Biology subjects

Cherry, J. L.

Publications and source records attributed to Cherry, J. L..

7 recordsLinked to original sources

bioRxiv2025

Heterozygote advantage cannot explain MHC diversity, but MHC diversity can explain heterozygote advantage

Several theoretical studies have concluded that heterozygote advantage makes at most a minor contribution to MHC diversity. Siljestam and Rueffler (2024) recently presented models in which heterozygote advantage alone can lead to realistically high diversity. Here I argue that heterozygote advantage cannot by itself explain MHC diversity, and that its contribution to diversity is unlikely to be large in most species. I first show that the high diversity reported by Siljestam and Rueffler is so sensitive to parameter values that the underlying phenomenon cannot explain the widespread diversity of MHC genes. I then consider a fundamental problem with explaining MHC diversity by heterozygote advantage alone: selective forces that favored heterozygotes would lead to the evolution of haplotypes having much higher fitness when homozygous, diminishing or eliminating heterozygote advantage. Diversity maintained by another force, however, might bring about adaptation to the more common heterozygous state at the expense of homozygous fitness. Thus, substantial heterozygote advantage may arise as a consequence of MHC diversity.

evolutionary biology↗

bioRxiv2024

GnT motifs: short nucleotide tracts of greater than or equal to 8bp that can increase T-G:C mutation rates >1000-fold in bacteria

Nucleotides across a genome do not mutate at equal frequencies. Instead, specific nucleotide positions can exhibit much higher mutation rates than the genomic average due to their immediate nucleotide neighbours. These mutational hotspots can play a prominent role in adaptive evolution, yet we lack knowledge of which short nucleotide tracts drive hotspots. In this work, we employ a combinatorial approach of experimental evolution with Pseudomonas fluorescens and bioinformatic analysis of various Salmonella species to characterise a short nucleotide motif ([≥]8bp) that drives T:A[->]G:C mutation rates >1000-fold higher than the average T[->]G rate in bacteria. First, we experimentally show that homopolymeric tracts ([≥]3) of G with a 3 T frequently mutate so that the 3 T is replaced with a G, resulting in an extension of the guanine tract, i.e., GGGGT [->] GGGGG. We then demonstrate that the potency of this T:A[->]G:C hotspot is dependent on the nucleotides immediately flanking the GnT motif. We find that the dinucleotide pair immediately 5 to a G4 tract and the nucleotide immediately 3 to the T strongly affect the T:A[->]G:C mutation rate, which ranges from [~]5-fold higher than the typical rate to >1000-fold higher depending on the flanking elements. Therefore the T:A[->]G:C hotspot motif is a product of several modular nucleotide components (1-4bp in length) which each exert a significant effect on the mutation rate of the GnT motif. This work advances our ability to accurately identify the position and quantify the mutagenicity of hotspot motifs predicated on short tracts of nucleotides.

molecular biology↗

bioRxiv2022

T Residues Preceded by Runs of G are Hotspots of T to G Mutation in Bacteria

The rate of mutation varies among positions in a genome. Local sequence context can affect the rate, and has different effects on different types of mutation. Here I report an effect of local context that operates to some extent in all bacteria examined: the rate of T[->]G mutation is greatly increased by preceding runs of three or more G residues. The strength of the effect increases with the length of the run. In Salmonella, in which the effect is strongest, a G run of length three increases the rate by a factor of ~26, a run of length four increases it by almost a factor of 100, and runs of length five or more increase it by a factor of more than 400 on average. The effect is much stronger when the T is on the leading rather than the lagging strand of DNA replication. Several observations eliminate the possibility that this effect is an artifact of sequencing error.

genetics↗

bioRxiv2022

Restriction Endonuclease-based Modification-Dependent Enrichment (REMoDE) of DNA for Metagenomic Sequencing

Metagenomic sequencing is a swift and powerful tool to ascertain the presence of an organism of interest in a sample. However, sequencing coverage of the organism of interest can be insufficient due to an inundation of reads from irrelevant organisms in the sample. Here, we report a nuclease-based approach to rapidly enrich for DNA from certain organisms, including enterobacteria, based on their differential endogenous modification patterns. We exploit the ability of taxon-specific methylated motifs to resist the action of cognate methylation-sensitive restriction endonucleases that thereby digest unwanted, unmethylated DNA. Subsequently, we use a distributive exonuclease or electrophoretic separation to deplete or exclude the digested fragments, thus, enriching for undigested DNA from the organism of interest. As a proof-of-concept, we apply this method to enrich for the enterobacteria Escherichia coli and Salmonella enterica by 11- to 142-fold from mock metagenomic samples and validate this approach as a versatile means to enrich for genomes of interest in metagenomic samples. ImportancePathogens that contaminate the food supply or spread through other means can cause outbreaks that bring devastating repercussions to the health of a populace. Investigations to trace the source of these outbreaks are initiated rapidly but can be drawn out due to the labored methods of pathogen isolation. Metagenomic sequencing can alleviate this hurdle but is often insufficiently sensitive. The approach and implementations detailed here provide a rapid means to enrich for many pathogens involved in foodborne outbreaks, thereby improving the utility of metagenomic sequencing as a tool in outbreak investigations. Additionally, this approach provides a means to broadly enrich for otherwise minute levels of modified DNA which may escape unnoticed in metagenomic samples.

