The three modifier mutations recovered in msl1 cluster around the PEHE domain.
The enhanced pigmentation we observe with the modifier mutations cannot be due to MSL1 haploinsufficiency, but rather the modifiers must make proteins with altered activities.
The dominant behaviour of the new modifier mutations might be explained if modifier MSL1 subunits dimerised in vivo with wild-type polypeptides made from the other allele.
Thus in that case, the modifier gene is another mutation on the same protein.
This dynamic produces indirect selection on linked recombination rate modifiers, whereby linked mutations on the drive/insensitive background that decrease recombination between distorter and responder will be favored (Charlesworth and Hartl 1978).
Previously, genetic modifier regions for the effect of the myostatin Mstn Cmpt-dl1Abc mutation on muscle mass have been identified on chromosomes 3, 5, 7, 11, 16, and X in a cross between Comp9 and CAST/Ei lines [ 23].
Further consider a modifier allele that on average has no main effect, but that increases variance in the trait (e.g. through epistatic interactions or by increasing mutation rate at the trait).
In the present study, we focused on investigating the association of variants in IGF1, IGFBP1, IGFBP2, IGFBP5, IGF1R, and IRS1 as potential disease modifiers in mutation carriers of BRCA1 and BRCA2.
Previous studies have shown that MDM2 SNP309 and p53 codon 72 have modifier effects on germline P53 mutations, but those studies relied on case-only studies with small sample sizes.
Thus, it can be considered a rare variant with a possible modifier effect on the phenotypic expression of the concomitant mutation.
