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  • Writer's pictureDale DeBakcsy

Breaking Neutral: The Population Genetics of Tomoko Ohta

We are all mutants, our genes loaded with the steadily acquired variations of three billion years that gradually changed a collection of over-achieving thermophiles into the dazzling collection of bugs, orangutans, orchids, and project managers that make up our world. But how did we get that way? How fast and loose does evolution play with our genetic material in the mad press to create new forms of life? Is selection what drives our genetic diversity, or is that simply the raw weight of blind statistics acting upon our chemical foundations?

These were some of the questions that the first generation of population geneticists sought to answer hot on the heels of the discovery of DNA's structure in 1953. Now that the composition and replicating mechanisms of our genetic material was settled, it was time to ask the deep questions about how that structure varied itself to produce the engine of evolution, and in the race to formulate and answer those questions two warring houses emerged, the Selectionists and the Neutralists. Their intellectual clash echoes still, a half century later, but one of its most powerful voices, had she been born but twenty years earlier, likely never would have had a chance at an education at all.

Tomoko Ohta (b. 1933) grew up in the small village of Miyoshi-cho in Aichi Prefecture, today the bustling location of Toyota Headquarters, but in the 1930s a sleepy village that was just accustoming itself to the idea of radio. For the first dozen years of her life, she experienced the education of most early 20th century Japanese girls. Broadly based formal Japanese education had only been laid down in the late nineteenth century, and featured a few years of primary and middle school as the summit of girls education.

Though by 1917 a robust 98.4% of girls attended primary school, progress in the universities largely had to wait for the grand civilizational reconstruction that followed Japan's defeat in the Second World War. In 1944, there were ten women studying university-level science in all of Japan, but after the war Japanese schools began modeling themselves on American co-educational systems, and the percent of women attending university began its achingly slow lurch forward. By the time Ohta began attending the University of Tokyo on the strength of her mathematical abilities, less than three percent of Japanese women were attending four year university programs, and Ohta's early years bear an indication of why that might have been.

Graduating with a degree in horticulture from the University of Tokyo, Ohta had difficulty finding work that employed her skills, and settled for two years of working a mind-numbing job at a publishing firm before her uncle found her work for four years as a cytogenetics researcher at a Yokohama research institute.

That was more interesting work than the grind of her publishing job, but it was still not exercising the full power of her mind. Ohta possessed keen mathematical skills in addition to her abilities as a biologist, but as of yet only a part of her mental arsenal was being employed by the world. Soon, however, the discipline would call forth the student and she found a place at North Carolina State University in 1962 where Professor Ken-ichi Kojima was teaching the emerging science of population genetics. It harnessed the power of statistical analysis to the awesome problem of determining how changes in the genetic code get fixed or dropped in a population over long strands of evolutionary time.

Here were questions of almost frightening scale, brought down to Earth with the analytic arsenal of mathematics, and here Tomoko Ohta found at last her intellectual home. The issues she faced required simultaneous thinking on the smallest and largest of scales, working out the probabilities of different mutations on the individual genetic level, and how those mutations then were seized upon or ignored by species across the vast stretches of biological time. After her time at NCSU, she found work with Motoo Kimura at the National Institute of Genetics, and was placed squarely in the middle of the age's greatest biological debate.

Kimura had co-originated a new approach to how we think about the uptake of mutations in populations called Neutralism. Biologists prior to Kimura had held that differences between species are the result of advantageous mutations getting positively selected for and kept by a population, and harmful mutations being selected against and thus weeded out. But neutral mutations, mutations which neither help nor harm an individual, were considered unimportant drivers of genetic change until Kimura's neutralist theory. He agreed about the ultimate fate of advantageous and harmful mutations, but held that neutral mutations, caused by random genetic processes that could be reckoned mathematically, played a major and steady role in defining the differences in species' genetic codes.

Ohta, after arriving at the National Institute, believed that Kimura was largely correct in his focus on the importance of neutral mutations, but that he had sacrificed accuracy for elegance in his mathematical treatments, and thus had missed the importance of borderline cases, which she would in 1973 come to call "nearly neutral" mutations. These mutations, which can be just slightly harmful or (in her later theories) slightly advantageous, have mathematics governing their uptake by a species that are more complicated than the strictly Neutralist model, but that allowed for the answering of a major conundrum in Neutralist theory, the generation problem.

It had been observed that the rate of uptake of new mutations seemed to follow a regular pattern that recurred across species of widely different population sizes and life expectancies. The regularity was predicted by Neutralism, with its focus on constantly acquired mutations driven by constantly occurring random genetic drift, but the fact that the rate seemed equal across species seemed odd. After all, shouldn't the rate of evolutionary change be slower in organisms that take longer to produce new generations? Ohta's nearly neutral theory explained this problem, by showing that, unlike in Neutralism, population size could change how relatively important genetic drift and selection were.

For large populations of short-lived creatures, Ohta's mathematics predicted, there are many generations, but the size of the population suppresses the effects of genetic drift, and keeps new mutations from fixing themselves in the population, thus keeping the evolution rate lower than it might otherwise be, whereas for smaller populations of longer-lived organisms, more mutations produced by genetic drift are allowed to slip into the population, creating a higher rate that just about exactly compensates for the longer generation time, resulting in a remarkable steadiness across species.

This was an important result for Ohta's interpretation of Neutralism. Kimura disagreed hotly with nearly-neutral theory for being overly complicated, but to his credit as a teacher he never prevented Ohta from developing or publishing her ideas, and over time incorporated some of them into his own thinking. For the broader community of evolutionary biologists, however, Kimura's simpler theory was far more attractive, and remained so for two decades until the development of cheap gene sequencing technology in the 1990s confirmed many of Ohta's insights and began winning her at long last the attention she deserved.

"My efforts seem to be endless," Ohta stated in a brief memoir she published in 2001, reflecting on the long years of misunderstanding among her fellow biologists, but today she stands as an elder scientific statesman, and a new generation of population geneticists is modeling itself on her example of braving mathematical thorniness in the name of producing ever more accurate models of how ever more complicated genetic phenomena occur in the code of life. Her work is cited as a foundational moment of statistical bravery in the face of self-assured elegance, and her honors have multiplied accordingly (including Japan's prestigious Order of Culture in 2015). We are mutants, driven in countless individually insignificant but cumulatively important ways by the forces of trial and chance, and there is something beautifully humbling in that thought, gifted us by a human who emerged from her country's greatest humiliation to offer one of its grandest contributions to humanity's quest for self-comprehension.


I have been meaning to do a piece on Ohta for something like four years now but somehow never quite had a critical mass of resources until the collection of biographies and memoirs of Saruhashi Prize Recipients, My Life: Twenty Japanese Women Scientists (2001) found its way into my hands. The volume could have used some copy editing prior to publication, but the selection of scientists is an invaluable addition to any bookshelf and the small essay on Japanese women's education in the back of the book is an interesting read. In addition, I'd recommend this piece by Ohta on the development and ideas of Nearly Neutral theory as a good starting point into her work.


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