Saturday 4 September 2010

Chemical patterns on DNA mark out obesity genes

Your genes play a big part in determining your body shape, but that role may not have been set in stone when your parents' egg and sperm got together. It now looks like chemical changes that happen to genes over a person's lifetime may influence how fat they become, without altering their inherited DNA sequences.

This is the first time that prolonged chemical changes to genes during life have been implicated in obesity and body weight.

The findings add to the mounting evidence that it's not only genes that dictate important bodily traits – environmental cues and conditions may also affect such traits by altering gene activity. These "epigenetic" changes influence whether genes are on or off, but do not change the DNA sequence.

The latest findings relate to epigenetic changes which involve methylation, the process by which the addition of chemicals called methyl groups to DNA can turn genes on or off, or moderate a gene's activity by changing the way it is read.

Icelandic obesity

A team led by Andrew Feinberg of Johns Hopkins University School of Medicine in Baltimore, Maryland, and Daniele Fallin of the Johns Hopkins Bloomberg School of Public Health, also in Baltimore, mapped methylation in the DNA of 74 adults with a range of body types, looking for patterns that seemed likely to have been prolonged and set early in life, or even in the womb.

To do this, they first screened the volunteers' DNA in 1991, and picked out 227 regions with methylation patterns that varied between the individual members of the group by an unusually large amount. They then screened the same people in 2002 to distinguish which methylation patterns had not changed over the 11 years, reasoning that the variation in these patterns must have occurred early in life, then become fixed, having a persistent effect on traits such as body weight or intelligence.

Of the 227 methylated sites, 119 were found to be the same in 2002 as they had been 11 years earlier. Feinberg and Fallin then matched these groups to the body type of the individual. They found 13 methylated genes that were more likely to be present in the participants who were overweight or obese.

These chemical changes could have arisen in response to environmental conditions, such as the childhood diet of the individual or even of their mother during pregnancy.

"We don't know yet the degree to which genes and environment add up to give these stable methylation changes, but we believe both are important," says Feinberg.

Usual suspects

The 13 methylated genes include those that make metalloproteinase enzymes, which have already been implicated in obesity through studies on mice. Another, called PRKG1, plays a role when insects and nematodes forage for food.

The researchers caution that it is not yet possible to say whether the methylation changes are a result of environment influence, perhaps in the diet, or whether they are ultimately genetic because they are orchestrated by other genes.

But if specific methylated genes linked with obesity can be identified, they may provide new ways to screen people for risk of becoming overweight or obese. "The results do suggest the importance of including epigenetic analysis with genetic analysis in personalised medicine research to predict risk," says Feinberg.

"Relationships between epigenetic markers such as methylation patterns and particular disease or body states are hard to establish with confidence," says Bryan Turner, a geneticist at the University of Birmingham, UK.

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