The Human Genome May Be Weeding Out Some Unwanted Mutations

Genetic variations linked to various health threats appear less frequently in people with longer lifespans, which suggests that natural selection is at work.

Evolution is usually associated with long periods of time, such as the millions of years it took for our ancestors to walk on two legs, or for tiny birds to evolve from larger dinosaurs.

A study analyzing the genomes of 210,000 people in the United States and the United Kingdom, however, finds humans are not only still evolving, but also natural selection can occur over just a few decades. The findings were published today in the journal PLOS Biology.

“With the availability of large human data sets, mostly for biomedical purposes, we are now beginning to have the power to look at small changes that happen within a few generations,” said co-author Molly Przeworski, an evolutionary biologist at Columbia University.

Przeworski, lead author Hakhamenesh Mostafavi, and their colleagues made the determinations after analyzing the genomes of 60,000 people of European ancestry genotyped by Kaiser Permanente in California and 150,000 people in Britain genotyped through the UK Biobank.

The researchers tracked the relative rise and fall of specific mutations across the recorded generations to infer which traits are spreading or dwindling. The mutations were associated with 42 common traits, ranging from height to body mass index, which is a weight to height ratio.

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To compensate for a lack of elderly individuals genotyped in the Biobank, the researchers used the participants’ parents age at death as a proxy as they looked for the influence of specific mutations on survival.

The scientists found that sets of genetic mutations that predispose people to heart disease, high cholesterol and LDL “bad” cholesterol, obesity, and asthma appeared less often in people who lived longer and whose genes are therefore more likely to be passed down and spread through the population.

In women over 70, the researchers saw a drop in the frequency of the genetic variant ApoE4, which is linked to Alzheimer’s disease. This is consistent with earlier research showing women with one or two copies of the gene tend to die well before those without it.

In middle aged men, the scientists saw a similar drop in the frequency of a mutation in the CHRNA3 gene associated with heavy smoking.

“If no one smokes, this mutation does not have an effect,” Mostafavi explained. “But among smokers, those who carry this mutation tend to smoke more, and consequently are more exposed to the adverse effects of smoking.”

He said the environment in which a person is raised can also influence the impact of genetic variants, which is affecting information on human height trends. In many cultures, people have been gradually growing taller over the decades. Yet, Mostafavi said, “it could be that we are getting taller because of environmental changes, but are getting genetically shorter.”

These changes could be due to factors like better nutrition and improved health care.

Due to the powerful effect of environmental influences, the researchers do not believe people who find out they carry potentially deleterious genetic mutations should avoid having children. Sometimes these individuals and their children are not harmed at all by the genetic variants.

“We have a specific example of this in the CHRNA3 variant, in that in an environment where people don’t smoke, this isn’t an ‘undesirable’ variant at all,” said co-author Joseph Pickrell of Columbia and the New York Genome Center. “It’s basically neutral.”

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Natural selection is continuing to weed out these and other genetic mutations. Pickrell said even if men with ApoE4 have just 0.1 percent fewer children on average than men without it, this would be enough for the variant to be removed quickly by natural selection.

On the upside, the researchers found those who are genetically predisposed to delayed puberty and childbearing tend to live longer. A one-year puberty delay lowered the death rate by 3–4 percent in both men and women, while a one-year childbearing delay lowered the death rate by 6 percent in women.

Taken together, the findings on puberty and the timing of first births suggest genetic variants influencing fertility are evolving in at least some US and UK populations and certain beneficial ones are being conserved.

“Our study serves as a proof of concept that it is now becoming possible to directly observe natural selection in contemporary humans with the availability of large data sets,” Mostafavi said.

“In our current study, we were mostly powered to look at the effect of common genetic variants on survival,” he added. “As these data sets are growing every day, applying this approach to even larger data sets and data sets with young individuals as well as older ones, we can look at rarer genetic variants across the genome and will gain a comprehensive picture of how much viability selection is ongoing in humans.”

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