Ancient evolutionary selection for alleles at a GDF5 enhancer that influences human height and osteoarthritis risk

In terms of gene-environment interactions, we’ve shared many examples in which the environment (diet, climate, and geographic region) has exerted strong selective forces, over time, to change the phenotype (trait). In the case of the attached study (and editorial), the growth differentiation factor-5 gene (GDF5) has been studied, in regard to its association with two traits –– both adult height and risk of osteoarthritis in humans. The study herein provides convincing evidence of positive selection for short stature at the GDF5 locus in modern humans (Homo sapiens), as well as in archaic Neanderthals (Homo neaderthalensis) and Denisovans (Homo denisova). Whereas the Neanderthals and Denisovians are believed to have diverged from one another >600,000 years ago, modern humans appeared ~300,000 years ago, with growing evidence for (at least some) past interbreeding with the two more ancient hominids,

This story begins back in 2007–2008 with the identification of single-nucleotide polymorphisms (SNPs or DNA variants) strongly associated with osteoarthritis risk and adult height. For both phenotypes, the most significant SNPs are near the GDF5 gene, which codes for a protein related to the bone morphogenetic protein (BMP) family within the transform­ing growth factor-β (TGF) superfamily. The GDF5 gene is expressed in cartilage and developing joints and bones. Importantly, GDF5 mutations in mice and humans are linked to skeletal defects, shorter bones, short stature, and increased osteoarthri­tis risk. Given these data, GDF5 represents an ideal (credible) candidate gene for the osteoarthritis and height association signals detected at this locus. However, the precise molecular mecha­nisms by which these SNPs modulate GDF5 have remained unknown. In the present report [attached], authors combine elegant transgenic experiments in mice with population genetic analyses in humans to identify a GDF5 enhancer that harbors a strong candidate causal SNP that is under positive selection.

Authors surveyed the mouse Gdf5 locus for regulatory regions in transgenic mice and fine-mapped separate enhancers –– controlling expression in joints versus growing ends of long bones. A large downstream regulatory region contains a novel growth enhancer (GROW1), which is required for normal Gdf5 expression at the ends of developing bones and for normal bone lengths in the intact mouse. Human GROW1 contains a common base-pair change that decreases enhancer activity and co-localizes with peaks of positive selection in humans. The derived allele is rare in (the taller) African, but common in shorter people in Eurasia and is also found in Neanderthals and Denisovans. These results suggest that an ancient regulatory variant in GROW1 has been repeatedly selected in northern environments and that past selection on growth phenotypes explains the high frequency of a GDF5 haplotype [“haplotype” is a group of genes within an organism that is inherited together, from one of the two parents] that also increases susceptibility to arthritis in many human populations.

Nature Genetics Aug 2o17; 49: 1202–1210 [whole article] & 1165-1166 [News’N’Views]

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