Mbarek H. Gordon S.D. Duffy D.L. Hubers N. Mortlock S. Beck J.J. Hottenga J.J. Pool R. Dolan C.V. Actkins K.V. et al. (2024) Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity. Human Reproduction 39: 240-257.
View on Pub Med (38052102)Twins and Twinning
The frequency of twins or higher order multiple births varies substantially across species and understanding the factors that control twinning is important for health and for managing livestock production systems. Dizygotic twin pregnancies in women are associated with a higher frequency of preterm birth, gestational hypertension, and pre-eclampsia with additional complications in monozygotic twin pregnancies. Twinning in cattle can be linked to health and reproductive problems in both mothers and offspring due to increased embryo and foetal losses, malpresentation and difficult births, and the high frequency of developmental problems in female twins born as cotwins to males. In contrast, an increased frequency of twins in sheep contributes to farm income and profitability in many productions systems.
Dizygotic twinning
Discovery of genes for twinning in sheep identified mutations in genes expressed in oocytes and ovaries (BMP15 and BMPR1) demonstrating the important role of this pathway in regulating ovulation rate and twinning within and across species (Galloway et al., 2000, 10888873; Montgomery et al., 1993, 8401591; Wilson et al., 2001, 11259271). There is evidence that mutations in GDF9 in some families (a gene closely related to BMP15 and active in the same pathway) is associated with increased twinning (Palmer et al., 2006, 16954162). Genome-wide association studies have identified variation in regulatory regions close to FSHB, SMAD3, GNRH1, and ZFPM1 associated with twinning (Mbarek et al., 2024, 38052102; Mbarek et al., 2016, 27132594). One interesting observation is that most genetic risk factors identified in the recent GWAS studies with mothers of DZ twins link directly to clear candidate genes from hypothalamic-pituitary-ovarian pathways confirming the important role of hormone signalling in intra-ovarian signalling pathways in regulation of ovulation rate and twinning (Montgomery, 2024, 39222471).
Identical twins
MZ twinning rarely runs in families, the frequency is similar in different populations and there is little evidence for genetic factors influencing MZ twinning. A fascinating recent insight revealed a unique epigenetic signature shared by MZ twins (van Dongen et al., 2021, 34584077). This stable DNA methylation signature is found in both childhood and adult somatic tissues. MZ twins keep this molecular signature across the lifespan, so this discovery allows new possibilities for understanding mechanisms of MZ twinning and for retrospective diagnosis of individuals who may have had an identical co-twin that vanished in the early stages of pregnancy.
Unusual cases of twins
Genetic marker technology was adopted early to test whether same sex twins are identical or non-identical as this in not always obvious. Genetic markers have also been useful in identifying some unusual cases of twins. These include a case of twins who shared a placenta like identical twins but were confirmed to be non-identical (Souter et al., 2003, 12853588). This and subsequent cases show this can be a complication of assisted reproduction. Two very unusual cases report a rare phenomenon of twins that have arisen from two eggs but a single sperm (Gabbett et al., 2019, 30811910; Souter et al., 2007, 17165045). The mechanism for this is not well understood.
References
2024
Montgomery G.W. (2024) Genetic regulation of ovulation rate and multiple births. Reproduction Fertility and Development 36: RD24083.
View on Pub Med (39222471)2021
van Dongen J. Gordon S.D. McRae A.F. Odintsova V.V. Mbarek H. Breeze C.E. Sugden K. Lundgren S. Castillo-Fernandez J.E. Hannon E. et al. (2021) Identical twins carry a persistent epigenetic signature of early genome programming. Nature Communications 12: 5618.
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Gabbett M.T. Laporte J. Sekar R. Nandini A. McGrath P. Sapkota Y. Jiang P. Zhang H. Burgess T. Montgomery G.W. et al. (2019) Molecular Support for Heterogonesis Resulting in Sesquizygotic Twinning. New England Journal of Medicine 380: 842-849.
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Mbarek H. Steinberg S. Nyholt D.R. Gordon S.D. Miller M.B. McRae A.F. Hottenga J.J. Day F.R. Willemsen G. de Geus E.J. et al. (2016) Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. American Journal of Human Genetics 98, 898-908.
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