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South Asia Population Study Highlights Founder Events, Recessive Disease Clues

NEW YORK (GenomeWeb) – Investigators from India and the US have started untangling recessive disease risk patterns in South Asia by uncovering historical founder events in these populations.

As they reported online today in Nature Genetics, the researchers analyzed new and available array-based genotyping profiles for thousands of individuals from more than 260 South Asian groups. Using a newly developed algorithm, they identified apparent founder events for dozens of the groups considered, suggesting that it may be possible to decrease recessive disease risk in parts of South Asia.

"The pervasive founder events in South Asia present a potential opportunity for decreasing disease burden in South Asia, as highlighted by studies of founder groups of European ancestry — including Ashkenazi Jews, Finns, Amish, Hutterites, Sardinians, and French Canadians — which have resulted in the discovery of recessive disease-causing mutations in each group," co-corresponding authors Kumarasamy Thangaraj of the Centre for Cellular and Molecular Biology in Hyderabad, India, David Reich of Harvard Medical School, and their colleagues wrote.

For their analysis, the researchers used Affymetrix Human Origins SNP arrays to genotype 1,663 individuals from 230 South Asian groups. To that, they added existing genotyping profiles for more than 1,200 individuals from dozens of South Asian groups and for seven Ashkenazi Jewish individuals.

Based on the length of sequences showing identity by descent in individuals from the same populations that were not recently related, the team retraced founder events in the 263 South Asian groups considered, with an eye to translating that information into recessive disease risk estimates.

The researchers' founder event analysis — validated with comparisons that relied on other methods that did not rely on IBD scores — pointed to significant founder events in 81 of the South Asian groups, including 14 populations with a million or more members.

They noted that these events "affect a large fraction of South Asian groups," and represent an avenue for dialing down recessive disease risk that "is very different from risk due to marriages among close relatives."

"[A]lthough most studies mapping recessive disease-associated genes in South Asia have focused on families that are the products of marriages between close relatives," the authors explained, "recessive diseases are also likely to occur at an elevated rate, even in non-consanguineous cases, because of distant shared ancestors."

To take a closer look at recessive disease patterns in a founder event context, the team focused on genome-wide SNP profiles for a dozen individuals from southern India who had been diagnosed with a skeletal condition called progressive pseudorheumatoid dysplasia.

Half of the individuals had the same substitution in the WISP3 gene, which has been implicated in the disease previously, along with surrounding sequences that were consistent with IBD, the team reported. The remaining individuals lacked this IBD, but were more likely to come from consanguineous marriages and had mutations associated with a distinct skeletal condition known as mucopolysaccharidosis IVA.

Based on their findings, the researchers argued some of the South Asian populations that are prone to founder effects may benefit from the same sorts of recessive disease allele databases used to prevent conditions such as Tay-Sachs in the Ashkenazi Jewish population, particularly among groups that practice arranged marriage.

"Given the potential for saving lives, this or similar types of research could be a valuable investment for future generations," the authors concluded.