PMC:3492649 / 2083-6515 JSONTXT

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Admixture mapping is a method for localizing disease-causing genetic variants that differ in frequency across populations. This approach was proposed by McKeigue in 1998 [1]; it is based on the association of local chromosomal ancestry with the disease, to test for the linkage of the disease or trait with parental ancestry at each locus, defined as 0, 1, or 2 allele copies inherited from the ancestral populations. However, the idea of using genetic architecture in admixed genomes to locate disease-associated genes was actually first proposed by Rife in 1954 [2], although the original idea was to use the admixture linkage disequilibrium (ALD) generated in recently admixed human populations to assign the traits to linkage groups.\nAdmixture of populations often leads to extended linkage disequilibrium (LD), which could greatly facilitate the mapping of human disease genes [3-6]. Gene mapping by admixture linkage disequilibrium (MALD) has been shown to have special value theoretically [4, 7-14] and empirically [15-29]. MALD has received much attention recently [3, 5]. The initial attraction of MALD was its significantly increased extension of LD (or extended LD) in admixed populations, which requires far fewer markers in mapping disease genes. Previous studies predicted that MALD typically requires only 2,000-3,000 ancestry informative markers (AIMs) for a genomewide search [1, 16]. The utility of MALD depends upon how far LD extends over a chromosomal interval, which, in turn, dictates the spacing and number of markers required for a genomewide scan. Therefore, it is imperative to characterize the magnitude and extent of ALD in the admixed population in which MALD will be performed.\nStephens et al. [10] showed that ALD in African-Americans (AfAs) could exist up to 10 cM, even after 9 generations by simulation. Parra et al. [30] reported strong LD between the FY-null and AT3 loci, which are 22 cM apart on chromosome 1q22. Substantially extended LD in AfA populations were reported in several regions or chromosomes [31-33] using primarily short tandem repeat markers. Patterson et al. [12] showed that strong ALD extends to 17 cM on average in AfAs. Contrarily, it was also reported that the LD in AfA populations is shorter than or similar to those seen in non-admixed populations using single-nucleotide polymorphisms (SNPs)-detectable to about 44 kb or larger [34]. The contradicting observations might be due to the selection of the markers based on their allele frequency difference between the parental populations, as shown theoretically by Chakraborty and Weiss [7]. It is therefore important to examine empirically the relationship of LD in the admixed population and allele frequency difference between parental populations. In fact, there have been many studies that have investigated LD patterns in recent admixed populations, such as the AfAs, Mexicans, and Hispanics. In Asia, the only study published so far is on the Uyghurs in Xinjiang, China [35].\nIn practice, the principle of admixture mapping, proposed by McKeigue [1], is a little different from that of MALD, because it is based on the association of local chromosomal ancestry with the disease rather than on LD between the marker and phenotype, but the information and essence are the same. It is most advantageous to apply this approach to populations that have descended from a recent mix of two ancestral groups that have been geographically isolated for many tens of thousands of years, providing new insights into population history and genotype-phenotype relationships. With the efforts of many scientists in this field, statistical methods, panels of AIMs for admixture typing, and software programs have been rapidly developed; in addition, recent advances in genotyping and sequencing technologies have facilitated genomewide investigation of human genetic variations. Admixture mapping has been applied to a wide range of traits and diseases, for which it is hypothesized that the differences in disease rates across populations are due to population-specific frequency differences of the causal variant(s)."}