HUMAN GENETICS

Same genomes, but different

The study of monozygotic twins has long been used to dissect the contributions of environmental influences versus genetic variation, the assumption being that the genetic background of siblings derived from a single zygote matches. A new study in Nature Genetics used whole-genome sequencing of monozygotic twins, their parents, partners and offspring to identify and characterize early developmental mutations, as well as the fate of mutated cells, showing that no two genomes are identical, even the genomes of ‘identical’ twins.

The team set out to identify postzygotic mutations (that is, mutations that occur after initial formation of the zygote) and time their occurrence by relating them to the specification of primordial germ cells (PGCS), which occurs a few weeks after the zygote has transitioned into a blastocyst. Mutations categorized as post-PGCS are found either in the germ line or the soma of one individual of a twin pair. By contrast, pre-PGCS mutations are present in both soma and germ line and were further analysed to determine whether they occurred in only one twin or both.

Credit: Richard Harding/Alamy

Looking at 381 monozygotic twin pairs and 2 triplets, the authors first estimated the number of postzygotic mutations present in one twin but not the other. Then, by sequencing genomes of family members (offspring and partners) for a subset of 181 monozygotic twin pairs, the researchers identified mutations present in offspring that were absent in the partner and twin of the proband. This analysis revealed that on average 1.3 pre-PGCS mutations were transmitted from a proband to each child. Considering the diploid genome of the proband and the same number of mutations in the proband’s twin, a difference on average of 5.2 (2 × 2.6) pre-PGCS mutations exists between twin genomes. The authors emphasize that the number of pre-PGCS mutations separating twins was highly variable. Nonetheless, 36 of 246 probands (15%) harboured nearly constitutional (present in all cells) pre-PGCS mutations that were passed on to 64 offspring and were absent in their twins.

“discordance between twin genomes may need to be taken into account”

Overall, the study suggests that some twins are formed from the same cell lineages of the pre-twinning cell population whereas others are not. Importantly, for twin studies, the discordance between twin genomes may need to be taken into account when analysing complex traits.

References

Original article

  1. Jonsson, H. et al. Differences between germline genomes of monozygotic twins. Nat. Genet. 53, 27–34 (2021)

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Related article

  1. van Dongen, J. et al. The continuing value of twin studies in the omics era. Nat. Rev. Genet. 13, 640–653 (2012)

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Correspondence to Linda Koch.

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Koch, L. Same genomes, but different. Nat Rev Genet (2021). https://doi.org/10.1038/s41576-021-00328-w

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