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Bacteriophages, infecting bacterial hosts in every environment on our planet, are a driver of adaptive evolution in bacterial communities. At the same time, the host range of many bacteriophages—and thus one of the selective pressures acting on complex microbial systems in nature—remains poorly characterized. Here, we computationally inferred the putative host ranges of 40 cluster P mycobacteriophages, including members from 6 subclusters (P1–P6). A series of comparative genomic analyses revealed that mycobacteriophages of subcluster P1 are restricted to the Mycobacterium genus, whereas mycobacteriophages of subclusters P2–P6 are likely also able to infect other genera, several of which are commonly associated with human disease. Further genomic analysis highlighted that the majority of cluster P mycobacteriophages harbor a conserved integration-dependent immunity system, hypothesized to be the ancestral state of a genetic switch that controls the shift between lytic and lysogenic life cycles—a temperate characteristic that impedes their usage in antibacterial applications.

Despite its important biological role, the evolution of recombination rates remains relatively poorly characterized. This owes, in part, to the lack of high-quality genomic resources to address this question across diverse species. Humans and our closest evolutionary relatives, anthropoid apes, have remained a major focus of large-scale sequencing efforts, and thus recombination rate variation has been comparatively well studied in this group—with earlier work revealing a conservation at the broad- but not the fine-scale. However, in order to better understand the nature of this variation, and the time scales on which substantial modifications occur, it is necessary to take a broader phylogenetic perspective. I here present the first fine-scale genetic map for vervet monkeys based on whole-genome population genetic data from ten individuals and perform a series of comparative analyses with the great apes. The results reveal a number of striking features. First, owing to strong positive correlations with diversity and weak negative correlations with divergence, analyses suggest a dominant role for purifying and background selection in shaping patterns of variation in this species. Second, results support a generally reduced broad-scale recombination rate compared with the great apes, as well as a narrower fraction of the genome in which the majority of recombination events are observed to occur. Taken together, this data set highlights the great necessity of future research to identify genomic features and quantify evolutionary processes that are driving these rate changes across primates.

Bacteriophages infecting bacteria of the genus

Mycobacterium canettii is a causative agent of tuberculosis in humans, along with the members of the Mycobacterium tuberculosis complex. Frequently used as an outgroup to the M. tuberculosis complex in phylogenetic analyses, M. canettii is thought to offer the best proxy for the progenitor species that gave rise to the complex. Here, we leverage whole-genome sequencing data and biologically relevant population genomic models to compare the evolutionary dynamics driving variation in the recombining M. canettii with that in the nonrecombining M. tuberculosis complex, and discuss differences in observed genomic diversity in the light of expected levels of Hill–Robertson interference. In doing so, we highlight the methodological challenges of estimating recombination rates through traditional population genetic approaches using sequences called from populations of microorganisms and evaluate the likely mis-inference that arises owing to a neglect of common model violations including purifying selection, background selection, progeny skew, and population size change. In addition, we compare performance when full within-host polymorphism data are utilized, versus the more common approach of basing analyses on within-host consensus sequences.

Recent advances in genomics have enabled researchers to shed light on the evolutionary processes driving human adaptation, by revealing the genetic architectures underlying traits ranging from lactase persistence, to skin pigmentation, to hypoxic response, to arsenic tolerance. Complicating the identification of targets of positive selection in modern human populations is their complex demographic history, characterized by population bottlenecks and expansions, population structure, migration, and admixture. In particular, founder effects and recent strong population size reductions, such as those experienced by the indigenous peoples of the Americas, have severe impacts on genetic variation that can lead to the accumulation of large allele frequency differences between populations due to genetic drift rather than natural selection. While distinguishing the effects of demographic history from selection remains challenging, neglecting neutral processes can lead to the incorrect identification of candidate loci. We here review the recent population genomic insights into the genetic basis of arsenic tolerance in Andean populations, and utilize this example to highlight both the difficulties pertaining to the identification of local adaptations in strongly bottlenecked populations, as well as the importance of controlling for demographic history in selection scans.

