A genomic portrait of human microsatellite variation

Abstract

Rapid advances in DNA sequencing and genotyping technologies are beginning to reveal the scope and pattern of human genomic variation. Although single nucleotide polymorphisms (SNPs) have been intensively studied, the extent and form of variation at other types of molecular variants remain poorly understood. Polymorphism at the most variable loci in the human genome, microsatellites, has rarely been examined on a genomic scale without the ascertainment biases that attend typical genotyping studies. We conducted a genomic survey of variation at microsatellites with at least three perfect repeats by comparing two complete genome sequences, the Human Genome Reference sequence and the sequence of J. Craig Venter. The genomic proportion of polymorphic loci was 2.7%, much higher than the rate of SNP variation, with marked heterogeneity among classes of loci. The proportion of variable loci increased substantially with repeat number. Repeat lengths differed in levels of variation, with longer repeat lengths generally showing higher polymorphism at the same repeat number. Microsatellite variation was weakly correlated with regional SNP number, indicating modest effects of shared genealogical history. Reductions in variation were detected at microsatellites located in introns, in untranslated regions, in coding exons, and just upstream of transcription start sites, suggesting the presence of selective constraints. Our results provide new insights into microsatellite mutational processes and yield a preview of patterns of variation that will be obtained in genomic surveys of larger numbers of individuals.

FIG. 1.

Genomic proportions of variable loci by repeat number and repeat length. Error bars represent 95% confidence intervals estimated by bootstrapping. The repeat number in the Venter sequence is used as the reference. Only repeat numbers with at least 50 loci (repeat range 3–32) are shown. Complete details and sample sizes appear in supplementary tables 1–6, Supplementary Material online.

FIG. 2.

Genomic proportions of variable loci by location. Error bars represent 95% confidence intervals estimated by bootstrapping. “5′ upstream” = loci within 1 kb upstream of transcription start sites.

FIG. 3.

Differences in repeat number among variable loci. Repeat number differences are shown as absolute values. Although small numbers of loci showed larger repeat number differences, the upper limit on the x axis is fixed at 20 to improve the clarity of presentation.