Can evidence from genome-wide association studies and positive natural selection surveys be used to evaluate the thrifty gene hypothesis in East Asians?

Xuan-Han Koh,Yik-Ying Teo,Xuanyao Liu,Fengfeng Zhou

doi:10.1371/journal.pone.0110974

Abstract

Body fat deposition and distribution differ between East Asians and Europeans, and for the same level of obesity, East Asians are at higher risks of Type 2 diabetes (T2D) and other metabolic disorders. This observation has prompted the reclassifications of body mass index thresholds for the definitions of “overweight” and “obese” in East Asians. However, the question remains over what evolutionary mechanisms have driven the differences in adiposity morphology between two population groups that shared a common ancestor less than 80,000 years ago. The Thrifty Gene hypothesis has been suggested as a possible explanation, where genetic factors that allowed for efficient food-energy conversion and storage are evolutionarily favoured by conferring increased chances of survival and fertility. Here, we leveraged on the existing findings from genome-wide association studies and large-scale surveys of positive natural selection to evaluate whether there is currently any evidence to support the Thrifty Gene hypothesis. We first assess whether the existing genetic associations with obesity and T2D are located in genomic regions that are reported to be under positive selection, and if so, whether the risk alleles sit on the extended haplotype forms. In addition, we interrogate whether these risk alleles are the derived forms that differ from the ancestral alleles, and whether there is significant evidence of population differentiation at these SNPs between East Asian and European populations. Our systematic survey did not yield conclusive evidence to support the Thrifty Gene hypothesis as a possible explanation for the differences observed between East Asians and Europeans.

Highlights

The past decade has seen a precipitous surge in obesity and diabetes globally, where the bulk of the increase has been in Asian populations such as China and India [1]
Starting with the list of 405 positively selected genomic regions in the 14 populations from HapMap and Singapore Genome Variation Project (SGVP), we identified six Type 2 diabetes (T2D)-associated index SNPs in or around nine genes from the genome-wide association studies (GWAS) catalogue (Table 1) that overlapped with evidence of positive selection in the East Asian populations in HapMap and SGVP (Table 2) [16,17,18,19,20,21,22,23,24]
Three of these SNPs were located in six genes (ARF5, PAX4, SND1, GCC1, C2CD4A, C2CD4B) that were identified to be associated with T2D in only East Asian populations, while HHEX was common to both East Asian and Europeans, and two genes (THADA, IDE) were specific to the Europeans

Summary

Introduction

The past decade has seen a precipitous surge in obesity and diabetes globally, where the bulk of the increase has been in Asian populations such as China and India [1]. For the same body mass index (BMI), an East Asian individual is more susceptible to insulin resistance, and is more predisposed to body fat and visceral adiposity than a European individual [3]. The observations that East Asians tend to develop T2D at a less severe stage of obesity compared to Europeans have contributed in part to the reclassification of the definitions of ‘‘overweight’’ and ‘‘obese’’ for East Asians. While the global surge in obesity and T2D has undoubtedly been attributed to the shift towards a high-fat high-sugar diet coupled with increasingly sedentary lifestyles, a fundamental question exists around the physiological differences in T2D etiology between East Asians and other populations. What are the molecular mechanisms that have resulted in the different types and location of adiposity, and what evolutionary processes could have driven these changes?

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Discussion

Conclusion