Somatic mutations make twins’ brain less similar

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There is a paradox at the heart of behavioural and psychiatric genetics. On the one hand, it is very clear that practically any psychological trait one cares to study is partly heritable – i.e., the differences in the trait between people are partly caused by differences in their genes. Similarly, psychiatric disorders are also highly heritable and, by now, mutations in hundreds of different genes have been identified that cause them.

However, these studies also highlight the limits of genetic determinism, which is especially evident in comparisons of monozygotic (identical) twins, who share all their genetic inheritance in common. Though they are obviously much more like each other in psychological traits than people who are not related to each other, they are clearly NOT identical to each other for these traits. For example, if one twin has a diagnosis of schizophrenia, the chance that the other one will also suffer from the disorder is about 50% – massively higher than the population prevalence of the disorder (around 1%), but also clearly much less than 100%.

What is the source of this extra variance? What forces make monozygotic twins less identical? I have argued previously that random variation in the course of development is a major contributor. The developmental programme that specifies brain connectivity is less like a blueprint than a recipe (a recipe without a cook) – an incredibly complicated set of processes carried out by mindless biochemical algorithms mediated by local interactions between billions of individual components. As each of these processes is subject to some level of “noise” at the molecular level, it is not surprising that the outcome of this process varies considerably, even between monozygotic twins.

While such developmental variation can be referred to as “non-genetic”, a new study suggests that one important component of this variation may be genetic after all, just not inherited. Mutations can be passed on from parents to offspring or arise during generation of sperm or eggs and thus be inherited, but they can also arise any time DNA is replicated. So, each time a cell divides as an embryo grows and develops, there is a very small chance of new mutations being introduced. These “somatic” mutations (meaning ones that happen in the body and not in the germline) will be inherited by all the cells that are descendants of that new cell and so will be present in some fraction of the final cells of the individual. Mutations arising earlier in development will be inherited by more cells than those arising later.

Each person will therefore be a mosaic of cells with slightly different genetic make-up. The vast majority of such mutations will not have any effect of course (with the obvious exception of those that cause dysregulation of cellular differentiation and result in cancer). But sometimes a new mutation will affect a trait and cause a detectable difference. The most obvious examples are in genes affecting hair or eye colour – where a patch of hair may be a different colour, or the two eyes may be different colours.

But what if the mutations in question are linked to a psychiatric disorder? If such a mutation arises early in the development of the brain and is therefore inherited by many of the cells in the brain then this could lead to the psychiatric disorder, just as if the mutation had been inherited in a germ cell.

A new study adds to the evidence that such mutations do indeed occur at an appreciable frequency and may help explain the discordance in phenotype between pairs of twins where one has schizophrenia and the other does not. The authors analysed the DNA from blood cells of pairs of twins discordant for schizophrenia and their parents. They were looking for two different kinds of mutation: ones that changes the identity of a single base of DNA (one letter of the genetic code to another), called point mutations, and ones that delete or duplicate whole chunks of chromosomes, called copy number variants, or CNVs.

As expected, they were able to detect both inherited mutations (present in one of the parents) and de novo mutations (present in both twins but not in the blood cells of either parent). What is more remarkable though, is that they also detected de novo mutations present in the blood cells of one twin but not the other – lots of them. About 1,000 point mutations and 2-3 new CNVs not shared by the other twin. The implication is that these mutations arose during the somatic development of one twin. They identify a couple CNVs in the twins affected by schizophrenia, raising the (very speculative) possibility that those mutations may contribute to the development of the disorder. It will obviously require a lot more work to test that specific hypothesis.

An earlier study also found a high rate of somatic mosaicism for CNVs – this time by analysing the DNA of multiple tissues taken from single (deceased) individuals. Across 34 tissue samples from 3 subjects they identified six CNVs present in one tissue but not others. What this implies is that not only do we carry additional mutations making us even more different from one another, our cells and tissues can also be genetically different from each other.

