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Uh-oh: Theorists Debate How ‘Neutral’ Evolution Really Is

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Viviane Callier writes in Quanta:

When Charles Darwin articulated his theory of evolution by natural selection in On the Origin of Species in 1859, he focused on adaptations — the changes that enable organisms to survive in new or changing environments. Selection for favorable adaptations, he suggested, allowed ancient ancestral forms to gradually diversify into countless species.

That concept was so powerful that we might assume evolution is all about adaptation. So it can be surprising to learn that for half a century, a prevailing view in scholarly circles has been that it’s not.

Selection isn’t in doubt, but many scientists have argued that most evolutionary changes appear at the level of the genome and are essentially random and neutral. Adaptive changes groomed by natural selection might indeed sculpt a fin into a primitive foot, they said, but those changes make only a small contribution to the evolutionary process, in which the composition of DNA varies most often without any real consequences.

But now some scientists are pushing back against this idea, known as neutral theory, saying that genomes show much more evidence of evolved adaptation than the theory would dictate. This debate is important because it affects our understanding of the mechanisms that generate biodiversity, our inferences about how the sizes of natural populations have changed over time and our ability to reconstruct the evolutionary history of species (including our own). What lies in the future might be a new era that draws from the best of neutral theory while also recognizing the real, empirically supported influence of selection.

An “Appreciable Fraction” of Variation

Darwin’s core insight was that organisms with disadvantageous traits would slowly be weeded out through negative (or purifying) selection, while those with advantageous features would reproduce more often and pass those features on to the next generation (positive selection). Selection would help to spread and refine those valuable traits. For most of the first half of the 20th century, population geneticists largely attributed genetic differences between populations and species to adaptation through positive selection.

But in 1968, the famed population geneticist Motoo Kimura resisted the adaptationist perspective with his neutral theory of molecular evolution. In a nutshell, he argued that an “appreciable fraction” of the genetic variation within and between species is the result of genetic drift — that is, the effects of randomness in a finite population — rather than natural selection, and that most of these differences have no functional consequences for survival and reproduction.

The following year, the biologists Jack Lester King and Thomas Jukes published “Non-Darwinian Evolution,” an article that likewise emphasized the importance of random genetic changes in the course of evolution. A polarized debate subsequently emerged between the new neutralists and the more traditional adaptationists. Although everyone agreed that purifying selection would weed out deleterious mutations, the neutralists were convinced that genetic drift accounts for most differences between populations or species, whereas the adaptationists credited them to positive selection for adaptive traits.

Much of the debate has hinged on exactly what Kimura meant by “appreciable fraction” of genetic variation, according to Jeffrey Townsend, a biostatistician and professor of evolutionary biology at the Yale School of Public Health. “Is that 50 percent? Is it 5 percent, 0.5 percent? I don’t know,” he said. Because Kimura’s original statement of the theory was qualitative rather than quantitative, “his theory could not be invalidated by later data.”

Nevertheless, neutral theory was rapidly adopted by many biologists. This was partly a result of Kimura’s reputation as one of the most prominent theoretical population geneticists of the time, but it also helped that the mathematics of the theory was relatively simple and intuitive. “One of the reasons for the popularity of the neutral theory was that it made things a lot easier,” said Andrew Kern, a population geneticist now at the University of Oregon, who contributed an articlewith Matthew Hahn, a population geneticist at Indiana University, to a special issue of Molecular Biology and Evolution celebrating the 50th anniversary of neutral theory.

To apply a neutral model of evolution to a population, Hahn explained, you don’t have to know how strong selection is, how large the population is, whether mutations are dominant or recessive, or whether mutations interact with other mutations. In neutral theory, “all of those very hard parameters to estimate go away.”

The only key inputs required by the neutral model are the rate at which random mutations occur per generation and the population size. From this information, the neutral model can predict how the frequency of mutations in the population will change over time. Because of its simplicity, many researchers adopted the neutral model as a convenient “null model,” or default explanation for the patterns of genetic variation they observed.

Some population geneticists were not convinced by Kimura’s argument, however. For instance, John Gillespie, a theoretical population geneticist at the University of California, Davis (and Kern’s doctoral adviser), showed in the early 1970s that some natural selection-based models could explain patterns observed in nature as well as neutral models, if not better.

More fundamentally, even when there aren’t enough data to disprove a neutral-theory null model, it doesn’t mean that natural selection isn’t happening, said Rebekah Rogers, an evolutionary geneticist at the University of North Carolina, Charlotte. “Any time you have limited data, the arguments get really fierce,” she said.

For decades, that was the crux of the problem: Kimura had proposed neutral theory at a time before inexpensive sequencing technology and the polymerase chain reaction became available, when gene sequence data were sparse. There was no simple way to broadly prove or disprove its tenets except on theoretical grounds because we didn’t know enough about genomic variation to resolve the dispute.

Strong Feelings About Neutrality

Today, 50 years after Kimura’s article, more affordable genomic sequencing and sophisticated statistical methods are allowing evolutionary theorists to make headway on quantifying the contribution of adaptive variation and neutral evolution to species differences. In species like humans and fruit flies, the data have revealed extensive selection and adaptation, which has led to strong pushback against Kimura’s original idea, at least by some researchers.

“The ubiquity of adaptive variation both within and between species means that a more comprehensive theory of molecular evolution must be sought,” Kern and Hahn wrote in their recent article.

Although the vast majority of researchers agree that strict neutrality as originally formulated is false, many also point out that refinements of neutral theory have addressed weaknesses in it. One of the original shortcomings was that neutral theory could not explain the varying patterns of genome evolution observed among species with different population sizes. For instance, species with smaller population sizes have on average more mutations that are deleterious.

To address this, one of Kimura’s students, Tomoko Ohta, now professor emeritus at Japan’s National Institute of Genetics, proposed the nearly neutral theory of molecular evolution in 1973. This modified version of neutral theory suggests that many mutations are not strictly neutral, but slightly deleterious. Ohta argued that if population sizes are large enough, purifying selection will purge them of even slightly deleterious mutations. In small populations, however, purifying selection is less effective and allows slightly deleterious mutations to behave neutrally.

Nearly neutral theory also had problems, Kern said: It did not explain, for example, why the rate of evolution varies as observed among different lineages of organisms. In response to such challenges, Ohta and Hidenori Tachida, now a professor of biology at Kyushu University, developed yet another variation of the nearly neutral model in 1990.

Opinions about the standing of nearly neutral theory can still differ sharply. “The predictions of nearly neutral theory have been confirmed very well,” said Jianzhi Zhang, who studies the evolution of genomes at the University of Michigan and also contributed to the special issue of Molecular Biology and Evolution.

Kern and Hahn disagree: Nearly neutral theory “didn’t explain much from the start and then was shuffled around in attempts to save an appealing idea from the harsh glare of data,” Kern wrote in an email.

How Much Evolves Neutrally?

For Townsend, the ongoing debate between neutralists and selectionists isn’t particularly fruitful. Instead, he said, “it’s just a quantitative question of how much selection is going on. And that includes some sites that are completely neutral, and some sites that are moderately selected, and some sites that are really strongly selected. There’s a whole distribution there.”

When Townsend first started studying cancer about a decade ago after training as an evolutionary biologist, he saw that

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Written by LeisureGuy

8 November 2018 at 5:05 pm

Posted in Evolution, Science

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