This week in PLoS Genetics, investigators at the University of Michigan describe the "pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J." In developing a mouse model of this severe form of Charcot-Marie-Tooth neuropathy "by expressing a Fig4-I41T cDNA transgene on the Fig4 null background," the team found that "FIG4-I41T is a hypomorphic allele encoding a protein that is unstable in vivo … suggesting that patients with CMT4J could be treated by increased production or stabilization of the mutant protein." The team suggests its transgenic mouse model for CMT4J will be useful for testing in vivo interventions going forward.
An international team led by researchers at the Wellcome Trust Centre for Human Genetics reports its fine-mapping of previously identified associations, with which it identifies novel, independent colorectal cancer predisposition SNPs near BMP4 and BMP2. "Our data emphasize that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases," the authors write.
In another PLoS Genetics paper, researchers at Florida State University and at the University of Idaho report on the effects of epistasis for beneficial mutations in the ssDNA bacteriophage ID11. The team found that epistatic interactions between beneficial mutations were all antagonistic in the 18 double mutants it created (out of the 36 total possible for the nine beneficial mutations). The researchers also identified "a number of cases of decompensatory interactions, an extreme form of antagonistic epistasis in which the second mutation is actually deleterious in the presence of the first."
And in PLoS One this week, investigators at Brown University report their use of integrative, genome-wide approaches to identify "CpG methylation profiles and mRNA alterations associated with low sperm motility." Of the CpG loci with significantly altered methylation, the team says 80 percent were hypomethylated, and "194 were associated with imprinted genes and were almost equally distributed into hypermethylated (predominantly paternally expressed) and hypomethylated (predominantly maternally expressed) groups."