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Friday, April 30, 2010

The most detailed genetic investigation ever of multiple sclerosis has produced more questions than answers

A Twins Study, Deepens Multiple Sclerosis Mystery

Using extremely fine-grained analytical tools, scientists compared genetic information in three sets of identical twins. One of each pair had MS, and the other didn’t — yet their genes proved essentially identical.

“We find no smoking gun on the genetic level,” said National Center for Genome Resources geneticist Stephen Kingsmore, co-author of the study published April 28 in Nature.

The research cost $1.5 million, and the scientists took 18 months to sequence 2.8 billion DNA units in each twin, and determine whether they came from the mother or father. Most genomic comparisons look for differences in a just handful of suspect genes, and even whole-genome approaches don’t differentiate between parental contributions.

The researchers also analyzed the twins’ CD4 cells, a type of white blood cell that plays a central role in the development of MS. In these cells, the researchers sequenced epigenomes — chemical instructions that turn genes on and off — and transcriptomes, or a chemical record of genes that are actively coding proteins.

These multiple layers of information represent the cutting edge of genomic analysis, and are expected to reveal what rougher tools cannot. “This was a technical tour de force, and potentially represents a new way of looking at disease states,” said Kingsmore. Nevertheless, they found no differences.

The absence of genetic differences doesn’t mean that genetics are irrelevant to multiple sclerosis. Identical twins, who are descended from the same egg, are six times more likely to develop MS than non-identical twins, who come from two different eggs.

It’s still possible that some as-yet-unknown genetic factor, undetectable by even the most advanced tools, may explain the discordance in the study. However, Kingsmore thinks the culprit is probably an unknown environmental influence. “There must be a nongenetic factor, probably environmental,” that combines with known genetic and environmental risks, he said.

The researchers would like to look at more twins, and other types of cells. Even so, the study “was a pioneering effort on a scale that hasn’t been done before,” said Kingsmore. “We’re left with this mystery.”

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