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Most genes are in our genomes for a reason. If they aren’t able to code proteins properly, then we simply won’t survive — or will be saddled with the symptoms of any number of serious diseases.

That’s been the conventional thought. But geneticists are beginning to question that idea. They’re finding more and more people who are perfectly healthy despite having defective copies of a supposedly “essential” gene — and those anomalies aren’t just making scientists rethink the workings of the human genome. They may well lead to new million-dollar, life-saving drugs.

“The amazing thing about these variants is that they provide us with a model — in fact, the only model — where we can see in a living human being what happens when a particular gene is inactivated,” said Daniel MacArthur, a geneticist at the Broad Institute and Massachusetts General Hospital.


A study, published Thursday in the journal Science, reported the newest crop of these rare genetic mutations. By sequencing genetic material from the Pakistani community of East London, in which marriage between cousins is common, the researchers were able to find a higher concentration of these disabled protein-coding genes than in other, more genetically diverse populations.

They even zeroed in on one woman who was lacking a gene that was thought to be essential for human reproduction — and found that she had had three kids.


“It was thought that if you had a knockout in those essential genes, you wouldn’t be here to talk about it. Turns out, whoa, that’s not necessarily the case,” said Dr. Eric Topol, a cardiologist and geneticist at the Scripps Translational Science Institute, who was not involved in the study.

“These knockouts are really a genetic gift from nature that allows us to study human biology in a way we couldn’t otherwise,” said geneticist David van Heel of Barts and the London School of Medicine and Dentistry, and one of the study’s lead authors.

Yet sometimes those knockouts are gifts in and of themselves, with repercussions well beyond the genetics community.

The most famous example emerged from the University of Texas Southwestern Medical Center, where researchers noticed that people who were missing the gene PCSK9 had remarkably low levels of dangerous cholesterol.

The link proved to be a lucrative one. In the summer of 2015, two drugs that mimic the knocking out of that gene won marketing approval for people with high cholesterol. Both are projected to earn billions for their manufacturers.

Finding other human knockout genes that might be similarly protective is no mean feat, though.

“The challenge is if we were to just take a random set of American individuals and looked for knockouts, we would actually find very few. Way less than 1 percent of the random outbred population in America has a rare knockout mutation,” said MacArthur.

The solution used in the latest paper was to look at a genetically homogenous population. But MacArthur, who is something of a star in the world of human knockouts, has been working on another one: reams and reams and reams of data.

A few years ago, he began to compile genetic sequences that other scientists had collected into a database called the Exome Aggregation Consortium, or ExAC. Most of these people had had the protein-coding portions of their genomes analyzed for diabetes or heart attack research. But now, stripped of any information by which the patients could be identified, all 20,000 genes of each of the 60,000-plus individuals were to be made available to researchers and the public alike, along with bits of their health records.

“This was a huge amount of data,” MacArthur said. “This was basically a petabyte of data, which is a thousand terabytes, so that’s like 4,000 laptops worth of data.”

Already, that data has been mined for knockouts that could be used for developing new drugs. Over the next few months, MacArthur’s lab, together with industry and other academic partners, will publish a paper showing that a mutation in a single gene may protect people from ulcerative colitis.

MacArthur declined to discuss those results, as the paper is still in review, but the manuscript is already accessible on bioRxiv, a website that makes scientific papers publicly available before they have been peer-reviewed and approved for publication.

Those kinds of findings, experts say, are going to snowball, because of the 4,000 laptops’ worth of data that MacArthur helped put together.

“People really do feel like it’s something that has enabled research and medical efforts,” said Dr. David Altshuler, a former colleague of MacArthur’s at the Broad Institute, who is now chief scientific officer at Vertex Pharmeceuticals.

Altshuler described ExAC as “an example of people coming together, not to advance any one person’s opportunities, [but] to allow everyone to work towards human health together.”

But Colin Fletcher of the National Human Genome Research Institute warned that human knockouts found in the ExAC database wouldn’t be yielding new drug targets left, right, and center. “I think it’s going to be more the rare nugget, but that’s incredibly valuable,” he said.

As for MacArthur, the possibilities that ExAC opens up are almost too huge. “We have hundreds of things that we can work on,” he said. “The challenge is trying to figure out what is the most interesting story, and what is the thing most interesting in investing the most time in.”