Distribution and evolution of CTG repeats at the myotonin protein kinase gene in human populations

We have analyzed the CTG repeat length and the neighboring Alu insertion/deletion (+/-) polymorphism in DNA samples from 16 ethnically and geographically diverse human populations to understand the evolutionary dynamics of the myotonic dystrophy-associated CTG repeat. Our results show that the CTG repeat length is variable in human populations. Although the (CTG)(5) repeat is the most common allele in the majority of populations this allele is absent among Costa Ricans and New Guinea highlanders. We have detected a (CTG)(4) repeat allele, the smallest CTG known allele, in an American Samoan individual. (CTG)(greater than or equal to 19) alleles are the most frequent in Europeans followed by the populations of Asian origin and are absent or rare in Africans. To understand the evolution of CTG repeats, we have used haplotype data from the CTG repeat and Alu(+/-) locus. Our results are consistent with previous studies, which show that among individuals of Caucasian and Japanese origin, the association of the Alu(+) allele with CTG repeats of S and greater than or equal to 19 is complete, whereas the Alu(-) allele is associated with (CTG)(11-16) repeats. However, these associations are not exclusive in non-Caucasian populations. Most significantly, we have detected the (CTG)(5) repeat allele on an Alu(-) background in several populations including Native Africans. As no (CTG)(5) repeat allele on an Alu(-) background was observed thus far, it was proposed that the Alu(-) allele arose on a (CTG)(11-13) background. Our data now suggest that the most parsimonious evolutionary model is (1) (CTG)(5)-Ala(+) is the ancestral haplotype; (2) (CTG)(5)-Alu(-) arose from a (CTG)(5)-Alu(+) chromosome later in evolution; and (3) expansion of CTG alleles occurred from (CTG)(5) alleles on both Alu(+) and Alu(-) backgrounds.