Genetic Study of More Than 60,000 People Reveals a Surprising Diversity of Mutations

In a great leap forward in the science of genetics, researchers have sequenced the exomes of 60,706 people from around the world. They published their findings in a suite of papers and commentary in Nature, Nature Genetics, and Genetics in Medicine.  The findings suggest that many genetic mutations thought to be responsible for a range of diseases may not be to blame after all.  

There are numerous ways to examine an organism’s DNA. Researchers could look at the whole genome, which includes all genetic material. This method can be useful because it casts a wide net, but investigating huge quantities of genetic data is also very expensive.

A newer, much cheaper technique is exome sequencing, which focuses exclusively on the protein-coding sequences, or exons. This technique is especially efficient in spotting variations related to cancer and Mendelian diseases (illnesses caused by mutations in a single gene), which are often most apparent in exons. The exome is very small—just 1.5 percent of your genetic material—but for many researchers, it’s where the action is.

The first exome research was very small in scale; one 2009 study included just 12 people. Less than a decade later, scientific advances have enabled researchers to draw upon much larger pools of genetic material. The recent study described in Nature was based on a massive international effort called the Exome Aggregation Consortium (ExAC), in which researchers were able to gather and sequence the exomes of 60,706 people of European, African, East Asian, South Asian, and Latino ancestry. 

They found that genetic variation as a phenomenon is startlingly common, appearing in one out of every eight sites in the exome. And those variants were, themselves, astonishingly diverse; those 60,706 exomes were home to 7.5 million mutations. More than half of those mutations were seen just once, in one person.  

The researchers then used this gigantic new pool of information to test long-held ideas about mutations associated with various Mendelian diseases. They compared their findings with those of earlier studies, scanning their test subjects’ exomes for variants that purportedly cause these illnesses. The outcome was not so good for the old theories; of 192 mutations, only 9 could be confirmed in the new data set.

In other words, it’s possible that 183 mutations thought to cause rare diseases could actually be benign.

Geneticist Jay Shendure at the University of Washington led the 12-person exome study in 2009. Writing in a commentary in Nature, Shendure praised the ExAC team for their ability to wrangle not only data but also scientists, calling the study “both a technical and political achievement.”

And yet this achievement is just the tip of the iceberg, he notes: "In the coming decade, the number of human genomes that will be sequenced in some manner will grow to at least tens of millions and, by the end of this century, perhaps even billions."

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