Gao, Z. — Page 14 | Search bioRxiv

bioRxiv2017

Worldwide Population Structure Of Escherichia coli Reveals Two Major Subspecies

Recombination is one of the most important mechanisms of prokaryotic species evolution but its exact roles are still in debate. Here we try to infer genome-wide recombination events within a species uti-lizing a dataset of 104 complete genomes of Escherichia coli from diverse origins, among which 45 from world-wide animal-hosts are in-house sequenced using SMRT (single-molecular real time) technology.Two major clades are identified based on evidences of ecological and physiological characteristics, as well as distinct genomic features implying scarce inter-clade genetic exchange. By comparing the synteny of identical fragments genome-widely searched for each genome pair, we achieve a fine-scale map of re-combination within the population. The recombination is rather extensive within clade, which is able to break linkages between genes but does not interrupt core genome framework and primary metabolic port-folios possibly due to natural selection for physiological compatibility and ecological fitness. Meanwhile,the recombination between clades declines drastically as the phylogenetic distance increases, generally 10-fold reduced than those of the intra-clade, which establishes genetic barrier between clades. These empirical data of recombination suggest its critical role in the early stage of speciation, where recombina-tion rate differs according to phylogentic distance. The extensive intra-clade recombination coheres sister strains into a quasi-sexual group and optimizes genes or alleles to streamline physiological activities,whereas shapely declined inter-clade recombination split the population into clades adaptive to divergent ecological niches.\n\nSignificance StatementRoles of recombination in species evolution have been debated for decades due to difficulties in inferring recombination events during the early stage of speciation, especially when recombination is always complicated by frequent gene transfer events of bacterial genomes. Based on 104 high-quality complete E. coli genomes, we infer gene-centric dynamics of recombination in the formation of two E. coli clades or subpopulations, and recombination is found to be rather intensive in a within-clade fashion, which forces them to be quasi-sexual. The recombination events can be mapped among individual genomes in the context of genes and their variations; decreased between-clade and increased intra-claderecombination engender a genetic barrier that further encourages clade-specific secondary metabolic portfolios for better environmental adaptation. Recombination is thus a major force that accelerates bacterial evolution to fit ecological diversity.

microbiology↗

bioRxiv2016

The population genetics of human disease: the case of recessive, lethal mutations

Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes, reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. The observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on variants with lower mutation rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in this study. Beyond the specific application, this study highlights the parameters likely to be important in shaping the frequencies of Mendelian disease alleles.\n\nAuthor SummaryWhat determines the frequencies of disease mutations in human populations? To begin to answer this question, we focus on one of the simplest cases: mutations that cause completely recessive, lethal Mendelian diseases. We first review theory about what to expect from mutation and selection in a population of finite size and further generate predictions based on simulations using a realistic demographic scenario of human evolution. For a highly mutable type of mutations, such as transitions at CpG sites, we find that the predictions are close to the observed frequencies of recessive lethal disease mutations. For less mutable types, however, predictions substantially under-estimate the observed frequency. We discuss possible explanations for the discrepancy and point to a complication that, to our knowledge, is not widely appreciated: that there exists ascertainment bias in disease mutation discovery. Specifically, we suggest that alleles that have been identified to date are likely the ones that by chance have reached higher frequencies and are thus more likely to have been mapped. More generally, our study highlights the factors that influence the frequencies of Mendelian disease alleles.

genetics↗