Selective sweep analysis using village dogs highlights the 1 pivotal role of the neural crest in dog domestication 2 3

14 Dogs (Canis lupus familiaris) were domesticated from gray wolves between 20-40kya in 15 Eurasia, yet details surrounding the process of domestication remain unclear. The vast array of 16 phenotypes exhibited by dogs mirror numerous other domesticated animal species, a 17 phenomenon known as the Domestication Syndrome. Here, we use signatures persisting in the 18 dog genome to identify genes and pathways altered by the intensive selective pressures of 19 domestication. We identified 37 candidate domestication regions containing 17.5Mb of genome 20 sequence and 172 genes through whole-genome SNP analysis of 43 globally distributed village 21 dogs and 10 wolves. Comparisons with three ancient dog genomes indicate that these regions 22 reflect signatures of domestication rather than breed formation. Analysis of genes within these 23 regions revealed a significant enrichment of gene functions linked to neural crest cell migration, 24 differentiation and development. Genome copy number analysis identified regions of localized 25 sequence and structural diversity, and discovered additional copy number variation at the 26 amylase-2b locus. Overall, these results indicate that primary selection pressures targeted genes 27 in the neural crest as well as components of the minor spliceosome, rather than genes involved in 28 starch metabolism. Smaller jaw sizes, hairlessness, floppy ears, tameness, and diminished 29 craniofacial development distinguish wolves from domesticated dogs, phenotypes of the 30 Domestication Syndrome that can result from decreased neural crest cells at these sites. We 31 propose that initial selection acted on key genes in the neural crest and minor splicing pathways 32 during early dog domestication, giving rise to the phenotypes of modern dogs. 33 34 35