Bacteriophages infecting pathogenic hosts play an important role in medical research, not only as potential treatments for antibiotic-resistant infections but also offering novel insights into pathogen genetics and evolution. A prominent example is cluster K mycobacteriophages infecting Mycobacterium tuberculosis, a causative agent of tuberculosis in humans. However, as handling M. tuberculosis as well as other pathogens in a laboratory remains challenging, alternative nonpathogenic relatives, such as Mycobacterium smegmatis, are frequently used as surrogates to discover therapeutically relevant bacteriophages in a safer environment. Consequently, the individual host ranges of the majority of cluster K mycobacteriophages identified to date remain poorly understood. Here, we characterized the complete genome of Stinson, a temperate subcluster K1 mycobacteriophage with a siphoviral morphology. A series of comparative genomic analyses revealed strong similarities with other cluster K mycobacteriophages, including the conservation of an immunity repressor gene and a toxin/antitoxin gene pair. Patterns of codon usage bias across the cluster offered important insights into putative host ranges in nature, highlighting that although all cluster K mycobacteriophages are able to infect M. tuberculosis, they are less likely to have shared an evolutionary infection history with Mycobacterium leprae (underlying leprosy) compared to the rest of the genus’ host species. Moreover, subcluster K1 mycobacteriophages are able to integrate into the genomes of Mycobacterium abscessus and Mycobacterium marinum—two bacteria causing pulmonary and cutaneous infections which are often difficult to treat due to their drug resistance.

Human cytomegalovirus (HCMV), one of the most prevalent viruses across the globe, is a common cause of morbidity and mortality for immunocompromised individuals. Recent clinical observations have demonstrated that mixed strain infections are common and may lead to more severe disease progression. This clinical observation illustrates the complexity of the HCMV genome and emphasizes the importance of taking a population-level view of genotypic evolution. Here we review frequently sampled polymorphisms in the glycoproteins of HCMV, comparing the variable regions, and summarizing their corresponding geographic distributions observed to date. The related strain-specific immunity, including neutralization activity and antigen-specific cellular immunity, is also discussed. Given that these glycoproteins are common targets for vaccine design and anti-viral therapies, this observed genetic variation represents an important resource for future efforts to combat HCMV infections.

As one of the most commonly utilized organisms in the study of local adaptation, an accurate characterization of the demographic history of Drosophila melanogaster remains as an important research question. This owes both to the inherent interest in characterizing the population history of this model organism, as well as to the well-established importance of an accurate null demographic model for increasing power and decreasing false positive rates in genomic scans for positive selection. Although considerable attention has been afforded to this issue in non-African populations, less is known about the demographic history of African populations, including from the ancestral range of the species. While qualitative predictions and hypotheses have previously been forwarded, we here present a quantitative model fitting of the population history characterizing both the ancestral Zambian population range as well as the subsequently colonized west African populations, which themselves served as the source of multiple non-African colonization events. We here report the split time of the West African population at 72 kya, a date corresponding to human migration into this region as well as a period of climatic changes in the African continent. Furthermore, we have estimated population sizes at this split time. These parameter estimates thus represent an important null model for future investigations in to African and non-African D. melanogaster populations alike.

