What Should We Be Worried About?

THE RISE IN GENOMIC INSTABILITY

ERIC J. TOPOL, M.D.

Professor of genomics, Scripps Research Institute; director, Scripps Translational Science Institute; author, The Creative Destruction of Medicine

We were taught wrong. The old elementary-school science lesson that our DNA sequence is a fifty-fifty split of our mother and father omitted the salient matter that there are new, so-called de novo mutations that spontaneously occur and are a big deal.

It wasn’t until this past year that we could sequence whole human genomes of families, and even of single sperm cells, to directly quantify how frequently these de novo mutations arise. Each of us has between about eighty and a hundred changes in our native (germline) DNA that are not found in our parents’ DNA. But the source is the genomic instability from their eggs or sperm. On average, about fifteen to twenty “spelling errors” come from our mother and thirty to sixty from our father. We have a new appreciation of the father’s biologic clock, with aging dads having more sperm DNA instability, and increasing evidence that this phenomenon is linked to a higher risk of autism and schizophrenia.

Although the new mutations are rare in any given individual—representing a tiny fraction, less than 0.001 percent of your genome—the chance that they will do harm is great. That’s because they are not subject to natural evolutionary selection. Whereas there’s a small chance the mutation could have a positive effect, the overwhelming likelihood is for a deleterious one, as we’ve seen with the recent studies of such mutations in children with severe intellectual disability and other neurodevelopmental diseases.

So, to respond to the 2013 Edge Question, What’s the worry? We should be concerned that this genomic instability in our germline DNA, and also in our somatic (body cell) DNA, is on the rise. We’re seeing more new cases of cancer, which represent DNA off the tracks, prototypic of genomic instability. And while the aging-father trend is a clear and global phenomenon and may contribute to a small part of the increased incidence of autism, the story may be much bigger than that. So far, we know only that there exists a relationship with easy-to-diagnose traits like schizophrenia and severe cognitive disability. What about the more subtle effect of such mutations on other conditions, such as mild cognitive impairment or susceptibility to diabetes? The question we really need to ponder is precisely why genomic instability is increasing with age, and why more people are getting diagnosed with cancer from year to year—about 1.7 million Americans in 2012 and an increased incidence for seven of the leading types of cancer, even adjusted for the advancing age of the population.

I think a significant portion of genomic instability is due to environmental effects. For example, exposure to increased radiation is a prime suspect—be it man-made thermal radiation from atmospheric greenhouse gases or via medical imaging that uses ionized radiation. There are probably many other environmental triggers in our “exposome” that have yet to be unraveled, such as the interaction of our native DNA with our gut microbiome or the overwhelming pervasive exposure we have to viruses that can potentiate genomic instability.

Although we now have an appreciation for the frequency of de novo mutations due to the spectacular advances in sequencing technology and analytics, we don’t have even a rudimentary understanding of what induces them in the first place—or of the more subtle effects that may track with a sort of devolution of humankind. What is especially disconcerting is that the signals of increased genomic instability are occurring in a relatively short time span in the context of human evolution over millions of years.

Thus it may take a long time for this to play out. But we could do something about it now, by conducting an in-depth study of de novo mutations and environmental interactions among hundreds of thousands of individuals and their offspring. Not that we want to suppress all human de novo mutations, but perhaps someday there will be a way forward to prevent or screen out deleterious ones—and foster those that prove favorable. It might be considered by some to represent unnatural selection, but that’s what it may take to turn the tide.