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Testing the thrifty gene hypothesis: the Gly482Ser variant in PPARGC1A is associated with BMI in Tongans.

ABSTRACT: the thrifty gene hypothesis posits that, in populations that experienced periods of feast and famine, natural selection favoured individuals carrying thrifty alleles that promote the storage of fat and energy. Polynesians likely experienced long periods of cold stress and starvation during their settlement of the Pacific and today have high rates of obesity and type 2 diabetes (T2DM), possibly due to past positive selection for thrifty alleles. Alternatively, T2DM risk alleles may simply have drifted to high frequency in Polynesians. To identify thrifty alleles in Polynesians, we previously examined evidence of positive selection on T2DM-associated SNPs and identified a T2DM risk allele at unusually high frequency in Polynesians. We suggested that the risk allele of the Gly482Ser variant in the PPARGC1A gene was driven to high frequency in Polynesians by positive selection and therefore possibly represented a thrifty allele in the Pacific.here we examine whether PPARGC1A is a thrifty gene in Pacific populations by testing for an association between Gly482Ser genotypes and BMI in two Pacific populations (Maori and Tongans) and by evaluating the frequency of the risk allele of the Gly482Ser variant in a sample of worldwide populations.we find that the Gly482Ser variant is associated with BMI in Tongans but not in Maori. In a sample of 58 populations worldwide, we also show that the 482Ser risk allele reaches its highest frequency in the Pacific.the association between Gly482Ser genotypes and BMI in Tongans together with the worldwide frequency distribution of the Gly482Ser risk allele suggests that PPARGC1A remains a candidate thrifty gene in Pacific populations.

SUBMITTER: Myles S

PROVIDER: S-EPMC3025936 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Testing the thrifty gene hypothesis: the Gly482Ser variant in PPARGC1A is associated with BMI in Tongans.

Myles Sean S Lea Rod A RA Ohashi Jun J Chambers Geoff K GK Weiss Joerg G JG Hardouin Emilie E Engelken Johannes J Macartney-Coxson Donia P DP Eccles David A DA Naka Izumi I Kimura Ryosuke R Inaoka Tsukasa T Matsumura Yasuhiro Y Stoneking Mark M

BMC medical genetics 20110118

<h4>Background</h4>the thrifty gene hypothesis posits that, in populations that experienced periods of feast and famine, natural selection favoured individuals carrying thrifty alleles that promote the storage of fat and energy. Polynesians likely experienced long periods of cold stress and starvation during their settlement of the Pacific and today have high rates of obesity and type 2 diabetes (T2DM), possibly due to past positive selection for thrifty alleles. Alternatively, T2DM risk alleles ...[more]

PMID: 21244673

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Project description:Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PPARGC1A) regulates the expression of energy metabolism's genes and mitochondrial biogenesis. The essential roles of PPARGC1A encouraged the researchers to assess the relation between metabolism-related diseases and its variants. To study Gly482Ser (+1564G/A) single-nucleotide polymorphism (SNP) after PPARGC1A modeling, we substitute Gly482 for Ser482. Stability prediction tools showed that this substitution decreases the stability of PPARGC1A or has a destabilizing effect on this protein. We then utilized molecular dynamics simulation of both the Gly482Ser variant and wild type of the PPARGC1A protein to analyze the structural changes and to reveal the conformational flexibility of the PPARGC1A protein. We observed loss flexibility in the RMSD plot of the Gly482Ser variant, which was further supported by a decrease in the SASA value in the Gly482Ser variant structure of PPARGC1A and an increase of H-bond with the increase of β-sheet and coil and decrease of turn in the DSSP plot of the Gly482Ser variant. Such alterations may significantly impact the structural conformation of the PPARGC1A protein, and it might also affect its function. It showed that the Gly482Ser variant affects the PPARGC1A structure and makes the backbone less flexible to move. In general, molecular dynamics simulation (MDS) showed more flexibility in the native PPARGC1A structure. Essential dynamics (ED) also revealed that the range of eigenvectors in the conformational space has lower extension of motion in the Gly482Ser variant compared with WT. The Gly482Ser variant also disrupts PPARGC1A interaction. Due to this single-nucleotide polymorphism in PPARGC1A, it became more rigid and might disarray the structural conformation and catalytic function of the protein and might also induce type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). The results obtained from this study will assist wet lab research in expanding potent treatment on T2DM.

