Twin sequencing study fails to find cause of multiple sclerosis

2 May 2010

Twin studies have historically been used in order to help disentangle the role of genetic and environmental factors on disease, and discordant twins (where one twin has a particular disease but the other doesn’t, or develops it at a much later age) are particularly useful for this purpose. Monozygotic (identical) twins essentially share their entire genetic makeup, while dizygotic (non-identical) twins share approximately half their genetic makeup, with the assumption that both types of twin essentially share their in utero and environmental exposures.
 
A new study published in Nature, compared the genomes, epigenomes, and transcriptomes of three pairs of identical twins discordant for multiple sclerosis (MS) including the full sequencing of a one (female) pair [Baranzini et al. (2010) Nature 464:1351-6]. Multiple sclerosis (MS) is an autoimmune disease leading to disability and neurodegeneration in young adults, in which both environment factors (such as viral infection) and genetic susceptibility are known to play a key role, with both human leukocyte antigen system (HLA) and non-HLA loci showing previous associations. By analysing and comparing the twin’s HLA regions, genome-wide single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), white blood cell DNA methylation and gene expression profiles, and even whole genomes in one pair, the authors hoped to uncover important clues about the underlying aetiology of MS. Surprisingly, however, they were unable to find any variation in genomic or epigenomic factors, or even differences in gene expression, within each twin pair that could be used to explain their disease discordance.
 
Comment: This is the first in-depth comparison between the genomes of two identical twins. Somewhat disappointingly, the research essentially showed that the discordance in disease seemed to have no detectable causal genetic or epigenetic basis. This essentially negative result is nonetheless extremely important, and highlights the fact that comprehensive genetic analysis will not provide the panacea that many seem to believe, and won’t always yield clear answers about the underlying basis of complex conditions. While it may be relatively unsurprising that identical twin pairs do not have major genetic differences, despite recent research indicating differing CNV profiles [Bruder CE, et al. (2008) Am J Hum Genet 82:763-71], the lack of substantial epigenetic differences or varying levels of gene expression in the white blood cells tested is rather unexpected.
 
Nonetheless, “there has to be some trigger that catalysed one to develop [the disease] and the other not” said first author Sergio Barazani in an accompanying news article in Nature, adding that a possible explanation is that “one [twin] was exposed to the perfect combination of environment triggers”. Given the relatively late age of onset of the disease, there may actually have been quite large differences in environmental exposures between the twins. Like many diseases, a complex web of genetic and environmental factors and their interactions may be critical to the underlying cause of MS.

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