Mutation rate variation shapes genome-wide diversity in Drosophila melanogaster

What shapes the distribution of nucleotide diversity along the genome? Attempts to answer this question have sparked debate about the roles of neutral stochastic processes and natural selection in molecular evolution. However, the mechanisms of evolution do not act in isolation, and integrative models that simultaneously consider the influence of multiple factors on diversity are lacking; without them, confounding factors lurk in the estimates. Here we present a new statistical method that jointly infers the genomic landscapes of genealogies, recombination rates and mutation rates. In doing so, our model captures the effects of genetic drift, linked selection and local mutation rates on patterns of genomic variation. Guided by our causal model, we use linear regression to estimate the individual contributions of these micro-evolutionary forces to levels of nucleotide diversity. Our analyses reveal the signature of selection in Drosophila melanogaster, but we estimate that the mutation landscape is the major driver of the distribution of diversity in this species. Furthermore, our simulation study suggests that in many evolutionary scenarios the mutation landscape will be a crucial force shaping diversity, depending notably on the genomic window size used in the analysis. We argue that incorporating mutation rate variation into the null model of molecular evolution will lead to more realistic inference in population genomics.

Accounting for the Biological Complexity of Pathogenic Fungi in Phylogenetic Dating

In the study of pathogen evolution, temporal dating of phylogenies provides information on when species and lineages may have diverged in the past. When combined with spatial and epidemiological data in phylodynamic models, these dated phylogenies can also help infer where and when outbreaks occurred, how pathogens may have spread to new geographic locations and/or niches, and how virulence or drug resistance has developed over time. Although widely applied to viruses and, increasingly, to bacterial pathogen outbreaks, phylogenetic dating is yet to be widely used in the study of pathogenic fungi. Fungi are complex organisms with several biological processes that could present issues with appropriate inference of phylogenies, clock rates, and divergence times, including high levels of recombination and slower mutation rates although with potentially high levels of mutation rate variation. Here, we discuss some of the key methodological challenges in accurate phylogeny reconstruction for fungi in the context of the temporal analyses conducted to date and make recommendations for future dating studies to aid development of a best practices roadmap in light of the increasing threat of fungal outbreaks and antifungal drug resistance worldwide.

How sequence context-dependent mutability drives mutation rate variation in the genome

The rate of mutations varies >100-fold across the genome, altering the rate of evolution, and susceptibility to genetic diseases. The strongest predictor of mutation rate is the sequence itself, varying 75-fold between trinucleotides. The fact that DNA sequence drives its own mutation rate raises a simple but important prediction; highly mutable sequences will mutate more frequently and eliminate themselves in favour of sequences with lower mutability, leading to a lower equilibrium mutation rate. However, purifying selection constrains changes in mutable sequences, causing higher rates of mutation. We conduct a simulation using real human mutation data to test if (1) DNA evolves to a low equilibrium mutation rate and (2) purifying selection causes a higher equilibrium mutation rate in the most important regions of the genome. We explore how this simple process affects sequence evolution in the genome, and discuss the implications for modelling evolution and susceptibility to DNA damage.

Mutation Rate Variability across Human Y-Chromosome Haplogroups

A common assumption in dating patrilineal events using Y-chromosome sequencing data is that the Y-chromosome mutation rate is invariant across haplogroups. Previous studies revealed interhaplogroup heterogeneity in phylogenetic branch length. Whether this heterogeneity is caused by interhaplogroup mutation rate variation or nongenetic confounders remains unknown. Here, we analyzed whole-genome sequences from cultured cells derived from >1,700 males. We confirmed the presence of branch length heterogeneity. We demonstrate that sex-chromosome mutations that appear within cell lines, which likely occurred somatically or in vitro (and are thus not influenced by nongenetic confounders) are informative for germline mutational processes. Using within-cell-line mutations, we computed a relative Y-chromosome somatic mutation rate, and uncovered substantial variation (up to 83.3%) in this proxy for germline mutation rate among haplogroups. This rate positively correlates with phylogenetic branch length, indicating that interhaplogroup mutation rate variation is a likely cause of branch length heterogeneity.

Low Mutational Load Allows for High Mutation Rate Variation in Gut Commensal Bacteria

Bacteria generally live in species-rich communities, such as the gut microbiota. Yet, little is known about bacterial evolution in natural ecosystems. Here, we followed the long-term evolution of commensalEscherichia coliin the mouse gut. We observe the emergence of polymorphism for mutation rate, ranging from wild-type levels to 1000-fold higher. By combining experiments, whole-genome sequencing andin silicosimulations, we identify the molecular causes and evolutionary conditions that allow these hypermutators to emerge and coexist within a complex microbiota. The hypermutator phenotype is caused by mutations in DNA polymerase III, which increase mutation rate by ~1000-fold (a mutation in the proofreading subunit) and stabilize hypermutator fitness (mutations in the catalytic subunit). The strong mutation rate variation persists for >1000 generations, with coexistence between lineages carrying 4 to >600 mutations. Thisin vivomolecular evolution pattern is consistent with deleterious mutations of ~0.01-0.001% fitness effects, 100 to 1000-fold lower than currentin vitroestimates. Despite large numbers of deleterious mutations, we identify multiple beneficial mutations that do not reach fixation over long periods of time. This indicates that the dynamics of beneficial mutations are not shaped by constant positive Darwinian selection but by processes leading to negative frequency-dependent or temporally fluctuating selection. Thus, microbial evolution in the gut is likely characterized by partial sweeps of beneficial mutations combined with hitchhiking of very slightly deleterious mutations, which take a long time to be purged but impose a very weak mutational load. These results are consistent with the pattern of genetic polymorphism that is emerging from metagenomics studies of the human gut microbiota, suggesting that we identified key evolutionary processes shaping the genetic composition of this community.

Nucleosome positioning stability is a significant modulator of germline mutation rate variation across the human genome

Understanding the patterns and genesis of germline de novo mutations is important for studying genome evolution and human diseases. Nucleosome organization is suggested to be a contributing factor to mutation rate variation across the genome. However, the small number of published de novo mutations and the low resolution of earlier nucleosome maps limited our understanding of how nucleosome organization affects germline mutation rates in the human genome. Here, we systematically investigated the relationship between nucleosome organization and fine-scale mutation rate variation by analyzing >300,000 de novo mutations from whole-genome trio sequencing and high-resolution nucleosome maps in human. We found that de novo mutation rates are elevated around strong, translationally stable nucleosomes, a previously under-appreciated aspect. We confirmed this observation having controlled for local sequence context and other potential confounding factors. Analysis of the underlying mutational processes suggests that the increased mutation rates around strong nucleosomes are shaped by a combination of low-fidelity replication, frequent DNA damage and insufficient/error-prone repair in these regions. Interestingly, strong nucleosomes are preferentially located in young SINE/LINE elements, implying frequent nucleosome re-positioning (i.e. shifting of dyad position) and their contribution to hypermutation at new retrotransposons during evolution. These findings provide novel insights into how chromatin organization affects germline mutation rates and have important implications in human genetics and genome evolution.