Wednesday, December 22, 2010

ruining genetics

TechnologyReview | In 2009, a group of researchers based in the Netherlands published a stunning study on the genetics of human height—stunning because it failed to find much of a genetic component in one of the most obvious of inherited human traits. The group analyzed 54 recently identified genetic locations that statistical analysis suggested were the main contributors to height and discovered that all of them together accounted for only 4 to 6 percent of the height variance in thousands of subjects.

The "missing heritability" in the height study typifies many recent research reports in which large-scale genetic screens, known as genome-wide association studies, have identified a multitude of genes (or at least genetic neighborhoods) that are statistically associated with a biological trait like height or a disease like obesity, yet account for mystifyingly little of its propensity to run in families. What is interesting about Nadeau's findings is that even though they diminish the significance of single genes and the DNA sequences of individuals, the research preserves—and in some ways increases—the significance of family history, since even the genetic variants that parents and grandparents don't pass down through DNA seem to influence the traits of their children or grandchildren.

Nadeau, who is silver-haired and cheerful, has been investigating what he sometimes calls "funky" genetic results ever since sophisticated sequencing technologies became available about 10 years ago. Some of those results have been hinted at by traditional epigenetics, which has begun to trace changes that are transmitted from one generation to the next in animals even though the basic DNA sequence remains the same. (For example, researchers have found that rats whose cognitive performance was improved through environmental factors can pass those improvements down to offspring.) But where that field has typically focused on chemical modifications of DNA, Nadeau's work expands the notion of epigenetics to include genetic effects that may be transmitted by different molecular players: ribonucleic acids (or RNAs), which exert powerful regulatory effects on DNA.

Key evidence for Nadeau's general views on unconventional modes of inheritance grew out of a dissertation project that one of his students began around 2001. In the long tradition of misguided doctoral advice, everyone told Man-Yee Lam that her project was boring, derivative, and hardly worth doing; for five or six years, nothing in her results suggested otherwise. The focus of the project was testicular germ-cell tumors. It didn't become clear until much later that the experiment represented the first rigorous demonstration of a transgenerational effect, showing that genetic variations in a parent—even though they were not passed along to offspring—could dramatically change disease risks in those offspring.

Lam set out to see if she could identify interactions between several "modifier" genes—interactions that would increase susceptibility to testicular cancer in mice. She found lots of these interactions (some quite strong), completed her thesis, and graduated. Then, when the group started to write up the results for publication, they noticed something very peculiar: the effects had also occurred in some of the control animals bred from the same original population. In other words, males that had been bred so as not to inherit the disease mutations still had a statistically significant increase in their risk for testicular cancer, simply because the parents possessed a particular genetic variant. The results suggested that there could be patches of DNA in parents that affected the traits of children, even if the children did not inherit this bit of parental DNA.

Even before publication in 2007, Nadeau began describing the findings—to decidedly mixed reviews. He says, "If they were geneticists, there were all sorts of technical [objections] or 'It's not fair to talk about this in public. This is just too complicating, too—it's too everything!' One even said, 'Are you trying to ruin genetics?' "