Phenotypic Variation Due to Epigenetic and Environmental Variation

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. (more…)

Evolutionary Variation as a ‘Lead Compound’

There is probably no more canonical example of the relevance of evolutionary genetics to clinical medicine than sickle cell disease.  The relevance of the sickle allele, in heterozygous form, at the beta-globin locus for resistance to falciparum malaria was published by Allison in 1954 (Lancet), and the precise amino acid substitution responsible for the phenotype of sickle cell disease, when the mutation is present in homozygous form, was identified by Ingram in 1956 (Nature).  Two recent papers (more…)

Methodological Foundations for Evolution by Engineered Variation and Selection

As biomedical technology advances, the probability increases that evolution guided, constrained, or facilitated by scientists will be relevant to medicine.  Of particular interest in this context is the increasing ability of investigators to engineer microbes to produce gene products of benefit to individuals in need of specific treatments or for the general maintenance of health.  Applications of a more industrial nature are also readily conceivable.

There are different possible paths to the eventual goal of tailored microbial genomes.  One approach is the de novo synthesis of whole bacterial genomes followed by transplantation into selected cells previously rendered genome-free (Gibson et al. Science, 2010).  I have previously expressed doubt that this scheme is necessarily the most likely means to achieve the goal of engineering bacteria to express gene products and functions of our choosing (Greenspan, 2010).  The alternative approaches I had in mind were based on the reasonable supposition that it would ultimately be easier and more efficient for most researchers to employ enhanced versions of already well-developed technologies based on mutation and selection of existing microbial strains.

Church and colleagues (Isaacs et al. Science, 2011) have now obliged by demonstrating the potential for advances in microbial genome engineering based on enhancements in current methods applied to existing bacterial strains and their genomes.  More specifically, Isaacs et al. developed new strategies for introducing multiple mutations into the genomes of E. coli cells. (more…)

A Genomic Perspective on Pathogen Adaptation to Antibiotics and Vaccines

Among human pathogens, Streptococcus pneumoniae holds an especially prominent place in the history of biomedical investigation.  Griffith (1928) described the transforming principle, a soluble substance released by dead, virulent pneumococci that could render living avirulent pneumococci able to effectively kill a mouse.  Oswald Avery’s commitment to curing pneumococcal pneumonia (http://profiles.nlm.nih.gov/ps/retrieve/Narrative/CC/p-nid/37) led him and his collaborators to determine that the pneumococcal transforming principle was DNA (Avery et al., 1944).  It was also Avery’s and his collaborators’ work on pneumococci that provided some of the first insights into the chemical nature of most bacterial capsules. (more…)