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It may not be that simple

Posted by JLightner on 20 Jan 2009 at 08:32 GMT

I found this research very interesting. The conclusions seem plausible given the information presented. However, there are several important underlying assumptions that were made. First, most non-synonymous substitutions should be associated with a change in phenotype; otherwise there is no real life mechanism to account for the purifying selection suggested by the statistical evaluation. Second, the statistical methods used require the assumption that the underlying mutations are essentially random.

At first glance these assumptions may seem quite reasonable. However, there is data from MC1R research that suggests this might not be the case at this locus. The same mutation (CTG→CCG) responsible for L102P in the pig appears in black cattle (L99P; the pig has a three amino acid duplication early in the amino acid chain; thereafter numbers are higher by 3 than most mammals when the sequences are aligned). Also, the same mutation (GAC→AAC) causing the D124N in pigs is found in black sheep (as D121N, of course). This was pointed out by Klungland and Våge (2000, p. 228). Since common ancestry seems an implausible explanation, they suggest that there may be a limited number of ways to form a constitutively active receptor and that this unexpected result may be due to strong selection. However, research in mustelids showed that an identical mutation (CTG→CCG causing L99P) in the American mink that lacked a black phenotype. There were 3 other nucleotide changes in mustelids that corresponded to locations where constitutively active receptors were formed in other species, yet surprisingly these mustelids showed no obvious selectable phenotype. Further, deletion events very similar to those found in melanistic cat species were identified in some mustelids that again lacked a melanistic phenotype (Hosoda et al., 2005). The appearance of identical or very similar mutations within this protein (which is 317 amino acids in most mammals, 320 in pigs) in very different species suggests that there may be something significantly biasing the underlying mutation pattern within this gene.

Another interesting MC1R pattern was found in humans. Harding et al (2000) found 5 haplotypes among the more than 100 Africans they studied, yet no amino acid variants. They concluded the MC1R is under strong functional constraint in Africa and suggested that since some mutations in this gene are associated with increased cancer risk, this explains the pattern seen since sun exposure, which is generally higher near the equator, is also a risk factor for these same cancers. The problem is that their conclusion ignores the epidemiology of these cancers. Certainly the risk of cancer is higher for at least some carrying MC1R mutations in equatorial regions, but when these diseases strike after the prime childbearing years (e.g. malignant melanoma, the deadliest of the cancers, has an average age of onset around 57 years) they certainly don’t explain the proposed purifying selection. I have discussed these interesting findings in more detail in a recent paper (Lightner 2008). It appears that other factors, perhaps even epigenetic factors, are biasing the underlying mutations within this gene.

RE: It may not be that simple

JLightner replied to JLightner on 20 Jan 2009 at 08:33 GMT

I tried to embed links for the articles, but I got an error message when I posted it. The full references for my previous comments are:

Harding, R. M., E. Healy, A. J. Ray, N. S. Ellis, E. Flanagan, C. Todd, C. Dixon, A. Sajantila, I. J. Jackson, M. A. Birch-Machin, and J. L. Rees. 2000. Evidence for variable selective pressures at MC1R. American Journal of Human Genetics 66:1351–1361.

Hosoda, T., J. J. Sato, T. Shimada, K. L. Campbell, and H. Suzuki. 2005. Independent nonframeshift deletions in the MC1R gene are not associated with melanistic coat coloration in three mustelid lineages. Journal of Heredity 96(5):607–613.

Klungland, H., and D. I. Våge. 2000. Molecular genetics and pigmentation in domestic animals. Current Genomics 1(3):223–242.

Lightner, J.K. 2008. Genetics of Coat Color I: The Melanocortin 1 Receptor (MC1R) Answers Research Journal 1:109-116.