We tend to think of mutations in the same way we think of car accidents: something dangerous that we should avoid. If we wear sunscreen, don't smoke, lay off grilled meat, avoid moldy peanuts, wear lead aprons during x-rays, and stay away from nuclear waste, then—or so our thinking goes—we won't pick up mutations that could damage our or our children's health. But mutations are unavoidable. Though we should certainly stay away from mutagens like cigarette smoke and nuclear waste, mutations are something we all acquire—billions over a lifetime—because they are inevitable consequence of being alive. We are all mutants, and with recent large-scale genetic studies, scientists are gaining a better understanding of the role of mutations in our lives, and in the human population as a whole.
The term "mutation" means different things to different people, but as used by geneticists, it usually refers to newly acquired changes in our DNA. New mutations are a subset of the broader category of genetic "variants," which include millions of DNA differences between individuals. Most of these genetic variants already exist in the human gene pool—they arose as new mutations a long time ago, and have been passed down for generations. Most of the genetic variants in our genomes are inherited from our parents, who in turn inherited their variants from their parents, and so on. These pre-existing variants are the major genetic influence on who we are, and they explain why we resemble our biological relatives.
Mutations are the inevitable byproduct of being alive, and, in the long run, they are the raw material of evolution.
But each of us also acquires brand-new mutations during our lives. Some of these are caused by dangerous environmental factors, like cigarette smoke. Most, however, are a byproduct of life's most fundamental processes, small chemical accidents that occasionally mar our DNA and genetic typos that occur as our genome gets copied over and over to produce the trillions of cells of which we're composed. While our cells correct many mutations (this year's chemistry Nobel is going to the researchers who figured out that process), some slip through.
That mutations are common is something geneticists have long known, but new DNA technology now makes it possible to study mutations more directly than ever before. With data from large-scale projects like the 1,000 Genomes Project, researchers are beginning to answer critical questions about mutations, such as how many we have, where they come from, and how they affect our health. In a recent paper, University of Washington geneticists Jay Shendure and Joshua Akey write that, thanks to these new projects, "the study of human mutations has entered an exciting new era." They sum up the results of some of the latest studies of mutations, and the numbers they cite show how shockingly common mutations are. Right at conception we pick up an average of 60 new mutations, which arose in the sperm or egg cell—as it turns out, usually the sperm cell—of our parents. These mutations, called germline mutations, are new entrants to the human gene pool: As we develop from a single fertilized egg into adults, these mutations are passed on to all cells in our body, including reproductive cells, and are thus inherited by our children.
A larger class of mutations are those we acquire after conception. These mutations happen here and there in individual cells, in different parts of our bodies. Called somatic mutations, they are localized to the tissue where they arose, and thus don't affect every part of us the way germline mutations do. They also aren't passed on to our children (unless they happen to occur in our reproductive cells). The number of somatic mutations we accumulate over a lifetime is enormous: Among our trillions of cells, we acquire billions of somatic mutations by the time we're 60. Some cells, like those in our skin or gut, are especially fertile grounds for mutation, in part because they are most exposed to outside influences, like sunlight or the things we eat. A study published earlier this year looked at mutations in normal human skin, and found that, even in perfectly healthy people, skin cells are so riddled with mutations that, from a genetic perspective, they essentially look like cancer.
But how do our mutations affect us? This has long been a major question in genetics, and researchers now have much better tools to answer it. For example, the frequency of germline mutations could previously only have been estimated indirectly, by looking at the frequency of certain childhood genetic diseases. Now, researchers can directly identify germline mutations by comparing the whole genomes of parents and children. In one recent study, researchers discovered more than 10,000 germline mutations in 250 Dutch families. These results confirm that germline mutations are common, and they also reveal a striking trend: The children of older fathers have more germline mutations than younger fathers.
This trend isn't unexpected—smaller studies have reported the same pattern, and since men produce millions of sperm, we know there are many more opportunities for mutations to occur in the father's reproductive cells than the mother's. But this latest study puts a number on the impact of the father's age: Considering mutations in actual genes (as opposed to potentially less-damaging mutations in the portions of the genome that don't carry genes), children born to 40-year-old fathers have twice as many germline mutations as children born to 20-year-old fathers. This result could explain the finding that children of older fathers are more likely to suffer from certain types of genetic diseases like autism. This doesn't mean that, if you're an older father, you should panic—most children of young and old parents alike are healthy, so most of these mutations are clearly not harmful. But on a population scale, this study shows how, as we increasingly tend to have children later in life, the prevalence of certain types of genetic diseases will change.
What about all those somatic mutations we pick up over a lifetime? Again, most are clearly benign, but somatic mutations—whether caused by environmental factors like cigarette smoke or by routine cellular errors—are the primary source of cancer. Because it almost always takes more than one mutation to produce cancer, the gradual lifetime accumulation of somatic mutations explains why we're more likely to develop cancer in our older years. But researchers are now discovering that the impact of somatic mutations on our health goes beyond cancer. In a study of patients with brain malformations published last year by Harvard geneticist Christopher Walsh, 30 percent of the cases were caused by somatic mutations. This is surprising, because the genetic diseases and congenital malformations patients are born with are usually thought to be caused by germline mutations. But somatic mutations can also be picked up before birth, and in some unlucky cases, a single, severe somatic mutation can result in disease. These types of early somatic mutations were largely undetectable a decade ago, because they occur only in a limited number of cells, and their impact is only now being recognized.
Rather than being freak events or the result of toxic exposure, mutations are a normal part of life. They are the inevitable byproduct of being alive, and, in the long run, they are the raw material of evolution—without mutations, life as we know it wouldn't exist. Until recently, most mutations were invisible, except in the most pathogenic cases. But new studies are showing that, to understand what makes us healthy and why we get sick, we need to understand mutations. We can't avoid them; we need to learn how to lead a healthy life with them.
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