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Cloning of the responder, a gene transmitted at up to 95% from male carriers to their progeny, showed that it encodes a novel protein kinase likely to control sperm motility. The gene can effectively be used to manipulate the transmission of autosomes or sex chromosomes. In the latter case, an excess of male or female offspring can be generated. The study was reported by a research group at the Max Planck Institute for Immunbiology in the 11 November issue of Nature.
The mouse t complex responder (Tcr) affects the transmission of the chromosome carrying it from males to their progeny whereas normally chromosomes are inherited at equal ratio. A high transmission ratio of Tcr (up to 95%) requires the action of additional mutant factors, the distorters (D1 to D5), while Tcr alone (on a wild type background) is transmitted at a low ratio (e.g. 17%).
Cloning of Tcr showed that it encodes a mutant form of a member of a novel protein kinase gene family, Smok, expressed during spermiogenesis, the process transforming round haploid spermatids into motile sperm cells. Smok kinases, Tcr and the distorters are probably involved in the control of sperm flagellar movement. The distorters affect the motility of sperm cells, the responder counterbalances the negative effect of the distorters and rescues normal sperm motility, but only in those spermatozoa carrying the responder gene. This creates a functional difference between the sperm cells carrying the responder and those lacking it, resulting in an advantage of Tcr sperm in reaching the eggs, and in distortion of the transmission ratio.
The transmission ratio distortion phenomenon is associated with the t complex, a large region of chromosome 17 which exists in two different forms in wild mouse populations. Transmission ratio distortion has been known for several decades and has been studied extensively by several generations of mouse geneticists. Genetic analyses had shown that the chromosome carrying Tcr is transmitted at high ratio when several mutant distorter loci are present, but at low ratio when distorters are lacking. Impaired motility had been observed in sperm derived from t/+ heterozygotes suggesting that + sperm was affected by distorter loci. But none of the factors involved in transmission ratio distortion had been isolated, leaving the molecular mechanism causing the phenomenon obscured.
"The difficulty in finding Tcr," Herrmann, the leader of the research group said, "was on the one hand the fact that the locus is embedded in a region which had been involved in several amplifications and rearrangements during evolution, and on the other hand that proof of having the right gene could only be obtained from testing of transgenic males. This was very time consuming and required a very careful analysis of the genomic region."
The cloning of Tcr paves the way for the molecular investigation of sperm motility and may turn up human genes involved in some forms of infertility. It is also possible that transmission ratio distortion may exist in other mammals or even in humans which can now be studied. Of course, this requires that Smok genes also exist in other mammals and in humans, and that is very likely.
Smok/Tcr may find a very important application in farm animal breeding. A likely scenario which may be achievable in the very near future, is integration of a Tcr-like transgene on the Y chromosome of farm animals such as cows, pigs, sheep etc. and generating males fathering mostly or exclusively female progeny. Integration on the Y chromosome would ensure that only the males are transgene carriers, but their female progeny are just like other females. This would not only save millions of unwanted farm animals every year which are usually discarded, but also enormously increase the productivity of animal farming.
Published: 10-11-99
Contact: Bernhard Herrmann
Max Planck Institute for Immunbiology,
Freiburg/Germany
E-Mail: Herrmann@Immunbio.mpg.de
Phone: +49 761 5108-582
Fax: +49 761 5108-569
Journal
Nature