Monday, January 18, 2021

Are identical twins really identical?


Sibling similarity in personality for monozygotic twins, dizygotic twins, and adoptees (Wikicommons)



Monozygotic and dizygotic twins who were separated early in life and reared apart (MZA and DZA twin pairs) are a fascinating experiment of nature. They also provide the simplest and most powerful method for disentangling the influence of environmental and genetic factors on human characteristics. (Bouchard et al. 1990)


Monozygotic twins are identical twins. They develop from a single fertilized egg and are assumed to be genetically identical. Any differences between them in mind or behavior must therefore have an environmental cause. Of course, "environmental cause" does not mean only things like diet, upbringing, education, or parental help with homework. It can also mean accidents during pregnancy or childbirth.


But are monozygotic twins really identical? Monozygotic twins begin to go their own ways long after the zygote has made its first division. It's actually around a week later that they begin to develop separately, when the zygote has already divided several times to form a mass of about sixteen cells. During that time, mutations may have occurred in one cell lineage or another, and not all of those mutations will be inherited by both twins. A twin may in fact develop from a single lineage or several lineages within the cell mass. The two twins may thus be genetically different.


Jónsson et al. (2021) have quantified these genetic differences between twins. They examined the body tissues of adult twins, specifically one sample from adipose tissue, 204 samples from buccal tissue, and 563 blood samples.  On average, one of the twins had 14 postzygotic mutations that were not present in the other. There was, however, considerable variability: 39 twin pairs differed at more than 100 loci, whereas 38 pairs did not differ at all.


Germ cells develop from a subset of cell lineages very early in embryonic development, and it is possible to see how twins differ genetically in their germ lines by looking at their offspring. In this case, there was a difference of 5.2 mutations between twins. Again, there was considerable variability, ranging from a minimum of no mutations at all in 207 offspring to a maximum of 8 mutations in 3 offspring.


If monozygotic twins are not genetically identical, we will have to revise upwards our estimates of the relative importance of nature versus nurture in different human traits:


Phenotypic discordance between monozygotic twins has generally been attributed to the environment. This assumes that the contribution of mutations that separate monozygotic twins is negligible; however, for some diseases such as autism and other developmental disorders, a substantial component is due to de novo mutations. Our analysis demonstrates that in 15% of monozygotic twins a substantial number of mutations are specific to one twin but not the other. This discordance suggests that in most heritability models the contribution of sequence variation to the pathogenesis of diseases with an appreciable mutational component is underestimated. (Jónsson et al. 2021)


In particular, we will have to revise upwards our estimates of the genetic component of intelligence, such as the 70% estimate offered by Bouchard et al. (1990):


Since 1979, a continuing study of monozygotic and dizygotic twins, separated in infancy and reared apart, has subjected more than 100 sets of reared-apart twins or triplets to a week of intensive psychological and physiological assessment. Like the prior, smaller studies of monozygotic twins reared apart, about 70% of the variance in IQ was found to be associated with genetic variation. On multiple measures of personality and temperament, occupational and leisure-time interests, and social attitudes, monozygotic twins reared apart are about as similar as are monozygotic twins reared together.


Or the 41% to 66% estimate offered by Haworth et al. (2020):


Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined.


My criticisms


Why focus on germline differences?


I have two criticisms of the study by Jónsson et al. (2020). First, their abstract highlights the median of 5.2 mutational differences in the germline, and not the larger median of 14 mutational differences in somatic tissues.


Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. (Jónsson et al. 2021)


Yes, "heritability" refers to genes that are passed on to the next generation, but most twin studies don't include the offspring of twins. The researchers simply examine pairs of monozygotic twins and see how they differ. Any differences would therefore reflect differences in somatic tissues and not the germline, or at least not solely the germline.


Undoubtedly, some of the somatic mutations occurred later in development, but they would still be relevant for any study on adult monozygotic twins.


Do these differences really make a difference?


We estimate the genetic component of a mental or behavioral trait by comparing monozygotic and dizygotic twins, i.e., identical and fraternal twins. A difference between monozygotic twins is assumed to be 100% environmental, and a difference between dizygotic twins is assumed to be partly environmental and partly genetic. Therefore, we can estimate the genetic component by subtracting one from the other, right?


This is where the study by Jónsson et al. (2021) comes in. They argue that the genetic component is always underestimated because some of the difference between monozygotic twins is also genetic. But is that additional genetic difference large enough to make a difference? If monozygotic twins differ from each other, on average, at 14 loci, and dizygotic twins differ from each other, on average, at 1400 loci, we might as well assume that monozygotic twins are genetically identical. Any upward revision of the heritability estimate would be slight.


Of course, the key lies in the words "on average." Some of the twins in this study differed at more than 100 loci. More importantly, around 15% of the twins had a substantial number of "near-constitutional" mutations, i.e., absent from one twin and present in almost all the tissues of the other. In those cases, we could see big differences in development between the two.


It's difficult to say without a point of comparison. In other words, the same kind of study should be done on dizygotic twins. How much more variable are they genetically?





Bouchard Jr., T.J., D.T. Lykken, M. McGue, N.L. Segal, and A. Tellegen. (1990). Sources of human psychological differences: the Minnesota Study of Twins Reared Apart. Science 250(4978): 223-228.


Haworth, C.M.A., M. J. Wright, M. Luciano, N.G. Martin, E.J.C. de Geus, et al. (2010). The heritability of general cognitive ability increases linearly from childhood to young adulthood. Molecular Psychiatry 15: 1112-1120.


Jónsson, H., E. Magnusdottir, H.P. Eggertsson, O.A. Stefansson, G.A. Arnadottir, et al. (2021). Differences between germline genomes of monozygotic twins. Nature Genetics 53: 27-34 (2021).


Morris said...

Quote "But are monozygotic twins really identical? Monozygotic twins begin to go their own ways long after the zygote has made its first division. It's actually around a week later that they begin to develop separately, when the zygote has already divided several times to form a mass of about sixteen cells"
I find that statement confusing. Can you elucidate for the obtuse?

iffen said...

The fingerprints of identical twins are very similiar, but distinguishable. They are an order of magnitude more similiar than the similarities observed in other 1st degree relations. There was a window in forensics when DNA tests could not distinguish between identical twins, but fingerprints always could.

Peter Frost said...


A zygote is the union of an egg cell with a sperm. It's the first stage of development. The zygote then splits in two. That's the first division. Those two cells then split, and so on. When there is a mass of sixteen cells, some of those cells may develop into one baby and some of the other cells may develop into another baby.

I used to think that the first division was the crucial stage. Those two cells would become two twins. I was wrong. The two twins begin to separate from each other later.


Isn't the development of fingerprints influenced by random factors in the womb? Has anyone estimated the heritability of fingerprints?

Morris said...

Thanks. I understand the stages of division but what puzzled me is why the first cell
division is not considered to be the start of separate babies but never mind.

Peter Frost said...


It isn't the start of separate babies because both cells may have subsequent lineages that end up in the same baby.

iffen said...

Isn't the development of fingerprints influenced by random factors in the womb?

Yes, because there is no other explanation. The fingerprints of monozygotic twins are extremely similiar. I'm not sure how it could be measured but the similarities are a cline that correlates with relatedness. But there is a "cliff", as I said, an order of magnitude difference, between the similarities observed in monozygotic twins and the similarities observed in other 1st degree relations..