Nicholas TJ, Cheng Z, Ventura M, Mealey K, Eichler EE, Akey JM. Copy number for each target was determined from ddPCR results from a single replication for 30 village dogs, 3 New Guinea singing dogs, and 5 breed dogs (Additionalfile1: Table S12), and averaged from two replicates for 48 breed dogs (Additionalfile1: Table S13). Genes Dev. Genetics. Likely due to the absence of village dogs in their study, some loci identified in Axelsson et al. Williams AL, Eason J, Chawla B, Bohnsack BL. J Cell Biol. XP-CLR has several advantages over other methods used to identify selection signatures, as it is less biased by demographic history, by uncertainty in recombination rates, and does not maintain strict window boundaries [41]. We found that only 41 of the 349 loci from [29] loci passed our filtrations (Additionalfile2: Figure S5c). Tameness or reduced fear toward humans was likely the earliest trait selected for by humans during domestication [3, 106, 107]. Characterization of Potocki-Lupski syndrome (dup (17)(p11. 2006;444(7118):444. Maden M. Retinoic acid in the development, regeneration and maintenance of the nervous system.
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Genet Test. The extreme AMY2B copy number expansion appears to be independent of the large-scale duplications, as ddPCR results show that some dogs without the large duplications still have very high AMY2B copy number. California Privacy Statement, Since this gene flow occurred in the ancestral lineage of both modern dogs and wolves (>20kya) [32, 34, 40] the jackal ancestry is expected to be similarly represented in all of our samples. Quantitative PCR results have suggested an ancient origin for the AMY2B copy number expansion, as 7-ky-old Romanian dogs exhibit elevated AMY2B copy number [38]. The above results suggest that the use of village dogs, rather than breed dogs, in selection scans identifies novel candidate domestication regions that are not confounded by breed formation. 2011;27(15):21568. Qanbari S, Pausch H, Jansen S, Somel M, Strom TM, Fries R, Nielsen R, Simianer H. Classic selective sweeps revealed by massive sequencing in cattle. 2007;80(4):63349. BMC Genomics. The set supported by multiple loci includes several categories related to the process noted above including the regulation of retinoic acid receptors (pperm=0.028), retinol metabolism (pperm=0.014), the secretion (pperm=0.01), transport (pperm=0.01), and signaling of GABA (pperm=0.03), dopamine receptor signaling (pperm=0.04), and cell maturation (pperm=0.012). SNPs within CDRs of interest were extracted from the SNP dataset using the PLINK make-bed tool with no missing data filter. RNPC3, which affects early development and is linked to dwarfism (isolated growth hormone deficiency; [128]), is also under selection in cats and humans [17, 77]. 2016;117(5):3016. 
Proc Natl Acad Sci. Bioinformatics. Sudmant PH, Huddleston J, Catacchio CR, Malig M, Hillier LW, Baker C, Mohajeri K, Kondova I, Bontrop RE, Persengiev S. Evolution and diversity of copy number variation in the great ape lineage. Seventy-one enriched (pperm<0.05) categories were identified using the same methods for the 89 genes intersecting the VST (copy number) candidate loci (Additionalfile1: Table S10). We performed enrichment tests using the parent-child model [68] in the topGO R package [69] with the intersecting 429 unique genes as the test set. Figure S12. Multiple genes are also involved in retinoic acid signaling, neurotransmission, and RNA splicing. Analogously, compared to the pricked ears of wolves, dogs predominantly have floppy ears [103], a hallmark feature of domesticates [18]. In total, 25/58 loci identified using FST in village dogs intersected with a putative sweep identified from at least one previous study (for specific overlaps, see Additionalfile1: Table S4). Canid genomes (Additionalfile1: Table S1) were processed using the pipeline outlined in [34] to produce a data set of single nucleotide polymorphisms (SNPs) using GATK [133]. Similar to other domestication scans [6, 9, 19], we did not find SNPs deleteriously altering protein sequence in our predicted sweeps, indicating that gene loss did not have a significant role in dog domestication. Estimating and interpreting FST: the impact of rare variants. [5] appear to contain selective sweeps associated with breed formation, as evidenced by the presence of the wild haplotype in ancient and village dogs (example in Fig. To eliminate noise in subsequent analyses, we removed all village dogs with greater than 5% wolf ancestry and wolves with greater than 5% dog ancestry.
