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A longstanding mystery: How do identical twins arise?

Scientists have discovered DNA methylation differences that are unique to identical twins, helping to unravel the exact molecular events that lead to division of a zygote.

Monozygotic twins, or identical twins, result from the fertilisation of a single egg with a single sperm. At some point during the very early pre-implantation stages of development, the zygote divides into two embryos. This is why each twin baby shares exactly the same genetic information and are always of the same sex.

Despite a century of scientific progress and technological advances, the mechanisms underlying the events that lead to monozygotic twins remains a mystery. In fact, why and how a zygote splits into two embryos have long been considered the enigmas of human developmental biology. The most trusted hypothesis among scientists is that the events occur at random because monozygotic twinning rarely runs in families. 

Epigenetics influences identical twins

Recently, a group of researchers from the Vrije Universiteit Amsterdam made some ground-breaking discoveries, which could lead to a new understanding of the mechanisms that drive the formation of monozygotic twins. The team, who published their results in Nature Communications, used epigenome wide association studies to measure the level of methylation at more than 400,000 DNA sites in over 6,000 twins.

They found 834 locations where the DNA methylation level was altered in monozygotic twins compared to non-twins. Moreover, these DNA methylation differences were not randomly distributed across the genome, but were enriched in regions near the telomeres and centromeres of genes that encode for heterochromatin and Polycomb-repressed complexes (PRCs). PRCs are families of proteins responsible for differentiation during development and are also important histone modifiers.

Essentially, the scientists revealed that DNA methylation signatures were different in monozygotic twins at genetic locations known to be involved in early embryonic development.

Further studies of zygote division

Excitingly, the findings from this study are likely to act as building blocks for further functional research aimed at unravelling the exact molecular events that lead to division of a zygote.

Professor Dorret Boomsma from the Netherlands Twin Register explained: “This is a very big discovery. The origin and birth of identical twins has always been a complete mystery. It is one of the few traits in which genetics plays no or very modest role. This is the first time that we have found a biological marker of this phenomenon in humans. The explanation appears not to lie in the genome, but in the epigenome.”

It is thought that as many as 12% of human pregnancies start as multiple conceptions, but only 2% carry to term. Although the vanishing of a twin is common, the phenomenon remains largely undetected and the contribution of monozygotic, compared to dizygotic (non-identical), cases is unknown. However, following on from this study, it could be possible to use tools, such as an epigenetic predictor, to recognise whether an individual was conceived as a monozygotic twin based on a simple blood DNA methylation profile. Additionally, the insight gained from this research may shed light on the molecular basis for congenital abnormalities that occur more often in monozygotic twins in the future.

Larger epigenome wide analysis studies or techniques with greater coverage, such as bisulfite sequencing, should be used to determine whether more differentially methylated DNA sites exist across the genome. Moreover, whether these methylation alterations represent a cause, effect or by-product of monozygotic twinning is unknown. Therefore, future research should focus on the possible phenotypic consequences of these methylation signatures and aim to determine the precise molecular underpinning of the events leading up to the splitting of a zygote.

Image credit: The Week

More on these topics

DNA Methylation / Epigenetics / GWAS