Genetics of Obesity
● Weight Watchers: How much you weigh depends on many metabolic pathways, brain signals that regulate appetite, and environmental factors such as your lifestyle and diet. At least some of this is coded by genes, but narrowing down which ones is like finding the proverbial needles in a haystack. There are millions of gene variants, known as single-nucleotide polymorphisms or SNPs (pronounced snips), between any two people, than can be read from a sample of DNA (from a cheek swab). A Genome Wide Association Study or GWAS (pronounced Gee-Wahs) compares gene variants between two groups of people, say skinny and overweight, to see if any particular variant is associated with a trait, like obesity. If any particular SNP is significantly more frequent in obese people, compared to the skinny group, then that SNP could mark a gene associated with body weight.
● The Manhattan Plot: Named for a city skyline rather than a Hollywood thriller, this scatter plot helps pinpoint the genetic variants associated with obesity. Each color represents a different chromosome, with the largest chromosome on the left, going down in size and ending with the X chromosome on the far right. Each colored dot is a SNP, and the higher it is on the vertical (y axis) the bigger the difference of that variant between the two groups. In this study, the most significant SNPs were on chromosome 16 (light gray dots), in a gene called FTO. In another study, researchers measured levels of the hunger hormone grehlin after a meal: in people with a high risk variant of the FTO gene, grehlin levels in the blood stayed high, instead of dropping to signal that they were full. FTO codes for an enzyme that alters chemical modification (methylation) on the RNA messages coding for many proteins. For more on FTO see the Wiki page (http://en.wikipedia.org/wiki/FTO_gene).
● The Thrifty Gene Hypothesis: In 1962, geneticist James Neel proposed that gene variants contributing to obesity may have been of selective advantage during ancient times of food scarcity. For example, mice with mutations in the Mrap2 gene gain more weight for the same number of calories consumed. Not to be outdone, biologist John Speakman countered with the Drifty Gene Hypothesis which suggests that the loss of threat from predators, about 2 million years ago, removed a key factor selecting against obesity! The biological battle of the bulge continues….
REF: A Genome-Wide Association Study on Obesity and Obesity-Related Traits. Kai Wang et al., PLoS ONE http://goo.gl/2QGOFR
Image: From +BPoD http://bpod.mrc.ac.uk/archive/2014/1/14