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Twins: from a genetic point of view 

Regardless of whether someone is a twin or has twins in the family, it is an interesting subject for many people. You may easily recall times you have met a set of twins or maybe you knew a pair of twins and prided yourself in being able to tell them apart. Indeed, the identical nature of twins is often one of the first things that comes to mind when considering the subject of twins. Your appearance, and that of twins, is dictated by genetics; furthermore, genetics can explain why certain traits (characteristics) or illnesses are seen to run in families and as described below, may offer insights into why twins sometimes seem to run in the family. Genetics is certainly key here, but it is not the whole story. It is interesting to note that global rates of twin births have been steadily increasing since the 1980s, which suggests that considering genetics alone would leave important information out of a discussion about twins [1]. 

Identical or fraternal – types of twins 

You may have heard different names used for sets identical or non-identical sets of twins. Put simply, identical twins are also called monozygotic twins, while non-identical twins are called fraternal or dizygotic twins. In order to understand the difference, we must briefly discuss biology. 

Monozygotic twins develop from a single egg that is fertilized by a single sperm (to produce a fertilized egg called a zygote) that splits early in development. You can see then, that the name comes from combining mono, meaning one and zygotic, which comes from the word zygote. The two developing embryos have the same genome, which means they share 100% of their genes and their DNA is identical, thus the twins will be identical and of the same sex [2]. 

Fraternal or dizygotic twins develop when two eggs are released at ovulation and fertilized by two sperm (the result is two zygotes). The two developing embryos have different DNA, they share about 50% of their genes, and the twins will not be identical in appearance, although they may share traits in the same way other siblings do, and they may be of the same or opposite sex [3]. Dizygotic twins are more common than monozygotic twins are [4]. Similar to monozygotic, the name comes from di, meaning two and zygotic

Girls and boys 

As mentioned above, monozygotic twins are always the same sex. The sex of all babies, including twins, is determined by the father, or specifically by the sex chromosome carried on the sperm. This is because we inherit one sex chromosome (X or Y) from each parent. Women have two X chromosomes so can only pass on an X chromosome. Sperm carries either an X or a Y chromosome and if a man passes on an X chromosome then the child will be a girl (XX) and if he passes on a Y chromosome, it will be a boy (XY).  

In the case of monozygotic twins, the sperm has determined the sex before the zygote splits. Therefore, monozygotic or identical twins will always be the same sex. 

The situation is different for fraternal twins; here the sex is determined by two sperm independent of each other. As a result, fraternal twins will not necessarily be the same sex, although they can be, and a girl-boy pair of twins will always be fraternal. 

Twins in the family 

In general, it is accepted that identical (monozygotic) twins occur by chance and do not tend to run in families while fraternal twins do. Indeed a woman is more likely to have fraternal twins if she has a female relative who has fraternal twins [4]. 

However, familial monozygotic twinning does occur and a possible cause is changes in a gene that affects cell-to-cell connections. These changes mean that the cells forming the embryo do not stick together well, causing the embryo to split and develop into two fetuses [5]. 

For fraternal twins to occur, more than one egg must be released at ovulation: this is called hyperovulation. Hyperovulation is influenced by a woman’s hormones: specifically, prolonged or unusually high levels of follicle-stimulating hormone (FSH) that occur quite naturally, as well as being a consequence of fertility drugs [6]. Why some women have more FSH or are more likely to hyperovulate is not entirely clear. For some women, age is a factor. It is known that FSH levels increase as a woman approaches menopause, increasing the chance that multiple eggs will be released at ovulation and therefore increasing the likelihood of having fraternal twins [7]. Other causes of hyperovulation are unclear; however, the fact that fraternal twinning runs in families, suggests genetic factors may also play a role in hyperovulation. 

There have been numerous studies aiming to identify genes and gene variants with a role in the inheritance and development of dizygotic twins (also called dizygotic twinning), but no clear outcomes. A study from 2010 used linkage analysis (use of chromosome locations to detect genes and assess disease patterns) to look for genes contributing to twinning in different geographical groups. It suggested that the FAM120B gene region of chromosome 6 may influence twinning, but geographical differences in the most strongly linked chromosome suggested the potential involvement of multiple genes. This led the authors to conclude that the inheritance of twinning is complicated and probably involves gene variants in multiple loci (genes) [8]. A later study in 2016 suggested gene variants in the FSHB and SMAD3 genes were risk variants for dizygotic twinning [9].  