Time will tell whether such mutations really do contribute to psychiatric disorders, but it certainly seems plausible that they might. This adds to a couple other potential mechanisms of increasing individual variance: the transposition of mobile DNA elements in somatic tissues, especially neurons, and the “epigenetic” silencing of regions of the genome, which may be clonally inherited in groups of cells and contribute to differences between twins.

This has one immediate and important consequence for clinical genetics. When a mutation in an offspring is not carried by either parent it is usually interpreted as having arisen de novo. The implication is that the risk of another offspring carrying the same mutation is negligible. Clinical geneticists are finding this is not necessarily always the case, however – apparently de novo mutations may have actually arisen at an early stage in the germline and not just at the final division generating the sperm or egg. The parent in question may not actually “carry” the mutation, but their germline does. Great care must therefore be taken when advising parents with one affected child of the risk to future offspring.

Maiti S, Kumar KH, Castellani CA, O’Reilly R, & Singh SM (2011). Ontogenetic de novo copy number variations (CNVs) as a source of genetic individuality: studies on two families with MZD twins for schizophrenia. PloS one, 6 (3) PMID: 21399695

Piotrowski, A., Bruder, C., Andersson, R., de Ståhl, T., Menzel, U., Sandgren, J., Poplawski, A., von Tell, D., Crasto, C., Bogdan, A., Bartoszewski, R., Bebok, Z., Krzyzanowski, M., Jankowski, Z., Partridge, E., Komorowski, J., & Dumanski, J. (2008). Somatic mosaicism for copy number variation in differentiated human tissues Human Mutation, 29 (9), 1118-1124 DOI: 10.1002/humu.20815

Fraga, M. (2005). From The Cover: Epigenetic differences arise during the lifetime of monozygotic twins Proceedings of the National Academy of Sciences, 102 (30), 10604-10609 DOI: 10.1073/pnas.0500398102

Mirrored from the Wiring the Brain blog


  1. Great post..

    I think part of the “nonshared environmental variation” is actually shared environmental variation that is ignored because of assumptions inherent in the behavioral genetic methods. See here for my discussion of this with regards to IQ:

  2. Correction to what I just wrote.. “nonshared environmental variation” should be “additive genetic variation”. There is of course no assumption in the calculation of e^2 because its just 1 – rMZ.

    The reason this matters is, once you have significant shared environmental variation, systematic causes of the nonshared environmental variation (e.g. peer groups, status competition, etc.) become plausible.

  3. Thanks ben, for your comments and your interesting post. My take on the shared environment data for IQ, even taking the caveats and assumptions of the study designs into account, is that if an effect exists at all it is fairly small. Does this mean family environment doesn’t matter for IQ? Not at all – it only means that differences in family environments across the ranges within each study do not contribute largely to differences in IQ across each study. The Flynn effect clearly indicates environmental effects on IQ (most likely nutritional but possibly also educational) and trans-national differences in average IQ likely reflect the same factors. So the lack of a contribution of family environmental variance to phenotypic variance in any given population (especially Western ones) may just mean that the variance across families is not that great for the kinds of factors that affect IQ.

  4. kjmtchl,

    We’re on the same page that shared effects are relatively small in the middle class populations they sample for these studies.

    To get a bit deeper, assuming the shared environmental figures are insignificant as you say, why do you think natural selection would favor such a high degree of biological determinism? Wouldn’t there be a selective advantage to organisms who psychologically adapt– not just in beliefs/values, but also in emotional and cognitive abilities tendencies– to the conditions they’re raised in? Of course, too much malleability would be a liability because your psychological development would be at the whims of other individuals, as well as environmental flukes. But still, don’t you think there would be a selective advantage to malleability beyond “give me the right biological inputs (nutrition, etc.) and I’ll develop my genetically programmed personality”?

  5. [...] Somatic mutations make twins’ brain less similar. A new study indicates that one of the reasons that even identical twins differ in their [...]

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