The Great DNA Data Deficit: Are Genes for Disease a Mirage?

Jonathan Latham and Allison Wilson

Just before his appointment as head of the US National Institutes of Health (NIH), Francis Collins, the most prominent medical geneticist of our time, had his own genome scanned for disease susceptibility genes. He had decided, so he said, that the technology of personalised genomics was finally mature enough to yield meaningful results. Indeed, the outcome of his scan inspired The Language of Life, his recent book which urges every individual to do the same and secure their place on the personalised genomics bandwagon.

So, what knowledge did Collins’s scan produce? His results can be summarised very briefly. For North American males the probability of developing type 2 diabetes is 23%. Collins’s own risk was estimated at 29% and he highlighted this as the outstanding finding. For all other common diseases, however, including stroke, cancer, heart disease, and dementia, Collins’s likelihood of contracting them was average.

Predicting disease probability to within a percentage point might seem like a major scientific achievement. From the perspective of a professional geneticist, however, there is an obvious problem with these results. The hoped-for outcome is to detect genes that cause personal risk to deviate from the average. Otherwise, a genetic scan or even a whole genome sequence is showing nothing that wasn’t already known. The real story, therefore, of Collins’s personal genome scan is not its success, but rather its failure to reveal meaningful information about his long-term medical prospects. Moreover, Collins’s genome is unlikely to be an aberration. Contrary to expectations, the latest genetic research indicates that almost everyone’s genome will be similarly unrevealing.

We must assume that, as a geneticist as well as head of NIH, Francis Collins is more aware of this than anyone, but if so, he wrote The Language of Life not out of raw enthusiasm but because the genetics revolution (and not just personalised genomics) is in big trouble. He knows it is going to need all the boosters it can get.

What has changed scientifically in the last three years is the accumulating inability of a new whole-genome scanning technique (called Genome-Wide Association studies; GWAs) to find important genes for disease in human populations. In study after study, applying GWAs to every common (non-infectious) physical disease and mental disorder, the results have been remarkably consistent: only genes with very minor effects have been uncovered. In other words, the genetic variation confidently expected by medical geneticists to explain common diseases, cannot be found.

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Surprisingly sloppy yeast genes

Contrary to popular belief, the gene expression of "housekeeping" proteins in yeast is not synchronized or even coordinated.

Instead, these essential genes -- which work together to build important cell complexes like ribosomes and proteasomes -- are turned on and off randomly, researchers report in today's online edition of Nature Structural and Molecular Biology.

"We all have our biases about how things work," said senior author Robert Singer of the Albert Einstein College of Medicine in New York. "Sometimes, we're just wrong."

The surprising finding may change the way scientists understand and assess some gene transcription networks.

"It's fantastic work," said Mads Kaern, Canada Research Chair in systems biology at the University of Ottawa, who was not involved in the research. "This challenges the idea that elaborate networks have evolved to regulate this class of genes. That is profound."

Multi-protein complexes -- like ribosomes, made up of 80 different proteins -- perform essential functions in cells. Scientists have long assumed the expression of the genes required to assemble such complexes is coordinated because often the resulting proteins have similar abundances in cells. Additionally, it made logical sense that widely varying levels of subunits would result in malformed complexes or a build-up of toxic levels of unused proteins.

But in 2008, Singer and colleagues studying the expression of genes in yeast noticed that many constitutive genes -- those transcribed throughout the cell cycle rather than on an as-needed basis -- had irregular, random expression patterns. The unexpected finding led them to predict that the expression of genes needed for multi-protein complexes might not be synchronized, either.

When the team measured the expression of several groups of genes -- those encoding subunits of a proteasome, a transcription factor, and RNA polymerase II -- they found that the mRNAs of each group's subunits were no more correlated than the mRNAs of genes that had no functional relationship to each other. Even two alleles of the same gene with identical promoters were not expressed equally.

"The genes are essentially clueless," said Singer. "They don't know what they're making or the actual destiny of protein. They're just there, cranking out proteins." In contrast, induced genes -- those triggered by stimuli, such as a nearby toxin or nutrient-rich media -- demonstrated highly coordinated expression.

Consequently, the researchers assume that the coordination of protein abundances for complexes happens after transcription. Because many proteins have longer half-lives than mRNA, for example, random fluctuations in mRNA levels may be inconsequential because proteins stick around for significantly longer. Or perhaps chaperone molecules impose checkpoints, stabilizing ribosomes or proteasomes to prevent dissociation until the next subunit arrives. Or both.

"We have this bias about cells being efficient, but the more we learn about them, the more inefficient we find out they are," said Singer. "But maybe that's the way biological systems have to work. If they had too many controls, there's a lot more opportunity for things to go wrong."

The un-coordinated expression of constitutive genes may have an important evolutionary function, suggested Kaern. "They may make cells more robust, less sensitive to mutations in upstream regulators," he said. If constitutive genes shared one upstream activator to turn them all on simultaneously, a single mutation in that activator could have catastrophic consequences for the cell, he speculated.

Overall, the research has important implications for systems biology and researchers studying gene networks of constitutive genes. "This opens up a conceptual door that was previously ignored," said Kaern, who suspects something similar may occur in mice and human cells. "But I think a lot of yeast biologists will not be surprised [this happens in yeast] because they know how sloppy yeast is," he added. "It has a tendency to survive whatever you throw at it."

Source: The Scientist