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Mendel's Laws: Foiled Again

24 May 2006 (All day)
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Minoo Rassoulzadegan

Impressive feet.
The inheritance of white feet and white tails in mice appears to be mediated by RNA.

Pity poor Gregor Mendel. During most of the 20th century, the laws of inheritance discovered by this modest priest and gardener ruled genetics. But over the past decade, researchers have spotted numerous violations of Mendel's laws. These exceptions, called epigenetic effects, are currently under intense study by biologists, who are searching for their underlying mechanisms (ScienceNOW, 12 April). A new study suggests that at least one of the perpetrators of these anti-Mendelian acts is none other than RNA, previously thought to be a loyal cog in the machinery of conventional genetics.

A team led by developmental geneticist Minoo Rassoulzadegan of the University of Nice-Sophia Antipolis in France, made the discovery while working with mice that carry a mutant version of the Kit gene, which plays a role in coat color. Mice that are homozygous for the mutant gene--that is, animals with two copies--die shortly after birth. But heterozygotes, with one mutant and one normal Kit gene, do fine, although their feet and the tips of their tails are white rather than gray. Heterozygotes can be mated to produce offspring with two normal copies of Kit, but to the researchers' surprise, most of these progeny also had white patches, even though the mutant gene was no longer present.

The effect appears to be due to RNA. In the 25 May issue of Nature, Rassoulzadegan and her colleagues report that the tissues of the heterozygous mice and their progeny had accumulated significant amounts of abnormally small RNA molecules. Recent research has shown that abnormal RNA can interfere with the function of normal RNA--a key player in the cell's protein production machinery. Because levels of normal RNA involved in producing the Kit protein were reduced in these mice, the team hypothesized that the abnormal RNA was altering the expression of the normal Kit gene. These disruptive RNA molecules may originally come from Kit mutant fathers, who harbor them in their sperm (ScienceNOW, 9 September 2002).

The role of RNA was bolstered by a final experiment, in which the team injected the abnormal RNA into normal mouse embryos at the one-cell stage. The result: Close to 50% of these offspring also had white feet and tail tips.

"These results are quite convincing," says Stephen Krawetz, a reproductive biologist at Wayne State University Medical School in Detroit, Michigan. Krawetz, whose lab was one of the first to show that sperm carry RNA into the egg, says that the work "opens a wider door" to understanding the role that RNA might be playing in epigenetic inheritance. Vicki Chandler of the University of Arizona, Tucson, a pioneer in the study of similar epigenetic effects in plants, comments that the study is "fundamentally exciting" and may ultimately have ramifications for the understanding of inherited human diseases.

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