Dataset Information

Genetic variants in melanogenesis proteins TYRP1 and TYR are associated with the golden rhesus macaque phenotype.

ABSTRACT: Nonhuman primates (NHPs) are vital translational research models due to their high genetic, physiological, and anatomical homology with humans. The "golden" rhesus macaque (Macaca mulatta) phenotype is a naturally occurring, inherited trait with a visually distinct pigmentation pattern resulting in light blonde colored fur. Retinal imaging also reveals consistent hypopigmentation and occasional foveal hypoplasia. Here, we describe the use of genome-wide association in 2 distinct NHP populations to identify candidate variants in genes linked to the golden phenotype. Two missense variants were identified in the Tyrosinase-related protein 1 gene (Asp343Gly and Leu415Pro) that segregate with the phenotype. An additional and distinct association was also found with a Tyrosinase variant (His256Gln), indicating the light-colored fur phenotype can result from multiple genetic mechanisms. The implicated genes are related through their contribution to the melanogenesis pathway. Variants in these 2 genes are known to cause pigmentation phenotypes in other species and to be associated with oculocutaneous albinism in humans. The novel associations presented in this study will permit further investigations into the role these proteins and variants play in the melanogenesis pathway and model the effects of genetic hypopigmentation and altered melanogenesis in a naturally occurring nonhuman primate model.

SUBMITTER: Peterson SM

PROVIDER: S-EPMC10542561 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Genetic variants in melanogenesis proteins TYRP1 and TYR are associated with the golden rhesus macaque phenotype.

Peterson Samuel M SM Watowich Marina M MM Renner Lauren M LM Martin Samantha S Offenberg Emma E Lea Amanda A Montague Michael J MJ Higham James P JP Snyder-Mackler Noah N Neuringer Martha M Ferguson Betsy B

G3 (Bethesda, Md.) 20230901 10

Nonhuman primates (NHPs) are vital translational research models due to their high genetic, physiological, and anatomical homology with humans. The "golden" rhesus macaque (Macaca mulatta) phenotype is a naturally occurring, inherited trait with a visually distinct pigmentation pattern resulting in light blonde colored fur. Retinal imaging also reveals consistent hypopigmentation and occasional foveal hypoplasia. Here, we describe the use of genome-wide association in 2 distinct NHP populations ...[more]

PMID: 37522525

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Project description:Quantitative genetic analyses can indicate how complex traits respond to natural selection by demonstrating the genetic relationships between features that constrain their evolution. Genetic correlations between dental measurements have been estimated previously in baboons, humans, and tamarins and indicate variable patterns of modularity by tooth type across these taxa. Here, heritabilities of, and genetic correlations between, linear dental measurements were estimated from the Cayo Santiago rhesus macaques (Macaca mulatta). Relationships between the genetic correlation matrix and matrices designed to test hypotheses of modularity by tooth type, region, function, and development were assessed using a random skewers approach. Dental measurements were found to be moderately to highly heritable, with 24 of 28 heritability estimates differing significantly (p < 0.05) from zero. Almost all genetic correlations between dental dimensions were positive. The genetic correlation matrix was most similar to a regionally modular matrix, with distinct anterior and postcanine tooth modules. This pattern is consistent with previous quantitative genetic analyses of baboons and previous phenotypic analyses of cercopithecoid primates. The existence of a genetic module for the canines and honing premolar was not supported. Ongoing selection pressures, rather than strong genetic constraints, are likely necessary to preserve functional relationships between the canines and honing premolar based on these findings. The genetic correlation matrix of the Cayo Santiago rhesus macaques mirrors patterns of phenotypic correlations observed for cercopithecoid primates broadly and demonstrates that genetic contributions to these patterns may be fairly stable over the course of cercopithecoid evolution. The quantitative genetic study of additional taxa will be necessary to determine whether the regional modularity of baboons and macaques, or the integrated pattern of humans and tamarins, is shared more broadly across primates.

Project description:BackgroundThe observed correlation between ultraviolet light incidence and skin color, together with the geographical apportionment of skin reflectance among human populations, suggests an adaptive value for the pigmentation of the human skin. We have used Affymetrix U133a v2.0 gene expression microarrays to investigate the expression profiles of a total of 9 melanocyte cell lines (5 from lightly pigmented donors and 4 from darkly pigmented donors) plus their respective unirradiated controls. In order to reveal signatures of selection in loci with a bearing on skin pigmentation in humans, we have resequenced between 4 to 5 kb of the proximal regulatory regions of three of the most differently expressed genes, in the expectation that variation at regulatory regions might account for intraespecific morphological diversity, as suggested elsewhere.ResultsContrary to our expectations, expression profiles did not cluster the cells into unirradiated versus irradiated melanocytes, or into lightly pigmented versus darkly pigmented melanocytes. Instead, expression profiles correlated with the presence of Bovine Pituitary Extract (known to contain alpha-MSH) in the media. This allowed us to differentiate between melanocytes that are synthesizing melanin and those that are not. TYR, TYRP1 and DCT were among the five most differently expressed genes between these two groups. Population genetic analyses of sequence haplotypes of the proximal regulatory flanking-regions included Tajima's D, HEW and DHEW neutrality tests analysis. These were complemented with EHH tests (among others) in which the significance was obtained by a novel approach using extensive simulations under the coalescent model with recombination. We observe strong evidence for positive selection for TYRP1 alleles in Africans and for DCT and TYRP1 in Asians. However, the overall picture reflects a complex pattern of selection, which might include overdominance for DCT in Europeans.ConclusionDiversity patterns clearly evidence adaptive selection in pigmentation genes in Africans and Asians. In Europeans, the evidence is more complex, and both directional and balancing selection may be involved in light skin. As a result, different non-African populations may have acquired light skin by alternative ways, and so light skin, and perhaps dark skin too, may be the result of convergent evolution.

Dataset Information

Genetic variants in melanogenesis proteins TYRP1 and TYR are associated with the golden rhesus macaque phenotype.

Publications

Genetic variants in melanogenesis proteins TYRP1 and TYR are associated with the golden rhesus macaque phenotype.

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