Sunday, July 3, 2022
HomeGeneticsNatural selection weeding out unfavourable genomes in Alzheimer's

Natural selection weeding out unfavourable genomes in Alzheimer's

In a study analysing the genomes of 210,000 people in the US and Britain, researchers at Columbia University find that the genetic variants linked to Alzheimer’s disease and heavy smoking are less frequent in people with longer lifespans, suggesting that natural selection is weeding out these unfavourable variants in both populations.

Researchers further find that sets of genetic mutations that predispose people to early puberty and childbearing, heart disease, high cholesterol, obesity, and asthma, also appear less often in people who lived longer and whose genes are therefore more likely to be passed down and spread through the population.

“It’s a subtle signal, but we find genetic evidence that natural selection is happening in modern human populations,” said study co-author Joseph Pickrell, an evolutionary geneticist at Columbia and New York Genome Centre.

New favourable traits evolve when genetic mutations arise that offer a survival edge. As the survivors of each generation pass on those beneficial mutations, the mutations and their adaptive traits become more common in the general population. Though it may take millions of years for complex traits to evolve, say allowing humans to walk on two legs, evolution itself happens with each generation as adaptive mutations become more frequent in the population.

The genomic revolution has allowed biologists to see the natural selection process in action by making the genetic blueprint of hundreds of thousands of people available for comparison. By tracking the relative rise and fall of specific mutations across generations of people, researchers can infer which traits are spreading or dwindling.

The researchers analysed 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. To compensate for the relative lack of old people 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.

Two population-level mutation shifts stood out. In women over 70, researchers saw a drop in the frequency of the ApoE4 gene linked to Alzheimer’s, consistent with earlier research showing that women with one or two copies of the gene tend to die well before those without it. Researchers saw a similar drop, starting in middle age, in the frequency of a mutation in the CHRNA3 gene associated with heavy smoking in men.

The researchers were surprised to find just two common mutations across the entire human genome that heavily influence survival. The high power of their analysis should have detected other variants had they existed, they said. This suggests that selection has purged similar variants from the population, even those that act later in life like the ApoE4 and CHRNA3 genes.

“It may be that men who don’t carry these harmful mutations can have more children, or that men and women who live longer can help with their grandchildren, improving their chance of survival,” said study co-author Molly Przeworski, an evolutionary biologist at Columbia.

Most traits are determined by dozens to hundreds of mutations, and even in a large sample like this one, their effect on survival can be hard to see, researchers said. To get around this, they examined sets of mutations associated with 42 common traits, from height to BMI, or body mass index, and for each individual in the study, determined what value of the trait they would predict based on their genetics, and whether it influenced survival.

They found that a predisposition for high cholesterol and LDL “bad” cholesterol, high body mass index or BMI, and heart disease was linked to shorter life spans. To a lesser extent, a predisposition for asthma was also linked to earlier death.

They also found that those genetically predisposed to delayed puberty and child-bearing lived longer – a one-year puberty delay lowered the death rate by 3% to 4% in both men and women; a one-year childbearing delay lowered the death rate by 6% in women.

Researchers take the results as evidence that genetic variants that influence fertility are evolving in some US and Britain populations. But they caution that environment plays a role, too, so that traits that are desirable now may not be in other populations or in the future.

“The environment is constantly changing,” said the study’s lead author, Hakhamenesh Mostafavi, a graduate student at Columbia. “A trait associated with a longer lifespan in one population today may no longer be helpful several generations from now or even in other modern-day populations.”

The study may be the first to take a direct look at how the human genome is evolving in a period as short as one or two generations. As more people agree to have their genomes sequenced and studied, researchers hope that information about how long they lived, and the number of kids and grandkids they had, can reveal further clues about how the human species is currently evolving.

Abstract
A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10−6 for fathers and P~2.0 × 10−3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10−3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.

Authors
Hakhamanesh Mostafavi, Molly Przeworski, Tomaz Berisa, Felix Day John Perry

[link url="http://news.columbia.edu/content/1734"]Columbia University material[/link]
[link url="http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2002458"]PLOS Biology abstract[/link]

Subscribe to our Newsletter

Receive Medical Brief's free weekly e-newsletter.

* indicates required