Functional divergence of the pigmentation gene melanocortin-1 receptor (MC1R) in six endemic Macaca species on Sulawesi Island

Abstract

Coat color is often highly variable within and between animal taxa. Among hundreds of pigmentation-related genes, melanocortin-1 receptor (MC1R) plays key roles in regulating the synthesis of the dark eumelanin and the red–yellow pheomelanin. The six species of macaques that inhabit Sulawesi Island diverged rapidly from their common ancestor, M. nemestrina. Unlike most macaques, Sulawesi macaques commonly have a dark coat color, with divergence in shade and color pattern. To clarify the genetic and evolutionary basis for coat color in Sulawesi macaques, we investigated the MC1R sequences and functional properties, including basal cAMP production and α-MSH-induced activity in vitro. We found fixed non-synonymous substitutions in MC1R in each species. Furthermore, we found that six species-specific variants corresponded with variation in agonist-induced and basal activity of MC1R. Inconsistent with the dark coat color, four substitutions independently caused decreases in the basal activity of MC1R in M. hecki, M. nigra, M. tonkeana, and M. ochreata. Selective analysis suggested MC1R of M. nigra and M. nigrescens underwent purifying selection. Overall, our results suggest that fixed differences in MC1R resulted in different functional characteristics and might contribute to divergence in color among the six Sulawesi macaque species.

Mendelian Randomization Analysis reveals Inverse Genetic Risks between Skin Cancers and Vitiligo

“…In rs6059655, ASIP was shown to have significantly decreased levels of expression with the risk phenotype. ASIP functions as an antagonist to MC1R through α-melanocyte-stimulating hormone to modulate melanin pigmentation ( Robbins et al., 1993 ; Yan et al., 2022 ), though an inverse expression quantitative trait loci association with MC1R was found to be nonsignificant. On the basis of 2008 case-control study, a haplotype near ASIP was found to confer an increased risk of cutaneous melanoma (OR = 1.27, 95% CI = 1.02–1.57) without adjustment for pigmentation characteristics, whereas MC1R did not ( Gudbjartsson et al., 2008 ).…”