Intrahost and interhost assessments of viral diversity are often treated as measures of separate and distinct evolutionary processes, with numerous investigations reporting seemingly incompatible results between the two. For example, in human cytomegalovirus, the nucleotide diversity estimates are 10-fold higher for interhost data, while the number of segregating (i.e., polymorphic) sites is 6-fold lower. These results have been interpreted as demonstrating that sampled intrahost variants are strongly deleterious. In reality, however, these observations are fully consistent with standard population genetic expectations. Here, we analyze published intra- and interhost data sets within this framework, utilizing statistical inference tools to quantify the fitness effects of segregating mutations. Further, we utilize population level simulations to clarify expectations under common evolutionary models. Contrary to common claims in the literature, these results suggest that most observed polymorphisms are likely nearly neutral with regard to fitness and that standard population genetic models in fact well predict observed levels of both intra- and interhost variability. IMPORTANCE With the increasing number of evolutionary virology studies examining both intrahost and interhost patterns of genomic variation, a number of seemingly incompatible results have emerged, revolving around the far greater level of observed intrahost than interhost variation. This has led many authors to suggest that the great majority of sampled within-host polymorphisms are strongly deleterious. Here, we demonstrate that there is in fact no incompatibility of these results and, indeed, that the vast majority of sampled within-host variation is likely neutral. These results thus represent a major shift in the current view of observed viral variation.

Given the strong selective pressures often faced by populations when colonizing a novel habitat, the level of variation present on which selection may act is an important indicator of adaptive potential. While often discussed in an ecological context, this notion is also highly relevant in our clinical understanding of viral infection, in which the novel habitat is a new host. Thus, quantifying the factors determining levels of variation is of considerable importance for the design of improved treatment strategies. Here, we focus on such a quantification of human cytomegalovirus (HCMV) - a virus which can be transmitted across the placenta, resulting in foetal infection that can potentially cause severe disease in multiple organs. Recent studies using genomewide sequencing data have demonstrated that viral populations in some congenitally infected infants diverge rapidly over time and between tissue compartments within individuals, while in other infants, the populations remain highly stable. Here, we investigate the underlying causes of these extreme differences in observed intrahost levels of variation by estimating the underlying demographic histories of infection. Importantly, reinfection (i.e. population admixture) appears to be an important, and previously unappreciated, player. We highlight illustrative examples likely to represent a single-population transmission from a mother during pregnancy and multiple-population transmissions during pregnancy and after birth.

Going Ape Over Genetic Maps Recombination is an important process in generating diversity and producing selectively advantageous genetic combinations. Thus, changes in recombination hotspots may influence speciation. To investigate the variation in recombination processes in humans and their closest existing relatives, Auton et al. (p. 193 , published online 15 March) prepared a fine-scale genetic map of the Western chimpanzee and compared it with that of humans. While rates of recombination are comparable between humans and chimpanzees, the locations and genetic motifs associated with recombination differ between the species.

Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age-effect mutations activate a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition.

The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GCTT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.

Instances in which natural selection maintains genetic variation in a population over millions of years are thought to be extremely rare. We conducted a genome-wide scan for long-lived balancing selection by looking for combinations of SNPs shared between humans and chimpanzees. In addition to the major histocompatibility complex (MHC), we identified 125 regions in which the same haplotypes are segregating in the two species, all but two of which are non-coding. In six cases, there is evidence for an ancestral polymorphism that persisted to the present in humans and chimpanzees. Regions with shared haplotypes are significantly enriched for membrane glycoproteins, and a similar trend is seen among shared coding polymorphisms. These findings indicate that ancient balancing selection has shaped human variation and point to genes involved in host-pathogen interactions as common targets.

Levels of nucleotide diversity vary greatly across the genomes of most species owing to multiple factors. These include variation in the underlying mutation rates, as well as the effects of both direct and linked selection. Fundamental to interpreting the relative importance of these forces is the common observation of a strong positive correlation between nucleotide diversity and recombination rate. While indeed observed in humans, the interpretation of this pattern has been difficult in the absence of high-quality polymorphism data and recombination maps in closely related species. Here, we characterize genetic features driving nucleotide diversity in Western chimpanzees using a recently generated whole genome polymorphism data set. Our results suggest that recombination rate is the primary predictor of nucleotide variation with a strongly positive correlation. In addition, telomeric distance, regional GC-content, and regional CpG-island content are strongly negatively correlated with variation. These results are compared with humans, with both similarities and differences interpreted in the light of the estimated effective population sizes of the two species as well as their strongly differing recent demographic histories.