Papers on :Normal pigmentation variation in humans

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Worldwide polymorphism at the MC1R locus and normal
pigmentation variation in humans.

Abstract
While there have been many advances in our understanding of the genetics of pathological skin pigmentation in humans, our knowledge
about what determines variation in normal skin color is still incomplete. Variation in one gene, melanocortin 1 receptor (MC1R), has been
associated with red hair and fair skin in Europeans. However, this gene might also play an important role in shaping pigmentation of other
human populations, where it experiences different selective pressures. Below we review what is currently known about polymorphism and
selection at the MC1R coding and promoter regions in human populations, the pattern of MC1R evolution in nonhuman primates, and the
interaction of MC1R with other genes.


The studies of Rana et al. [35] and Harding et al. [15] found
no nonsynonymous substitutions and only three synonymous
substitutions among 25 and 53 African individuals screened,
respectively. This is unexpected since (1) African populations
are usually more polymorphic than other populations as they
are most ancient [34]; and (2) some African individuals are
at one extreme of skin color (thus, there could be variants
specific to Africans). The level of polymorphism at theMC1R
coding region is the lowest in African populations.

However, the antagonistic agouti signaling
protein (ASIP) can compete with
-MSH for binding
to the MC1R. When ASIP is able to completely block or
inhibit
-MSH, pheomelanin is produced instead of eumelanin
(Fig. 1).

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Evidence for Variable Selective Pressures at MC1R
Rosalind M. Harding,1 Eugene Healy,2,* Amanda J. Ray,2 Nichola S. Ellis,2 Niamh Flanagan,2 Carol Todd,2 Craig Dixon,2 Antti Sajantila,3 Ian J. Jackson,4 Mark A. Birch-Machin,2 and Jonathan L. Rees2,†



It is widely assumed that genes that influence variation in skin and hair pigmentation are under selection. To date, the melanocortin 1 receptor (MC1R) is the only gene identified that explains substantial phenotypic variance in human pigmentation. Here we investigate MC1R polymorphism in several populations, for evidence of selection. We conclude that MC1R is under strong functional constraint in Africa, where any diversion from eumelanin production (black pigmentation) appears to be evolutionarily deleterious. Although many of the MC1R amino acid variants observed in non-African populations do affect MC1R function and contribute to high levels of MC1R diversity in Europeans, we found no evidence, in either the magnitude or the patterns of diversity, for its enhancement by selection; rather, our analyses show that levels of MC1R polymorphism simply reflect neutral expectations under relaxation of strong functional constraint [glow=red,2,300]outside[/glow] Africa.


www.ncbi.nlm.nih.gov/pmc/articles/PMC1288200/

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Chain of molecular events that increases skin cancer risk identified

2010-06-03 16:50:00


Scientists have identified a chain of molecular events that increase one's risk of sun-induced skin cancer.

The study, appearing online in The FASEB Journal, may lead to new tests that access personal skin cancer risk as well as a new generation of sunscreens that increase the skin's ability to protect itself from the sun's damaging rays.

Zalfa A. Abdel-Malek, a researcher involved in the work from the Department of Dermatology at the University of Cincinnati, said: Our study heralds the onset of personalized medicine for individuals who carry a change in the MC1R gene.

"The data we have obtained allows us to better predict which individuals will be at risk for skin cancer, as well as potentially why and to what degree. In the future, genetic testing for MC1R gene changes may be clinically available so that individuals can be made aware of the molecular basis of their risk prior to development of cancer."

Abdel-Malek and colleagues found that when a pigmentation gene called the "melanocortin 1 receptor" or MC1R does not function properly, skin cells do not respond to a hormone, called a-MSH, which causes cells to produce dark pigmentation to protect themselves from ultraviolet rays.

To make this discovery, the researchers studied 21 human skin cell cultures that express the MC1R gene in different ways.

Each culture was studied for expression of genetic changes of MC1R, pigment levels and the ability to respond to a-MSH.

The researchers also exposed the cell cultures to ultraviolet rays and measured the amount of DNA damage and the rate of its repair, as well as the percent of surviving melanocytes.

Then the scientists inserted a normal version of the MC1R gene into the skin cells and found that they responded properly to ultraviolet light by producing the pigment necessary to protect themselves.

These results give researchers testable strategies to reduce or prevent skin cancer.

The results also suggest that it may be possible to develop drugs or a new generation of sunscreens that restore the lost function of MC1R.

Gerald Weissmann, Editor-in-Chief of The FASEB Journal, said: "This research permits us know our own, personal risk for skin cancer.

"We've known for a long time that smearing on sunscreen is the best way to avoid skin cancer, but never how much or what kind.

This study points the way to new kinds of sunscreens that restore their skin's ability to protect itself from DNA damage." (ANI)

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