GENETIC FITNESS IN HUNTINGTONS-DISEASE AND SPINOCEREBELLAR ATAXIA-1 -A POPULATION-GENETICS MODEL FOR CAG REPEAT EXPANSIONS

An analysis of genetic fitness was performed in Huntington's Disease ( HD) and Spinocerebellar Ataxia 1 (SCA1) families. Two partially overla pping samples were used: clinically defined HD and SCA1 patients from families ascertained in definite geographical areas, and molecularly t yped carriers of HD and SCA1 mutations (CAG trinucleotide expansions). In both cases, a control group of normal relatives was used. HD and S CA1 patients born before 1915-20 had more children than normal control s. Carriers of HD and SCA1 mutations, all in the low/medium expansion range (37-49 and 47-54 CAG repeats respectively), had a higher number of children than controls up to more recent times (1935-1950). The rep roduction of heterozygotes for large expansions could be analysed only in subjects born after 1950 and provided indirect evidence of a lower than normal number of children. The above results fit a model based o n a differential fitness according to the degree of expansion. Such a model predicts that 1) up to relatively recently the frequency of alle les in the low/medium range has been maintained or even increased by t he increased fitness of their carriers, as well as by new mutations, a nd 2) the frequency of large expansions, part of which are lost at eac h generation, is maintained through further expansions of alleles in t he low/medium expansion range. The implications of such a model on lin kage disequilibrium and the possible spread of these diseases in futur e generations are discussed.