The genetics behind fraternal twinning

An extra egg cell is released during ovulation, fertilised by two different sperms, to form two embryos. Photo: Reuters   | Photo Credit: STRINGER/INDIA

Two genes that affect a woman’s likelihood of giving birth to twins have been identified in a new study published in American Journal of Human Genetics. This could have implications for fertility research and help predict how women will respond to treatments for infertility.

Identical, or monozygotic (MZ), twins occur at a fairly stable frequency of 3 to 4 per 1,000 births all around the world. In contrast, the occurrence of fraternal, or dizygotic (DZ) twins (non-identical twins) varies wildly across different kinds of populations — only 6 per 1,000 in Asia but 40 per 1,000 in Africa. Older mothers are four times more likely to have non-identical twins than younger ones; taller, heavier women who smoke and have family history of twinning are also reportedly more prone to having fraternal twins. All of this lends to the long-held suspicion that there exist genetic factors that affect a woman’s susceptibility to give birth to fraternal twins.

Usually, ovulation involves the maturation and release of exactly one egg, called the “single dominant follicle.” This chosen egg, if fertilised by a sperm cell, can lead to a pregnancy. The result of this is a fused cell called the zygote which then develops into an embryo. Very rarely, the zygote divides early on into two and each one develops into an individual embryo, ending up in identical twins. In the case of non-identical or fraternal twins, an extra egg cell is released during ovulation, opening the possibility of both getting fertilised by two different sperms and the formation of two non-identical embryos.

Before they arrived at the two genes, the scientists combed through the entire genomes of 1,980 mothers of non-identical twins and 12,953 control subjects (mothers with no non-identical twins). They found 30 spots that seemed to be linked with twinning and kept narrowing down. “Two genetic variants, one near FSHB gene and the second one in SMAD3 gene showed a statistically significant association,” said Hamdi Mbarek from Vrije Universiteit in Amsterdam, who led the study, in an email to me.

Mothers who had one specific variant of the FSHB gene were more likely to have given birth to non-identical twins. This variant is linked to increased production of follicle stimulating hormone (FSH), leading to more than one egg maturing and consequently multiple ovulation. The second, SMAD3, likely affects how the ovaries respond to FSH. Mothers of non-identical twins were significantly more likely to carry a variant of SMAD3 which makes her ovaries more sensitive to the same amount of FSH.

Lessons from past failures

Efforts to characterise the genes that contribute to non-identical twinning in humans had been largely unsuccessful until this study. But these failures did not go in vain. “They taught us that non-identical twinning in humans is a polygenic trait and that much more powerful genome-wide association studies (like this one) are required to find the genes which may offer insights for new treatments,” said Mbarek. He added that rigorous selection of their cohort mothers to make sure none received any kind of fertility treatment was also a crucial factor for enabling these results.

The scientists stress that their findings are probably just the beginning. “There is a very clear suggestion and indication that more loci are contributing,” said co-author Dorret Boomsma in a press release.

Knowing one’s predisposition to multiple births can be very useful in the light of risks like premature birth associated with twinning. Mbarek added that future studies into SMAD3, the totally new candidate for twinning, may offer a novel avenue for fertility treatments, particularly in women who poorly respond to ovarian stimulation and also help in prevention of premature ovarian ageing.

(Nandita Jayaraj is a freelancer based in Bengaluru.)

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Printable version | Oct 2, 2020 1:10:40 AM |

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