Noisy genes and the limits of genetic determinism

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Mirrored from http://wiringthebrain.blogspot.com

Why are genetically identical monozygotic twins not phenotypically identical? They are obviously much more similar than people who do not share all their DNA, but even in outward physical appearance are not really identical. And when it comes to psychological traits or psychiatric disorders, they can be quite divergent (concordance between monozygotic twins for schizophrenia for example is only around 50%). What is the source of this phenotypic variance? Why are the effects of a mutation often variable, even across genetically identical organisms?

“Nurture” has been the answer proffered by many, but there is good evidence that environmental or experience-dependent effects can not explain all the extra phenotypic variance and in most cases contribute very little to it. (See post on “Nature, nurture and noise” on June 24th, 2009 for more on this: http://wiringthebrain.blogspot.com/2009/06/nature-nurture-and-noise.html).

An alternative source of variation is intrinsic to the developmental programme itself. In particular, small, random fluctuations in the expression of genes at various times during development can have large effects on the phenotypic outcome. A new study in Nature by Raj and colleagues directly illustrates this point for the first time and highlights several important principles of developmental systems.

They studied the effects of mutations in components of a genetic network involved in the specification of a small number of intestinal cells in the nematode, Caenorhabditis elegans. This is the perfect organism for such studies, as the cells in question are individually identifiable and generated in an invariant pattern in wild-type animals. Mutations in one of the components led to an incompletely penetrant mutant phenotype: some animals made intestinal cells and others did not (even though all had the identical geneotype).

To determine whether noise in gene expression could explain this diversity the authors directly measured the precise number of messenger RNA molecules being transcribed from the genes encoding other components of this developmental pathway in particular cells of each embryo and correlated these measurements with phenotypic outcome. They showed that the expression of one of these genes in particular became highly variable in the mutant background. If, by chance, the level of expression crossed a particular threshold it turned on the master gene responsible for intestinal cell specification and these cells were generated. If the levels did not cross the threshold then the cells were not generated. In this way, a bimodal phenotypic distribution can arise from an identical starting genotype.

This study illustrates several important principles of complex regulatory systems that apply not just to developmental and genetic networks but also to neuronal networks. First, a certain amount of noise is a normal part of the system – a feature, not a bug – that increases robustness to external variation. Developmental systems are normally buffered, however, to reduce noise in gene expression and to absorb its effects. This buffering can be disrupted when individual components of a regulatory system are removed; this is why when genes are mutated, one expects (and always sees) not just a change in phenotype but an increase in phenotypic variability. The effects of stochastic fluctuations in expression levels of various genes can lead to a continuous distribution of phenotypic outcomes or, as in this case, dramatically different phenotypes. Interlocking positive and negative feedback loops can generate extremely discrete thresholds, where once a certain level of a component is reached it will reinforce its own expression and shift the network into a different state. Such bistability is a common feature of complex systems and is sometimes taken advantage of to generate phenotypic diversity or plasticity.

This study elucidates a molecular mechanism of intrinsic variation in developmental systems and shows that it can have a large effect on the eventual phenotype, even in genetically identical organisms. No matter how precise the recipe, you can’t bake the same cake twice.

Raj, A. (2010). Variability in Gene Expression Underlies Incomplete Penetrance in C. Elegans: Using Single Molecules To Study the Development of Single Cells Biophysical Journal, 98 (3), 14-14 DOI: 10.1016/j.bpj.2009.12.087

9 Comments

  1. You should link to your previous post on “noise” & heredity:
    http://www.gnxp.com/wp/uncategorized/nature-nurture-and-noise

  2. Whoops, you did, just with a mirror url.

  3. Interlocking positive and negative feedback loops…

    On a slightly different take whenever two feedback loops pertain to two different but somewhat related functionalities this is the recipe for strange attractors (growth along one dimension, shrinking along the other), and strange attractors generate wild random looking features (though perfectly deterministic).

  4. I was friends with a set of twins when I was in grade school. They did not really look alike other than hair, skin and eye color, but claimed they were identical twins because the doctor said they were both in the same gestational sac. This was so long ago they weren’t tested or anything.

  5. kjmtchl,

    To revisit your previous post, what are your thoughts on Turkheimer’s idea that the environment does have effects, but that they are nonsystematic simply because of the generally unfixed nature of environmental influences as compared to genes:

    “Genotype..will exert a constant pull on the phenotype.. regardless of the other complex dynamics the system produces. The environment, in contrast, is in a constant state of flux induced by its reciprocal interactions with phenotype… the environment, therefore is a source of variability in outcome but not a source of systmeatic variability”

    http://www.subjectpool.com/ed_teach/y4person/6_genes/Turkheimer.Spinach.pdf

  6. ben g,

    Thanks for your comment. I will have to read more from Turkheimer. I agree, of course, that the environment will be less stable than a person’s genotype and in fact all the twin and adoption studies tell us about the environment is that a shared family environment tends not to have much effect on the outcome for most psychological traits. This was a big surprise, really, that the “nurture” component should be so minor. Of course, other environmental factors could influence phenotype and these may be so variable that they will be hard to detect as systematic effects in epidemiological studies. However, assuming that the rest of the variance is due to “non-shared environment” (if that is taken in the normal sense of the word environment) is not justified, especially if the system is characterised by a large amount of intrinsic noise.

  7. this was a fantastic post. thanks so much for writing this!

  8. I agree that noise is not “environment” in the social science sense. The noise effect would actually increase biological determinism even as it limits genetic determinism.

  9. Thanks. Very helpful.

    I was doing some research recently on twins and I realized that there a quite a few pairs where nobody seems to be sure if they are identical or not — for example, the 7-foot-tall Lopez twins and the 7-foot Collins twins in the NBA, or the Olsen twins of TV fame.

    This can help explain this phenomenon of twins who seem too similar to be fraternal but not quite similar enough to be identical.

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