Linkage disequilibrium in human populations

Abstract

Whereas the human linkage map appears on limited evidence to be constant over populations, maps of linkage disequilibrium (LD) vary among populations that differ in gene history. The greatest difference is between populations of sub-Saharan origin and populations remotely derived from Africa after a major bottleneck that reduced their heterozygosity and altered their Malecot parameters, increasing the intercept M that reflects association in founders and decreasing the exponential decline ɛ. Variation among populations within this ethnic dichotomy is much smaller. These observations validate use of a cosmopolitan LD map based on a sizeable sample representing a large population reliably typed for markers at high density. Then an LD map for a region or isolate within an ethnic group may be created by fitting the sample LD to the cosmopolitan map, estimating Malecot parameters simultaneously. The cosmopolitan map scaled by ɛ recovers 95% of the information that a local map at the same density gives and therefore more than the information in a low-resolution local map. Relative to a Eurasian cosmopolitan map the scaling factors are estimated to be 0.82 for isolates of European descent, 1.53 for Yorubans, and 1.74 for African Americans. These observations are consistent with a common bottleneck (perhaps but not necessarily speciation) ≈173,500 years ago, if the bottleneck associated with migration out of Africa was 100,000 years ago. Eurasian populations (especially isolates with numerous cases) are efficient for genome scans, and populations of recent African origin (such as African Americans) are efficient for identification of causal polymorphisms within a candidate sequence

A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands

“…63,65 Conflicting evidence has, however, been reported regarding the actual degree of homogeneity of isolated populations. 64 A previous study on the Faroese population 25 indicated extensive LD among the 15 markers surveyed. Furthermore, the allelic diversity was smaller, although nonsignificant in the Faroese population compared to outbred populations.…”

“…Furthermore, background LD may due to random genetic drift extend over greater genetic distances in isolated populations, thereby reducing the sample size and the number of markers needed to identify specific genes. 63,64 In addition, isolated populations may be more suitable for association mapping because of the more homogeneous environmental background. 63,65 Conflicting evidence has, however, been reported regarding the actual degree of homogeneity of isolated populations.…”

A map of the human genome in linkage disequilibrium units

“…Linkage and LD are separate but complementary, with their different evidence as unconfounded, as is consistent with the goal of enhancing resolution of the linkage map without degrading the LD map. It remains to be determined whether one linkage map will suffice for different populations and whether a single composite LD map will be efficient for association mapping in samples with different Malecot parameters (7).…”

“…Using the HapMap data (3) to construct linkage disequilibrium (LD) maps measured in LD units (LDU) (4) and interpolating them into the sex-specific linkage map enhances the resolution of the linkage map as a by-product of our main objective, which is to construct genomewide LD maps with additive LDU distances. Such maps are applicable to association mapping (5,6), population comparisons (7)(8)(9), and identification of genomic regions that are influenced by selection (10). LD mapping has begun the task of explaining and exploiting complexities (8) that do not affect application of the Malecot model (4) to create an LD map but determine how the map should be used to increase resolution of the linkage map.…”

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.…”