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New Hope toward Understanding Causes of Obesity with Discovery of Thinness Gene

Tim Boyer's picture

Scientists at last have found a promising candidate gene for understanding the causes of obesity. What they found was that approximately one out of every 2,000 people carries a duplication of a particular genetic region on chromosome 16. For men possessing this duplication, it makes them 23 times more likely to be underweight. Women who carry this duplication are five times more likely to be underweight. In a recent study—of groundbreaking significance - published in the journal Nature, researchers describe this genetic region and tell us that when duplicated it causes thinness, and when missing - causes morbid obesity.

Genes and their expression make us who we are physically. They provide the basic blueprint that guides our development. As stated by Professor Philippe Froguel, from the School of Public Health at Imperial College London, who led the study on the discovery of the thinness gene, "The dogma is that we have two copies of each gene, but this isn't really true. The genome is full of holes where genes are lost, and in other places we have extra copies of genes. In many cases, duplications and deletions have no effect, but occasionally they can lead to disease.”

Our genome possesses a little over 3 billion base pairs of DNA. Within those 3 billion base pairs of DNA we possess roughly 25,000 genes. These genes can occur either singularly or in multiple copies. The copies may be in tandem or they may be separated by non-coding regions. In fact, the majority of our DNA does not directly code for genes. Rather, the majority of our genome consists of metaphorical stretches of genetic deserts.

What this means is that our genes have room to move around somewhat during meiotic events in the creating of the haploid male and female germ cells we inherit from our parents before sperm meets egg. Sometimes we inherit a different number of copies of a specific gene from one parent over the contribution from the other parent. Sometimes this means that we will have a higher expression level of a particular protein or less expression of a particular protein. Sometimes this is critical, but usually it is not. And, in some case it is beneficial. Particularly when one parent passes on a mutated allele of a gene that codes for an inactive protein, but the other parent passes on a normal copy of the gene. Think of this as similar to organ redundancy—one kidney can make up for the loss or poor performance of its sister kidney.

The point of this basic genetics lesson is that typically we can tolerate minor changes in certain genes or genetic regions. In fact, on average we each differ by 1 base pair out of approximately every 100 base pairs along that long stretch of 3 billion base pairs. Between us and chimpanzees, it is approximately 3 to 4 base pair changes for every 100 base pairs.

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Thinness gene

However, sometimes changes occur in or near a gene and have an effect on our development. The duplication of the genetic region called “chromosome 16p11.2” in the thinness gene study is apparently one where extra copies of it results in thinness and loss of it makes a person 43 times more likely to become morbidly obese. Compared to many other genes, it is relatively genetically simple and this is the reason why it holds promise for understanding obesity in the near future. According to Dr. Froguel, "It's also the first example of a deletion and a duplication of one part of the genome having opposite effects. At the moment we don't know anything about the genes in this region. If we can work out why gene duplication in this region causes thinness, it might throw up new potential treatments for obesity and appetite disorders. We now plan to sequence these genes and find out what they do, so we can get an idea of which ones are involved in regulating appetite."

However, to keep such optimism from turning overly optimistic too soon, the authors of the paper also tell us that half of the children who inherit this duplication are diagnosed as “failure to thrive,” and that one-quarter of those with the duplication suffer from microcephaly, which is a condition where the head and brain are abnormally small. Microcephaly is associated with neurological defects and a shorter life expectancy.

In addition, it should also be noted that the part of chromosome 16 identified in the study contains 28 genes where duplications in this region have been linked with schizophrenia, and deletions with autism.

However, this is still an exciting discovery and one in which we should all keep on eyes on as we seek answers for genetic reasons why some cases of obesity are so difficult to cure.

Source: S. Jacquemont et al. 'Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.' Nature, 31 August 2011.

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