Complex Inheritance of Melanoma and Pigmentation of Coat and Skin in Grey Horses

Ino Curik,Elisabeth Sundström,Johann Sölkner,Thomas Druml,Gerli Rosengren Pielberg,Leif Andersson,Monika Seltenhammer,Mike E. Goddard

doi:10.1371/journal.pgen.1003248

Abstract

The dominant phenotype of greying with age in horses, caused by a 4.6-kb duplication in intron 6 of STX17, is associated with a high incidence of melanoma and vitiligo-like skin depigmentation. However, the progressive greying and the incidence of melanoma, vitiligo-like depigmentation, and amount of speckling in these horses do not follow a simple inheritance pattern. To understand their inheritance, we analysed the melanoma grade, grey level, vitiligo grade, and speckling grade of 1,119 Grey horses (7,146 measurements) measured in six countries over a 9-year period. We estimated narrow sense heritability (h2), and we decomposed this parameter into polygenic heritability (h2 POLY), heritability due to the Grey (STX17) mutation (h2 STX17), and heritability due to agouti (ASIP) locus (h2 ASIP). A high heritability was found for greying (h2 = 0.79), vitiligo (h2 = 0.63), and speckling (h2 = 0.66), while a moderate heritability was estimated for melanoma (h2 = 0.37). The additive component of ASIP was significantly different from zero only for melanoma (h2 ASIP = 0.02). STX17 controlled large proportions of phenotypic variance (h2 STX17 = 0.18–0.55) and overall heritability (h2 STX17/h2 = 0.28–0.83) for all traits. Genetic correlations among traits were estimated as moderate to high, primarily due to the effects of the STX17 locus. Nevertheless, the correlation between progressive greying and vitiligo-like depigmentation remained large even after taking into account the effects of STX17. We presented a model where four traits with complex inheritance patterns are strongly influenced by a single mutation. This is in line with evidence of recent studies in domestic animals indicating that some complex traits are, in addition to the large number of genes with small additive effects, influenced by genes of moderate-to-large effect. Furthermore, we demonstrated that the STX17 mutation explains to a large extent the moderate to high genetic correlations among traits, providing an example of strong pleiotropic effects caused by a single gene.

Highlights

Recent developments in molecular genetics have enabled molecular dissection of quantitative traits in humans [1], model organisms [2] and domestic animals [3]
Clarifying the genetic architecture of complex traits is a problem with profound implications for agriculture, biology, and medicine
Using data from Lipizzan horses with the grey coat phenotype, we present an example of a single mutation that explains 18%–55% of phenotypic variation in four complex traits, while polygenic background additive effects explain 11%–57% of phenotypic variation

Summary

Introduction

Recent developments in molecular genetics have enabled molecular dissection of quantitative traits in humans [1], model organisms [2] and domestic animals [3]. Genome-wide association (GWA) studies suggest that variability of complex traits is caused by many loci, most exerting tiny effects, whereas loci exerting moderate-tolarge effects or loci that explain more than 5–10% of phenotypic variation are rare [3,4,5]. In human populations, those genes with moderate-to-large effects do appear in low frequency as rare or ‘‘private’’ mutations [6]. The genetic variation of several complex traits in Grey horses is considerably affected by at least one gene of moderate-to-large effect.

Methods

Results

Discussion

Conclusion