Overall, the menstrual cycle and pregnancy are complex processes involving the interactions of several hormones; it is therefore probable that they can be influenced by multiple genetic factors that may also have the potential to influence twinning. 

It is not all genetics 

As mentioned earlier, the number of twin births worldwide has increased since the 1980s: from 9.1 per 1000 births between 1980 and 1985 to 12.0 per 1000 births between 2010 and 2015 [10]. This increase is due in part to non-genetic factors that contribute to the likelihood woman of having twins. 

It is well known that a woman is more likely to have fraternal twins following fertility treatment, and the use of fertility treatments has increased since the 1980s. Fertility drugs designed to stimulate ovulation and aid fertility can cause hyperovulation and increase the chance of having fraternal twins. In vitro fertilization (IVF) is a method of assisted reproduction that involves the implantation of multiple embryos in a woman’s womb to increase the pregnancy success rate. Consequently, the chance of having a twin or multiple pregnancy increases. Furthermore, as mentioned previously, older women are more likely to have fraternal twins, as there is a greater chance that two eggs are released at ovulation. Other factors such as ethnicity, diet, number of previous pregnancies or even height can also influence the likelihood of having twins [7]. 

What about nature versus nurture 

You have probably heard about “nature versus nurture”. This phrase is used to debate whether nature—your genes and genetics—or nurture—the surrounding environment including upbringing and childhood experiences—exerts the greatest influence on personality and behavior characteristics. The reality is complicated and outside the scope of this article, but in summary, both genetic and environmental factors (nature and nurture) interact to influence a person’s characteristics. 

Twin studies offer researchers a unique chance to study the effects of nature or nurture. Remember, that identical twins share 100% of their genes and fraternal twins share around 50%, meaning that differences between traits seen in sets of identical twins are more likely to have environmental causes than genetic causes.  

By investigating the similarity of a trait in identical twins and comparing it to the similarity of the same trait in fraternal twins, researchers can estimate how heritable the trait is. Heritable means capable of being inherited or passed on and an estimate of heritability describes how much variation is due to genetics. It means that if the trait shows more similarity in identical twins than in fraternal twins, it is assumed to be more heritable and therefore due to genes rather than the environment [11]. Height is a highly heritable trait, meaning it is strongly influenced by your genes. It is important to remember that the heritability only indicates the influence of nature or nurture and does not tell us anything about which genes or environmental factors may be involved [12]. Despite these limitations, twin studies are a popular research tool; in 2015, a publication called a meta-analysis examined data from more than 2,700 twin studies looking at nearly 18,000 traits [13]! 

Twin studies can contribute to our understanding of genetic disorders by looking at concordance rates in sets of twins (i.e., whether both twins have the disorder). Here too, the heritability can be assessed indicating the environmental or genetic impact, but it is important to remember that is only an indication, and that in reality genetic and environmental factors often interact. Autism and type I diabetes have high heritability. 

Differences between identical twins: epigenetic changes 

Even identical twins, who share almost their entire DNA, do not always get the same disease or exhibit the same trait despite no obvious environmental differences. One reason for differences between identical twins is epigenetic changes. These are changes to gene expression (meaning a gene is switched “on” or “off”) altering how or which proteins are made. Epigenetic changes are caused by environmental and lifestyle factors, they can occur at any time and may not be permanent [14] and they may be one link between genetics and the environment. Twin studies are useful to assess whether epigenetic changes are heritable as well as the stability of these changes and whether they contribute to observed differences between twins [15]. One Spanish study reported a third of the monozygotic twins studied had epigenetic changes influencing gene expression and that they were more distinct in older twins with differing lifestyles [16]. 

Epigenetic studies in identical twins are therefore of particular interest to researchers, as studies in diseasediscordant monozygotic twins (where only one twin is affected) can detect relevant disease-related epigenetic differences. In fact, there have been numerous epigenetic studies into diseases such as autism spectrum disorders, breast cancer and psoriasis in discordant monozygotic twins [17]. 

Conclusion 

We can see that there are many factors, including genetics, that influence the likelihood of having twins, and that genetic factors cannot currently be separated from other factors that influence both monozygotic and dizygotic twinning (such as age, diet and lifestyle factors). As scientific research into fertility and human genetics continues, our understanding of the genetics behind the development of twins will improve, as will our understanding of complex genetic and environmental interactions. Twin studies have provided valuable information about many traits and diseases and contributed to our understanding of the interactions between nature and nurture, and studies in twins and their families will likely continue to contribute to our knowledge of genetics and genetic disorders. 

