Roughly one in 250 births result in humans who baffle scientists. These are identical twins — the Tia and Tamara Mowrys of the world — and we don’t really know why they exist (other than to pull off elaborate pranks Parent Trap style).
Dorret Boomsma, a genetics and twins researcher at the Vrije University in Amsterdam, tells Inverse identical twins are “described as one of the ‘enigmas in developmental biology.’”
So Boomsma, first author Jenny van Dongen, and colleagues decided to try to solve this mystery and explore the genesis of identical twins. The results of their work, published Tuesday in Nature Communications, finally shed some light on what causes a fertilized egg to split.
The key might not be in the genetic code itself, but instead in epigenetic changes — chemical markers associated with how the DNA is read. The study has implications beyond understanding the genesis of identical twins: the findings could also inform our understanding of congenital disorders associated with identical twins.
There are severe congenital disorders that show an overrepresentation in identical twin populations, Boomsma explains: “Our study may shed light on risks for these disorders and give results for regions in the genome to further study in the lab.”
What causes twins?
When you learned about twins in high school biology, you probably were taught the difference between fraternal and identical twins.
Fraternal twins occur when two egg cells are each fertilized by a different sperm cell in the same menstrual cycle. Identical twins, meanwhile, result when one egg is fertilized by one sperm, but early in development, that egg splits into two.
Why that happens is a mystery that’s confounded geneticists.
No such mystery exists with fraternal twins. Fraternal (technically known as dizygotic, or DZ) twins, occur in roughly one in 100 live births. They run in families, suggesting there is a genetic component to the development of fraternal twins. In some cases, that genetic component may be hyperovulation, in which more than one egg is released during ovulation.
Identical (technically known as monozygotic or MZ) twins don’t appear to have a clear genetic component. We know how identical twins develop — when a fertilized egg splits into two — but we don’t know why that happens. We haven’t known what causes the egg to split.
How the discovery was made — To better understand why twins exist, the researchers looked at twin registries from the Netherland, Great Britain, Finland, and Australia.
Instead of focusing on genomics, the researchers looked at epigenomics. Specifically, they examined methylation levels at more than 400,000 sites in the DNA of more than 6,000 twins.
Methylation, Boomsma explains, is an epigenetic process.
“During DNA methylation, methyl groups are added to the DNA molecule,” she says. “Methylation can change the activity of a DNA segment without changing the DNA sequence.”
Methylation was of interest for two reasons:
1) Imprinting disorders show an overrepresentation of identical twins
2) Breakthroughs in technology now allow researchers to measure hundreds of thousands of epigenetic, or methylation marks, at an epidemiological scale.
What they discovered — The researchers found 834 locations in the DNA where the methylation level was different in identical twins than in non-identical twins (fraternal twins as well as non-twins).
The researchers first ran the analysis in the Netherlands Twin Register and found there were a large number of non-random clustering across the genome, specifically at centromeres — which are involved in the transmission of the genome during cell division — and telomeres. These are repetitive nucleotide sequences associated with specialized proteins found at the ends of linear chromosomes.
When the study team expanded their sample to look at twin databases in other countries, they found the same thing: all the identical twins in all the countries they evaluated had these non-random clusters.
This held true among different tissues and among twins of different ages, which Boomsma says shows “this epigenetic signature to be very stable.”
To the researchers, these findings suggest unusual methylation patterns in genes involved in cell adhesion, which they posit could be why there is “spontaneous fission” of an early developing embryo into two identical halves.
This finding may also provide important clues to the origin of numerous birth defects known to be strongly associated with MZ twinning.
What it means for the future — Now that the researchers have more understanding about why a fertilized egg splits in some and not others, they’re eager to learn more about that “why” (in science, one why almost always leads to another why).
“There is a lot of follow-up work to be done,” Boomsma says. “We are partnering with scientists in Sioux Falls who will assess epigenetic profiles in larger groups whose chorionicity is known.”
Chorionicity is the number of placentae that exist during pregnancy. Some identical twins will share one placenta. Those twins are called monochorionic twins and have significant predispositions to congenital birth defects. The vast majority, roughly 70 percent, of identical twins share a placenta.
The researchers hope that this research will ultimately help them better understand where in the genome researchers tackling these birth defects should focus.
There is something inherently fascinating about identical twins, if for no other reason than they’re a fairly rare occurrence in pregnancies. Another person who looks like you? That’s already wild.
But those who study developmental biology have a different fascination with identical twins: the mystery about why they exist. Boomsma and her colleagues’ findings offer a significant piece of that enigmatic puzzle.
Abstract: Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during the pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.