Friday, December 9, 2011

Random gene expression really can be random

It's rather surprising that authors of a commentary ("Genetics: Noise rules") for a major science journal (Nature) feel the need to remind people that identical twins don't always have the same personalities or the same disease risk.
Notable advances in DNA sequencing during the past few years have made it possible to define the genotype of any individual rapidly and cheaply. As a result, scientists glibly talk about the possibility of pinpointing individual genes that influence every aspect of our being, from our propensity to get cancer to our chances of living to be 100 years old. However, this appealing vision oversimplifies a much more complex reality. There is no one-to-one relationship between genotype and phenotype — even identical twins can have radically different personalities, disease susceptibilities and life trajectories.
Astonishing.  Though what's truly astonishing is that so many scientists do still glibly talk about genes for traits. Indeed, evolutionary psychology thrives, genetics percolates into fields like economics, and direct-to-consumer companies sell the promise of prediction from genes to (too) many believing customers.

Heritability in twin studies is almost always far from 100%, clearly showing that environment plus statistical variation (chance aspects of development, exposures, mutations, and so on) are important, even if the inherited genome is identical (but every cell division introduces new mutations, so even identical twins are not identical in their genes, any more than you are in the genomes in your different cells!).

But, clearly people still need to hear the message, whether or not it sinks in.  And the message in a paper in this week's Nature by Ben Lehner et al. is that phenotype is due to 'noise' -- random gene expression -- and the fact that genes act together with other genes to 'form functional cellular networks'.  That is, genetic background determines the effect any given allele has on phenotype.  Why this is Nature-worthy isn't entirely clear, given that both phenomena are well-known -- perhaps because it is elegantly demonstrated.

The authors wondered why so many mutations only have a detrimental effect on a subset of individuals who carry them.  Genetic background and gene by environment interactions are the usual answer, but what about incomplete penetrance?  That is, the situation where an allele isn't expressed, or isn't completely expressed, for whatever reason.  They propose 'a model for incomplete penetrance based on genetic interaction networks.'
C. elegans;  public domain photo Bob Goldstein

Briefly, using the C elegans, a tiny and very well-characterized worm, as their model, the proposed "that in the absence of additional genetic variation, it is stochastic variation in the abundance or activity of genetic interaction partners (genes that influence the outcome of a mutation when genetically altered) that determines the outcome of a mutation."

To test their hypothesis, among other things, they looked at the effects of a mutation in a known transcription factor gene, tbx-9.  Half of the mutant worms had abnormal development of the epidermis and muscle -- that is, effects of the mutation were incompletely penetrant.  Tbx-9 is related to another transcription factor, tbx-8, and inactivation of tbx-8 causes incompletely penetrant defects as well, but loss of both genes is lethal.  And, while half of the worms lacking tbx-9 develop normally, overexpression of tbx-8 eliminates the effects of tbx-9 mutations, and loss of tbx-9 upregulated tbx-8.  Further, differences in tbx-8 expression were a predictor of the effects of loss of tbx-9. 

However, variability of tbx-8 expression didn't fully explain variation in expression of the tbx-9 mutation.  The authors propose that the remaining variability is due to molecular chaperones, proteins that help other proteins to take their shape, that somehow dampen the effects of some mutations.  They found correlated fluctuation in penetrance of mutation effects with molecular chaperone levels.
Lehner and colleagues found that the observed variability in penetrance of tbx-9 loss in their study can, to a remarkable degree, be accounted for by variations in expression of tbx-8 and daf-21 [a chaperone gene].
So, basically they are following a causative pathway, trying to explain what looks stochastic, but that they propose can be explained molecularly.  What this means, in effect, is that phenotypic variation that may appear random, is instead genetically determined, even if you have to climb up or down a genetic pathway to identify the causative genes.

Incomplete penetrance is an interesting concept, because it assumes that there's a correct level of gene expression, and that anything short of that is not right and must be explained.  But deterministic explanations may not be as pervasive as the hunger for them is.  It has often been shown that stochastic levels of regulatory gene expression can make very large differences in response, even in  bacterial responses to environments.  Non-determinance is not mysticism, since probabilistic events involve real physical substances, so nobody thinks twins differ for miraculous reasons, but such things are not predictable in the usual sense and are not specifically determined by DNA sequence alone.


Hollis said...

We're probably stuck with "incomplete penetrance" -- and other relics of the expectations of classical genetics.

Ken Weiss said...

I think you're probably right, but it does damage to conceptual science and may slow down progress that could be made. Incomplete penetrance implies deterministic effects that, somehow, are not deterministic. Instead, we should have probabilistic or quantitative concepts about genotype to phenotype relationships. Mendel helped us in many great ways, but by introducing 'dominance' and so on,in situations he carefully selected because they worked neatly, he put a conceptual cage that we're still in.

Hollis said...

I totally agree, I was just complaining! Mendel et al. have led us to a dead end, and using the old vocabulary can make it harder to envision new possibilities, to get unstuck.