An intronic copy number variation inSyntaxin 17determines speed of greying and melanoma incidence in Grey horses

Abstract

AbstractThe Greying with age phenotype involves loss of hair pigmentation whereas skin pigmentation is not reduced and a predisposition to melanoma. The causal mutation was initially reported as a duplication of a 4.6 kb intronic sequence inSyntaxin 17. The speed of greying varies considerably among Grey horses. Here we demonstrate the presence of two differentGreyalleles,G2carrying two tandem copies of the duplicated sequence andG3carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. Our results reveal a remarkable dosage effect where theG3allele is associated with fast greying and high incidence of melanoma whereasG2is associated with slow greying and low incidence of melanoma. Epigenetic analysis, based on nanopore sequencing of genomic DNA, reveals a drastic reduction in DNA methylation in part of the duplicated sequence harboring MITF binding sites. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (G2andG3) and a drastically elevated risk of melanoma (G3only).