Linkage disequilibrium in the human genome

Abstract

With the availability of a dense genome-wide map of single nucleotide polymorphisms (SNPs), a central issue in human genetics is whether it is now possible to use linkage disequilibrium (LD) to map genes that cause disease. LD refers to correlations among neighbouring alleles, reflecting 'haplotypes' descended from single, ancestral chromosomes. The size of LD blocks has been the subject of considerable debate. Computer simulations and empirical data have suggested that LD extends only a few kilobases (kb) around common SNPs, whereas other data have suggested that it can extend much further, in some cases greater than 100 kb. It has been difficult to obtain a systematic picture of LD because past studies have been based on only a few (1-3) loci and different populations. Here, we report a large-scale experiment using a uniform protocol to examine 19 randomly selected genomic regions. LD in a United States population of north-European descent typically extends 60 kb from common alleles, implying that LD mapping is likely to be practical in this population. By contrast, LD in a Nigerian population extends markedly less far. The results illuminate human history, suggesting that LD in northern Europeans is shaped by a marked demographic event about 27,000-53,000 years ago.

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

“…In agreement with previously published surveys of LD, [59][60][61] the overall rate of LD decay in African-Americans is greater than among Asians and European-Americans (Figure 4). However, LD decay is not homogeneous across Figure 2 The distribution of cSNPs in the UGT1A locus.…”

Conceptualizing human variation

“…Several competing, but not necessarily exclusive, hypotheses exist to describe the genetic contribution to complex disease, including the common disease-common variant (CDCV) hypothesis and the multiple rare variants (MRV) hypothesis [27][28][29][30][31][32] . If it turns out to be that much of the genetic variation contributing to disease is old and shared by most human populations, as implied by the CDCV hypothesis, then differences in the health status of population groups (health disparities) will be largely due to differences in exposure to cumulative environmental insults.…”

Extreme population differences across Neuregulin 1 gene, with implications for association studies

“…[33][34][35][36][37][38][39] The general pattern found in the regions examined so far is a series of discrete tracts of low recombination, high LD and therefore with a reduced number of haplotypes, the so-called 'haplotype blocks' bounded by recombination hotspots. Haplotype block structure has been found to vary according to genomic region (due to genomic factors affecting its pattern) and also between different global populations (due to demographic factors), 33,36,[38][39][40][41][42][43][44] see Bertranpetit et al 45 for a review. In fact, the goal of the International HapMap Project (http://www.hapmap.org) is to develop a haplotype map of the human genome, the HapMap, which will describe the common patterns of human DNA sequence variation in four distinct human populations.…”