A gene duplication affecting expression of the ovine ASIP gene is responsible for white and black sheep

Abstract

Agouti signaling protein (ASIP) functions to regulate pigmentation in mice, while its role in many other animals and in humans has not been fully determined. In this study, we identify a 190-kb tandem duplication encompassing the ovine ASIP and AHCY coding regions and the ITCH promoter region as the genetic cause of white coat color of dominant white/tan (A Wt ) agouti sheep. The duplication 5Ј breakpoint is located upstream of the ASIP coding sequence. Ubiquitous expression of a second copy of the ASIP coding sequence regulated by a duplicated copy of the nearby ITCH promoter causes the white sheep phenotype. A single copy ASIP gene with a silenced ASIP promoter occurs in recessive black sheep. In contrast, a single copy functional wild-type (A +

A genome-wide scan study identifies a single nucleotide substitution in ASIP associated with white versus non-white coat-colour variation in sheep (Ovis aries)

“…The ASIP gene encodes a secreted protein that affects the quality of hair pigmentation and has been shown to have a central role in neuroendocrine functions of melanocortin action (for example, Norris and Whan 2008). Previous studies have also identified the ASIP protein as a competitive antagonist of the melanocyte-associated melanocortin receptor (MC1R) gene, which inhibits the binding of melanocyte stimulating hormone (a-MSH) and subsequent induction of eumelanin synthesis (Lu et al, 1994;Parsons et al, 1999).…”

“…The highest-ranked SNP (s66432.1; F ST ¼ 0.731), which showed a single and strong selection signal, was located at the position 67.95 Mb within the ASIP gene. In sheep, the duplicated ASIP allele (s) was (were) found to account for the white and black sheep (for example, Norris and Whan, 2008;Fontanesi et al, 2011), and ASIP displayed strong evidence for positive selection in a quite recent study across a worldwide collection of breeds (Kijas et al, 2012). A total of four genomic regions containing X9 consecutive significant average values o0.05 were identified to be under positive selection using the five-SNP sliding-window analysis (Table 2), whereas no region was observed with balancing selection.…”

“…For example, alleles at the ASIP gene were found primarily to determine presence or absence of white coat colour (Norris and Whan, 2008). Hence, we implemented additional analyses among individuals without white coat colour and compared those with white coat coloured individuals to evaluate whether there were loci at one or both of the phenotypic axes.…”

“…To date, all investigations for genes associated with sheep coat colours have used linkage (for example, Våge et al, 2003;Beraldi et al, 2006) and candidate gene analytic methods (for example, Loehr Norris and Whan, 2008;Gratten et al, 2010). Whereas linkage analysis is a useful tool for identifying rare genetic variants with relatively large phenotypic effects that follow Mendelian laws of inheritance, GWAS is the method of choice for detecting common genetic variants associated with phenotypic variation (for example, Kayser et al, 2008), and a higher resolution can be achieved.…”

“…The standard wild-type coat colour in sheep is generally a dark body with a pale belly (Sponenberg, 1997), which is relatively rare in domestic sheep. Coat colour is a key breed characteristic and economically important production trait in sheep, unlike in their wild mouflon (Ovis aries orientalis) ancestors where the lack of artificial selection for coat colour allows variants to arise and segregate (Norris and Whan, 2008). After a long-term strong artificial selection for white fibres, the phenotype of white coat colour has accumulated into a high frequency in some sheep breeds and shows a pattern of autosomal dominant inheritance (Adalsteinsson, 1970;Li et al, 2011).…”