$8.2 million federal research grant awarded to The Jackson Laboratory

Bar Harbor, Maine—A Jackson Laboratory research team headed by Professor Ken Paigen, Ph.D., has received a five-year, $8.2 million grant to research early steps in the formation of sperm and eggs.

Ken Paigen, Ph.D.The multidisciplinary research team headed by Paigen will research the early steps in the formation of sperm and eggs. includes a molecular biologist, Research Scientist Petko Petkov, Ph.D.; a cytogeneticist, Senior Research Scientist Mary Ann Handel, Ph.D.; and a computational biologist, Assistant Professor Gregory Carter, Ph.D.

The team will focus on a key protein, known as PRDM9, that members of the team discovered several years ago controls the initiation of genetic recombination, the exchange of parts between pairs of chromosomes that is essential for the successful production of sperm or eggs.

"Recombination makes every sperm or egg genetically different from the rest," Paigen explains, "and these differences are what make all of us—except identical twins, which come from the same sperm and egg—a genetically unique individual. Recombination also made the evolution of all sexually reproducing species possible, including humans."

Because recombination is so essential, he says, humans and mice lacking PRDM9 are sterile, and spontaneous abortions and birth defects result when recombination goes awry.

What gives PRDM9 the ability to control genetic recombination is its array of zinc fingers. These are literally finger-like extensions of the PRDM9 molecule that make contact with DNA, recognizing the local DNA sequence. Individuals can vary in the collection of zinc fingers on their PRDM9, and when a particular set of PRDM9 fingers finds its correct match along the DNA, it settles down and uses another part of its molecule to chemically modify other neighborhood proteins attached to DNA. The result is a dramatic change in the three-dimensional arrangement of DNA, allowing genetic recombination to begin.

Using male mice, the JAX research team will focus their research on the molecular details of how PRDM9 manages its multiple tasks, including how its zinc fingers manage to read the sequence of DNA, something that is still largely unknown. They hope that solving this last mystery will have implications that go far beyond genetic recombination and reproduction.

"Our bodies contain over 800 proteins with zinc fingers, each with its own arrangement of fingers; they are by far the most common device all organisms have to regulate how their DNA works," Paigen says. "Each of these proteins has its own special function, involved in everything from nerve transmission to the origins of cancer."

The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif., and a new genomic medicine institute in Farmington, Conn. It employs a total staff of more than 1,500. Its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P01GM099640. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.