DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence

This study of allelic association using three Intra- and twoextragenlc markers within 150 kb of the Huntlngton disease (HD)mutation has provided evidence for linkage disequilibrium forfour of five markers. Haplotype analysis of 67 HD families usingmarkers in strong linkage disequilibrium with HD Identifiedtwo haplotypes underlying 77.6% of HD chromosomes. Normal chromosomeswith these two haplotypes had a mean number of CAG repeats significantlylarger than and an altered distribution of CAG repeats comparedwith other normal chromosomes. Furthermore, haplotype analysisof five new mutation families reveals that HD has arisen onthese same two chromosomal haplotypes. These findings suggestthat HD arises more frequently on chromosomes with specificDNA haplotypes and higher CAG repeat lengths. We then studiedCAG and CCG repeat lengths In the HD gene on 896 control chromosomesfrom different ancestries to determine whether the markedlyreduced frequency of HD in Finland, Japan, China and AfricanBlacks Is associated with an altered frequency of DNA haplotypesand subsequently lower CAG lengths on control chromosomes comparedto populations of Western European descent. The results showa highly significant positive correlation between CAG size onnormal chromosomes and the frequency of HD and a significantinverse relationship between CAG and CCG repeat lengths. Inpopulations with lowered prevalence rates of HD, CAG repeatlengths are smaller and the distribution of CCG alleles Is markedlydifferent from Western European populations. These findingssuggest that, in addition to European emigration, new mutationsmake a contribution to geographical variation of prevalencerates and is consistent with a multistep model of HD developingfrom normal chromosomes with higher CAG repeat lengths.