Admixture mapping is a genetic method for locating genes that contribute to diseases, particularly those that appear at different rates across various ancestral groups. It operates by analyzing the genetic makeup of populations that have a history of interbreeding between two or more previously separate populations. This approach scans a person’s genetic information to find broad regions linked to ancestry, which can then be connected to disease risk.
The Principle of Genetic Admixture
Genetic admixture is the result of interbreeding between two or more populations that were previously isolated from one another. This process creates subsequent generations whose chromosomes are a mosaic, composed of segments from each of the ancestral populations. Each time a new generation is produced, these chromosomal segments are shuffled through a process called recombination, creating a unique genetic tapestry for every individual.
Scientists study recently formed admixed populations where this process has occurred. A primary example is the African American population, which has ancestry from both West Africa and Europe. Another widely studied group is the Hispanic/Latino population, which has a combination of European, Native American, and African ancestry.
The assumption is that if a disease is more common in one of the original ancestral populations, then the genetic variants influencing that disease risk will also be more frequent on the chromosome segments inherited from that population. For instance, if a disease is more prevalent in individuals of West African descent compared to those of European descent, researchers hypothesize that the genes increasing risk are located on chromosomal segments of West African origin. By identifying these segments in an admixed population, scientists can narrow the search for the specific genes involved.
The Admixture Mapping Process
The execution of an admixture mapping study begins with careful population selection. Researchers focus on an admixed population where a particular disease shows a notable difference in prevalence between its founding ancestral groups. For example, to study a disease more common in individuals of West African ancestry, scientists would recruit African American participants.
DNA samples are collected from a large cohort of individuals, including people who have the disease (cases) and people who do not (controls). The process then involves several steps:
- Genotyping: The genetic information from DNA samples is analyzed in a laboratory to identify specific genetic markers across the entire genome for each participant.
- Ancestry Assignment: Using a specialized set of genetic markers called Ancestry-Informative Markers (AIMs), researchers determine the likely ancestral origin—for instance, European or African—of each chromosomal block in every individual.
- Statistical Analysis: Researchers perform a statistical scan across the genome, comparing the ancestry of each chromosomal region between the case and control groups. If a specific region from one ancestry is overrepresented in the cases, it provides evidence that a gene influencing the disease is located within that segment.
Identifying Disease Genes
Admixture mapping has successfully guided researchers to specific genes for diseases that show different rates across ancestral populations. One prominent discovery involves kidney disease in African Americans, who have a higher risk for certain types of kidney failure. The method pointed to a specific region on chromosome 22.
Subsequent investigations of this region identified two variants in the apolipoprotein L1 (APOL1) gene. These gene variants, common in people of West African descent, are strongly associated with a higher risk of developing kidney disease. The discovery provided a clear biological explanation for the observed health disparity.
Another finding relates to prostate cancer. The risk for this cancer is higher in men of African descent compared to men of other ancestries. Admixture mapping studies in African American men highlighted a region on chromosome 8, specifically at a location designated 8q24, which is a regulatory region that influences the activity of other genes.
Further analysis of the 8q24 region has revealed several genetic variants linked to increased prostate cancer risk. These findings have helped explain a portion of the increased susceptibility observed in men of African ancestry. This demonstrates how admixture mapping can uncover genetic factors even in complex regions of the genome.
Admixture Mapping and Other Genetic Methods
Admixture mapping is one of several tools available to geneticists, and it occupies a unique space alongside other methods like Genome-Wide Association Studies (GWAS). A GWAS scans the entire genome of many individuals to find small, single-letter changes in the DNA code, known as single nucleotide polymorphisms (SNPs), that are associated with a specific disease.
The primary difference is their scale. Admixture mapping identifies large chromosomal segments, spanning millions of DNA letters, that are linked to a disease because of their ancestral origin. In contrast, GWAS homes in on tiny, individual points of genetic variation.
These two methods are not mutually exclusive; they are complementary. Researchers often use admixture mapping as a first step to survey the genome and identify a broad chromosomal region of interest. Fine-mapping techniques like GWAS and direct DNA sequencing can then be used to search within that region for the specific gene or variants responsible for the disease association.