For a damaged chromosome, "getting by with a little help from my friends" means using other chromosomes as repair templates. At the University of California, Davis, geneticist Neil Hunter is elucidating the molecular mechanisms of this template-directed repair process known as homologous recombination. The exchange of genetic material that can accompany recombination is central to reproduction and evolution; defects in this process can cause birth defects and diseases such as cancer.
Chromosomes come in pairs: each cell contains closely related maternal and paternal chromosomes, and before a cell divides each chromosome duplicates to produce an identical "sister." In most cells of the body (the somatic cells), the identical sister chromosome is the preferred recombination template, but in germline cells, maternal and paternal chromosomes must undergo recombination before they can be distributed into sperm and egg cells. Hunter is providing fundamental insights into the complex regulation of recombination in somatic and germline cells.
Hunter began working on recombination through "a series of fortunate accidents." Born and raised in England, he left school at the age of 16 "essentially ignorant of the wonders of experimental biology." But after four years of "youthful soul searching," he returned to education and majored in biochemistry at the University of Manchester. There, he was exposed to the fundamental research being done on cell division using yeast as a model organism. "I got the yeast bug!" exclaims Hunter.
During graduate school at the University of Oxford, he worked with two Americans, Rhona Borts and Edward Louis, who study recombination in yeast. "I was taken by their unrestrained enthusiasm," he says. "They were a refreshing contrast to the more reserved style typical of the British." He then came to America, and Harvard, to work with Nancy Kleckner because he wanted to research a specific problem: the molecular mechanisms involved in recombination during meiosis, the process that produces egg and sperm cells. "I didn't consider other labs," he says. "Kleckner's work really stood out, and I knew I wanted to be part of it."
Since moving to the University of California, Davis, in 2002, Hunter has been probing more deeply into the molecular details of meiotic recombination. During meiosis, each chromosome is purposefully broken at several locations. The chromosomes then associate as paternal-maternal pairs and form complex DNA structures to repair these breaks. Hunter has developed several innovative techniques to monitor these structures, revealing unexpected steps in the process that point toward a molecular mechanism for recombination that differs from the currently accepted textbook models. Especially in yeast, where meiosis occurs in just a few hours and can be precisely manipulated, he has been able to observe "an unparalleled level of detail."
When a chromosome is broken and repaired during meiosis, the original chromosome usually emerges intact. But for around 10 percent of breaks, the two chromosomes swap partners, leading to new chromosomes that are a mixture of the original maternal and paternal chromosomes. Hunter has been studying defects in this process that can lead to a variety of health problems in humans, including infertility and miscarriage in pregnancy.
The shuffling of chromosomes during meiosis also plays a critical role in evolution by combining genetic variants in novel ways to create the variation in offspring that drives evolutionary change. In addition, the recombination process helps separate out deleterious genetic variants without sacrificing the evolutionarily advantageous parts of the chromosomes. "Natural selection holds onto advantageous variants and eliminates bad ones," Hunter says.
Recombination can have more immediate effects on human health. When DNA repair processes go awry, cells may exhibit behaviors characteristic of cancer, including uncontrolled cell division. In 2007, Hunter and several colleagues published a paper in Cell explaining the effects of mutating a yeast gene that encodes a protein involved in unwinding the DNA helix during recombination. When the analogous gene is mutated in humans, it causes a rare genetic disease called Bloom's syndrome in which people typically develop cancer in their 20s.
Recently, Hunter began studying recombination in mice, which are more closely related to humans than yeast and therefore could serve as a better model for the processes occurring in our cells. His future findings might someday lead to therapies to fix infertility and strategies to prevent cancer. "Several human diseases have been linked to defects in recombination," Hunter says, "but there are still many fundamental questions to be answered."
