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John R Speakman - One of the best experts on this subject based on the ideXlab platform.

  • the evolution of body fatness trading off disease and predation risk
    The Journal of Experimental Biology, 2018
    Co-Authors: John R Speakman
    Abstract:

    Human obesity has a large Genetic component, yet has many serious negative consequences. How this state of affairs has evolved has Generated wide debate. The Thrifty Gene Hypothesis was the first attempt to explain obesity as a consequence of adaptive responses to an ancient environment that in modern society become disadvantageous. The idea is that Genes (or more precisely, alleles) predisposing to obesity may have been selected for by repeated exposure to famines. However, this idea has many flaws: for instance, selection of the supposed magnitude over the duration of human evolution would fix any Thrifty alleles (famines kill the old and young, not the obese) and there is no evidence that hunter-gatherer populations become obese between famines. An alternative idea (called Thrifty late) is that selection in famines has only happened since the agricultural revolution. However, this is inconsistent with the absence of strong signatures of selection at single nucleotide polymorphisms linked to obesity. In parallel to discussions about the origin of obesity, there has been much debate regarding the regulation of body weight. There are three basic models: the set-point, settling point and dual-intervention point models. Selection might act against low and high levels of adiposity because food unpredictability and the risk of starvation selects against low adiposity whereas the risk of predation selects against high adiposity. Although evidence for the latter is quite strong, evidence for the former is relatively weak. The release from predation ∼2-million years ago is suggested to have led to the upper intervention point drifting in evolutionary time, leading to the modern distribution of obesity: the drifty Gene Hypothesis. Recent critiques of the dual-intervention point/drifty Gene idea are flawed and inconsistent with known aspects of energy balance physiology. Here, I present a new formulation of the dual-intervention point model. This model includes the novel suggestion that food unpredictability and starvation are insignificant factors driving fat storage, and that the main force driving up fat storage is the risk of disease and the need to survive periods of pathogen-induced anorexia. This model shows why two independent intervention points are more likely to evolve than a single set point. The molecular basis of the lower intervention point is likely based around the leptin pathway signalling. Determining the molecular basis of the upper intervention point is a crucial key target for future obesity research. A potential definitive test to separate the different models is also described.

  • analysis of positive selection at single nucleotide polymorphisms associated with body mass index does not support the Thrifty Gene Hypothesis
    Cell Metabolism, 2016
    Co-Authors: Guanlin Wang, John R Speakman
    Abstract:

    Summary The "Thrifty Gene Hypothesis" suggests Genetic susceptibility to obesity arises because of positive selection for alleles that favored fat deposition and survival during famines. We used public domain data to locate signatures of positive selection based on derived allele frequency, Genetic diversity, long haplotypes, and differences between populations at SNPs identified in genome-wide association studies (GWASs) for BMI. We used SNPs near the lactase ( LCT ), SLC24A5 , and SLC45A2 Genes as positive controls and 120 randomly selected SNPs as negative controls. We found evidence for positive selection (p

  • a mathematical model of weight loss under total starvation evidence against the Thrifty Gene Hypothesis
    Disease Models & Mechanisms, 2013
    Co-Authors: John R Speakman, K R Westerterp
    Abstract:

    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.

  • Thrifty Genes for obesity an attractive but flawed idea and an alternative perspective the drifty Gene Hypothesis
    International Journal of Obesity, 2008
    Co-Authors: John R Speakman
    Abstract:

    Almost 50 years ago Neel proposed a Hypothesis to explain the prevalence of obesity and diabetes in modern societyFthe ‘Thrifty Gene’ Hypothesis. The fundamental basis of the Hypothesis was that, in our early evolutionary history, Genes, that promoted efficient fat deposition would have been advantageous because they allowed their holders to survive at periods of famine. In modern society, such Genes are disadvantageous because they promote fat deposition in preparation for a famine that never comes, and the result is widespread obesity and diabetes. In recent years I, and others, have questioned some of the fundamental assumptions of this HypothesisFparticularly focusing on whether differential survival of lean against obese in famines provides sufficient selective pressure for the spread of so-called ‘Thrifty Genes’. These arguments have been criticized because famines not only affect survival but also fecundity, and obese people would be expected to sustain fecundity longer in the face of food shortages. In this paper, I show that the reduced fecundity argument is flawed because famines are almost universally followed by periods of enhanced fecundity, which offsets the decline observed during the famine itself. The net effect of famines on fecundity is consequently insufficient to rescue the Thrifty Gene idea. Elsewhere, I have suggested an alternative scenario that subsections of the population have a Genetic predisposition to obesity due to an absence of selection, combined with Genetic drift. The scenario presented earlier was based on evidence from prehistory concerning the release of our ancestors from heavy predation pressure around 2 million years ago. I suggest here that this is one of a number of potential scenarios based on random Genetic drift that may explain the specific aetiology of the obesity epidemic. Together, these alternatives, based on central notion that Genetic drift rather than positive selection was a dominant factor, may be called the ‘drifty Gene’ Hypothesis.

Yik Ying Teo - One of the best experts on this subject based on the ideXlab platform.

  • can evidence from genome wide association studies and positive natural selection surveys be used to evaluate the Thrifty Gene Hypothesis in east asians
    PLOS ONE, 2014
    Co-Authors: Xuanhan Koh, Xuanyao Liu, Yik Ying Teo
    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.

Graham R S Ritchie - One of the best experts on this subject based on the ideXlab platform.

  • revisiting the Thrifty Gene Hypothesis via 65 loci associated with susceptibility to type 2 diabetes
    American Journal of Human Genetics, 2014
    Co-Authors: Qasim Ayub, Loukas Moutsianas, Yuan Chen, Kalliope Panoutsopoulou, Vincenza Colonna, Luca Pagani, Inga Prokopenko, Graham R S Ritchie
    Abstract:

    We have investigated the evidence for positive selection in samples of African, European, and East Asian ancestry at 65 loci associated with susceptibility to type 2 diabetes (T2D) previously identified through genome-wide association studies. Selection early in human evolutionary history is predicted to lead to ancestral risk alleles shared between populations, whereas late selection would result in population-specific signals at derived risk alleles. By using a wide variety of tests based on the site frequency spectrum, haplotype structure, and population differentiation, we found no global signal of enrichment for positive selection when we considered all T2D risk loci collectively. However, in a locus-by-locus analysis, we found nominal evidence for positive selection at 14 of the loci. Selection favored the protective and risk alleles in similar proportions, rather than the risk alleles specifically as predicted by the Thrifty Gene Hypothesis, and may not be related to influence on diabetes. Overall, we conclude that past positive selection has not been a powerful influence driving the prevalence of T2D risk alleles.

Xuanhan Koh - One of the best experts on this subject based on the ideXlab platform.

  • can evidence from genome wide association studies and positive natural selection surveys be used to evaluate the Thrifty Gene Hypothesis in east asians
    PLOS ONE, 2014
    Co-Authors: Xuanhan Koh, Xuanyao Liu, Yik Ying Teo
    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.

Guanlin Wang - One of the best experts on this subject based on the ideXlab platform.