Neandertals, diabetes, and drug discovery
In our 2010 end-of-year blog article entitled “2010: Breakthroughs, Newsmakers, And Deals Of The Year”, we proposed an alternative nominee for the life science breakthrough of the year: the determination of the sequence of approximately two-thirds of the Neandertal genome by Svante Pääbo (Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany.) and his colleagues. We stated that this momentous achievement was “of great cultural significance, since it indicates that Neandertals contributed some 1-4 percent of the genome sequences of non-African present-day humans.” (This figure is now thought to be 1.5 to 2.1 percent.)
However, we also said that we had not blogged on this work “simply because it [had] nothing to do with drug discovery and development.” We then further stated that “perhaps someday, for example, some of the products of genes that are found in present-day humans but not in Neandertals could emerge as potential drug targets…researchers [had] begun studying some of these gene products in cell culture systems.”
Now, as of early 2014, one of the genes identified via sequencing Neandertal genomes has been implicated in a novel pathway involved in type 2 diabetes in present-day humans. However, rather than being a modern human gene not present in Neandertals, it is a haplotype that introgressed into modern humans via admixture with Neandertals.
The study that identified this gene initially had no connection with Neandertal genome studies at all. I was published by the SIGMA (Slim Initiative in Genomic Medicine for the Americas) Type 2 Diabetes Consortium in the 6 February 2014 issue of Nature. SIGMA is a joint U.S.-Mexico project funded by the Carlos Slim Foundation. It focuses on several important diseases that have particular relevance to public health in Mexico and Latin America, including type 2 diabetes and cancer. Type 2 diabetes has approximately twice the prevalence in Mexican and other Latin American populations, as compared to U.S. non-Hispanic whites.
The researchers performed a genome-wide association study (GWAS), in which they analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans, including 3,848 with type 2 diabetes and 4,366 non-diabetic controls. As a result of that analysis, the researchers replicated the identification of haplotypes previously associated with type 2 diabetes. They also identified a novel locus associated with type 2 diabetes at genome-wide significance. This locus spans the genes that encode the solute carrier proteins SLC16A11 and SLC16A13. The risk haplotype carries four amino acid substitutions, all in SLC16A11. It is present at approximately 50% frequency in Native American individuals and around 10% in East Asians, but is rare in Europeans and Africans.
Each copy of the risk newly-identified haplotype is associated with an approximately 20% increased risk of type 2 diabetes. The haplotype would thus be expected to contribute to the higher burden of type 2 diabetes in Mexican and Latin American populations. Mutations in SLC16A11 had never before been associated with type 2 diabetes. SLC16A11 thus represents a novel type 2 diabetes pathway.
The Neandertal connection
The researchers noted that the sequence of the risk haplotype is highly divergent, with an estimated time to the most recent common ancestor of both the novel haplotype and a European haplotype of 799,000 years. This is long before modern humans migrated from Africa into Eurasia. Moreover, the novel haplotype is not found in Africans and is rare in European populations. The researchers therefore hypothesized that the novel haplotype entered modern human populations via admixture with Neandertals.
At the time that this research was being conducted, the variant was not seen in published Neandertal (or Denisovan) genome sequences. However, with the help of Svante Pääbo, the researchers obtained access to a then-unpublished full-length Neandertal genome sequence from a Central Asian specimen. The Central Asian Neandertal genome sequence was homozygous across 5 killobases for the risk haplotype including all four missense SNPs in SLC16A11 . Over a span of 73 kb, the Neandertal sequence is nearly identical to that of individuals from the 1000 Genomes Project who are homozygous for the risk haplotype. The full-length Central Asian Neandertal genome has recently been published.
Moreover, the genetic length of the 73-kb risk haplotype is longer than would be expected if it had undergone recombination for the approximately 9,000 generations since the split with Neandertals. This is consistent with the hypothesis that the risk haplotype is not only similar to the Neandertal sequence, but was probably introduced into modern humans relatively recently through archaic admixture. Although this particular Neandertal-derived haplotype is common in the Americas, Native Americans and Latin Americans have the same proportion of Neandertal ancestry genome-wide as other Eurasian-derived populations. In general, although non-African populations have about the same percentage of Neandertal genes, different populations have different complements of genes derived from Neandertals.
