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Spotty mice flout Mendels Law

  May, 25 2006 16:58
your information resource in human molecular genetics
As we have all been taught, Mendelian inheritance requires the presence of two alleles. Their relative dominance denoting trait acquisition. A recent paper throws the Mendelian cassock to the winds.

The scientists suggest RNA, not DNA, passes on the characteristic - in this experiment, a spotty tail - to later generations.

But more work may be needed to confirm the conclusions of the study, which appears in the journal Nature.
The research focuses on a gene called Kit, which comes in two varieties: "normal" and "mutant".

The mice inherit two Kit genes, one from each parent; a mutant version gives them a spotty tail.

According to Mendel's laws of genetic inheritance, the combination of normal and mutant Kit genes inherited by the mice should alone determine whether the mouse has a spotted or unspotted tail.
But then the murine criminals laugh in the face of the law:
The scientists, based at the French Institute of Health and Medical Research (Inserm) and the University of Nice-Sophia Antipolis, used mice which carry one normal version of Kit and one mutant version, giving them spotted tails.

They bred these mice together, producing offspring with a range of Kit gene combinations:
- two mutant genes (these are shown to die shortly after birth)
- one mutant and one normal gene (these should be "spotty" like their parents)
- two normal genes (these should not be spotty).

However, the researchers found that mice born with two normal versions of Kit also had a spotted appendage.

"We were very surprised to see this," said Professor Minoo Rassoulzadegan, a geneticist at the University of Nice and lead author on the paper.

"Perhaps this research may eventually help us to understand perhaps why we are all so different from each other."
After further investigation, the scientists suggested the transfer of RNA molecules as the cause.

RNA is a polynucleotide, like DNA, and plays an important role in protein synthesis and in other chemical activity in the body.

They found the mutant Kit gene produces large amounts of messenger RNA molecules (a type of RNA which acts as a template for the creation of proteins) which accumulate in the sperm of these mice.

The scientists believe the RNA molecules pass from the sperm into the egg, and they "silence" the Kit gene activity in the offspring - even those who do not inherit a copy of the mutant gene. Silencing the activity in this gene leads to a spotted tail.

"We then looked to see what would happen if a preparation of RNA from the sperm [of a mutant mouse] was injected into a fertilised mouse egg," explained Professor Rassoulzadegan.

"It was clear when we saw the mice born after this injection that RNA could be responsible for the inheritance of the white tail phenotype."
The phenomenon whereby the characteristic of a gene is "remembered" and seen in later generations, even if that particular version of the gene is no longer present, is called paramutation.

It has previously been identified in plants, but this is the first time it has been shown in animals together with a proposed mechanism - if the explanation is confirmed in future experiments.

"As the authors suggest, more experiments need to be done," commented Dr Andrew Hamilton, a molecular biologist from the UK's Glasgow University.

"RNA-directed paramutation, which this study suggests, sounds very exciting, but I think major questions surrounding the gene specificity still remain".

In recent years researchers have amassed much circumstantial evidence to show that transmission of genes made of nuclear DNA is not the sole factor affecting inheritance.

Could transfer of RNA in sperm explain other so-called epigenetic phenomena as well?

That it could is hinted at in a commentary on the new research, also published in Nature, by Professor Paul Soloway from Cornell University in the US.
"A particularly intriguing possibility," he writes, "is that such RNAs regulate other non-genetic modes of inheritance, such as metabolism or behavioural imprinting."

The Nice-based team now plans to look for other characteristics in mice which can be transferred through RNA.

But the eventual scope of research in this field may widen to include other organisms, including humans.

Message posted by: Simon Chandler

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