Understanding the genetic changes underlying phenotypic variation in sheep (Ovis aries) may facilitate our efforts towards further improvement. Here, we report the deep resequencing of 248 sheep including the wild ancestor (O. orientalis), landraces, and improved breeds. We explored the sheep variome and selection signatures. We detected genomic regions harboring genes associated with distinct morphological and agronomic traits, which may be past and potential future targets of domestication, breeding, and selection. Furthermore, we found non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds. We identified PDGFD as a likely causal gene for fat deposition in the tails of sheep through transcriptome, RT-PCR, qPCR, and Western blot analyses. Our results provide insights into the demographic history of sheep and a valuable genomic resource for future genetic studies and improved genome-assisted breeding of sheep and other domestic animals.

Animal Production and Health Laboratory Joint FAO IAEA Division of Nuclear Techniques in Food and Agriculture International Atomic Energy Agency Vienna Austria

CAAS ILRI Joint Laboratory on Livestock and Forage Genetic Resources Institute of Animal Science Chinese Academy of Agricultural Sciences Beijing China

CAS Key Laboratory of Animal Ecology and Conservation Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China

Center for Tropical Livestock Genetics and Health the Roslin Institute University of Edinburgh Easter Bush Midlothian EH25 9RG Scotland UK

College of Animal Science and Technology China Agricultural University Beijing 100193 China

College of Animal Science and Technology Sichuan Agricultural University Chengdu 611130 China

CSIRO Livestock Industries St Lucia Brisbane QLD Australia

Department of Animal Science Faculty of Agriculture Shahid Bahonar University of Kerman Kerman Iran

Department of Biological Sciences University of Alberta Edmonton Alberta T6G 2E9 Canada

Department of Microbial Cellular and Molecular Biology Addis Ababa University Addis Ababa Ethiopia

Faculty of Veterinary Medicine Utrecht University Utrecht the Netherlands

Grass Feeding Livestock Engineering Technology Research Center Ningxia Academy of Agriculture and Forestry Sciences Yinchuan China

Institute of Animal Breeding and Genetics Justus Liebig University Giessen Germany

Institute of Animal Husbandry and Veterinary Medicine Xinjiang Academy of Agricultural and Reclamation Sciences Shihezi 832000 China

Institute of Molecular Genetics of the ASCR v v i Vídeňská 1083 142 20 Prague 4 Czech Republic

Institute of Sheep and Goat Science Nanjing Agricultural University Nanjing 210095 China

LiveGene Program International Livestock Research Institute Addis Ababa Ethiopia

Livestock Genetics Program International Livestock Research Institute Nairobi Kenya

Novogene Bioinformatics Institute Beijing 100083 China

Production Systems Natural Resources Institute Finland FI 31600 Jokioinen Finland

School of Biosciences Cardiff University Cathays Park Cardiff CF10 3AX Wales UK

School of Life Sciences University of Nottingham University Park Nottingham NG7 2RD UK

Shandong Binzhou Academy of Animal Science and Veterinary Medicine Binzhou 256600 China

Small Ruminant Genomics International Centre for Agricultural Research in the Dry Areas Addis Ababa Ethiopia

State Key Laboratory of Sheep Genetic Improvement and Healthy Breeding Xinjiang Academy of Agricultural and Reclamation Sciences Shihezi 832000 China

Sustainable Places Research Institute Cardiff University CF10 3BA Cardiff Wales UK

University of Chinese Academy of Sciences Beijing 100049 China

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Alberto FJ, et al. Convergent genomic signatures of domestication in sheep and goats. Nat. Commun. 2018;9:813. PubMed PMC

Naval-Sanchez M, et al. Sheep genome functional annotation reveals proximal regulatory elements contributed to the evolution of modern breeds. Nat. Commun. 2018;9:859. PubMed PMC

Xu SS, Li MH. Recent advances in understanding genetic variants associated with economically important traits in sheep (Ovis aries) revealed by high-throughput screening technologies. Front. Agr. Sci. Eng. 2017;4:279–288.

Meyer RS, et al. Domestication history and geographical adaptation inferred from a SNP map of African rice. Nat. Genet. 2016;48:1083–1088. PubMed

Zhou Z, et al. Resequencing 302 wild and cultivated accessions identifies genes related to domestication and improvement in soybean. Nat. Biotechnol. 2015;33:408–414. PubMed

Daetwyler HD, et al. Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle. Nat. Genet. 2014;46:858–865. PubMed

Jiang Y, et al. The sheep genome illuminates biology of the rumen and lipid metabolism. Science. 2014;344:1168–1173. PubMed PMC

Varshney RK, et al. Whole-genome resequencing of 292 pigeonpea accessions identifies genomic regions associated with domestication and agronomic traits. Nat. Genet. 2017;49:1082–1088. PubMed

Kijas JW, et al. Genome-wide analysis of the world’s sheep breeds reveals high levels of historic mixture and strong recent selection. PLoS Biol. 2012;10:e1001258. PubMed PMC

Ryder ML. A survey of European primitive breeds of sheep. Ann. Genet. Sel. Anim. 1981;13:418. PubMed PMC

Du, L. X. Animal Genetic Resources in China (China Agriculture Press, Beijing, 2011).

