Global analysis of ATM polymorphism reveals significant functional constraint

ATM, the gene that is mutated in ataxia-telangiectasia, is associated with cerebellar degeneration, abnormal proliferation of small blood vessels, and cancer. These clinically important manifestations have stimulated interest in defining the sequence variation in the ATM gene. Therefore, we undertoo k a comprehensive survey of sequence variation in ATM in diverse human popu lations. The protein-encoding exons of the gene (9,168 bp) and the adjacent intron and untranslated sequences (14,661 bp) were analyzed in 93 individu als from seven major human populations. In addition, the coding sequence wa s analyzed in one chimpanzee, one gorilla, one orangutan, and one Old World monkey. In human ATM, 88 variant sites were discovered by denaturing high- performance liquid chromatography, which is 96%-100% sensitive for detectio n of DNA sequence variation. ATM was compared to 14 other autosomal genes f or nucleotide diversity. The noncoding regions of ATM had diversity values comparable to other genes, but the coding regions had very low diversity, e specially in the last 29% of the protein sequence. A test of the neutral ev olution hypothesis, through use of the Hudson/Kreitman/Aguade' statistic, r evealed that this region of the human ATM gene was significantly constraine d relative to that of the orangutan, the Old World monkey, and the mouse, b ut not relative to that of the chimpanzee or the gorilla. ATM displayed ext ensive linkage disequilibrium, consistent with suppression of meiotic recom bination at this locus. Seven haplotypes were defined. Two haplotypes accou nted for 82% of all chromosomes analyzed in all major populations; two othe rs carrying the same D126E missense polymorphism accounted for 33% of chrom osomes in Africa but were never observed outside of Africa. The high freque ncy of this polymorphism may be due either to a population expansion within Africa or to selective pressure.