The Genetics of Obesity, Part III

Genetics Loads the Gun, Environment Pulls the Trigger

Thanks to a WHS reader* for reminding me of the above quote by Dr. Francis Collins, director of the US National Institutes of Health**. This is a concept that helps reconcile the following two seemingly contradictory observations:

1. Roughly 70 percent of obesity risk is genetically inherited, leaving only 30 percent of risk to environmental factors such as diet and lifestyle.
2. Diet and lifestyle have a large impact on obesity risk. The prevalence of obesity has tripled in the last 30 years, and the prevalence of extreme obesity has increased by almost 10-fold. This is presumably not enough time for genetic changes to account for it.

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The Genetics of Obesity, Part II

Rodents Lead the Way

The study of obesity genetics dates back more than half a century. In 1949, researchers at the Jackson Laboratories identified a remarkably fat mouse, which they determined carried a spontaneous mutation in an unidentified gene. They named this the "obese" (ob/ob) mouse. Over the next few decades, researchers identified several other genetically obese mice with spontaneous mutations, including diabetic (db/db) mice, "agouti" (Avy) mice, and "Zucker" (fa/fa) rats.

At the time of discovery, no one knew where the mutations resided in the genome. All they knew is that the mutations were in single genes, and they resulted in extreme obesity. Researchers recognized this as a huge opportunity to learn something important about the regulation of body fatness in an unbiased way. Unbiased because these mutations could be identified with no prior knowledge about their function, therefore the investigators' pre-existing beliefs about the mechanisms of body fat regulation could have no impact on what they learned. Many different research groups tried to pin down the underlying source of dysfunction: some thought it was elevated insulin and changes in adipose tissue metabolism, others thought it was elevated cortisol, and a variety of other hypotheses.

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The Genetics of Obesity, Part I

Choosing the Right Parents: the Best Way to Stay Lean?

In 1990, Dr. Claude Bouchard and colleagues published a simple but fascinating study demonstrating the importance of genetics in body fatness (1). They took advantage of one of the most useful tools in human genetics: identical twins. This is what happens when a single fertilized egg generates two embryos in utero and two genetically identical humans are born from the same womb. By comparing identical twins to other people who are not genetically identical (e.g., non-identical twins), we can quantify the impact of genes vs. environment on individual characteristics (2).

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Beyond Ötzi: European Evolutionary History and its Relevance to Diet. Part III

In previous posts, I reviewed some of the evidence suggesting that human evolution has accelerated rapidly since the development of agriculture (and to some degree, before it). Europeans (and other lineages with a long history of agriculture) carry known genetic adaptations to the Neolithic diet, and there are probably many adaptations that have not yet been identified. In my final post in this series, I'll argue that although we've adapted, the adaptation is probably not complete, and we're left in a sort of genetic limbo between the Paleolithic and Neolithic state.

Recent Genetic Adaptations are Often Crude

It may at first seem strange, but many genes responsible for common genetic disorders show evidence of positive selection. In other words, the genes that cause these disorders were favored by evolution at some point because they presumably provided a survival advantage. For example, the sickle cell anemia gene protects against malaria, but if you inherit two copies of it, you end up with a serious and life-threatening disorder (1). The cystic fibrosis gene may have been selected to protect against one or more infectious diseases, but again if you get two copies of it, quality of life and lifespan are greatly curtailed (2, 3). Familial Mediterranean fever is a very common disorder in Mediterranean populations, involving painful inflammatory attacks of the digestive tract, and sometimes a deadly condition called amyloidosis. It shows evidence of positive selection and probably protected against intestinal disease due to the heightened inflammatory state it confers to the digestive tract (4, 5). Celiac disease, a severe autoimmune reaction to gluten found in some grains, may be a by-product of selection for protection against bacterial infection (6). Phenylketonuria also shows evidence of positive selection (7), and the list goes on. It's clear that a lot of our recent evolution was in response to new disease pressures, likely from increased population density, sendentism, and contact with domestic animals.

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Beyond Ötzi: European Evolutionary History and its Relevance to Diet. Part I

In the previous post, I explained that Otzi descended in large part from early adopters of agriculture in the Middle East or nearby. What I'll explain in further posts is that Otzi was not a genetic anomaly: he was part of a wave of agricultural migrants that washed over Europe thousands of years ago, spreading their genes throughout. Not only that, Otzi represents a halfway point in the evolutionary process that transformed Paleolithic humans into modern humans.

Did Agriculture in Europe Spread by Cultural Transmission or by Population Replacement?

There's a long-standing debate in the anthropology community over how agriculture spread throughout Europe. One camp proposes that agriculture spread by a cultural route, and that European hunter-gatherers simply settled down and began planting grains. The other camp suggests that European hunter-gatherers were replaced (totally or partially) by waves of agriculturalist immigrants from the Middle East that were culturally and genetically better adapted to the agricultural diet and lifestyle. These are two extreme positions, and I think almost everyone would agree at this point that the truth lies somewhere in between: modern Europeans are a mix of genetic lineages, some of which originate from the earliest Middle Eastern agriculturalists who expanded into Europe, and some of which originate from indigenous hunter-gatherer groups including a small contribution from neanderthals. We know that modern-day Europeans are not simply Paleolithic mammoth eaters who reluctantly settled down and began farming.

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Lessons From Ötzi, the Tyrolean Ice Man. Part I

This is Otzi, or at least a reconstruction of what he might have looked like. 5,300 years ago, he laid down on a glacier near the border between modern-day Italy and Austria, under unpleasant circumstances. He was quickly frozen into the glacier. In 1991, his slumber was rudely interrupted by two German tourists, which eventually landed him in the South Tyrol Museum of Archaeology in Italy.

Otzi is Europe's oldest natural human mummy, and as such, he's an important window into the history of the human species in Europe. His genome has been sequenced, and it offers us clues about the genetic history of modern Europeans.

Otzi's Story

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