Genetic Info May Pass Without DNA

Dad's RNA can deliver instructions even when original gene is gone, study suggests

WEDNESDAY, May 24, 2006 (HealthDay News) -- Scientists may have uncovered a new genetic mechanism by which our ancestors come back to haunt us.

A team of researchers in France have found evidence that RNA (ribonucleic acid) from the father can ensure that certain characteristics are passed on, even if the genes themselves are not passed on.

This appears to be the first evidence in animals -- in this case, mice -- that RNA, rather than DNA, can transport genetic information from one generation to the next. The phenomenon had already been observed in plant species and in one worm species.

It seems like basic science, but experts say the finding, which appears in the May 25 issue of Nature, may someday impact public health.

"It does not have an immediate application to human health and disease, although it's pretty likely that the phenomenon is relevant to human health and disease," said Paul Soloway, a professor of nutritional sciences at Cornell University College of Agriculture and Life Sciences and author of a "news and views" article which accompanied the study.

Each of the thousands of genes in the human genome arrive in two copies, one from each parent. This duplication can be a lifesaver, because if one copy ("allele") doesn't work, we can turn to the other. With a few exceptions, each allele usually functions independently of the other.

In more unusual instances, however, alleles interact even though they're on separate chromosomes or in separate generations.

One example is "paramutation," where orders from an allele in one generation are "remembered" and followed in later generations -- even if the allele issuing the order is no longer around. Paramutation is considered a form of "epigenetic regulatory phenomena," where genes are regulated without changing the DNA sequence.

This study sought to explain how such odd genetic events occur. To do this, French researchers at the University of Nice Sophia Antipolis zeroed in on an allele of the Kit gene in mice.

Heterozygous mice -- mice with one normal and one mutated version of the Kit gene -- have white spots at the tips of their tail.

The researchers knew that when heterozygous mice are mated with normal mice, they produce progeny with two versions of the normal gene. However, these mice still retained the spots associated with a heterozygous mouse -- even though they failed to carry the mutated gene.

How did this happen? The researchers theorized that sperm-cell precursors from the males had mutated versions of the alleles, and that abnormal RNA from that allele was being transmitted to the next generation.

To test the theory, they injected RNA from tissues containing mutated Kit RNAs into fertilized mouse eggs. Sure enough, the babies were born with spotting.

"This paper identified a possible mechanism which seems to involve some aberrant species of RNA that emanate from untransmitted alleles," Soloway said. This RNA-based transmission route gives rise to genetic outcomes "that are inherited, even though the allele is not transmitted," he said.

The bottom line: The new research decribes "a potential example of genetic information transferred from one generation to the next by RNA rather than by DNA," Soloway said.

He cautioned, however, that scientists still lack solid proof supporting this theory.

A second study, appearing in the same journal, looked at RNA interference, a process whereby a fragment of RNA is added to cells as a means of "switching off" a particular disease-linked gene.

The Stanford University researchers used a virus to deliver "short hairpin RNAs" (shRNAs) to mouse liver cells, hoping to cure hepatitis.

Unfortunately, of 49 shRNAs delivered, 36 caused liver injury and 23 ultimately caused death.

But the investigators are still hopeful.

"In one respect it did work out, because we were able to really knock down Hepatitis B replication in mouse models using this gene therapy approach, and it worked," said senior study author Mark M.A. Kay, a professor of pediatrics and genetics at Stanford University. Unfortunately, "what we [also] stumbled on was a kind of toxicity observed in some cases," he said.

Kay is continuing the quest.

"We're interested in fine-tuning this, and we do have sequences that we think could work," he said. "We want to understand the exact molecular mechanisms that cause the toxicity so we can design better strategies."

More information

For more on human genetics, visit the U.S. National Human Genome Research Institute.

SOURCES: Paul D. Soloway, Ph.D., professor, nutritional sciences, Cornell University College of Agriculture and Life Sciences, Ithaca, N.Y.; Mark M.A. Kay, Ph.D., professor, pediatrics and genetics, Stanford University; May 25, 2006, Nature
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