Generators of Phenotypic Diversity in the Evolution of Pathogenic Microorganisms

All organisms run the gauntlet of Darwinian selection. Poignant examples include microbial pathogens, which must survive and thrive in their hosts. The process of pathogen adaptation to the host is diverse and is now known to involve a panoply of diversity generators, such as sexual/parasexual reproduction, aneuploidy, prions, mutators, telomeric silencing/recombination, and Hsp90 as a capacitor for evolution [1], [2] (Figure 1). Given the vast diversity of known mechanisms that can generate phenotypic and genotypic assortments, others likely remain to be discovered. Figure 1 Generators of phenotypic diversity illustrated as a game of chance. Sexual and Parasexual Reproduction Create Diversity Most eukaryotic microorganisms are either known or suspected to undergo sexual reproduction. However, as recently as two decades ago, most pathogenic eukaryotic microbes, including fungi and parasites, were thought to be clonal and asexual [3], [4]. Over the past decade, we have witnessed a renaissance in this field and now appreciate that most, and perhaps all, pathogenic fungi and parasites have retained sexual capacity [5], [6]. In many cases, their sexual cycles can be difficult to observe, due to being cryptic or having a unisexual or even parasexual cycle. These modes of reproduction share the ability to promote some level of genetic exchange, but involve inbreeding or even selfing in many instances, helping to preserve well-adapted genomic configurations while simultaneously generating limited genetic diversity that may promote adaptation to less rapidly changing host or environmental niches. Pathogenic microbes can reproduce parasexually or sexually. Parasexuality involves cell–cell fusion and ploidy reduction through stochastic, random chromosome loss. This phenomenon was originally described by Pontecorvo for Aspergillus nidulans [7], and has been more recently described in Candida albicans by Forche and colleagues [8]. Parasex can produce genetic diversity via independent chromosomal assortment, mitotic recombination, and the ability of the diploid state to act as a capacitor for evolution by enabling the accumulation of recessive mutations that are deleterious individually but beneficial in combination (so-called reciprocal sign epistasis) [9]. Sexual reproduction can accelerate evolution by purging the genome of deleterious mutations or by bringing together combinations of advantageous alleles. Opposite-sex mating promotes genetic exchange via outcrossing, whereas unisexual reproduction can involve inbreeding or selfing to yield more limited genetic exchange. The capacity to engage in opposite sexual, unisexual, and asexual reproduction may be a bet-hedging strategy that enables microbes to better adapt to a range of environments, including the host. The fact that two of the most common human fungal pathogens, C. albicans and Cryptococcus neoformans, have retained the capacity for a sexual cycle involving opposite-sex mating as well as the capability of unisexual reproduction, provides an illustration of convergent evolution [10], [11]. Recent discoveries on the sexual nature of parasitic pathogens, including examples of unisexuality and selfing [12], [13], unify this paradigm across the two major groups of eukaryotic pathogens.