Functional studies of SLC16A11
Although the risk haploype encodes four missense mutations in a single gene, the gene for SLC16A11, there is no formal genetic proof that SLC16A11 is responsible for increased risk of type 2 diabetes. Therefore, the researchers performed preliminary functional studies of SLC16A11.
Via immunofluorescence studies, the researchers found that SLC16A11 was expressed in the liver, the salivary glands and the thyroid. When the gene for SLC16A11 was introduced into HeLa cells, SLC16A1 was found to localize in the endoplasmic reticulum, but not in the plasma membrane, Golgi apparatus, or mitochondria. Other SLC16 family members show distinct intracellular localization pattern within the membranous structures of the cell.
SLC16A11, and other SLC16 family members, are solute carrier transporters (SLCs). We discussed SLCs and their role in transporting small-molecule nutrients and drugs across the blood-brain barrier in our 2009 book-length report, Blood-Brain Barrier: Bridging Options for Drug Discovery and Development, published by Cambridge Healthtech Institute. We also discussed SLCs in a 2009 article entitled “Strategies to Overcome Blood-Brain Barrier” in Genetic Engineering and Biotechnology News.
SLC16 family proteins are monocaboxylate transporters, which transport such compounds as lactate, pyruvate and ketone bodies, as well as thyroid hormone and aromatic amino acids, across biological membranes. As of 2008, of the 14 known members of this family, eight (including SLC16A11) had unknown functions.
The SIGMA researchers expressed SLC16A11 (or control proteins) in HeLa cells, and looked for changes in intracellular concentrations of approximately 300 polar and lipid metabolites. Expression of SLC16A11 resulted in substantial increases in intracellular triacylglycerol (triglyceride) levels, with smaller increases in intracellular diacylglycerols, and decreases in lysophosphatidylcholine, cholesteryl esters, and sphingomyelin. Since triglyceride synthesis occurs in the endoplasmic reticulum of hepatocytes, the researchers hypothesized that SLC16A11 may have a role in hepatic lipid metabolism.
Moreover, serum levels of triglycerides and accumulation of intracellular lipids are associated with insulin resistance, the metabolic syndrome, and the risk of developing type 2 diabetes. Thus, although further functional studies of SLC16A11 are needed, the researchers hypothesize that the novel risk allele for type 2 diabetes that they identified may exert its pro-diabetic effect by altering lipid metabolism in the liver.
This study, a GWAS in Mexican and other Latin American samples, is an illustration of how genetic mapping studies in understudied populations may identify previously undiscovered aspects of disease pathogenesis.
The risk gene identified in this study, SLC16A11, has not previously been associated with type 2 diabetes. It thus potentially represents a novel diabetes pathway, which might yield new targets for drug discovery. This new pathway might be important in type 2 diabetes not only in Native Americans and Latin Americans, but in other populations as well, even in those that lack mutations in SLC16A11.
The study initially had nothing to do with Neandertal genetics. However, the researchers noted unusual population genetics features of the risk haplotype that they identified, which led them to identify this haplotype as having entered modern human populations via introgression from Neandertals. Via the initial introgression, natural selection and/or genetic drift, the haplotype became fixed in Native Americans and some East Asians, but not in other Eurasian-derived populations such as Europeans and Euro-Americans.
It is extremely unlikely that either Neandertals, or Native Americans and Latin Americans in pre-modern times, had type 2 diabetes. However, modern diets, perhaps in concert with other risk genes, produced type 2 diabetes in carriers of the mutant SLC16A11 gene. The well-know case of the Pima Indians indicates that change from native diets and high levels of physical activity to processed foods and a more “Western” lifestyle is the major cause of the high levels of type 2 diabetes and obesity in this genetically-predisposed population. (It is not known, however, whether SLC16A11 is a factor in Pima Indians.)
As for studies of the Neandertal genome, John Hawks, Ph.D. (University of Wisconsin), an anthropologist who has been active in studies of the genetics of Neandertals and of Upper Paleolithic modern humans, believes that studies of the genomes of these ancient peoples may have relevance for the biology of present-day humans. [I took a Massive Open Online Course (MOOC) led by Dr. Hawks, entitled “Human Evolution: Past and Future” between late January and early March, 2014.]
Other researchers who study ancient genomes generally agree. As indicated by the SIGMA diabetes study, both genes for modern humans that were not present in Neandertals, and genes introgressed from Neandertals into modern humans may be relevant to modern human biology—and perhaps eventually to drug discovery.
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