DNA from single sperm spurs gene studies.

DNA from single sperm spurs gene studies

In an advance important to solving many difficult problems in human genetics, a team of researchers has announced the first mass production of copies of DNA taken from a single sperm cell. The technique should prove useful, they say, in locating the genes responsible for a number of inherited diseases and in making detailed genetic maps.

Mapping where genes lie in chromosomes is now done through selective breeding experiments or by analyses of animals with many offspring. Because the first option cannot be used to study humans, scientists studying the human genome must analyze large families, which can be hard to find.

The construction of a genetic map is based on the fact that, as sperm is made, genes are "shuffled" in a process called crossing over, in which segments of DNA are switched with similar segments on the same chromosome. If two genes sit very close together along a chromosome, chances are they will remain together on the segment that crosses over. It is much rarer that the DNA breaks between them so that one gene moves and the other is left behind. For instance, if nearsightedness and a misshapen toe always show up together in members of a family, it could indicate the genes for these conditions lie close together on the chromosome.

But finding out how close requires a statistical analysis of how often the genes become separated. This demands the study of a family with many children. Families must be particularly large if scientists want to find the distance between genes that are close together, because closely paired genes are infrequently separated in a crossover. Such families are "a rare commodity," says Randall Saiki of Cetus Corp. in Emeryville, Calif., one of the researchers describing the new work in the Sept. 29 NATURE.

The new technique gives scientists the chance to analyze DNA of thousands of individual sperm, each with different genetic shufflings. This, in effect, enables them to analyze the DNA of thousands of children. The number of sperm that can be analyzed will "depend on the extent to which the process can be automated," says Norman Arnheim of the University of Southern California in Los Angeles, who led the study.

Arnheim, Honghua Li and their colleagues at USC and Cetus were able to analyze DNA from sperm cells because they worked out how to make many copies of the sperm's DNA using the relatively new technique called polymerase chain reaction. This technique has previously been used to analyze the DNA obtained from groups of cells, including hair cells, and to find AIDS virus hidden in the cells of those infected with it (SN: 4/23/88, p.262; 6/4/88, p.357).

The scientists say that applying the technique to sperm should help analyze chromosomal "hotspots" where genetic crossovers seem to occur far more frequently than they do throughout most of the genome. The analysis of individual sperm also offers a chance to learn whether some people have a greater propensity to shuffle genes than others.

The method should also provide a kind of golden spike to link up the two great lines of genetic analysis: that of genetic "distance" (actually not a true distance but rather the probability of genes being separated during crossing over) and that of isolating and directly measuring much smaller gene fragments. "Now we can get some idea of what the real relationship is between physical distance and genetic distance," Arnheim says.