninsula, representing both subspecies (Fig. 1B). We also sequenced a close relative, snowshoe hare (Lepus americanus), to deduce the ancestral state at polymorphic sites. Short sequence reads were aligned to our assembly; SNP calling resulted in the identification of 50 million high quality SNPs and 5.6 million insertion/deletion polymorphisms after filtering (Table S5). The numbers of SNPs at non-coding conserved sites and in coding sequences were 719,911and 154,489, respectively. The per site nucleotide diversity (π) within populations of wild rabbits was in the range of 0.6-0.9% (Fig. 1C). Thus, rabbit is one of the most polymorphic mammals sequenced so far, presumably due to a larger long-term effective population size relative to other sequenced mammals (5). Identity scores confirm that the domestic rabbit is most closely related to wild rabbits from Southern France (Fig. S1A), and we inferred a strong correlation (r = 0.94) in allele frequencies at most loci between these groups (Fig. S1B). The average nucleotide diversity of each sequenced population is consistent with a bottleneck and reduction in genetic diversity when rabbits from the Iberian Peninsula colonized Southern France and a second bottleneck during domestication (3)(Figs. 1B,C). 5 Selective sweeps occur when beneficial genetic variants increase in frequency due to positive selection together with linked neutral sequence variants (6). This results in genomic islands of reduced heterozygosity, and increased differentiation between populations around the selected site. We compared genetic diversity between domestic rabbits as one group to wild rabbits representing 14 different locations in France and the Iberian Peninsula. We calculated FST values between wild and domestic rabbits, and average pooled heterozygosity (H) in domestic rabbits, in 50 kb sliding windows across the genome (hereafter referred to as FST-H outlier approach). We identified 78 outliers with FST>0.35 and H<0.05 (Figs. 2A, S2, Database S1). We also
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