Considerable attention has been focused on the effect of deleterious mutations caused by the recent relaxation of selective constraints on human health, including the prevalence of
obesity, which might represent an adaptive response of energy-conserving metabolism under the conditions of modern society.
Mitochondrial DNA (
mtDNA) encoding 13 core subunits of oxidative phosphorylation plays an important role in metabolism. Therefore, we hypothesized that a relaxation of selection constraints on
mtDNA and an increase in the proportion of deleterious mutations have played a role in
obesity prevalence. In this study, we collected and sequenced the
mtDNA genomes of 722 Uyghurs, a typical population with a high prevalence of
obesity. We identified the variants that occurred in the Uyghur population for each sample and found that the number of nonsynonymous mutations carried by Uyghur individuals declined with elevation of their BMI (P = 0.015). We further calculated the nonsynonymous and synonymous ratio (N/S) of the high-BMI and low-BMI haplogroups, and the results showed that a significantly higher N/S occurred in the whole
mtDNA genomes of the low-BMI haplogroups (0.64) than in that of the high-BMI haplogroups (0.35, P = 0.030) and ancestor haplotypes (0.41, P = 0.032); these findings indicated that low-BMI individuals showed a recent relaxation of selective constraints. In addition, we investigated six clinical characteristics and found that fasting plasma
glucose might be correlated with the N/S and selective pressures. We hypothesized that a higher proportion of deleterious mutations led to mild
mitochondrial dysfunction, which helps to drive
glucose consumption and thereby prevents
obesity. Our results provide new insights into the relationship between
obesity predisposition and mitochondrial genome evolution.