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We then removed any locus with FST, HP, and HP levels not passing our thresholds.
Software (fastCN and QuicK-mer) implemented in this article are available for download in a GitHub repository (https://github.com/KiddLab/).
Caddick SJ, Wang C, Fletcher CF, Jenkins NA, Copeland NG, Hosford DA. Dev Dyn. Significance threshold for window filtration was set as the 0.1th percentile of the HP distribution from the simulated genomes. Droplet digital polymerase chain reaction, Cross-population composite likelihood ratio. 1998;273(41):262614. J Archaeol Sci. Am Sci. Mech Dev. 2003;56(3):15972. Cookies policy. 2014;30(12):i28392. https://github.com/KiddLab/fastCN. AT and ALP assessed population structure. Mouse Fkbp8 activity is required to inhibit cell death and establish dorso-ventral patterning in the posterior neural tube. Figure S11. Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K. Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. Further, these remains indicate jaw size reduction also occurred, as evidenced by tooth crowding [95]. Hum Mol Genet. First, the nature of the GO ontology relationships introduces non-independence among related GO terms and genes, a problem partially ameliorated by the parent-child model [68]. Schubert M, Jonsson H, Chang D, Der Sarkissian C, Ermini L, Ginolhac A, Albrechtsen A, Dupanloup I, Foucal A, Petersen B, et al. Genomic and archaeological evidence suggest a dual origin of domestic dogs. PubMed Central Koestner U, Shnitsar I, Linnemannstns K, Hufton AL, Borchers A. Semaphorin and neuropilin expression during early morphogenesis of Xenopus laevis. Dev Dyn. Copy number estimates for the AMY2B gene using fastCN were based on a single window located at chrUn_AAEX03020568: 4873-8379. Numerous candidate loci contain genes influencing neurological function and behavioral responses including genes in the dopamine, serotonin, glutamate, and GABA neurotransmission pathways, as well as genes contributing to the connectivity and development of synapses and dendrites. [18] established that the vast array of phenotypes displayed in the animal domestication syndrome mirror those exhibited in mild human neurocristopathies, whose pathology stems from aberrant differentiation, division, survival, and altered migration of neural crest cells (NCCs). Selection scan statistics surrounding the RNA-binding region (RNP1, RRM) containing 3 (RNPC3) locus (chr5: ~46.947.3Mb). Ancient European dog genomes reveal continuity since the Early Neolithic. Zhang Z, Wang W. RNA-Skim: a rapid method for RNA-Seq quantification at transcript level.
Alterations of activity by genes such as SERPINH1 and those regulating NCC migration may have reduced the numbers of NCCs in dog ears, contributing to the floppy phenotype [18]. Edery P, Marcaillou C, Sahbatou M, Labalme A, Chastang J, Touraine R, Tubacher E, Senni F, Bober MB, Nampoothiri S. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Absence of Sf3b1 disrupts proper NCC specification, survival, and migration [129]. Instead, the method considers patterns of contiguous SNPs to isolate loci that, based on the size of the affected region, had more rapid correlated changes in allele frequency than expected by genetic drift [41]. Chromosomal localization of gene for human glutamate receptor subunit-7. CAS This suggests that copy number expansion or contraction may not have made as significant contributions to the phenotypic changes associated with domestication. Nature. J Biol Chem. Genes Dev. We argue that swept haplotypes identified in modern village dogs and also present in Neolithic dogs more likely represent signals of ancient selection events. The simulation is designed to capture key aspects impacting dog and wolf diversity, rather than a definitive depiction of their demography. Demographically-based evaluation of genomic regions under selection in domestic dogs.
