Natural selection depends on heritable phenotypic variation.  The most obvious source of phenotypic variation is genotypic variation.  A new study, by Casanueva et al. in Science (2012) suggests that in addition to genotypic variation, variation in life history and stochastic variations in gene expression can substantially affect phenotypic variation.

These authors studied mutation penetrance in Caenorhabditis elegans  overexpressing a transgenic transcription factor (heat shock factor 1 or HSF-1) that controls the expression of genes encoding proteins that are involved in stress responses.  The worms expressing high levels of the HSF-1 transgene (hsf-1) were previously shown to be better able to cope with diverse environmental stresses than otherwise identical worms not expressing the HSF-1 transgene. 

Casanueva et al. then crossed HSF-1 transgenic worms with worms that harbored a variety of mutations that affect embryonic or post-embryonic development .  In the majority of these crosses, the overexpression of HSF-1 was associated with reduced penetrance of these genetic variants.  For animals with a mutation that deleted the gene (ifb-1) encoding an intermediate filament, lethality in the embryo was decreased from 33% in wild-type worms to 17% in worms expressing the HSF-1 transgene.  This result was highly statistically significant (P = 5.7 x 10-12).  All of the mutations for which HSF-1 attenuated the consequences were associated with temperature-sensitive outcomes, consistent with the notion that HSF-1 overexpression works at least in part by minimizing protein misfolding (a function of so-called chaperone proteins).

The authors then asked whether the penetrance of various mutations could be influenced through the elicitation of the stress response via the manipulation of environmental conditions instead of overexpressing HSF-1 through genetic manipulation.  So, C. elegans larvae were subjected to heat shock and allowed to develop into adults.  Then, these animals were assessed with respect to late-acting developmental mutations.  

One such mutation was an inactivating substitution in the transcription factor LIN-29 that resulted in altered migration of the male gonads.  In the non-stressed control worms, 46% of the animals exhibited the mutant phenotype.  For the animals that were subjected to a heat stress as larvae, only 30% had abnormal migration of the male gonads (P = 5 x 10-4).

Next, the authors addressed whether spontaneous interindividual variation in stress response-related gene expression among isogenic worms would affect the penetrance of a mutation that caused abnormal development of the vulva.  They found that worms with greater expression of a stress-related reporter gene exhibited a lower probability of the mutant vulva phenotype. Prior work indicating that mutations enhancing the ability to resist environmental stresses could reduce fecundity prompted the authors to determine whether a similar trade-off applied isogenic individuals.  Worms that exhibited greater responses to a heat stress, who were subsequently more resistant to a severe heat stress, also proved to be less fecund.  Similar experiments with a second transcription factor, DAF-16, involved in the C. elegans stress response also revealed a trade-off between stress resistance and fecundity.       

Finally Casanueva et al. used a number of interfering RNAs that inhibited expression of genes encoding chaperone proteins to assess the extents to which different mutation-related phenotypes exhibited dependence on particular chaperones.  They found that variation in chaperone expression could be associated with variation in the penetrance of a particular mutation even in the absence of any intentionally applied environmental perturbation.  

These studies raise numerous interesting questions.  How much variation in stress signaling and responsiveness is possible among isogenic organisms or cells?  What magnitude of mutation of buffering is possible?  Do similar sorts of phenomena occur in most species, including humans?  Is interindividual epigenetic variation among genetically-identical individuals, of the sort studied by Casanueva et al., subject to natural selection or does it arise entirely and inevitably as a consequence of fundamental properties of the relevant biochemical systems?  To what extent can mutation buffering due to the mechanisms implicated here influence the course of evolution?  Future work offers the prospect of providing significant insights into these and related questions.

References

Casanueva MO, Burga A, Lehner B. Fitness trade-offs and environmentally induced mutation buffering in isogenic C. elegans. Science. 2012 Jan 6;335(6064):82-5. Epub 2011 Dec 15. PubMed PMID: 22174126.