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

Abstract

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.

Genetic diversity patterns at the human clock gene period 2 are suggestive of population-specific positive selection

“…A low nucleotide diversity can be the consequence of either local gene history (for example natural selection) or low mutation rate. 37 We estimated a sequence divergence value between human and chimp PER2 equal to 1.3%, very similar to that reported for the human-chimp genome-wide comparison (1.2%). 16 Thus, based on the assumption that in any genomic region, the amount of observed inter-species sequence divergence largely depends on the mutation rate, 37 a low mutation rate for the human PER2 gene seems to be unlikely.…”

Using haplotype blocks to map human complex trait loci

“…Block-like patterns have now been observed in the immunoglobulin cluster on 5q31 [6], within HLA [13] and throughout chromosomes 21 [9] and 22 [14]. In one study [13], these blocks were flanked by precisely localized recombination hotspots, leading to suggestions that PUNCTATE RECOMBINATION could be a general phenomenon underlying block structure [8,10,11].…”

“…It is also clear that understanding LD patterns in common haplotypes will be insufficient for studies of rare variants. Nevertheless, if blocks do prove to be ubiquitous features of the genome [10,11], the simplicity of block structure within high LD regions could enhance association studies of common alleles, because recombination sites could delimit boundaries for candidate genes and indicate how far to extend the search for functional variants. In addition, when all common haplotypes in a region have been evaluated, additional genotyping would provide little additional information.…”

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

“…More recently, studies have reported that the genome can be divided into blocks defined by LD between pairs of marker in a range from 5 to 100 kb with population differences in the extension. 42,54,55,57,67,68 Most of these studies report LD data for markers spanning large genomic regions, and used pre-ascertained SNPs from public databases with limited marker density. 56,[69][70][71] The identification of smaller blocks within candidate genes is probably beyond the resolution of these studies because of inadequate marker density for detection of LD patterns.…”