Genome news flash: We’re all a little bit broken

February 16, 2012

We’ve all had cars with a bunch of broken parts that get us where we want to go for years with no obvious problem. Does the human genome have the same tolerance for permanent damage?

The answer is: Sure.

A new study estimates that the average person goes through life with 20 genes permanently out of commission. With each of us possessing about 20,000 genes, that means 0.1 percent of our endowment is broken from the start — and we don’t even know it.

Whether being born with 20 broken genes is horrifying (“Get me customer service!”) or reassuring (“Whew, only 20!”) depends on one’s expectation of perfection.

“It does suggest that human beings have a bigger tolerance for mutation than we thought,” said Daniel G. MacArthur of the Wellcome Trust Sanger Institute in England, who led the study published Thursday in the journal Science. “That we can actually have 20 genes knocked out and still be walking around without suffering any ill effects — that was surprising.”

Mark Gerstein of Yale University, one of the 50 scientists around the world who assisted him, agreed: “This is a testament to how robust people are.”

Which genes are inactivated differs from person to person. Across the entire species, however, at least 250 of them — and probably a lot more — are expendable. They’re not part of the essential tool kit for making and running a human being.

As one might expect, genes that can go missing without being missed aren’t involved in essential functions. They control things that are nice to have (like a certain smell receptor) but aren’t required for survival (like an enzyme in a basic metabolic pathway). They’re the radio and door lock, not the drive shaft and brake pedal.

The point of the research, however, goes far beyond a Rorschach test of self-image. It’s the latest deep-dive into the human genome, our species’s 3-billion-letter instruction manual for self.

The normal function of many of the “expendable” genes isn’t known. They’re simply recognized as broken because of certain molecular signatures in the sequence of their nucleotides (“letters”) or other detectable abnormalities.

However, by determining which genes can be tolerated in that state — and labeling what their molecular damage consists of — the researchers are building a reference book that will prove useful to other scientists trying to learn the function of all the human genes. It will help especially in determining whether newly discovered mutations are likely to cause disease or are probably “benign.”

As biologists come to understand better how genes interact with one another in complex networks, they may be able to discover how much of what makes each of us unique is a product of what we lack, and not just what we have.

What the researchers did in the new study is carefully read a book — an individual’s genome — in which some of the sentences — a single gene — have suffered a typographical catastrophe. Words have been changed, their order changed, or whole phrases have been dropped. Whatever the cause, the result is a sentence that no longer makes sense. In genetic terms, these are “loss-of-function variants.”

Most of the time this isn’t a problem. That’s because (with a few exceptions) we get two copies of every gene — one from the mother and the other from the father. If one copy is broken, the other takes over.

In the new study, MacArthur and his many collaborators sequenced the genes of 185 people from four regions and ethnicities — Chinese, Japanese, Ni­ger­ian and Western European. They repeated and checked their work, filtering out variants that were simply laboratory errors. They ended up with a list of 1,285 loss-of-function variants. The number of genes involved was slightly fewer — 1,035 — because a few of the genes had more than one loss-of-function variant.

On further study, the researchers found that there were 253 genes in which both copies were inactivated in at least 1 of the 185 people without obvious effect. And they found that each person in the sample carried about 20 such inactivated genes.

What is the function of those genes that we don’t seem to need? For many, that can’t be answered yet. But a look at their structure gave some hints.

Expendable genes tend to be ones that have evolved recently. They aren’t ancient ones shared by everything from fungi to oysters to orangutans, and therefore probably essential for life. About 13 percent are involved in smell, which is a sensation necessary for some the survival of some species but not Homo sapiens.

The proteins these genes make also don’t interact much with other proteins. That makes sense, because one missing piece in such a network could cause lots of problems and would probably be visible. Only one of the expendable genes is involved in “morphogenesis” — body planning — a function that people need to get right.

While this is the most complete list to date, it will almost certainly grow as researchers sequence more genomes in more populations.

“I think this number will go up to many thousands of genes,” said Michael Snyder, a geneticist at Stanford University.

Part of the reason, he believes, is the experience with genetic “knockouts.” They are organisms in which specific genes are inactivated, or knocked out. “Knockout” yeast, worms and mice help scientists learn the function of genes, and are models for human diseases.

Between a third and a half of all yeast genes are ones that can be knocked out individually with no apparent consequence to the cell. The yeast continues to grow (although in some cases if environmental conditions change the loss becomes apparent).

The fact that we’re all “knockouts” — at least in this regard — doesn’t bother Snyder, who has had his genome sequenced and found about 20 inactivated genes in it. But he thinks not everyone will feel that way.

“If you’re a worrier, you should not get your genome sequenced because you will find these things,” he said.

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