Robert J. Woods

Second-order selection for evolvability in a large Escherichia coli population

Descendants of bacterial lineages that retained adaptation potential outcompeted competitors of higher fitness. In theory, competition between asexual lineages can lead to second-order selection for greater evolutionary potential. To test this hypothesis, we revived a frozen population of Escherichia coli from a long-term evolution experiment and compared the fitness and ultimate fates of four genetically distinct clones. Surprisingly, two clones with beneficial mutations that would eventually take over the population had significantly lower competitive fitness than two clones with mutations that later went extinct. By replaying evolution many times from these clones, we showed that the eventual winners likely prevailed because they had greater potential for further adaptation. Genetic interactions that reduce the benefit of certain regulatory mutations in the eventual losers appear to explain, at least in part, why they were outcompeted.

The genetic basis of parallel and divergent phenotypic responses in evolving populations of Escherichia coli

Pleiotropy plays a central role in theories of adaptation, but little is known about the distribution of pleiotropic effects associated with different adaptive mutations. Previously, we described the phenotypic effects of a collection of independently arising beneficial mutations in Escherichia coli. We quantified their fitness effects in the glucose environment in which they evolved and their pleiotropic effects in five novel resource environments. Here we use a candidate gene approach to associate the phenotypic effects of the mutations with the underlying genetic changes. Among our collection of 27 adaptive mutants, we identified a total of 21 mutations (18 of which were unique) encompassing five different loci or gene regions. There was limited resolution to distinguish among loci based on their fitness effects in the glucose environment, demonstrating widespread parallelism in the direct response to selection. However, substantial heterogeneity in mutant effects was revealed when we examined their pleiotropic effects on fitness in the five novel environments. Substitutions in the same locus clustered together phenotypically, indicating concordance between molecular and phenotypic measures of divergence.

Arthritis in new world monkeys: Osteoarthritis, calcium pyrophosphate deposition disease, and spondyloarthropathy

Analyses of New World skeletal populations for the presence of erosions and other osseous alterations and their character, distribution, and radiologic appearance shows that osteoarthritis is predominantly a disease of animals raised in artificially constrained environments. Primary calcium pyrophosphate deposition disease (CPPD) was also found only in artificially constrained animals, although hyperparathyroidism (overproduction of parathyroid hormone) may have been responsible. CPPD was observed once as a secondary phenomenon, complicating another form of arthritis in free-ranging animals. Limited in occurrence to two genera,Alouatta andCebus, the frequency of spondyloarthropathy was similar to that noted in humans and significantly lower than that observed in gorillas and chimpanzees. The many dichotomies ofCebus andAlouatta place them almost at opposite ends of the New World monkey spectrum, making a common susceptibility factor difficult to identify.

Antibiotic resistance management

Antibiotic resistance genes arose long ago in response to naturally occurring antibiotics. Modern medicine has driven further evolution of some of these genes. Resistance can also arise spontaneously by mutation. In bacteria, genes can be inherited or they can be acquired from non-relatives on mobile genetic elements like plasmids. This horizontal gene transfer (HGT) can occur between very different bacteria.

How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient

When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence—and when it can be bettered.

INFLAMMATORY ARTHRITIS IN CANIDS: SPONDYLOARTHROPATHY

Abstract Spondyloarthropathy was observed in 25 (2.8%) of 895 preserved canid museum specimens and was catalogued by species. The associated skeletal alterations in canids are indistinguishable grossly and physiologically from those in humans with spondyloarthropathy of the reactive type. Rate of affliction was independent of captive or wild-caught status or gender. In canids, spondyloarthropathy was much more common than osteoarthritis (0.3%), which predominantly is limited to captive animals. Animal well-being may be enhanced by recognition of the condition and initiation of specific treatment.