Muigai AWT, Hanotte O. The origin of African sheep: archaeological and genetic perspectives. Afr. Archaeol. Rev. 2013;30:39–50. PubMed PMC

Porter, V., Alderson, L., Hall, S.J.G. & Sponenberg, D.P. Mason’s Wold Encyclopedia of Livestock Breeds and Breeding: 2 volume pack (CAB International, Wallingford, 2016).

Hu ZL, Park CA, Reecy JM. Building a livestock genetic and genomic information knowledgebase through integrative developments of Animal QTLdb and CorrDB. Nucleic Acids Res. 2019;47:D701–D710. PubMed PMC

Dickinson RE, et al. Involvement of the SLIT/ROBO pathway in follicle development in the fetal ovary. Reproduction. 2010;139:395–407. PubMed PMC

Szewczuk M. Association of a genetic marker at the bovine Janus kinase 2 locus (JAK2/Rsal) with milk production traits of four cattle breeds. J. Dairy Res. 2015;82:287–292. PubMed

Wang Z, et al. Genome-wide association study for wool production traits in a Chinese Merino sheep population. PLoS ONE. 2014;9:e107101. PubMed PMC

Cristancho AG, et al. Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cells. Proc. Natl Acad. Sci. USA. 2011;108:16271–16276. PubMed PMC

Niu Y, et al. Biallelic β-carotene oxygenase 2 knockout results in yellow fat in sheep via CRISPR/Cas9. Anim. Genet. 2017;48:242–244. PubMed

Ilardo MA, et al. Physiological and genetic adaptations to diving in Sea Nomads. Cell. 2018;173:569–580. PubMed

Lv FH, et al. Adaptations to climate-mediated selective pressures in sheep. Mol. Biol. Evol. 2014;31:3324–3343. PubMed PMC

Yang J, et al. Whole-genome sequencing of native sheep provides insights into rapid adaptations to extreme environments. Mol. Biol. Evol. 2016;33:2576–2592. PubMed PMC

Gao C, et al. Genome-wide study of subcutaneous and visceral adipose tissue reveals novel sex-specific adiposity loci in Mexican Americans. Obesity. 2018;26:202–212. PubMed PMC

Taye M, et al. Exploring evidence of positive selection signatures in cattle breeds selected for different traits. Mamm. Genome. 2017;28:528–541. PubMed

Redon R, et al. Global variation in copy number in the human genome. Nature. 2006;444:444–454. PubMed PMC

Xu SS, et al. Genome-wide association analyses highlight the potential for different genetic mechanisms for litter size among sheep breeds. Front. Genet. 2018;9:118. PubMed PMC

Onteru SK, et al. A whole-genome association study for pig reproductive traits. Anim. Genet. 2012;43:18–26. PubMed

Lai FN, et al. Whole-genome scanning for the litter size trait associated genes and SNPs under selection in dairy goat (Capra hircus) Sci. Rep. 2016;6:38096. PubMed PMC

Johnston SE, et al. Genome-wide association mapping identifies the genetic basis of discrete and quantitative variation in sexual weaponry in a wild sheep population. Mol. Ecol. 2011;20:2555–2566. PubMed

Peng WF, et al. A genome-wide association study reveals candidate genes for the supernumerary nipple phenotype in sheep (Ovis aries) Anim. Genet. 2017;48:570–579. PubMed

Chandramouli A, Hatsell SJ, Pinderhughes A, Koetz L, Cowin P. Gli activity is critical at multiple stages of embryonic mammary and nipple development. PLoS ONE. 2013;8:e79845. PubMed PMC

Harburg G, et al. SLIT/ROBO2 signaling promotes mammary stem cell senescence by inhibiting Wnt signaling. Stem Cell Rep. 2014;3:385–393. PubMed PMC

Rubin CJ, et al. Whole-genome resequencing reveals loci under selection during chicken domestication. Nature. 2010;464:587–591. PubMed

Larson G, Bradley DG. How much is that in dog years? The advent of canine population genomics. PLoS Genet. 2014;10:e1004093. PubMed PMC

Qiu Q, et al. Yak whole-genome resequencing reveals domestication signatures and prehistoric population expansions. Nat. Commun. 2015;6:10283. PubMed PMC

Carneiro M, et al. Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication. Science. 2014;345:1074–1079. PubMed PMC

Medugorac I, et al. Whole-genome analysis of introgressive hybridization and characterization of the bovine legacy of Mongolian yaks. Nat. Genet. 2017;49:470–475. PubMed

Sahlan M, Zako T, Yohda M. Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond. Biophys. Rev. 2018;10:339–345. PubMed PMC

Schubert C. The genomic basis of the Williams-Beuren syndrome. Cell Mol. Life Sci. 2009;66:1178–1197. PubMed PMC

Trut L, Oskina I, Kharlamova A. Animal evolution during domestication: the domesticated fox as a model. Bioessays. 2009;31:349–360. PubMed PMC

vonHoldt BM, et al. Structural variants in genes associated with human Williams-Beuren syndrome underlie stereotypical hypersociability in domestic dogs. Sci. Adv. 2017;3:e1700398. PubMed PMC

Guerrini M, et al. Molecular DNA identity of the mouflon of Cyprus (Ovis orientalis ophion, Bovidae): Near Eastern origin and divergence from Western Mediterranean conspecific populations. Syst. Biodivers. 2015;13:472–483.

