The Genome's Dark Matter

Evidence is growing that your DNA sequence does not determine your entire genetic fate. Joseph Nadeau is trying to find out what accounts for the rest.

Somethings missing: Geneticist Joseph Nadeau has been finding examples of what he calls funky genetic effects that could help explain the mystery of missing heritability.

What we know about the fundamental laws of inheritance began to take shape in a monastery garden in Moravia in the middle of the 19th century, when Gregor Mendel patiently cross-bred pea plants over the course of several years, separated the progeny according to their distinct traits, and figured out the mathematical foundations of modern genetics. Since the rediscovery of Mendels work a century ago, the vocabulary of Mendelian inheritancedominant genes, recessive genes, and ultimately our own eras notion of disease geneshas colored every biological conversation about genetics. The message boils down to a single premise: your unique mix of physiological traits and disease risks (collectively known as your phenotype) can be read in the precise sequence of chemical bases, or letters, in your DNA (your genotype).

But what ifexcept in the cases of some rare single-gene disorders like Tay-Sachs diseasethe premise ignores a significant portion of inheritance? What if the DNA sequence of an individual explains only part of the story of his or her inherited diseases and traits, and we need to know the DNA sequences of parents and perhaps even grandparents to understand what is truly going on? Before the Human Genome Project and the era of widespread DNA sequencing, those questions would have seemed ridiculous to researchers convinced they knew better. But modern genomics has run into a Mendelian wall.

Large-scale genomic studies over the past five years or so have mainly failed to turn up common genes that play a major role in complex human maladies. More than three dozen specific genetic variants have been associated with type 2 diabetes, for example, but together, they have been found to explain about 10 percent of the diseases heritabilitythe proportion of variation in any given trait that can be explained by genetics rather than by environmental influences. Results have been similar for heart disease, schizophrenia, high blood pressure, and other common maladies: the mystery has become known as the missing heritability problem. Francis Collins, director of the National Institutes of Health, has sometimes made grudging reference to the dark matter of the genomean analogy to the vast quantities of invisible mass in the universe that astrophysicists have inferred but have struggled for decades to find.

Joseph H. Nadeau has been on a quest to uncover mechanisms that might account for the missing components of heritability. And he is finding previously unsuspected modes of inheritance almost everywhere he looks.

Nadeau, who until recently was chair of genetics at Case Western Reserve University in Cleveland and is now director of research and academic affairs at the Institute for Systems Biology in Seattle, has done studies showing that certain traits in mice are influenced by specific stretches of variant DNA that appeared on their parents or grandparents chromosomes but do not appear on their own. Transgenerational genetics, as he calls these unusual patterns of inheritance, fit partly under the umbrella of traditional epigeneticsthe idea that chemical changes wrought by environmental exposures and experiences can modify DNA in ways that either muffle a normally vocal gene or restore the voice of a gene that had been silenced. Researchers have begun to find that these changes are heritable even though they alter only the pattern of gene expression, not the actual genetic code. Yet its both more disconcerting and more profound to suggest, as he does, that genes an ancestor carried but didnt pass down can influence traits and diseases in subsequent generations.

Consider the results of an experiment Nadeau and his colleague Vicki R. Nelson published last August. They created an inbred strain of mice and then compared two sets of females that were genetically identical except for one small difference: one set had a father whose Y chromosome came from another strain of mouse and contained a different set of genetic variants. That shouldnt have affected the daughter mice at all, because females dont inherit the Y chromosome. But the presence of that uninherited DNA in the previous generation exerted a profound effect on many of the more than 100 traits tested in the two sets of female offspring, whose own DNA was exactly the same. These results, Nelson and Nadeau concluded, suggest that transgenerational genetic effects rival conventional genetics in frequency and strength.

In a separate but similarly unsettling line of experiments, Nadeau and his collaborators are finding that the impact of any given gene depends on all the other genes surrounding it. Nadeau is hardly the only scientist to identify these complex gene-gene interactions, but he and his colleagues have created a unique set of genetically engineered mice that is giving them and other scientists unprecedentedly precise tools for dissecting these situational genetics to show how the variants in a genes molecular neighborhood affect the way it behaves.

Findings like these, taken together, could shed light on the missing-heritability problem, but at the cost of upending the dominance of traditional Mendelian ideas about how inheritance works. Sitting on the outside deck of the Institute for Systems Biology one recent afternoon, munching on a sandwich as seaplanes descended toward the skyline of Seattle, Nadeau recalled giving a talk about all this at a conference several years ago and discovering afterward that a prominent Ivy League geneticist in attendance, whom he declined to name, simply couldnt get the heretical ideas out of his head. He came up to me after the talk, Nadeau recalled, and said, This cant be true in humans. I ran into him at breakfast the next day and he said, This cant be true in humans. And then when the meeting was over, I ran into him at the airport, and he came up to me and said, This cant be true in humans. Or as another leading genome scientist once told Nadeau at a meeting in Europe, If transgenerational effects happen in humans, were screwed.

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The Genome's Dark Matter