Daniel hartl

Daniel Hartl, PhD, of Harvard University is the recipient of the 2019 Genetics Society of America (GSA) Thomas Hunt Morgan Medal for his influential contributions to experimental and theoretical genetics research. His extraordinarily broad research program combines mathematical models with cutting-edge experimental techniques to tackle important questions in evolutionary biology and genomics.

The Morgan Medal recognizes lifetime achievement in genetics research. Like Thomas Hunt Morgan, Hartl has conducted many of his studies on the fruit fly Drosophila melanogaster.

“By every objective measure, Dan has shaped the fields of population genetics and evolution,” says Rebekah Rogers, a professor of bioinformatics and genomics at the University of North Carolina at Charlotte and one of the scientists who nominated Hartl for the Morgan Medal. “His influence in the field is wide-reaching, and his record of training other researchers is unparalleled.”

Hartl grew up in rural northern Wisconsin, with little exposure to genetics in high school and no firm plans to attend college. Encouraged by high school teacher Robert Meyer to apply for a scholarship, he attended the University of Wisconsin at Marathon County Center in Wausau for two years before transferring to the state’s flagship campus, the University of Wisconsin, Madison, which offered one of the world’s best genetics programs. A few classes taught by renowned geneticist James Crow were all it took for him to find his true calling in population genetics.

After earning his PhD in genetics in 1968, Hartl moved to the University of California, Berkeley, for his postdoctoral studies with Spencer Brown. Starting in 1969, his academic career included faculty positions at the University of Minnesota, Purdue University, Washington University, and Harvard University, the latter being his professional home since 1993.

Hartl’s interest in experimental evolution—a fast-forward model of natural evolution— began at the University of Minnesota and continued at Purdue. By culturing different types of Escherichia coli bacteria together under tightly controlled chemical conditions, Hartl and postdoctoral fellow Daniel Dykhuizenset up a growth competition between strains that differed only in a single amino acid in one enzyme. The research question was whether these subtle protein variants, which arise in nature from random DNA mutations, resulted in fitness differences or were selectively neutral.

Under constant conditions, any growth differences between the strains were undetectable. But by changing the composition of the nutrient mix, differences between the strains became apparent. In other words, their fitness depended on the environmental context. These results intrigued Hartl so much that he was determined to understand their theoretical basis. This initiated a highly productive collaboration with the gifted mathematician Stanley Sawyer, who joined Purdue University a few years after Hartl.

Sawyer and Hartl showed that a mathematical process called a Poisson random field describes how multiple randomly occurring DNA mutations are passed through generations in finite populations. The observed frequencies of these mutations vary from one generation to the next. However, the mathematical model showed that the expected frequencies at any time are precisely determined. According to the model, these expected frequencies differ for mutations that change a protein’s function and those that don’t.

This theory explains the accumulation of sequence differences between populations over time. When natural selection acts upon these genetic differences, the two populations may eventually become two distinct species. For the constant environment of Hartl’s original E. coli experiments, the theory showed that the subtle DNA variants were slightly deleterious. However, the effect was small enough to appear selectively neutral.

An important implication of this work is that most randomly arising DNA variants in a population are quickly lost, but the few favorable ones become fixed over time as differences between species. The theorem, published in GENETICS in 1992, is frequently used in comparative genomics today to analyze species differences in whole-genome sequences.

The work with Sawyer was driven by a specific question, but Hartl also came to appreciate the role of serendipity in science. When he moved his lab from Purdue to Washington University in August 1981, the moving van held some 6,000 half-pint milk bottles of Drosophila cultures, along with a few trainees. Somewhere between West Lafayette and St. Louis, a random mutation resulted in peach-colored fruit fly eyes speckled with red. They brought to mind the mosaic corn kernels that helped geneticist Barbara McClintock win a Nobel Prize in 1983, but zooming in on the specific explanation took a few more years.

As in the corn kernels, the cause was a transposable element capable of jumping from one genomic location to another. James Jacobson, the graduate student who characterized this repetitive DNA element, later named it the mariner transposon, after his newborn daughter Marin. The unusual eyes continued to fascinate many members of Hartl’s lab, including Emilie, the 8-year-old daughter of postdoctoral fellow Pierre Capy, whose Crayola drawing of the mutant eyes Hartl included in a 2001 review paper. The mariner transposon is not confined to flies; it has shaped the genomic history of many species, including humans. Prior to the advent of CRISPR gene editing, it was frequently used as a tool to transfer genetic material from one cell to another in studies of multiple organisms.

In the mid-1990s, Hartl’s interest expanded beyond DNA sequences to gene expression data. Using newly developed microarray technology, his group found between-species expression differences in Drosophila flies to be much larger for genes that are differentially expressed in males and females. This suggested that sex-dependent selection may drive the evolution of gene expression differences between species. The researchers also discovered that the Y chromosome affects the expression of hundreds of genes across the genome for as-yet-unknown reasons.

Today, Hartl is especially proud of his malaria research, which addresses a major global health problem. Although 219 million malaria cases were identified worldwide in 2017, transmission rates in parts of Africa have been reduced so much that they are difficult to estimate with traditional sampling methods. This complicates the evaluation of new interventions. Hartl and colleagues showed that malaria control efforts have changed the genetic properties of parasite populations. This result means that researchers can test new interventions by applying statistical models to parasite samples.

The malaria research is related to Hartl’s other ongoing projects on antibiotic resistance. For example, he and colleagues study whether amino acid changes in bacterial and viral proteins modify drug resistance, and, conversely, how changes in a drug’s chemical structure affect the proteins that confer resistance to it.

“Dan has employed equations, microbes, fruit flies, and the malaria parasite to discover how genes are organized into genomes, vary within populations, and change over evolutionary time,” says Colin Meiklejohn, a professor of biological sciences at the University of Nebraska and one of the scientists who nominated Hartl for the Morgan Medal. “By combining theory and experiments, he has made seminal contributions to transmission, population, evolutionary, and medical genetics.”

Hartl is the Higgins Professor of Biology in the Department of Organismic and Evolutionary Biology at Harvard University. He is an elected fellow of the National Academy of Sciences and the American Academy of Arts and Sciences. He credits much of his success to the 37 graduate students and 38 postdoctoral fellows he has mentored since 1969.

Hartl joined the GSA a graduate student. He was on the GSA Board of Directors from 1984 to 1986, served as an Associate Editor for the GSA journal GENETICSfrom 1977 to 1985, and as the GSA President in 1989. The Thomas Hunt Morgan Medal will be presented at The Allied Genetics Conference, which will be held April 22–26, 2020, in the Metro Washington, DC, region.

The award was named in honor of Thomas Hunt Morgan (1866-1945), the 1933 Nobel Laureate who provided the first experimental evidence that chromosomes are the carriers of genetic information. He also developed the first recombinant genetic maps, a tool that would later help identify numerous genes for monogenic and complex human diseases.

Silke Schmidt, PhD, is a freelance science writer and former genetic epidemiologist. She writes about genetics, medical research and the environment from Madison, Wisconsin.

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