Fels Institute for Cancer Research; Temple University Medical School
The establishment and erasure of epigenetic marks on alleles at imprinted loci is often assumed to be universal. This assumption is based most often on the analysis of parental origin dependent gene expression in small numbers of individuals or inbred strains. However, the universal applicability of these small scale studies to large, genetically diverse populations is unlikely to be valid. In fact, the existence of population level variability in the presence of epigenetic marks at such loci would present a valuable opportunity to examine the roles of genetic and/or environmental factors in the establishment and erasure of these marks.
At the population level, variability in the erasure of epigenetic marks is predicted to result in the distortion of allelic inheritance ratios away from the 1:1 ratio predicted by Mendel's second law. As a test of this hypothesis, we have analyzed the transmission of alleles at loci on the X chromosome in forty-seven normal, genetic disease-free families. Because the X chromosome is subject to both parental origin dependent and non-parental origin dependent epigenetic marking processes (i.e. in addition to containing a number of imprinted genes, the X chromosome is subject to an inactivation process that may be imprinted (in extraembryonic tissues) or stochastic (in embryonic tissues)), failure to erase either type of modification is predicted to result in the failure of the marked allele to appear in the subsequent generation. We have found a significant deviation from the expected Mendelian 1:1 ratio of grandpaternal: grandmaternal alleles at loci in Xp11.4-p21.1. The distortion in inheritance ratio was found only among male offspring and was manifested as a strong bias in favor of the inheritance of the alleles of the maternal grandfather. Our analysis of recombinant chromosomes inherited by male offspring indicates that an 11.6 cM-interval on the short arm of the X chromosome, bounded by DXS538 and DXS7, contains an imprinted gene that affects the survival of male embryos.