Germ- line genetic mutations or epigenetic modifications of mismatch- repair genes, MLH1 and MSH2, have been associated to hereditary nonpolyposis colorectal cancer. In this paper, authors claimed that they have found evidence of germ- line epimutation of MLH1 in a woman with cancer and in her son, thus supporting transgenerational epigenetic inheritance in humans, something that has been previously demonstrated in other species, like mice. Although they favour their epigenetic inheritance hypothesis, they did not discard other possible explanations:
Hitchins MP. et al. 2007. N Engl J Med 356(7):697-705
An alternative explanation for our findings is that epimutations are not inherited per se. Rather, they are erased in gametogenesis but reestablished in successive generations because of cis-acting or even trans-acting genetic factors that increase susceptibility to MLH1 epimutations. Examples of epigenetic silencing that are driven by genetic events in cis include deletion of imprint-control centers in imprinted disorders and expansion of triplet repeats within the FMR1 promoter in the fragile X syndrome. Such a mechanism may also explain the recently reported strongly heritable pattern of epimutation in MSH2, since the methylation state segregated faithfully with the genetic haplotype. In contrast, in the two families described in our study, we found no evidence of a fully penetrant in cis defect. Rather, they showed epimutations that were meiotically reversible and transmitted in a nonmendelian fashion. A simple explanation for this pattern is that epimutations can occur on any haplotype, and although they usually are cleared in the germ line, they may be retained at low but uncertain frequency.However, their observations could account for other possibilities, for example: Why isn't this an effect of the same shared environment, rather than an inherited trait? This would be in agreement with the spontaneous reversion of the MLH1 epimutation to normality during spermatogenesis that they found in one of the patients. Besides, epigenetic marks may vary through time, so any reseach that hopes to demonstrate transgenerational epigenetic inheritance should follow up the variation of methylation and histone marks periodically. For example, Fraga et al used pairs of twins of different age groups in a paper previously discussed here. As a consequence, in my opinion their observations are inconclusive to demonstrate epigenetic inheritance in humans, as was a controversial paper by Chan et al. (2006), that was previously discussed here.
Hitchins MP. et al. 2007. N Engl J Med 356(7):697-705
epigenetics
More comments can be found in the same issue of the NEJM, in this article of Gastroenterology, and at the Faculty of 1000 website.