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2003;19(2):2956. 2003;4(10):806. 2017;58(2):108497. 2011;12(2):216. Bocciardi R, Giorda R, Marigo V, Zordan P, Montanaro D, Gimelli S, Seri M, Lerone M, Ravazzolo R, Gimelli G. Molecular characterization of at (2; 6) balanced translocation that is associated with a complex phenotype and leads to truncation of the TCBA1 gene. Prfer K, Racimo F, Patterson N, Jay F, Sankararaman S, Sawyer S, Heinze A, Renaud G, Sudmant PH, De Filippo C. The complete genome sequence of a Neanderthal from the Altai Mountains. Although all autosomal sweeps identified by [8] intersected with CDRs from our study, seven of their X chromosome windows did not meet the thresholds of significance from our SNP sets (example in Additionalfile2: Figure S1). 2015;33(4):408. Mol Ecol. The regions share haplotypes with ancient dogs, suggesting that the detected signals are not the result of recent selection. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. 2016;291(12):616981. Retinoic acid induced-1 (Rai1) regulates craniofacial and brain development in Xenopus. Proc Natl Acad Sci. G3 (Bethesda).
Inhibition of nuclear hormone receptor activity by calreticulin. A custom script [141] then converted the Eigenstrat genotype files into matrices for visualization using matrix2png [142]. Mathew R, Hartmuth K, Mhlmann S, Urlaub H, Ficner R, Lhrmann R. Phosphorylation of human PRP28 by SRPK2 is required for integration of the U4/U6-U5 tri-snRNP into the spliceosome. Chromosoma. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Windows that did not return a value (failed) or did not have at least five grids were removed. Dev Biol. PLoS Comput Biol. CAS 
Mutations in RAI1 associated with SmithMagenis syndrome. Nat Biotechnol. 2013;29(4):197205. Williams SR, Zies D, Mullegama SV, Grotewiel MS, Elsea SH. Once PCA confirmed clear genetic distinctions between these dogs and wolves, this final sample set was used for subsequent analyses. 2008;82(4):95970. Whole-genome resequencing reveals loci under selection during chicken domestication. 2015;6:10283. Ensembl Canis familiaris database. Trut LN, Plyusnina I, Oskina I. Altogether, we conclude that while primary selection during domestication likely targeted tameness, genes that contribute to determination of this behavioral change are also involved in critical, far-reaching pathways that conferred drastic phenotypic changes in dogs relative to their wild counterparts. 2013;48(1):3648. Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation. Kelleher J, Etheridge AM, McVean G. Efficient coalescent simulation and genealogical analysis for large sample sizes. By considering multi-mapping reads, copy number profiles will be shared among related gene paralogs, making it difficult to identify specific sequences that are potentially variable. In: Neural Crest Cells. Am J Hum Genet. Nat Genet. Axelsson E, Ratnakumar A, Arendt ML, Maqbool K, Webster MT, Perloski M, Liberg O, Arnemo JM, Hedhammar A, Lindblad-Toh K. The genomic signature of dog domestication reveals adaptation to a starch-rich diet. Such traits include increased tameness, shorter muzzles/snouts, smaller teeth, more frequent estrous cycles, floppy ears, reduced brain size, depigmentation of skin or fur, and loss of hair. Truong HT, Solaymani-Kohal S, Baker KR, Girirajan S, Williams SR, Vlangos CN, Smith AC, Bunyan DJ, Roffey PE, Blanchard CL. 2010;2(0):1-26. Table S8. Development. PLoS Genet. Google Scholar. Development. Genome structural variation discovery and genotyping. Snchez-Villagra MR, Geiger M, Schneider RA. Cagan A, Blass T. Identification of genomic variants putatively targeted by selection during dog domestication. Foundation for modern Crop Science. Figure S7.
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Cite this article. 2007;134(7):136983. Gene enrichment results for XP-CLR candidate domestication regions following p value adjustment (BLAST2GO). BMC Genomics. 1992;19(2):181204. Pendleton, A.L., Shen, F., Taravella, A.M. et al. a Per site FST scores for all SNPs are indicated along with the FST significance threshold determined by the 99th percentile of simulations (red dashed line). Therefore, reassessment of population-specific copy number changes would be improved by the use of a wolf genome reference [132]. Treating village dogs and wolves as separate populations, VST values [66] were calculated for genomic windows with evidence of copy number variation. Gray MM, Granka JM, Bustamante CD, Sutter NB, Boyko AR, Zhu L, Ostrander EA, Wayne RK. nature. Wang GD, Zhai W, Yang HC, Wang L, Zhong L, Liu YH, Fan RX, Yin TT, Zhu CL, Poyarkov AD, et al. Neurol Sci. Ancient genomic changes associated with domestication of the horse. Predicted effects of SNP variants were obtained by the processing of the total variant VCF file of all canine samples by variant effect predictor (VEP; [42]). Copy number estimated through read depth strongly correlated with estimates from ddPCR (Additionalfile2: Figure S10) confirming the presence of standing copy number variation of AMY2B in dogs (range of 2n A map of human genome variation from population-scale sequencing. CAS Int J Dev Biol. BMC Genomics. 2012;13(6):587. On the origin of mongrels: evolutionary history of free-breeding dogs in Eurasia. Finally, we perform a scan for copy number differences between village dogs and wolves, and identify additional copy number variation at the starch-metabolizing gene amylase-2b (AMY2B) that is independent of the AMY2B tandem expansion previously found in dogs [5, 36,37,38].
