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Close look at DNA reveals basic processes of sex cell

Some scientists really throw themselves into their research, but Stanford University biophysicist Stephen Quake has taken the all-in approach to a whole new level.

Using his sperm, Quake and colleagues compiled the first-ever genetic blueprint for a single sperm cell. The results shed new light on molecular processes such as mutation and recombination in humans, Quake and his colleagues report in the July 20 Cell.

Figuring out how often humans make mistakes in copying DNA so that single DNA units are changed, or mutated, is important for a variety of reasons, including figuring out how long ago humans diverged from other species, says Laure Ségurel, an evolutionary geneticist at the University of Chicago. “Every calculation is based on this mutation rate,” she says.

In past studies, scientists estimated this rate either by comparing human DNA with that of other species to see how many changes have occurred since that species split from humans, or by studying families to see where children have different DNA than their parents. By studying individual sperm cells, Quake and colleagues calculate the human mutation rate at 2 to 4 changes per 100 million DNA units per generation. That is higher than the rate calculated by looking at families (SN Online: 6/13/11), but consistent with evolutionary estimates.

The new work also offers insights into how humans scramble their DNA so that children inherit different combinations of parental DNA. This process, called recombination, is thought to be directed by a protein called PRDM9, which latches on to DNA and governs where the breaks that allow gene swapping will happen (SN: 8/13/11, p. 17).

But the Stanford researchers found that PRDM9 isn’t always necessary for recombination. Many of the new recombination hot spots fall within transposons — mobile pieces of DNA often called “jumping genes” — that don’t have obvious places for PRDM9 to grab.

Just because PRDM9 doesn’t seem to grasp DNA directly everywhere recombination happens doesn’t mean the protein isn’t involved in every gene swap, says Ségurel.

Regardless of PRDM9’s involvement, the data suggest that transposons may have had an important hand in shaping human evolution, Quake says. “This is a nice mark in the transposon column.”

The work also represents a technical accomplishment: Researchers have begun deciphering the genetic makeup of single cells, such as cancer cells, but this is the first time anyone has compiled a genetic blueprint from a single sperm.

Sperm are challenging for genetic analysis because they contain so little DNA, says Stanford biological engineer Jianbin Wang, a study coauthor. Sperm and eggs each contain half as much genetic material as a typical body cell.

On the flip side, sperm have given scientists an advantage when analyzing the small portion of the genome that contains protein-coding genes, Quake says. With only one copy of each gene per sperm, researchers don’t mix up two copies with each other.

“For 99 percent of the genome it is more challenging,” Quake says of single sperm analysis, “but for 1 percent it’s easier. That’s a pretty important 1 percent.”

Source:  Science News / Tina Hesman Saey /

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