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US Team Publishes Multi-Tiered Genomic Study of Multiple Sclerosis Discordant Twins

By Andrea Anderson

NEW YORK (GenomeWeb News) – Non-inherited influences — or inherited factors that can't be assessed by existing technology — appear to contribute to multiple sclerosis risk, according to a genomic, epigenomic, and transcriptomic study of MS discordant identical twins appearing online today in Nature.

An American research team sequenced and compared the genomes of two females — monozygotic twins who were discordant for MS — as well as the epigenomes and transcriptomes from the same individuals and two more MS-discordant twin sets. Although twins in each pair carried several known risk factors for MS, the study did not turn up any clear genetic, epigenetic, or expression patterns explaining why one twin in each set got the disease while the other did not.

"In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance," senior author Stephen Kingsmore, president of the National Center for Genome Resources in Santa Fe, NM, and his colleagues wrote.

Multiple sclerosis is a neurodegenerative disease in which an individual's own immune system attacks components of his or her central nervous system, eventually leading to motor and cognitive problems. It is typically diagnosed between the ages of 18 and 35 years old and is particularly common in individuals of European ancestry.

MS is thought to involve alterations in human leukocyte antigens, though previous genome-wide association studies have also identified at least a dozen non-HLA loci as being associated with the disease. In addition, several environmental factors ranging from viral infection to birth latitude have been implicated in MS.

Consistent with the idea that environmental factors are crucial to MS risk, nearly 70 percent of monozygotic twins and more than 95 percent of non-identical twins are discordant for the disease.

In an effort to directly compare the genomes of identical twins and look for genetic and epigenetic clues to multiple sclerosis risk, Kingsmore and his co-workers used the Illumina Genome Analyzer II to sequence the genomes of two female twins of Ashkenazi Jewish ancestry — one with MS and one without — to an average of around 22 times coverage each.

They also used bisulfite and messenger RNA sequencing to look at CpG methylation and gene expression patterns, respectively, in CD4+ T cells isolated from three discordant identical twin sets.

"Technically, this is sort of a multi-tiered approach to a genome," Kingsmore told GenomeWeb Daily News. "It gives us a dynamic view of the genome."

Twins in each set carried a substantial number of known genetic risk factors for MS, Kingsmore noted.

But the researchers did not find any reproducible SNP, indel, CNV, or epigenetic differences within each twin pair that could explain why one twin had the disease and the other did not. On the contrary, the team detected almost no somatic, epigenetic, or gene expression differences between twins from each pair.

For example, their analyses uncovered between two and 176 twin-to-twin methylation differences at the two million CpG dinucleotides evaluated. In contrast, they explained, unrelated individuals typically have around 800 such differences.

"[A] singular, genetic, epigenetic or transcriptomic mechanism underpinning MS-discordance in monozygotic twins was not detected in a study of unprecedented resolution," the researchers wrote.

The researchers did see hundreds of between-twin differences in the transcripts expressed from maternally or paternally inherited chromosomes, Kingsmore said. But, he added, more research is needed to investigate this allelic imbalance, which seems to be far more common than epigenetic differences.

And while the current study suggests yet-unidentified environmental factors could be behind MS, Kingsmore cautioned, the researchers still cannot rule out additional genomic or epigenomic factors. For instance, he explained, it's possible that genetic differences between twins went undetected due to gaps in the human reference genome or that epigenetics occur in other cell types that aren't obvious in the CD4+ T cells.

Consequently, the team noted, additional studies are needed to continue unraveling the relative contributions of genetic and environmental factors in MS as well as triggers for the disease.

"Although disease-discordant monozygotic twins seem to provide a framework for analysis of complex disorders that has fewer variables, further stratification and/or concomitant measures of several data types may be necessary to yield molecular mechanisms underpinning disease," they concluded.

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