Abstract
Background: Diabetes and obesity cause serious complications worldwide, including stroke and cardiovascular disease, and are a global health burden. Diabetes is strongly related with obesity and both are significantly heritable. The prevalence of diabetes and obesity are higher in African populations than in European and Asian populations. In human evolution, natural selection is a key process of genetic survival over generations. Thus, the selection for diabetes- and obesity-related genes is a key mechanism for survival during times of feast and famine. Loss-of-function variations in the adenylate cyclase 3 ( ADCY3 ) gene are associated with obesity and diabetes, while mutations in ADCY3 are also associated with childhood obesity. ADCY3 -deficient mice showed severe obesity, impaired insulin sensitivity, and reduced physical activity. Here, we researched evidence for natural selection at ADCY3 . Methods: We used a three-step genetic method to identify natural selection at ADCY3 using data on four populations from the 1000 Genomes Project and HapMap: Utah residents with Northern and Western European ancestry (CEU), the Yoruba in Ibadan, Nigeria (YRI), Han Chinese in Beijing (CHB) and Japanese in Tokyo (JPT). First we used Wright’s F-statistics (Fst) as a measure of population differentiation to find ethnic diversity at ADCY3 . We then used a long-range haplotype (LRH) test to find significant long haplotypes, and then the integrated haplotype score (iHS) to find natural selection at ADCY3 . Results: We observed high Fst values and significant ethnic diversity at four ADCY3 body mass index (BMI)-associated variations (rs7586879, rs6545814, rs11676272 and rs10182181) between the non-African and African populations. Both LRH and iHS also provided evidence for natural selection at ADCY3 . Conclusions: These observations show evidence for natural selection and ethnic diversity at ADCY3 . Further exploration into the evolution of obesity- and Type 2 diabetes-associated genes is needed.
Natural selection and type 2 diabetes-associated mortality in an isolated indigenous community in the valley of Oaxaca, southern Mexico