Intrasegmental recombination does not contribute to the long-term evolution of group A rotavirus

Rotavirus is a genetically diverse pathogen with an eleven-segmented, double-stranded RNA genome. Intrasegmental recombination has been proposed as a potential mechanism to generate antigenic diversity and a possible route of escape from vaccine-imposed selective pressure. Here intrasegmental recombination was studied by performing a genome-wide scan across the eleven genome segments of 797 publically available rotavirus strains. Sixty-two sequences, or 0.7% of sequences analyzed, have evidence of intrasegmental homologous recombination. None of the specific recombination events is seen in more than one sequence. This uniqueness is consistent with either a spurious finding of recombination or the possibility that recombinant sequences arise naturally but are rapidly purged from the rotavirus population through selection. Arguments for the former explanation are presented. This analysis finds no evidence that intrasegmental recombination leads to ongoing transmission or plays a constructive role in rotavirus evolution. These results have practical implications for phylogenetic analyses and suggest a fundamental constraint that may have shaped rotavirus genome structure and evolution.

The evolutionary dynamics of influenza A virus within and between human hosts

The global evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define the dynamics of influenza A virus populations in human hosts through next generation sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected over 5 seasons from individuals in a prospective community-based cohort, they are broadly representative of natural human infections with seasonal viruses. We used viral sequence data from 35 serially sampled individuals to estimate a within host effective population size of 30-70 and an in vivo mutation rate of 4x10-5 per nucleotide per cellular infectious cycle. These estimates are consistent across several models and robust to the models9s underlying assumptions. We also identified 43 epidemiologically linked and genetically validated transmission pairs. Maximum likelihood optimization of multiple transmission models estimates an effective transmission bottleneck of 1-2 distinct genomes. Our data suggest that positive selection of novel viral variants is inefficient at the level of the individual host and that genetic drift and other stochastic processes dominate the within and between host evolution of influenza A viruses.A complete understanding of influenza virus evolution requires studies at all levels, as viral evolutionary dynamics may differ across spatial and temporal scales. The relative contribution of deterministic processes, such as selection, and stochastic processes, such as genetic drift, is influenced by the virus’ effective population size. While the global evolution of influenza A virus (IAV) is dominated by the positive selection of novel antigenic variants that circulate in the tropics, much less is known about the virus’ evolution within and between human hosts. With few exceptions, most of the available data derive from studies of chronically infected, immunocompromised hosts, experimental infections with attenuated viruses, or animal models. Here we define the evolutionary dynamics of IAV in human hosts through next generation sequencing of 249 upper respiratory specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected over 5 seasons from individuals in a prospective community-based cohort, they are broadly representative of natural human infections with seasonal viruses. Within host genetic diversity was low, and we found little evidence for positive selection of minority variants. We used viral sequence data from 35 serially sampled individuals to estimate a within host effective population size of 30-50. This estimate is consistent across several models and robust to the models’ underlying assumptions. We also identified 43 epidemiologically linked and genetically validated transmission pairs. Maximum likelihood optimization of multiple transmission models estimates an effective transmission bottleneck of 1-2 distinct genomes. Our data suggest that positive selection of novel viral variants is inefficient at the level of the individual host and that genetic drift and other stochastic processes dominate the within and between host evolution of influenza A viruses.

Clinical management of resistance evolution in a bacterial infection: a case study

This chronic bacterial infection evolved extensive resistance, killing the patient. Evolutionary science is insufficiently developed to better manage such life-threatening evolution.

UNIQUE ASPECTS OF WEST COAST TREPONEMATOSIS

Skeletal populations from the western coast of North America clearly were afflicted with a treponemal disease very different from that previously documented elsewhere in North America. Six populations from west of the Sierra Cascades were compared with 5 sites east of the Cascades. A high population frequency (both in adults and subadults) of pauci-ostotic, periostitis was noted in the six western skeletal populations, identical to that reported previously with bejel in Negev Bedouins, Sudanese Nubians, and the Kit site from Iraq. Early populations, from east of the Cascades, had a very different polyostotic disease pattern, characteristic of yaws, and identical to that previously reported in Guam. Both patterns were clearly distinguished from syphilis, which appears to be a later development (mutation?). This study provides evidence that the treponematoses were transported to the New World by way of at least two migrations, one bringing yaws; the other, bejel. The population with bejel likely derived from a different population than that with yaws. Given the absence of treponemal disease variation in the very wide spectrum of environments represented by the bejel-afflicted populations, it is clear that environment is not the factor determining disease character. This study expands on animal studies documenting that the individual treponematoses are separate diseases and not simply climate-induced variation.