Project description:BACKGROUND:The gene PPARGC1A, in particular the Gly482Ser variant (rs8192678), had been proposed to be subject to natural selection, particularly in recent progenitors of extant Polynesian populations. Reasons include high levels of population differentiation and increased frequencies of the derived type 2 diabetes (T2D) risk 482Ser allele, and association with body mass index (BMI) in a small Tongan population. However, no direct statistical tests for selection have been applied. METHODS:Using a range of Polynesian populations (Tongan, M?ori, Samoan) we re-examined evidence for association between Gly482Ser with T2D and BMI as well as gout. Using also Asian, European, and African 1000 Genome Project samples a range of statistical tests for selection (F ST, integrated haplotype score (iHS), cross population extended haplotype homozygosity (XP-EHH), Tajima's D and Fay and Wu's H) were conducted on the PPARGC1A locus. RESULTS:No statistically significant evidence for association between Gly482Ser and any of BMI, T2D or gout was found. Population differentiation (F ST) was smallest between Asian and Pacific populations (New Zealand M?ori???0.35, Samoan???0.20). When compared to European (New Zealand M?ori???0.40, Samoan???0.25) or African populations (New Zealand M?ori???0.80, Samoan???0.66) this differentiation was larger. We did not find any strong evidence for departure from neutral evolution at this locus when applying any of the other statistical tests for selection. However, using the same analytical methods, we found evidence for selection in specific populations at previously identified loci, indicating that lack of selection was the most likely explanation for the lack of evidence of selection in PPARGC1A. CONCLUSION:We conclude that there is no compelling evidence for selection at this locus, and that this gene should not be considered a candidate thrifty gene locus in Pacific populations. High levels of population differentiation at this locus and the reported absence of the derived 482Ser allele in some Melanesian populations, can alternatively be explained by multiple out-of-Africa migrations by ancestral progenitors, and subsequent genetic drift during colonisation of Polynesia. Intermediate 482Ser allele frequencies in extant Western Polynesian populations could therefore be due to recent admixture with Melanesian progenitors.

Project description:ObjectivesMuscle health is essential for children's physical development and future health. PPARGC1A gene encode the peroxisome proliferator-activated receptor coactivator 1α which coactivates transcription factors that control mediating skeletal muscle fiber type conversion and skeletal muscle fiber formation. The PPARGC1A rs8192678 Gly/Ser (Gly482Ser) polymorphism was associated with the regulation of skeletal muscle fibre type. This paper aims to explore the association between the PPARGC1A rs8192678 (Gly482Ser) polymorphism and muscle fitness in Chinese schoolchildren.MethodsWe detected the distribution of the PPARGC1A rs8192678 (Gly482Ser) polymorphism by DNA typing of saliva samples from untrained Southern Chinese Han children aged 7-12 years. Considering that muscle studies in children cannot use invasive sampling, we analyzed the association between alleles and genotypes with high validity tests of muscle fitness assesment in children(handgrip strength, standing long jump, sit-ups and push-ups).ResultsThe results showed no significant differences in height, weight or body mass index between the sexes. The grip strength indicators were correlated with age in boys and height and weight in girls. Sit-ups were significantly higher in girls with the PPARGC1A Gly/Gly genotype than in boys, and handgrip strength and standing long jump were significantly lower in girls with the PPARGC1A rs8192678 (Gly482Ser) genotype than in boys. Genetic model analysis showed that the Gly482 allele had a dominant genetic effect on the Gly482 allele is hypothesized to influence the expression of type I fibers in skeletal muscle in girls, while the Ser482 allele affects on type II fibers in girls. The two alleles had little genetic effect on boys.ConclusionsThe results suggested the possible association of the PPARGC1A rs8192678 (Gly482Ser) polymorphism on myofibril type-related phenotypes in Han Chinese children in southern China, with a particular impact on girls.

Project description:The thrifty-gene hypothesis (TGH) posits that the modern genetic predisposition to obesity stems from a historical past where famine selected for genes that promote efficient fat deposition. It has been previously argued that such a scenario is unfeasible because under such strong selection any gene favouring fat deposition would rapidly move to fixation. Hence, we should all be predisposed to obesity: which we are not. The genetic architecture of obesity that has been revealed by genome-wide association studies (GWAS), however, calls into question such an argument. Obesity is caused by mutations in many hundreds (maybe thousands) of genes, each with a very minor, independent and additive impact. Selection on such genes would probably be very weak because the individual advantages they would confer would be very small. Hence, the genetic architecture of the epidemic may indeed be compatible with, and hence support, the TGH. To evaluate whether this is correct, it is necessary to know the likely effects of the identified GWAS alleles on survival during starvation. This would allow definition of their advantage in famine conditions, and hence the likely selection pressure for such alleles to have spread over the time course of human evolution. We constructed a mathematical model of weight loss under total starvation using the established principles of energy balance. Using the model, we found that fatter individuals would indeed survive longer and, at a given body weight, females would survive longer than males, when totally starved. An allele causing deposition of an extra 80 g of fat would result in an extension of life under total starvation by about 1.1-1.6% in an individual with 10 kg of fat and by 0.25-0.27% in an individual carrying 32 kg of fat. A mutation causing a per allele effect of 0.25% would become completely fixed in a population with an effective size of 5 million individuals in 6000 selection events. Because there have probably been about 24,000 famine events since the evolution of hominins 4 million years ago, there has been ample time even for genes with only very minor impacts on adiposity to move to fixation. The observed polymorphic variation in the genes causing the predisposition to obesity is incompatible with the TGH, unless all these single nucleotide polymorphisms (SNPs) arose in the last 900,000 years, a requirement we know is incorrect. The TGH is further weakened by the observation of no link between the effect size of these SNPs and their prevalence, which would be anticipated under the TGH model of selection if all the SNPs had arisen in the last 900,000 years.

Dataset Information

Testing the thrifty gene hypothesis: the Gly482Ser variant in PPARGC1A is associated with BMI in Tongans.

Publications

Testing the thrifty gene hypothesis: the Gly482Ser variant in PPARGC1A is associated with BMI in Tongans.

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