LaRochelle WJ, et al. PDGF-D, a new protease-activated growth factor. Nat. Cell Biol. 2001;3:517–521. PubMed

Dani C, Pfeifer A. The complexity of PDGFR signaling: regulation of adipose progenitor maintenance and adipocyte-myofibroblast transition. Stem Cell Investig. 2017;4:28. PubMed PMC

Olson LE, Soriano P. PDGFRβ signaling regulates mural cell plasticity and inhibits fat development. Dev. Cell. 2011;20:815–826. PubMed PMC

Sarjeant K, Stephens JM. Adipogenesis. Cold Spring Harb. Perspect. Biol. 2012;4:a008417. PubMed PMC

Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–1760. PubMed PMC

Li H, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–2079. PubMed PMC

McKenna A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–1303. PubMed PMC

Korneliussen TS, Albrechtsen A, Nielsen R. ANGSD: analysis of next generation sequencing data. BMC Bioinformatics. 2014;15:356. PubMed PMC

Cheng AY, Teo YY, Ong RT. Assessing single nucleotide variant detection and genotype calling on whole-genome sequenced individuals. Bioinformatics. 2014;30:1707–1713. PubMed

Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164. PubMed PMC

Abyzov A, Urban AE, Snyder M, Gerstein M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 2011;21:974–984. PubMed PMC

Rausch T, et al. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28:i333–i339. PubMed PMC

Chen X, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32:1220–1222. PubMed

Jeffares DC, et al. Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast. Nat. Commun. 2017;8:14061. PubMed PMC

Vilella AJ, et al. EnsemblCompara GeneTrees: complete, duplication-aware phylogenetic trees in vertebrates. Genome Res. 2009;19:327–335. PubMed PMC

Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 2011;88:76–82. PubMed PMC

Alexander DH, Novembre J, Lange K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res. 2009;19:1655–1664. PubMed PMC

Purcell S, et al. PLINK: a tool set for whole genome whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 2007;81:559–575. PubMed PMC

Reynolds J, Weir BS, Cockerham CC. Estimation of the coancestry coefficient: basis for a short-term genetic distance. Genetics. 1983;105:767–779. PubMed PMC

Excoffier L, Lischer HE. Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol. Ecol. Resour. 2010;10:564–567. PubMed

Felsenstein J. PHYLIP - Phylogeny Inference Package (Version 3.2) Cladistics. 1989;5:164–166.

Hill WG, Robertson A. Linkage disequilibrium in finite populations. Theor. Appl. Genet. 1968;38:226–231. PubMed

Danecek P, et al. The variant call format and VCFtools. Bioinformatics. 2011;27:2156–2158. PubMed PMC

Li H, Durbin R. Inference of human population history from individual whole-genome sequences. Nature. 2011;475:493–496. PubMed PMC

Zhao YX, et al. Genomic reconstruction of the history of native Sheep reveals the peopling patterns of nomads and the expansion of early pastoralism in East Asia. Mol. Biol. Evol. 2017;34:2380–2395. PubMed PMC

Barbato M, Orozco-terWengel P, Tapio M, Bruford MW. SNeP: a tool to estimate trends in recent effective population size trajectories using genome-wide SNP data. Front. Genet. 2015;6:109. PubMed PMC

Chen H, Patterson N, Reich D. Population differentiation as a test for selective sweeps. Genome Res. 2010;20:393–402. PubMed PMC

Szpiech ZA, Hernandez RD. Selscan: an efficient multithreaded program to perform EHH-based scans for positive selection. Mol. Biol. Evol. 2014;31:2824–2827. PubMed PMC

Crawford NG, et al. Loci associated with skin pigmentation identified in African populations. Science. 2017;358:eaan8433. PubMed PMC

Pagani L, et al. Genomic analyses inform on migration events during the peopling of Eurasia. Nature. 2016;538:238–242. PubMed PMC

Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat. Genet. 2012;44:821–824. PubMed PMC

Bradbury PJ, et al. TASSEL: software for association mapping of complex traits in diverse samples. Bioinformatics. 2007;23:2633–2635. PubMed

Goeman JJ, Solari A. Multiple hypothesis testing in genomics. Stat. Med. 2014;33:1946–1978. PubMed

Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–842. PubMed PMC

Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq experiments with HISAT, String Tie and Ballgown. Nat. Protoc. 2016;11:1650–1667. PubMed PMC

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCt method. Methods. 2001;25:402–408. PubMed

Natural Earth Home Page, https://www.naturalearthdata.com (2020).

Whole-Genome Resequencing of Worldwide Wild and Domestic Sheep Elucidates Genetic Diversity, Introgression, and Agronomically Important Loci

Historical Introgression from Wild Relatives Enhanced Climatic Adaptation and Resistance to Pneumonia in Sheep