Prospects of admixture linkage disequilibrium mapping in the African-American genome.

Abstract

Linkage disequilibrium (LD) is the phenomenon where alleles at two separate genetic loci are found more often together at the population level than would be expected based on their individual allelic frequencies. Possible causes of LD include recent mutation, founder effects, or selection. LD that arises because of these factors is rare and generally observed only between very tightly linked loci. Another potential cause of LD is population admixture. Admixture linkage disequilibrium (ALD) arises when two populations that have been separated for a long time recombine. If allele frequencies at the same loci are markedly different, then LD can even occur between alleles at locus pairs on different chromosomes. ALD between unlinked loci quickly dissipates over a couple of generations, but LD between linked loci decays more slowly and may be detectable 10 to 20 generations after the initial admixture (1). An important concept related to ALD is the method by which the two populations are mixing. Recently, Pfaff et al. (2) described how different models of admixture can affect the observed LD over time. Figure 1 describes the two models. In the hybrid-isolation (HI) model, admixture occurs in a single generation and is followed by recombination and drift with no further contribution from either parent population. In the continuous-gene-flow (CGF) model, admixture occurs at a steady but reduced rate in every generation such that the cumulative admixture at generation Gt is equal to the HI model. Whereas the HI model introduces a higher level of LD into the hybrid population in the initial generations, the CGF model retains LD in the hybrid population longer and at a higher level than the HI model after approximately 15 generations from the initial admixture. In the case of the African-American gene pool, the CGF model is probably most appropriate. The history of African Americans can be traced back to 1619 when the first Africans arrived at the British colonies, although the presence of African slaves may have predated this by almost 100 years. Institutional slavery began in the 16 th century, but it was not until the beginning of the 18 th century that slave importation rates were significant, reaching their peak around 1800. The generally accepted number of total Africans that were brought to North America as slaves ranges between 380,000 and 570,000. The 2000 census estimate of the United States African-American population is approximately 35 million. The African slave trade affected mainly west and west central Africa, but, even in this defined geographic area, a number of genetically distinct populations were involved. More importantly, in terms of admixture of long-isolated populations, is the mixing of the native African populations with European and Native American populations. The gene pool of African-Americans in the United States has between 10 ‐ 20% Caucasian admixture (3). Admixture mapping using LD can be used as a potential alternative to traditional linkage analysis as a gene mapping tool. Genetic associations that arise between a disease gene and marker locus due to LD may be detected either in a case‐ control or family study with substantially fewer subjects than are required in traditional linkage studies (4). The current most dense genetic maps that use polymorphic markers in the form of short tandem repeats have marker spacing in the range of 2 to 3 cM throughout the genome (5). However, in most populations of European origin, LD rarely extends beyond 1 cM. Although future genetic maps that use single nucleotide base pair substitutions will provide a denser coverage of the human genome, such maps are currently incomplete. Therefore, it is questionable whether LD can be used as a genomescanning tool at this time in Caucasians.