Human genome sequence variation and the influence of gene history, mutation and recombination


Variation in the human genome sequence is key to understanding susceptibility to disease in modern populations and the history of ancestral populations. Unlocking this information requires knowledge of the patterns and underlying causes of human sequence diversity. By applying a new population-genetic framework to two genome-wide polymorphism surveys, we find that the human genome contains sizeable regions (stretching over tens of thousands of base pairs) that have intrinsically high and low rates of sequence variation. We show that the primary determinant of these patterns is shared genealogical history. Only a fraction of the variation (at most 25%) is due to the local mutation rate. By measuring the average distance over which genealogical histories are typically preserved, these data provide the first genome-wide estimate of the average extent of correlation among variants (linkage disequilibrium). The results are best explained by extreme variability in the recombination rate at a fine scale, and provide the first empirical evidence that such recombination 'hot spots' are a general feature of the human genome and have a principal role in shaping genetic variation in the human population.

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Figure 1: Correlation in heterozygosity.
Figure 2: Cis versus trans comparisons.
Figure 3: Impact of gene history on the correlation in heterozygosity.
Figure 4: Correlation in mutation rate (inferred from sequence divergence).
Figure 5: Correlation in gene history.
Figure 6: Comparison of the observed and simulated correlation in gene history under a range of models of human demographic history and recombination.

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We thank T. Lavery, A. Rachupka and J. Platko for assistance with great ape sequencing; B. Gilman for computer support; D. Cutler, P. Donnelly, J. Hirschhorn, L. Kruglyak, S. Myers, J. Pritchard and J. Wakeley for discussions and advice; and the laboratory of E. Green and the Baylor Sequencing Center for depositing large-insert chimpanzee sequences into GenBank. D.E.R. was supported in part by a National Defense Science and Engineering fellowship. D.A. is a Charles E. Culpeper Scholar of the Rockefeller Brothers Fund and a Burroughs Wellcome Fund Clinical Scholar in Translational Research. This work was supported by grants from The SNP Consortium to E.S.L. and D.A., the Massachusetts General Hospital to D.A. and the National Institutes of Health to E.S.L..

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Correspondence to David Altshuler.

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