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2/3/2015 Copy number variation – Concept and consequences Copy number variation in livestock and companion animals A window to domestication and other evolutionary processes • Copy number variation (CNV) can be defined as genomic duplications or deletions, with sizes between 50 bp and several Mb, that are polymorphic amongst individuals of a given species. • CNVs can have effects on phenotypes by altering the expression or the structure of transcripts encoded by genes located within or nearby them. • Studies carried out in Drosophila suggest that 21% of genes contained within CNVs have an increased expression variance, but probably this figure is much larger (Zhou et al. 2011). Marcel Amills Center for Research in Agricultural Genomics Copy number variation modifies expression time courses Chaignat et al. (2011) Genome Res. 21: 106–113. The Neolithic revolution and domestication Domestication involved changes in animal behavior and aspect ASPECT -Reduced brain size. -Piebald coloration. -Snout shortening -Decrease in molar length Demography and drift Artificial selection PHYSIOLOGY -Earlier sexual maturity BEHAVIOR -Less territorial and aggressive -Reduced fear to humans. -Increased tolerance to stress. -Reduced wariness Dong et al. 2014. Annu. Rev. Anim. Biosci. 2:65–84 • Domestication may be understood as a mutualistic long-term relationship between humans and plant or animal species that involves a selective advantage for both partners. • Domestication can be interpreted as an ongoing process. Many human and mouse neurodevelopmental pathologies are produced by CNVs Part of these changes may have been produced by CNVs A comparison of CNV distribution in wild boars and pigs Paudel et al. (2013) BMC Genomics 14: 449 • European (N=3) and Asian (N=3) wild boar plus 10 domestic pigs are sequenced x7-x10, leading to the discovery of 3,118 CNV with an average size of 13 kb. • CNVRs contain 545 genes Functional enrichment: - Sensory perception of smell - Neurological function - Signal transduction - Metabolism Homozygous genotypes for the 15q11.2 deletion: higher risk of schizophrenia • The large majority of CNVR are shared between wild boar and domestic pigs. Heterozygous genotypes: diffficulties in learning mathematics and reading 1 2/3/2015 A comparison of CNV distribution in wild boars and pigs Similar distribution of CNVs in dogs and wolves Ramírez et al. (2014) BMC Genomics 15: 465 Rubin et al. (2012) PNAS 14: 449 • Sequencing of pig and wild boar pools reveals a large number of copy number variants. • The comparison of CNV distribution in dogs and wild canids shows that: - around 50% are shared • However, only five of them show positional concordance with candidate selective sweep regions showing an excess of homozygosity. - approximately 12% are dog-specific • No gene-ontology category is overrepresented in the dog-specific CNV regions. • Identification of 25 CNVR with highest VST between dogs and wolves (in red). • Six genes involved in neurological function (EML5, ZNF500, SLC6A11, ELAVL2, RGS7, TOP3B). • SLC6A11: related with schizophrenia and autism. Behavioral traits have a complex genetic architecture Glove test for measuring aggressivity in rats (Albert et al. 2009. Genetics 182: 541) Artificial selection created an enormous amount of phenotypic diversity in domestic animals Chromosome distribution of significant anxietyrelated LOD scores across the mouse genome (Saffron et al. 2006. Eur J Human Genet 14: 721) • F2 mouse intercross from two lines selected for high aggressivity and tameness (Heyne et al. 2014). An approach that assumes that causative mutations are segregating within lines identifies 4 times more loci than another one assuming fixation. • Identification of two additive QTL that explain 7% of tameness variance in rats plus an epistatic network of five loci that explain 14% of it (Albert et al. 2009). • Studies performed in Drosophila also suggest a polygenic basis for behavioral traits combined with extensive pleiotropy and epistasis (Mackay et al. 2008). Practical reasons for selecting color • In the world, there are around 300-400 pig breeds with different coat colors, shapes and production performances. All of them, descend from the wild boar. • Coat color has been selected by humans from immemorial times. • The genetic determinism of coat color is much simpler than that of behavior Religious and cultural reasons for selecting color White pigs are much easier to spot than their wild ancestors. "Speak unto the children of Israel, that they bring thee a red heifer without spot, wherein is no blemish (Numbers 19:2). White wool can be dyed more easily than the colored one. Tallensi tribe from Ghana Sizes and colors of sacrificed animals have different meanings and values In traditional Chinese mythology, the colour black is associated with water. "In a supplication rite for rains, we should use black sheep, and there will then be heavy rain" 2 2/3/2015 White color in pigs is associated with the duplication of the KIT gene White color in sheep is associated with the duplication of the ASIP gene Rubin et al. (2012) PNAS 14: 449 • Normal KIT signaling is required for development and survival of neural crest-derived melanoblasts. • The agouti signaling protein stimulates the synthesis of pheomelanin (yellow). • Dominant white is associated with a 450-kb duplication (DUP1) encompassing the entire KIT gene and a splice mutation causing exon skipping (Giuffra et al. 2002). • A 190 kb tandem duplication of the ASIP gene is associated with a white coat in sheep (Norris et al. 2008. Genome Res. 18: 1282) • Patch has only the 450-kb duplication, while Belt is associated with a duplication 100 kb upstream the KIT gene (DUP2, regulatory role?). • The duplicated copy is regulated by an ITCH promoter and shows an ubiquitous pattern of expression. Comb shape in chicken is determined by copy number variation Pea comb in chicken is determined by a CNV mapping to the SOX5 gene Wright et al. (2009) PLoS Genet 5: e1000512 ROSE COMB PEA COMB qPCR analysis of the SOX5 CNV Normal (green) and ectopic (red) expression of SOX5 in pea-comb chicken WALNUT • A CNV at intron 1 of the SOX5 gene is associated with the pea comb phenotype. • Blood circulation through the comb and wattles helps to dissipate body heat. • Mutant combs could represent an adaptation to cold climates (diminish heat loss and avoid frostbite). • Immunostaining shows an ectopic expression of SOX5 in the embryonic ectodermal region that yields comb and wattles. Adaptation to a starch-rich diet in dogs Conclusions • The majority of studies performed in domestic species have revealed that CNVs are enriched in genes influencing neural development. Axelsson et al. (2013) Nature 495:360 Freedman et al. (2014) PLoS Genet 10: e1004016 • Little success in establishing functional links between CNV and behavioral traits of key importance during the process of domestication. • Causal relationships between CNV and Mendelian aspect-related traits selected during or after domestication. • Future developments: • Copy number variation of the AMY2B gene in dogs and wolves, with a very substantial increase in the former. - Dissecting behavior through GWAS/sequencing approaches in wild x domestic crosses or in divergently selected domestic lines. - Paleogenomics: characterizing genetic variation of ancient specimens. • Low copy number in dog breeds (Dingo and Husky) not linked to agrarian societies. - Technical improvements: Quality of reference genomes, creation of CNV databases, better genome annotation etc. • Increased amylase activity might represent an ancient adaptation to feeding on agricultural refuse. 3