Editors' ChoiceType 2 Diabetes

A Metabolic Relic

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Science Translational Medicine  22 Jan 2014:
Vol. 6, Issue 220, pp. 220ec16
DOI: 10.1126/scitranslmed.3008436

By using the wealth of genetic diversity in human populations, studies across ethnic groups offer an approach to accelerate the biological and evolutionary understanding of disease. This goal can be accomplished by identifying genetic risk factors frequent in one—but not all—genetic ancestries. Factors matching this pattern are particularly interesting, owing to excess burden of disease in many non-European groups. Motivated by this framework, the Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes (T2D) consortium recently reported their efforts to characterize genetic risk in samples of Mexican and Latin American ancestry.

This study—involving more than 8200 subjects—first examined whether established T2D risk factors previously identified from studies of European and Asian populations were also implicated in the Americas. At 82% of sites, the reported risk allele was the same across ancestries, with several sites also convincingly associated in the Americas. Next, they reported two new associations, one of which was tagged by a risk haplotype carrying four missense variants in the SLC16A11 gene (which encodes a solute carrier) and was replicated in ~22,000 additional samples. Notably, this risk haplotype is common among Mexican and Latin ancestries, but absent in Africa and Europe and infrequent in Asia, explaining why this observation escaped previous scrutiny. Functional experiments demonstrated SLC16A11 mRNA expression in liver, salivary gland, and thyroid, and localization studies placed this gene at the endoplasmic reticulum. Further expression studies of SLC16A11 in HeLa cells (which do not normally express the gene) followed by metabolomics experiments revealed increases in triacylglycerol, a biomarker with previous reported association with T2D in prospective cohorts. In a final note of interest, the group also found that the risk haplotype matched a sequence from an unpublished genome of a Neanderthal from Denisova Cave, with identity extending a massive 73 kilobase in haplotype carriers. Population genetics analysis supported one possible explanation: The haplotype was introduced relatively recently into modern humans through archaic admixture (that is, interbreeding of modern humans with Neanderthals and Denisovans).

A formal demonstration of causality for SLC16A11 and triacylglycerol biology still requires additional evidence. But, the work illustrates that a great deal of evolutionary and biological mysteries of the genome remain to be found. Genetic relics from our very distant ancestors seem still to have a role to play in the phenotypic diversity observed in modern humans.

The SIGMA Type 2 Diabetes Consortium, Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature published online 25 December 2013 (10.1038/nature12828). [Abstract]

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