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Recapitulating such selection, numerous physiological and morphological characteristics, including domestication syndrome phenotypes (i.e., floppy ears, altered craniofacial proportions, and unseasonal timing for mating), appeared within 20 generations when researchers selected only for tameness in a silver fox breeding population [1, 108]. There was no overlap of these copy number outliers with regions identified through FST or XP-CLR. Popova N, Kulikov A, Avgustinovich D, Votenko N, Trut L. Effect of domestication of the silver fox on the main enzymes of serotonin metabolism and serotonin receptors. Dev Biol. Anim Genet. Genetics. Gene intersect statistics from randomized permutations of XP-CLR gene positions. J Cell Biol.
3; Additionalfile1: Table S4). Changes in the chondrocyte and extracellular matrix proteome during post-natal mouse cartilage development. Neurosci Lett. Both pipelines analyze sequencing read-depth within predefined windows, apply GC-correction and other normalizations, and are able to convert read depth to a copy-number estimate for each window (Additionalfile3: Note 3.1). QuicK-mer Precomputed K-mers. Genome Res. Serres-Armero A, Povolotskaya IS, Quilez J, Ramirez O, Santpere G, Kuderna LF, Hernandez-Rodriguez J, Fernandez-Callejo M, Gomez-Sanchez D, Freedman AH. Structural variants in genes associated with human Williams-Beuren syndrome underlie stereotypical hypersociability in domestic dogs. Racimo F. Testing for ancient selection using cross-population allele frequency differentiation. 
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1d). 2013;23(9):151421. Solomon KS, Kudoh T, Dawid IB, Fritz A. Zebrafish foxi1 mediates otic placode formation and jaw development. Wang Z, Yonezawa T, Liu B, Ma T, Shen X, Su J, Guo S, Hasegawa M, Liu J. Domestication relaxed selective constraints on the yak mitochondrial genome. We thank Shiya Song for advice and assistance in the processing of canid variation data and Laura Botigue for discussion of results utilizing ancient DNA.
First, through ADMIXTURE [39] and identity-by-state (IBS) analyses, we identified a collection of 43 village dog and 10 gray wolf samples (Additionalfile1: Table S1) that have less than 5% dog-wolf admixed ancestry and excludes close relatives (Fig. 2017;28(8):105465. Genetics. Genome Res. 
We further excluded sites with missing genotype calls in any sample, triallelic sites, and X-nonPAR positions where any male sample was called as heterozygous. Table S10. Several studies [5, 8, 26, 28, 29] using related approaches have attempted to identify genomic regions which are highly differentiated between dogs and wolves, with the goal of identifying candidate targets of selection during domestications (candidate domestication regions, CDRs [5]).
2017;18(1):977. Distribution of selection scan statistics for real and simulated FST windows. Elsea SH, Girirajan S. SmithMagenis syndrome. Arendt M, Fall T, Lindblad-Toh K, Axelsson E. Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes. Bioinformatics. 2009;5(1):e1000341. Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/-catenin signaling. Bioinformatics. A recent study in canines linked behavioral changes in breed dogs to structural variants near WBSCR17, a Williams-Beuren syndrome gene [117]. PLoS Genet. Nucleic Acids Res. 2009;41(10):1061. Most modern breeds arose ~300years ago [30] and contain only a small portion of the genetic diversity found among the vast majority of extant dogs.
