There is a great degree of robustness in development. Without fail, the majority of embryos are capable of growing from a single-celled egg into a functional adult comprised of billions of interacting cells. How this happens is the holy grail of developmental biology, and is a major field of study in science. But development can be an extremely sloppy process as well, a phenomenon known as developmental stochasticity. Molecules randomly bounce around and between cells, genes regulate other genes with varying degrees of effectiveness, and cells constantly migrate around the developing body. The huge numbers of developmental defects attest to how easy it is for this process to screw up. Although the concept of developmental stochasticity has been around since the early 1900’s, it is only recently that scientists have had the genetic tools to consider this phenomenon in real functional detail.
Andrew Oates at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, just published a very interesting review of developmental stochasticity in the journal Development. Because it covers so many ideas, I thought I would break the paper down into its parts, and address each theme independently.
The first idea is known as incomplete penetrance. Perhaps it isn’t the best name for a phenomenon, but it gets the point across: incomplete penetrance is when the same mutation has different effects on individuals in a population. For example, while a genetic mutation might give one animal dark fur, the same mutation might have no effect on another member of the species.
Oates focused on recent progress on the genetics behind incomplete penetration from Alexander van Oudenaarden’s group at MIT, which studies the nematode worm Ceanorhabditis elegans:
One of the reasons this worm has become a model organism in developmental biology is that it has invariant development, meaning each cell is pre-programmed to differentiate into its final cell-type (mammal cells, on the other hand, usually need chemical cues from surrounding cells to know what type of cell to ultimately become). You might think that since C. elegans development is so deterministic, there wouldn’t be much room for mutation-caused variability, but in a Nature paper published by Raj et al. (2010), van Oudenaarden's team discovered how incomplete penetrance affects development of the worm’s intestine.
In normal (wild-type) worms, the gene skn-1 regulates the formation of the intestine. Below is the skn-1 gene network in C. elegans. If you’re unfamiliar with gene networks, the arrows show you the direction of genetic control. For example, skn-1 has arrows pointng from it to three other genes (end-1, end-3 and med-1/2), meaning that the gene skn-1 regulates the expression of these genes (you could also say that skn-1 is upstream of these genes). elt-2 is downstream of end-3 and end-1, and the gene also regulates itself (hence the circular arrow). This means the protein product of elt-2 encourages the production of more elt-2.
Normally, skn-1 mutants are unable to complete this gene network, so they fail to develop a proper intestine. However, this is not always the case. Sometimes, skn-1 mutants had no intestine, but other times skn-1 mutants did. Below is an image of developing C. elegans worms; on the right are normal embryos expressing elt-2 (labeled pink) in the developing intestine. On the left are skn-1 mutants; although they all have the same mutation, some still show elt-2 expression:
This led to the discovery that most of the mutations created in skn-1 still allowed for the regulation of the gene end-1. end-1 shows stochastic expression; if enough the end-1 protein product is created that the gene crosses a threshold, then it can turn the gene elt-2 on, even without the rest of the gene network:
At least four cells are needed to express end-1 to generate proper expression of elt-2. This is a great example of how development can be robust against mutation, and how chance fluctuations in gene product can cause the same mutation to have different effects.
Works Cited
Oates AC (2011). What's all the noise about developmental stochasticity? Development (Cambridge, England), 138 (4), 601-7 PMID: 21266404
Raj A, Rifkin SA, Andersen E, & van Oudenaarden A (2010). Variability in gene expression underlies incomplete penetrance. Nature, 463 (7283), 913-8 PMID: 20164922
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