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Why microbes are better than people at keeping DNA mutations at bay

TEMPE, ARIZONA—Kelley Harris wishes humans were more like paramecia. Every newborn's DNA carries more than 60 new mutations, some of which lead to birth defects and disease, including cancers. "If we evolved parameciumlike replication and DNA repair processes, that would never happen," says Harris, an evolutionary biologist at the University of Washington in Seattle. Researchers have learned that these single-cell protists go thousands of generations without a single DNA error—and they are figuring out why human genomes seem so broken in comparison.

The answer, researchers reported at the Evolution of Mutation Rate workshop here late last month, is a legacy of our origins. Despite the billions on Earth today, humans numbered just thousands in the early years of our species. In large populations, natural selection efficiently weeds out deleterious genes, but in smaller groups like those early humans, harmful genes that arise—including those that foster mutations—can survive.

Support comes from data on a range of organisms, which show an inverse relationship between mutation rate and ancient population size. This understanding offers insights into how cancers develop and also has implications for efforts to use DNA to date branches on the tree of life. "Clarifying why mutation rates vary is crucial for understanding all areas of biology," says evolutionary biologist Michael Lynch of Arizona State University (ASU) here.

Mutations occur, for example, when cells copy their DNA incorrectly or fail to repair damage from chemicals or radiation. Some mistakes are good, providing variation that enables organisms to adapt. But some of these genetic mistakes cause the mutation rate to rise, thus fostering more mutations.

For a long time, biologists assumed mutation rates were identical among all species, and so predictable that they could be used as "molecular clocks." By counting differences between the genomes of two species or populations, evolutionary geneticists could date when they diverged. But now that geneticists can compare whole genomes of parents and their offspring, they can count the actual number of new mutations per generation.

That has enabled researchers to measure mutation rates in about 40 species, including newly reported numbers for orangutans, gorillas, and green African monkeys. The primates have mutation rates similar to humans, as ASU co-organizer Susanne Pfeifer reported in the December 2017 issue of Evolution. But, as Lynch and others reported at the meeting, bacteria, paramecia, yeasts, and nematodes—all of which have much larger populations than humans—have mutation rates orders of magnitude lower.

The highs and lows of mutation rates

The rate at which new mutations appear in a genome (sizes of circles) is inversely proportional to the so-called effective population size of the species. Microbes (right) have the largest populations and lowest mutation rates.

African green monkey Human Chimpanzee Orangutan Honey bee Mouse Gorilla Fruit fly Circle size representsrelative mutation rate Butterfly Tetrahymenathermophila Escherichia coli Pseudomonasaeruginosa 0 Effective population in thousands of individuals 160 800 2000 50000 250000 Parameciumtetraurelia

The variation suggests that in some species, genes that cause high mutation rates—for instance, by interfering with DNA repair—go unchecked. In 2016, Lynch detailed a possible reason, which he calls the drift barrier hypothesis. It invokes genetic drift, or chance genetic changes—"noise in the evolutionary process that is greater than the directional force" of selection, as he puts it. Genetic drift plays a bigger role in smaller populations. In large populations, harmful mutations are often counteracted by later beneficial mutations. But in a smaller population with fewer individuals reproducing, the original mutation can be preserved and continue to do damage.

Today, 7.6 billion people inhabit Earth, but population geneticists focus on the effective population size, which is the number of people it took to produce the genetic variation seen today. In humans, that's about 10,000—not so different from that of other primates. Humans tend to form even smaller groups and mate within them. In such small groups, Harris says, "we can't optimize our biology because natural selection is imperfect."

Harris detected those imperfections even among populations of people—further evidence, she notes, to support the drift barrier hypothesis. Rather than look at the overall number of DNA changes, Harris focused on the frequency of changes in each kind of DNA base in the populations she studied. That "mutation spectrum" varies widely between different groups of people, she reported. In 2017, she and her colleagues estimated that between 15,000 and 2000 years ago, Europeans had an unusually high number of some conversions of the base cytosine to thymine. She has since found differences in the mutation spectrum between Japanese and other East Asian populations. "The way the genome tends to break is not the same in Europeans" as in people elsewhere, she says.

Now, Harris and researchers at the University of Copenhagen have extended the analysis to ancient DNA. Among Europeans, the excess cytosine to thymine mutations existed in early farmers but not in hunter-gatherers, she reported. She speculates that these farmers' wheat diet may have led to nutrient deficiencies that predisposed them to a mutation in a gene that in turn favored the cytosine-to-thymine changes, suggesting environment can lead to changes in mutation rate. Drift likely played a role in helping the mutation-promoting gene stick around.

Eventually she hopes to pinpoint the pathways and the genes responsible. That's increasingly necessary, says Charles Baer, an evolutionary biologist at the University of Florida in Gainesville. It's become clear that "mutation rates can evolve pretty quickly and in all sorts of ways. If you really want to understand mutation rate, you have to put a fine magnifying glass to it."