Ancient Origins of a Human Gene Associated with Diabetes

Ancient peopleRecently, researchers of the SIGMA Type 2 Diabetes Consortium published a paper in Nature identifying a new locus associated with a higher risk of type 2 diabetes (1). Considering the increasing prevalence of this metabolic disease in today’s sugar-filled world, any discovery that helps us understand diabetes is exciting news. However, the most interesting discovery published in this paper might not be this new gene variant but rather the origin of this variant in modern human populations: Neandertals.

In this Nature paper, researchers analyzed 9.2 million single nucleotide polymorphisms (SNPs) in 8,214 Mexicans and other Latin Americans, 3,848 of whom had type 2 diabetes, to find novel genes that are associated with a higher diabetes risk. In these screens, they confirmed several loci that are already associated with an increased risk of type 2 diabetes, but they also identified an additional locus that was previously unreported. This locus is located at chromosome 17p13.1 and includes SLC16A11 and SLC16A13, two poorly characterized members of the monocarboxylic acid transporter family of solute carriers. A variant of SLC16A11 with 4 missense mutations and a silent mutation, dubbed the 5 SNP haplotype, had the strongest link to type 2 diabetes. Each copy of this variant is associated with a 20% increase in developing type 2 diabetes, and individuals with the 5 SNP haplotype develop the disease 2.1 years earlier and at a lower body mass index than noncarriers.

Curious about the function of SLC16A11, the scientists expressed SLC16A11 or a control protein in HeLa cells, which do not normally express SLC16A11 at detectable levels, and examined the cellular profiles of ~300 lipids and lipid metabolites. Interestingly, SLC16A11 expression in HeLa cells dramatically increased triacylglycerol (TAG) levels, a hallmark of insulin resistance and a good indicator of future risk of type 2 diabetes (2). They also examined tissue distribution and cellular localization and learned that the SLCA16A11 protein is expressed in human liver, salivary gland and thyroid within the endoplasmic reticulum (ER). Based on these experimental results and the knowledge that TAG synthesis occurs in the ER of liver cells, the researchers hypothesize that SLC16A11 influences the risk of type 2 diabetes through its role in TAG metabolism in the liver. Future experiments are required to understand the exact relationship between the 5 SNP haplotype and development of type 2 diabetes.

The researchers then examined the 5 SNP haplotype frequency in various human populations and discovered that this risk haplotype is found most often in Latin American and Asian populations (28% and 12%, respectively) and less often in European and African populations (<2% and 0%, respectively). These trends held true in a second database of human genomes, where people with >95% Native American ancestry had this 5 SNP haplotype ~50% of the time.

The consortium members then placed this new discovery in an interesting context: human evolution. They calculated the time to most recent ancestor for the 5 SNP and European haplotypes and determined that they diverged approximately 799,000 years ago, well before the migration of modern humans out of Africa. However, modern African populations do not exhibit this 5 SNP haplotype. If this haplotype was not carried out of Africa by modern humans as they migrated to other continents, where did this variant originate?

Here is a where a little history of human evolution and migration comes in handy. Archaeological and genetic data support scientists’ timeline that modern humans (Homo sapiens) originated in Africa at least 200,000 years ago and migrated to the Near East (~125,000 years ago), South Asia (50,000–75,000 years ago), Europe and Australia (~40,000 years ago), East Asia and Siberia (~30,000 years ago) and finally the Americas (~15,000 years ago). Along their way, our ancestors encountered several resident populations of early hominids, including Neandertals and Denisovans, both of which are closely related to modern humans and to each other. Genetic analyses of modern humans and these early hominids suggest that there was interbreeding between these species (3–5), and as modern humans dispersed across Eurasia, Neanderthals genes came to constitute as much as 1–4% of their genomes.

This genetic admixture seems to be the source of the 5 SNP variant of the SLC16A 11 gene. When the consortium members examined genome sequences of four Neandertal individuals and one Denisovan, they found one Neandertal sequence that was homozygous for the 5 SNP haplotype. Upon sequencing, 73kb of the Neandertal sequence surrounding the 5 SNP was nearly identical to that of modern humans homozygous for the 5 SNP. The sequences were so similar in fact that the 73kb sequence from Neandertals was more closely related to the modern DNA sequence than to the European nonrisk haplotype. The near identity of this 73kb DNA sequence is unexpected if this locus had undergone recombination for the ~9,000 generations since the split between ancestors of Neandertals and modern humans.

So, this research supports the hypothesis that interbreeding with Neandertals introduced the 5 SNP into modern human populations. However, I can’t help but wonder why the frequency of this 5 SNP haplotype is so unequal across continents. Afterall, while the 5 SNP haplotype is much more common in American populations, over the entire human genome Latin Americans and Europeans share approximately the same proportion of Neandertal DNA. Was there a geographical gradient of 5 SNP haplotype frequency across Eurasia DNA such that early immigrants to the Americas exhibited the risk haplotype more often? Was there a selective advantage conferred by the 5 SNP haplotype in the new world? These are interesting questions for future studies.

References

  1. The SIGMA Type 2 Diabetes Consortium (2013) Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature DOI: 10.1038/nature12828.
  2. Rhee, E.P. et al. (2011) Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. J. Clin. Invest. 121, 1402–11.
  3. Green, R.E. et al. (2010) A draft sequence of the Neandertal genome. Science 328, 710–22.
  4. Meyer, M. et al. (2012) A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–6.
  5. Prüfer, K. et al. (2014) The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9.
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Terri Sundquist

Terri has worked as a Scientific Communications Specialist at Promega Corporation for more than 13 years, and prior to that, spent more than 5 years solving problems and answering questions as a Promega Technical Services Scientist. She graduated with B.S. degrees in Chemistry and Biology at the University of Wisconsin—River Falls, then earned her M.S. in Molecular Biology from the Mayo Graduate School in Rochester Minnesota.

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