Identical twins may be genetically different due to somatic variations, and a new study by Bruder and colleagues finds that large deletions contribute to some of that difference:
The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These ndings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics (Bruder et al. 2008:1).
If this is a large source of phenotypic discordance between twins -- that is, one twin gets a disease and the other doesn't because of a non-shared somatic CNV -- then our estimates of the heritability of phenotypes based on MZ-DZ twin comparisons will all be too low. This research group is involved in finding genetic risk factors for Parkinson's disease, and they think somatic SNVs are a promising avenue to explain phenotypic discordance where one twin has Parkinson's and the other does not.
But their study cannot say (because of a lack of power) that phenotypically discordant MZ twins have CNVs that explain the discordance. It's possible that most of the CNVs they observe have no phenotypic effect.
MZ twins represent an excellent focus for such studies [of somatic CNVs] because any genotypic difference between twins derived from the same zygote highlights an irrefutable case of somatic variation. It is likely that the confirmed CNVs shown here represent only the "tip of an iceberg" of all CNVs that are actually present in the studied twins. The notion of somatic variation being more far more common than previously assumed agrees well with our other, recent results showing CNVs between normal, fully-differentiated tissues within an individual human subject (Bruder et al. 2008:4).
This does raise an important question. CNVs are a newly-understood component of human genetic variation, for example in the current paper by Jakobsson and colleagues (2008). But if people often exhibit CNV mosaicism, then some of the rare variants in global samples may be somatic mutations that do not occur in the gene pool of their respective populations. And if there are "hotspots" of CNV mutations, then multiple people might show somatic mutations for the same
variant. It's probably a rare event, but given how little we know about the evolution of CNVs, it might be nice to know how rare.
Bruder CEG and 21 others. 2008. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 82:1-9. doi:10.1016/j.ajhg.2007.12.011
Jakobsson M and 23 others. 2008. Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451:998-1003. doi:10.1038/nature06742