Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci.

Abstract

Admixture between genetically different populations may produce gametic association between gene loci as a function of the genetic difference between parental populations and the admixture rate. This association decays as a function of time since admixture and the recombination rate between the loci. Admixture between genetically long-separated human populations has been frequent in the centuries since the age of exploration and colonization, resulting in numerous hybrid descendant populations today, as in the Americas. This represents a natural experiment for genetic epidemiology and anthropology, in which to use polymorphic marker loci (e.g., restriction fragment length polymorphisms) and disequilibrium to infer a genetic basis for traits of interest. In this paper we show that substantial disequilibrium remains today under widely applicable situations, which can be detected without requiring inordinately dose linkage between trait and marker loci. Very disparate parental allele frequencies produce large disequilibrium, but the sample size needed to detect such levels of disequilibrium can be large due to the skewed haplotype frequency distribution in the admixed population. Such situations, however, provide power to differentiate between disequilibrium due just to population mixing from that due to physical linkage of loci-i.e., to help map the genetic locus of the trait. A gradient of admixture levels between the same parental populations may be used to test genetic models by relating admixture to disequilibrium levels. Admixture between two populations with different allele frequencies at two loci will produce a gametic association between these loci in any admixed population (1). Here, we refer to such gametic association as "mixture disequilibrium" to distinguish it from gametic association between closely linked loci. Such mixture disequilibrium will decay over time, but Earlier, we (3) showed the utility of using admixed populations for fitting genetic models of inheritance of complex diseases. The objective of the present paper is to show that the observed levels of disequilibrium between any two loci in such an array of admixed populations may be used to detect their linkage relationship and to differentiate the case of mixture disequilibrium between loci from the disequilibrium that can be ascribed to genetic linkage.MATHEMATICAL TREATMENT Mixture Disequilibrium in an Admixed Population. As in the case of traditional admixture models, we consider two loci (A and B) that are not affected by selection. Let A and a, B and b be the two segregating alleles at these loci, respectively. Suppose that an admixed population (Z) obtains a fraction (m) of its genes from ancestral population X, and a fraction (1 -m) from ancestral population Y. We assume that the admixture event has taken place in a single pulse at generation 0, and the populations are surveyed t generations after this event. This theory is discussed in more detail elsewhere (ref. 2 and unpublished work). Let r denote the recombination ...

Admixture as the basis for genetic mapping

“…Applications in ecology and evolution Although the potential of admixture mapping in evolutionary biology has been recognized for 15-20 years [25,26], the first successful applications were focused on human traits Figure 1. A schematic illustrating chromosomes of diploid recombinants that are suitable for coarse-and fine-scale mapping.…”

Replication in genetic studies of complex traits

“…On the other hand, recent admixture between lowand high-risk populations generates a systematic linkage disequilibrium which resembles that found in experimental line-cross designs of animals or plants. For this reason, many authors propose using recently admixed human populations with a known or estimated history (Chakraborty & Weiss, 1988;Briscoe et al 1994;Stephens et al 1994;McKeigue, 1997McKeigue, , 1998McKeigue et al 2000).…”

Distribution of ancestral chromosomal segments in admixed genomes and its implications for inferring population history and admixture mapping

“…[14][15][16] Theoretical and experimental analyses have shown that admixture mapping is a potentially promising tool for the identification of genetic variants compared with other gene mapping methods. 2,[15][16][17][18] The statistical power of admixture mapping relies on the elevated linkage disequilibrium (LD) and the ancestral chromosomal segments created by population admixture.…”

“…2,[15][16][17][18] The statistical power of admixture mapping relies on the elevated linkage disequilibrium (LD) and the ancestral chromosomal segments created by population admixture. 15,19,20 Although the features of LD pattern under different admixture models and their implications in admixture mapping have been investigated in various studies, 14,20,21 the influences of LACS distribution on the signatures of association have never been explored.…”