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[Entry posted at 28th April 2010 06:00 PM GMT]
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In the first ever sequencing of twin genomes, researchers searched deep into the genetics of multiple sclerosis, coupling DNA sequencing with a panoramic look at the regulation and expression of genes, only to come up empty-handed.
"It's really a tour de force," said Eric Topol, director of the Scripps Translational Science Institute, who was not involved in the research. "It's a fascinating study. It's sobering that they didn't find obvious [genetic factors]."
Image: National Institute of
General Medical Sciences
The study, published this week in Nature, included three pairs of identical twins, two female pairs and one male, in which one had multiple sclerosis (MS) and the other did not. No one knows the cause of MS. Some evidence points to a genetic root of the neurodegenerative disorder: In thirty percent of identical twins where one has MS, so does the other. Changes to the human leukocyte antigen (HLA) region of chromosome 6 has been linked to an increased susceptibility to MS, and 6 genome-wide association studies implicate 12 other loci in the disease.
However, strong evidence also suggests environmental risk factors for MS: In the majority of identical twin cases, only one has MS, and epidemiological studies have suggested month of birth and decreased sunlight exposure can increase risk of developing MS. "It's one of those complicated diseases where there are both genetic effects and environmental effects," said Stephen Kingsmore, senior author on the study and CEO of the National Center for Genome Resources in Santa Fe, New Mexico.
In order to systematically dissect the effects of genetics versus environment in MS, Kingsmore and collaborators, including researchers at the Multiple Sclerosis Genetics Research Laboratory at the University of California, San Francisco, first sequenced the genomes of CD4+ lymphocytes -- cells believed to attack brain tissue and strip myelin from neurons in patients with MS. They sequenced the entire genome of one pair of female identical twins, one of whom had MS, and confirmed that they indeed had identical genomes.
"Then we started to look under more rocks," said Kingsmore. Adding an additional two pairs of discordant twins to the study, the team moved onto the epigenome, analyzing the methylation of each twin's genome, genetic modifications that alter gene expression. They found no differences there either. Finally, the team looked at the expressed genome, the transcriptome, for any significant differences in levels of gene expression. There were none.
"For everything we did, we tried to use several different technologies to validate our findings," said Kingsmore, including assessing variation in single nucleotide polymorphisms, copy number variations, and HLA sequences. In the end, with three levels of genomic analysis, the team found no significant genetic, epigenetic, or transcriptome differences between individuals with MS and those without.
"There was nothing obvious, which is amazing considering how much effort they put in," said Topol. This type of panoramic view of the genome, or pan-omics, as Topol calls it, is a comprehensive method that will likely be used to study other complex diseases.
The results, or lack thereof, point to a strong environmental trigger for MS, said Kingsmore, yet neither he nor others are ready to rule out a genetic component. "It's a problem of missing heritability," said Topol. "There's lots more to be done before we wave our hands," he added. For example, the researchers only looked at the genomes of T cells, believed to be the aggressors in MS but not the only possible players. Kingsmore hopes to repeat the analysis with brain tissue, where the actual demyelination of neurons occurs. "It is possible the [cause] is in the brain, just being recognized by the CD4 lymphocytes," said Kingsmore. "It's a missing piece before we can definitively say we looked at twins and there are no differences."
"Obviously this would be an easier sell if we'd found something," added Kingsmore, "But we did rule out a lot of things."
S.E. Baranzini et al., "Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis," Nature 464(29):1351-6, 2010.