Arthrosis is a side effect of adaptation to cold

The spread of arthritis was explained by the exodus of a person from Africa

Denis Strigun, Naked Science

Despite the ambiguous value of genome-wide association search (GWAS), the occurrence of individual mutations makes it possible to predict the propensity of populations to certain diseases. For example, single nucleotide polymorphisms (SNP) of the GDF5 rs143383 and rs143384 genes are associated with a 1.3–1.8-fold increased risk of osteoarthritis in residents of Japan and China. In addition to arthritis, defects in this gene encoding growth differentiation factor 5 (growth differentiation factor 5) are associated with growth abnormalities, in particular, a decrease in bone length. At the same time, the analysis of such SNPs shows that they probably underwent positive natural selection and served as adaptive traits in ancient times.

The reasons why mutations associated with small stature and arthritis were selected are unclear. To fill the gap, experts from Harvard University and other institutions studied the genome of humans and mice. At the first stage, the authors derived rodent lines with different polymorphisms of the Gdf5 orthologue. The fact is that past work does not allow us to establish the exact location of the target changes: the possible range exceeds 100 kilobases (thousands of nucleotide pairs). Then the skeletal deformations were tracked in the experimental individuals. The analysis showed that critical bone damage was caused by cis-regulatory elements within 30 kilobases below Gdf5. In human embryos, the region included 37 kilobases.

In addition, in the area of the human GDF5 locus, scientists discovered a previously unknown DNA region, called GROW1, with an inverse function. Unlike polymorphisms, it stimulated the growth of long bones and had a structure typical of enhancers that promote the development of chondrocytes (cartilage tissue cells). After that, the team used the 1000 Genomes database to examine a large region of the gene for defects in human populations. This made it possible to identify a common polymorphism rs4911178 – it occurred in an extremely conservative sequence within GROW1, and in humans it usually assumed the replacement of guanine with adenine, and in other placentals – on the contrary.

The prevalence of polymorphic locus GROW1 depending on the region of origin. Red color corresponds to the absence, blue – to the presence of a pathological A-allele (from an article in Nature Genetics). As further experiments have shown, such a replacement leads to suppression of the enhancer.

Finally, to clarify the appearance of the trait, the scientists compared the structure of the site corresponding to rs4911178 in the genome of different races. In total, they examined 1,091 haplotypes. According to the results, the absence of polymorphism was accompanied by a high diversity of sequences and was more often observed in Africans. All carriers of the mutation, in turn, also turned out to have closely related haplotypes, and, as a rule, originated from Eurasia. Similar defects were found in samples of Neanderthals and Denisov man – extinct representatives of the genus Homo, who shared a common territory with modern man.

According to scientists, the data obtained suggest that the suppression of the GROW1 enhancer in some populations could have occurred during the migration of a common human ancestor from Africa to Asia about 130-50 thousand years ago. The climate change that accompanied the outcome required people to adapt to the cold snap – and it manifested itself in a reduction in the size of the skeleton, which helps to save heat. This is consistent with Allen's rule: animals living in northern latitudes develop less protruding body parts compared to related taxa in the south. Thus, the need for heat preservation, the authors believe, could surpass the side effects in the form of joint pain.

Article by Capellini et al. Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk is published in the journal Nature Genetics.

Portal "Eternal youth" http://vechnayamolodost.ru  05.07.2017