Paris, 31 August 2011

Gene duplication identified as cause of insufficient weight

The primary genetic cause for being severely underweight has been identified by an international collaborative project involving researchers at the Laboratoire Génomique et Maladies Métaboliques (Genomics and Metabolic Diseases, CNRS / Université Lille 2 / Institut Pasteur, Lille) and the London Imperial College, under the supervision of Philippe Froguel, and a Swiss team headed by Jacques S. Beckmann at Université de Lausanne. They have shown that the duplication of a region of chromosome 16 causes carriers of this genetic mutation to be significantly underweight. Their results build on previous discoveries that have shown how this same chromosomal region plays a role in obesity when it is underrepresented. Their findings were published in the August 31, 2011 issue of Nature.

A region located on the short arm of chromosome 16 is known to be subject in certain cases to variations in its number of gene duplications. While the vast majority of individuals have two of each gene in this region, namely one inherited from the mother and one from the father, approximately one person in 2,500 has only one of each gene and one person in 2,000 has three. The international team that conducted this study had already determined in 2010(1) that the absence of duplications in this fragment of chromosome 16 could explain 1% of the cases of severe obesity. This genetic anomaly supplemented the researchers' other recent discoveries in the field of hereditary obesity.

Their latest study shows that people who are carriers of the opposite anomaly, in other words an excess of genetic material in the form of three of each gene in this region, are significantly underweight, sometimes severely. For example, adult carriers of such duplication of this part of chromosome 16 have up to 20 times more risks of being underweight (defined as having a body mass index, or BMI(2), of less than 18.5) than the rest of the population. The researchers believe that having extra genes in this region increases sensation of satiety. In children, half of the carriers of this duplication are underweight and have difficulty thriving.

This is the first study to reveal a genetic cause for being pathologically underweight. Previously, there were no known genetic indicators for this potentially dangerous condition, which is associated with a high death rate. To achieve these results, the researchers organized a large-scale international collaboration to look for the "three gene" mutation of chromosome 16 in some 100,000 subjects, which enabled them to identify 138 carriers of the mutation. In one-third of cases, the mutation was spontaneous (absent in the parents), and in the remaining two-thirds it was hereditary.

This study demonstrates that an excess or deficiency of certain genes (three or only one of each gene) in the same genetic region can have "mirror effect" pathological consequences, in this case, insufficient weight or obesity. The authors of the study have yet to determine the mechanisms that cause these physical characteristics.

The region of chromosome 16 affected by this duplication phenomenon comprises 28 genes. The next phase of the project will consist of identifying which of these genes is responsible for the undesirable effects on appetite and body weight. The researchers do not exclude the possibility of narrowing it down to a single gene or a combination of several genes.


1 - A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature. 2010 Feb 4;463(7281):671-5 : View web site
2 - Index calculated from body height and weight (BMI=weight/height2) defined by the World Health Organization (WHO) as the standard for evaluating risks linked to obesity in adults. The WHO has also defined standard intervals (underweight, normal weight, overweight, obesity) based on statistical correlations between BMI and death rate.


Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
Nature, 31 August 2011
The study, headed by Philippe Froguel, is signed by more than 150 international researchers.


Philippe Froguel l T 03 20 87 79 54

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Muriel Ilous l T 01 44 96 43 09


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