EXAMINATION OF FACTORS ASSOCIATED WITH INSTABILITY OF THE FMR1 CGG REPEAT

We examined premutation-female transmissions and premutation-male tran smissions of the FMR1 CGG repeat to carrier offspring, to identify fac tors associated with instability of the repeat. First we investigated associations between parental and offspring repeat size. Premutation-f emale repeat size was positively correlated with the risk of having fu ll-mutation offspring, confirming previous reports. Similarly, premuta tion-male repeat size was positively correlated with the daughter's re peat size. However, increasing paternal repeat size was associated als o with both increased risk of contraction and decreased magnitude of t he repeat-size change passed to the daughter. We hypothesized that the difference between the female and male transmissions was due simply t o selection against full-mutation sperm. To test this hypothesis, we s imulated selection against full-mutation eggs, by only examining premu tation-female transmissions to their premutation offspring. Among this subset of premutation-female transmissions, associations between mate rnal and offspring repeat size were similar to those observed in premu tation-male transmissions. This suggests that the difference between f emale and male transmissions may be due to selection against full-muta tion sperm. Increasing maternal age was associated with increasing ris k of expansion to the full mutation, possibly because of selection for smaller alleles within the offspring's soma over time; a similar effe ct of increasing paternal age may be due to the same selection process . Last, we have evidence that the reported association between offspri ng sex and risk of expansion may be due to ascertainment bias. Thus, f emale and male offspring are equally likely to inherit the full mutati on.