Identical (monozygotic) twins are born at a rate of 3-4 per 1000 births worldwide. They arise when an embryo splits, presumably before two weeks after conception. How often and why this occurs in human pregnancies is a mystery: the event cannot be observed in vivo and might be more common than typically recognized. Monozygotic twinning may be an overlooked cause of congenital malformations of unknown etiology that occur more often in monozygotic twins.
There is no clear evidence yet for a genetic contribution to having monozygotic twins. However, based on work by Prof Bruno Reversade (King Abdullah University of Science and Technology) and Prof Claudio Stern (University College London) in some rare cases MZ twinning seems to be segregating in families. Thus far, no genetic variant associated with MZ twinning has been identified. The Twinning Genetics Consortium is conducting large-scale genetic and epigenetic studies of monozygotic twinning.
By analysing genome-wide DNA methylation profiles from nearly 6000 twins, we discovered that monozygotic twins carry a robust DNA methylation signature. This signature consists of a few hundred differentially methylated locations, enriched for loci with a role in embryonic processes, cell adhesion, and metastable epi-alleles whose epigenetic state is thought to be stochastically established early in development and subsequently mitotically inherited.
In new research, we are investigating the time of establishment of the methylation signature by analyzing DNA methylation profiles from pre- and perinatal samples from twins and study the link with congenital disorders. Because identical twins keep a lifelong DNA methylation signature, we can use it as a biomarker to retrospectively diagnose if a person was conceived as monozygotic twin (even if one of the twins died very early, referred to as vanishing twin syndrome, which can happen without the mother’s or doctor’s knowledge). This finding has opened up novel opportunities to examine links between monozygotic twinning and congenital disorders, because we can test if patients who were born as singleton carry the monozygotic twinning methylation signature, indicative of a vanished twin. We are applying this approach to study the connection between monozygotic twinning and Amyoplasia, a non-heritable disorder of unknown cause with a 10-fold higher frequency of monozygotic twins among patients (https://www.amcsupport.org/research).
To identify genetic variants associated with MZ twinning, we are performing a GWAS meta-analysis on monozygotic twinning (using data from twin cohorts) and on the DNA methylation signature of monozygotic twinning (using data from twin and non-twin cohorts). For the latter, we collaborate with the Genetics of DNA methylation Consortium (GoDMC,http://www.godmc.org.uk/).