Academic journal article Genetics

A Domestic Cat X Chromosome Linkage Map and the Sex-Linked Orange Locus: Mapping of Orange, Multiple Origins and Epistasis over Nonagouti

Academic journal article Genetics

A Domestic Cat X Chromosome Linkage Map and the Sex-Linked Orange Locus: Mapping of Orange, Multiple Origins and Epistasis over Nonagouti

Article excerpt

ABSTRACT

A comprehensive genetic linkage map of the domestic cat X chromosome was generated with the goal of localizing the genomic position of the classic X-linked orange (O) locus. Microsatellite markers with an average spacing of 3 Mb were selected from sequence traces of the cat 1.9× whole genome sequence (WGS), including the pseudoautosomal region 1 (PAR1). Extreme variation in recombination rates (centimorgans per megabase) was observed along the X chromosome, ranging from a virtual absence of recombination events in a region estimated to be >30 Mb to recombination frequencies of 15.7 cM/Mb in a segment estimated to be <0.3 Mb. This detailed linkage map was applied to position the X-linked orange gene, placing this locus on the q arm of the X chromosome, as opposed to a previously reported location on the p arm. Fine mapping placed the locus between markers at positions 106 and 116.8 Mb in the current 1.9×-coverage sequence assembly of the cat genome. Haplotype analysis revealed potential recombination events that could reduce the size of the candidate region to 3.5 Mb and suggested multiple origins for the orange phenotype in the domestic cat. Furthermore, epistasis of orange over nonagouti was demonstrated at the genetic level.

THE domestic cat displays a broad diversity of phenotypic variation, including an array of coloration patterns resulting from interacting genotypes at multipleloci.Pigmentationgeneshavebeenidentifiedon thebasis ofcomparativegeneticdata supportedbygenetic linkage or association studies [agouti locus (melanism), ASIP (Eizirik et al. 2003); albino locus (siamese, burmese, and albino), TYR (O'Brien et al. 1986; Lyons et al. 2005; Schmidt-Küntzelet al.2005; Imes et al.2006); brownlocus (chocolate and cinnamon), TYRP1 (Schmidt-Küntzel et al. 2005); dilute locus (dilute), MLPH (Ishida et al. 2006)]. Other genes involved in domestic cat pigmentation remain unknown, including the X-linked orange (O) locus (Searle 1968; Vella et al. 1999). This locus has attracted the attention of geneticists for over a century (e.g., Doncaster 1904; Wright 1918). Orange controls an unknown molecular mechanism that causes the suppression of black-brownish pigmentation (eumelanin) in favor of orange-yellowish coloration (pheomelanin) (Vellaet al. 1999). The resulting orange phenotype is likely caused by the exclusive presence of pheomelanic pigments in the hair shaft (Figure 1A).

Pheomelanic phenotypes have been reported in other species. In mice, cattle, horses, pigs, humans, dogs, bears, rabbits, and chickens, mutations in the Melanocortin 1 receptor (MC1R) have been reported as causative of red/yellow/white hair or plumage (Robbins et al. 1993; Klungland et al. 1995;Marklund et al. 1996; Kijas et al. 1998; Rees et al. 1999; Newton et al. 2000; Ritland et al. 2001; Kerje et al. 2003; Fontanesi et al. 2006). However, the autosomal location of MC1R, mapped to chromosome E2 in the domestic cat (Eizirik et al. 2003), eliminates this gene as causal for X-linked orange. An X-chromosomal region for the cat orange locus was previously proposed on the basis of exclusion mapping (Grahn et al. 2005). Only one other mammal, the Syrian hamster (Mesocricetus auratus), has been reported to have an X-linked pheomelanic phenotype (sex-linked yellow; Robinson 1966). Mapping of Sexlinked yellow in the hamster is presented in an accompanying article by Alizadeh et al. (2009, this issue).

Two striking phenotypic variants are seen in the tortoiseshell (mottled orange and nonorange) and the calico (mosaic pattern of large patches of orange, non- orange, and white) cats (Figure 1A). The coloration of the nonorange patches is influenced by the genetic background at other pigmentation loci, which segregate independently of the O locus (e.g., the brown locus in Lamoreux 1973). The tortoiseshell/calico phenotypes are a consequence of embryonic X inactivation whereby the alternative expression of orange vs. wild-type alleles in different skin patches creates a mosaic color patterning characteristic of female cats heterozygous at theOlocus (Lyon 1999). …

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