Local Ancestry Association, Admixture Mapping, and Ongoing Challenges.

Abstract

Genome-wide association is the most widely used methodology for mapping of disease genes for complex traits. Among many limitations of this approach is the requirement for investigating large disease populations and use of sizeable number of genetic markers, which necessitates correction for multiple comparisons and is a reason for its reduced power for signal detection. These limitations have prompted alternative approaches to identify novel disease loci. One such approach is the admixture mapping, which provides a more powered alternative for gene discovery in admixed populations for a trait that is differentially distributed in the ancestral populations. One such example is the African American population, which is at increased risk for chronic and end-stage renal disease, HIV-associated nephropathy, and focal segmental glomerulosclerosis, which are believed to originate from African ancestry. See Article by Shendre et al In the classical sense, admixture is the result of breeding between individuals from ≥2 isolated populations. The consequence of the gene flow is temporary generation of long haplotype blocks that contains genetic variants of one or another population. The approach in admixture mapping is based on the assumption that in the admixed populations the disease-causing alleles will be more frequent on chromosome segments derived from the ancestral population with the higher prevalence for the disease. The admixture mapping associates ancestry of haplotype block with a specific trait using differences in allele frequencies of the ancestral population. The haplotype blocks become shorter with increasing age of the admixed population through higher recombination events during each meiosis. Shorter admixed linkage disequilibrium (LD) blocks require a higher density of markers to differentiate chromosome ancestry transition. In admixed populations such as African Americans or Hispanics, the gene flow has originated within the last several hundred years, resulting in linked alleles that show extended LD relative to the ancestral populations. …