LONDON - For several decades, geneticists have been puzzled by the observation that, in wild mice, a particular version of chromosome 17 has a 95 percent chance of being transmitted to the next generation instead of the 50 percent chance that would be predicted by Mendel's theory.

The elucidation of the control of this process has been an important goal for scientists. Finding how this happens could make it possible to influence the inheritance ratio of other chromosomes, too. Now the discovery of one of the genes involved could pave the way to engineering male animals that father, say, 99 females for every 1 male.

Bernhard Herrmann, senior scientist at the Max Planck Institute of Immunobiology in Freiburg, Germany, told BioWorld International: "This finding will allow us to interfere with the inheritance of sex. This has important implications for animal husbandry. In the future, we will be able to design chromosomes which lead to the exclusive transmission of the X chromosome to the offspring, so that a farmer who wants dairy cows will be able to obtain sperm that will lead solely to female calves."

Herrmann predicted the discovery would help increase the agricultural productivity of developing countries. He also expects to be able to apply the technique even to those farm animals for which artificial insemination is not the norm. He said, "We will need to find out from farmers exactly what sex ratios are required for different species. For example, farmers may want to obtain rams which father, say, 95 female sheep for every 5 males."

An account of the work was published in the Nov. 11 Nature in a paper titled: "A protein kinase encoded by the t complex responder gene causes non-Mendelian inheritance."

Herrmann and his team are seeking partners to develop the work. "I believe there is room for many partners to get involved in developing this project for many different species," he said. "There could be a lot to gain for many companies."

Herrmann's interest in the phenomenon known as "transmission ratio distortion" in mice began in the 1980s when he was studying the t-complex, a region of chromosome 17. A mutant form of this region occurs naturally in wild mice, and has been crossed into the genome of laboratory strains.

Studies of the t-complex by various researchers have shown that two groups of genes are involved in non-Mendelian inheritance: the distorters and the responder. The distorters act in all sperm cells and cause hyperactive but nonprogressive motility. The responder acts only in the sperm cells that carry this gene and seems to cancel out, or "rescue," the sperm from the effects of the distorters. These latter sperm behave normally and are thus more likely to fertilize eggs, and to pass on the chromosomes they carry to the offspring.

As reported in the Nature paper, Herrmann, together with colleagues at Max Planck, has cloned the responder gene and investigated the role of the protein it makes. The group found that the gene encodes a new protein kinase.

Herrmann has constructed a model that suggests the distorter group of genes creates a high level of signal transduction, with the effect of increasing flagellar movement. When the responder is also present, it downregulates this high activity back to normal levels. The result is that the sperm with the responder behave normally, while sperm lacking the responder have hyperactive but nonprogressive motility.

When Herrmann and his colleagues inserted a transgene containing the responder into the Y chromosome, these transgenic males fathered twice as many males as females. This demonstrated, he said, that the responder can function on any chromosome into which it is inserted.

In scientific terms, Herrmann said, the finding is significant because it makes it possible to understand how both non-Mendelian inheritance and sperm motility are controlled. He added: "It also gives us the knowledge to create responder transgenes in vitro producing non-Mendelian inheritance in the animal, to allow certain chromosomes to be passed on to offspring at a higher or a lower rate than usual, with implications for animal breeding."

The team is now focusing its attention on optimizing the expression and activity of responder transgenes and on identifying the genes that encode the distorters. "We want to find the equivalent genes in farm animals, and design them in a way that will allow us to obtain the desired ratio of female to male offspring," Herrmann concluded. n