References 

[1] Wilson C. 12 March 2021. The number of twins in the world is the highest it has ever been. New Scientist. Retrieved 11 May 2022 from https://www.newscientist.com/article/2270822-the-number-of-twins-in-the-world-is-the-highest-it-has-ever-been/ 

[2] National Human Genome Research Institute. Identical Twins. Retrieved 5 May 2022 from https://www.genome.gov/genetics-glossary/identical-twins 

[3] National Human Genome Research Institute. Fraternal Twins. Retrieved 5 May 2022 from https://www.genome.gov/genetics-glossary/Fraternal-Twins 

[4] National Library of Medicine, Medline Plus. Is the probability of having twins determined by genetics? Retrieved 5 May 2022 from https://medlineplus.gov/genetics/understanding/traits/twins/  

[5] Spiro R. 1 October 2015 Does Identical Twinning Run in Families? Washington State Twin Registry. Retrieved 11 May 2022 from https://wstwinregistry.org/2015/10/01/does-mz-twinning-run-in-families/  

[6] Shirazi T. Seeing double: The science behind (natural) hyperovulation. A Modern Fertility Blog. Retrieved 19 May 2022 from https://modernfertility.com/blog/hyperovulation/ 

[7] Spiro R. 1 October 2015. What factors are related to fraternal twinning? Washington State Twin Registry. Retrieved 11 May 2022 from https://wstwinregistry.org/2015/10/01/what-factors-are-related-to-dz-twinning/ 

[8] Painter JN et al. A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins. Hum Reprod 2010 25(6):1569-80 doi: 10.1093/humrep/deq084. Epub 2010 Apr 8. PMID: 20378614; PMCID: PMC2912534. https://academic.oup.com/humrep/article/25/6/1569/2915779 

[9] Mbarek H et al. Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. Am J Hum Genet 2016 98(5):898-908 doi: 10.1016/j.ajhg.2016.03.008. Epub 2016 Apr 28. PMID: 27132594; PMCID: PMC4863559. https://pubmed.ncbi.nlm.nih.gov/27132594/ 

[10] Monden C et al. Twin Peaks: more twinning in humans than ever before. Hum Reprod 2021 36(6):1666–1673 https://doi.org/10.1093/humrep/deab029 

[11] Sahu M, Prasuna JG. Twin Studies: A Unique Epidemiological Tool. Indian J Community Med 2016 41(3):177-82 doi: 10.4103/0970-0218.183593. PMID: 27385869; PMCID: PMC4919929.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919929/

[12] National Library of Medicine, Medline Plus. What is heritability? Retrieved 19 May 2022 from https://medlineplus.gov/genetics/understanding/inheritance/heritability/ 

[13] Polderman T et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet 2015 47:702–709 https://doi.org/10.1038/ng.3285 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919929/ 

[14] Centers for Disease Control and Prevention. What is Epigenetics? Retrieved 19 May 2022 from https://www.cdc.gov/genomics/disease/epigenetics.htm 

[15] Bell JT, Spector TD. A twin approach to unraveling epigenetics. Trends Genet 2011 27(3):116-25 doi: 10.1016/j.tig.2010.12.005. Epub 2011 Jan 21. PMID: 21257220; PMCID: PMC3063335. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063335/ 

[16] Fraga M et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005 102(30):10604-9 doi: 10.1073/pnas.0500398102. Epub 2005 Jul 11. PMID: 16009939; PMCID: PMC1174919. https://www.pnas.org/doi/full/10.1073/pnas.0500398102

[17] Castillo-Fernandez JE et al. Epigenetics of discordant monozygotic twins: implications for disease. Genome Med 2014 31;6(7):60 doi: 10.1186/s13073-014-0060-z. PMID: 25484923; PMCID: PMC4254430. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254430/ 

Further reading 

Hoekstra C et al. Dizygotic twinning, Human Reproduction Update 2008 14:37–47 doi: 10.1093/humupd/dmm036. Epub 2007 Nov 16. PMID: 18024802. https://doi.org/10.1093/humupd/dmm036 

Lewis CM et al. Genetic contribution to DZ twinning. Am J Med Genet 1996 61(3):237-46 doi: 10.1002/(SICI)1096-8628(19960122)61:3<237::AID-AJMG7>3.0.CO;2-R  PMID: 8741868.  

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