Evidence for Variable Selective Pressures at MC1R

Harding, Rosalind M.; Healy, Eugene; Ray, Amanda; Ellis, Nichola S.; Flanagan, Niamh; Todd, Carol; Dixon, Craig; Sajantila, Antti; Jackson, Ian J.; Birch‐Machin, Mark A.; Rees, Jonathan

doi:10.1086/302863

Cited by 369 publications

(363 citation statements)

References 40 publications

(46 reference statements)

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“…African and non-African data suggest times to the most recent common ancestor of approximately one million years. The functionally significant Arg151Cys and Arg160Trp alleles we estimate at ages of around 80,000 years and for the Arg142His and Asp294His alleles 30,000 years, with standard deviations about half these expectations (42). Such ages are compatible with the geographic pattern of alleles we have observed, and are testable in further studies of MC1R diversity.…”

Section: Population Genetics Of the Mc1rsupporting

confidence: 81%

“…Over 30 MC1R alleles have been identified to date [ (1,16,38,(42)(43)(44)(45) and unpublished]. Whereas the Arg142His, Arg151Cys, Arg160Trp and Asp294His alleles appear to be clear loss-of-function mutants, the phenotypic consequences of some of the other alleles are uncertain.…”

Section: The Diversity Of Mc1r Allelesmentioning

confidence: 99%

“…Two studies have explored these issues, one from Rana et al (44) and the other from my own group in collaboration with Rosalind Harding (42). The two studies, whilst showing many similarities, come to different conclusions.…”

Section: Population Genetics Of the Mc1rmentioning

confidence: 99%

“…In other words, whilst the data provide evidence for selective pressure acting to maintain wild-type MC1R status in Africa, in Europe the data are compatible with a removal of constraint rather than selection in favour of loss-of-function mutants. There are, however, several caveats to this conclusion [for a full discussion of these see (42)]. …”

Section: Population Genetics Of the Mc1rmentioning

confidence: 99%

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The Melanocortin 1 Receptor (MC1R): More Than Just Red Hair

Rees

2000

Pigment Cell Research

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170

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The melanocortin 1 receptor, a seven pass transmembrane G ing loss-of-function mutations. Activating mutations of the protein coupled receptor, is a key control point in melanogen-MC1R in man have not been described. The MC1R is particesis. Loss-of-function mutations at the MC1R are associated ularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of in animals at least, lead to enhanced eumelanin synthesis. In MC1R diversity is compatible with functional constraint operman, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired ating in Africa, whereas the greater allelic diversity seen in persons) are compound heterozygotes or homozygotes for up to non-African populations is consistent with neutral predictions five frequent loss-of-function mutations. A minority of redrather than selection. Whether this conclusion is as a result of heads are, however, only heterozygote. The MC1R is, thereweakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great fore, a major determinant of sun sensitivity and a genetic risk interest for studies of human skin colour evolution. factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote Key words: MC1R, Loss-of-function mutation, Red-heads, effect on skin type, with up to 30% of the population harbourRed hair, Skin type, Skin colour other genetically complex states. Most genes involved in human pigmentation, including the MC1R, have been identified on the back of the resource and tractable experimental system provided by the marriage of the mouse mutant resource and modern molecular genetics (4 -7). So far, however, the MC1R is the only gene that is known to explain physiological variation in human pigmentation (rather than just rare Mendelian phenotypes such as albinism) (8, 9). Much potential interest in the MC1R therefore relates to the methodological problems inherent in relating sequence data to physiological state with a simple Mendelian framework. Work on the MC1R is therefore facing a combination of methodological problems that have not arisen with other pigment genes, including the presence of a large number of alleles; the relation between follicular and interfollicular pigmentation; and perhaps the most significant of all, how to assay human pigmentation and the cutaneous response to ultraviolet radiation in such a way that it is amenable to a

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Section: Population Genetics Of the Mc1rsupporting

confidence: 81%

Section: The Diversity Of Mc1r Allelesmentioning

confidence: 99%

Section: Population Genetics Of the Mc1rmentioning

confidence: 99%

Section: Population Genetics Of the Mc1rmentioning

confidence: 99%

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The Melanocortin 1 Receptor (MC1R): More Than Just Red Hair

Rees

2000

Pigment Cell Research

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170

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“… The melanocortin-1 receptor (MC1R), a G protein-coupled receptor, plays a crucial role in human and mouse pigmentation 1–8 . Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) 9 stimulates cAMP signaling and melanin production and enhances DNA repair after UV irradiation (UVR) 10–16 .…”

mentioning

confidence: 99%

Palmitoylation-dependent activation of MC1R prevents melanomagenesis

Chen

Zhu

Yin

et al. 2017

Nature

172

173

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The melanocortin-1 receptor (MC1R), a G protein-coupled receptor, plays a crucial role in human and mouse pigmentation1–8. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH)9 stimulates cAMP signaling and melanin production and enhances DNA repair after UV irradiation (UVR)10–16. Individuals carrying MC1R variants, especially those associated with red hair color, fair skin and poor tanning ability (RHC-variants), are associated with higher risk of melanoma5,17,18,19,20. However, how MC1R activity might be modulated by UV irradiation, why redheads are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit remain unresolved questions. Here we demonstrate a potential MC1R-targeted intervention strategy to rescue loss-of-function MC1R in MC1R RHC-variants for therapeutic benefit based on activating MC1R protein palmitoylation. Specifically, MC1R palmitoylation, primarily mediated by the protein-acyl transferase (PAT) ZDHHC13, is essential for activating MC1R signaling that triggers increased pigmentation, UVB-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-MC1Re/eJ mice expressing MC1R RHC-variants we show that pharmacological activation of palmitoylation rescues the defects of MC1R RHC-variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.

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