microbiology↗

bioRxiv2022

Origins and Evolution of Seasonal Human Coronaviruses

Four seasonal human coronaviruses (sHCoVs) are endemic globally (229E, NL63, OC43, and HKU1), accounting for 5-30% of human respiratory infections. However, the epidemiology and evolution of these CoVs remain understudied due to their association with mild symptomatology. Using a multigene and complete genomes analysis approach, we find the evolutionary histories of sHCoVs to be more complex than previously recognized, owing to frequent recombination of CoVs, including within and between sHCoVs. Within sHCoV recombination rate was highest for 229E and OC43, and within genus highest for betaCoVs, whereas substitutions per recombination event inversely highest in NL63 and HKU1, and the alphaCoVs. Depending on the gene studied, OC43 may have ungulate, canine, or rabbit CoV ancestors, while 229E may have origins in a bat, camel or an unsampled intermediate host. HKU1 had the earliest most recent common ancestor (MRCA: 1809-1899), comprised two genetically divergent genotypes (A and B) possibly representing two independent transmission events from murine CoVs, and genotype B was genetically more diverse than all the other sHCoVs. Finally, we found shared amino acid substitutions in multiple proteins along the non-human to sHCoV host-jump branches. The complex evolution of CoVs and their frequent host switches could benefit from continued surveillance of CoVs across non-human hosts.

evolutionary biology↗

bioRxiv2022

Evolution of influenza A virus hemagglutinin H1 and H3 across host species

The Influenza A virus (IAV) hemagglutinin protein (HA) has been studied extensively, but its evolution has not been thoroughly compared among major host species. We compared H3 and H1 evolutionary rates among 49 lineages differentiated by host (avian, canine, equine, human, swine), phylogeny, and geography. Rates of nonsynonymous evolution, relative to synonymous rates, were higher in mammalian than avian hosts. Human seasonal HA and classical swine H1 accumulated 11-13 glycosylation sites, primarily in the antigenically important head domain, whereas lower numbers were maintained in other hosts. Canines had the highest ratio of nonsynonymous to synonymous changes in the more conserved stalk domain. Amino acid changes in canine viruses occurred disproportionately at residues located at protein interfaces. This suggests that they were adaptations affecting the major structural rearrangement of HA, which is critical for cell entry. These findings invite further study of how host ecology and physiology affect natural selection. AUTHOR SUMMARYInfluenza virus evolution is of practical importance to health in addition to being an excellent system for the study of parasite/host evolution. Our work explores a largely untapped aspect of influenza evolution: sequence evolution in non-human hosts. This is important in its own right, in terms of both science and domestic animal health. It also puts the evolution of human influenza in a larger, comparative context. Our results also provide evidence concerning the evolution of the hemagglutinin stem domain, which has not been a focus of study but has new importance due to the development of stem-based universal influenza vaccines.

evolutionary biology↗

bioRxiv2021

Extreme C-to-A Hypermutation at a Site of Cytosine-N4 Methylation

Methylation of cytosine in DNA at position C5 increases the rate of C[->]T mutations in bacteria and eukaryotes. Methylation at the N4 position, employed by some restriction-modification systems, is not known to increase the mutation rate. Here I report that a Salmonella enterica Type III restriction-modification system that includes a cytosine-N4 methyltransferase causes an enormous increase in the rate of mutation of the methylated cytosines, which occur at the overlined C in the motif [Formula]. Mutations consist mainly of C[->]A transversions, the rate of which is increased ~500-fold by the restriction-modification system. The rate of C[->]T transitions is also increased, and somewhat exceeds that at C5-methylated cytosines in Dcm sites. Two other Salmonella N4 methyltransferases investigated do not have such dramatic effects, although in one case there is a modest increase in C[->]A mutations along with an increase in C[->]T mutations. Sensitivity of the C[->]A rate to orientation with respect to both DNA replication and transcription is higher at hypermutable sites than at other cytosines, suggesting a fundamental mechanistic difference between hypermutation and ordinary mutation. IMPORTANCEMutation produces the raw material for adaptive evolution, but also imposes a burden because most mutations are deleterious. The rate of mutation at a particular site is affected by a variety of factors. In both prokaryotes and eukaryotes, methylation of C at the C5 position, a naturally-occurring DNA modification, greatly increases the rate of C[->]T mutation. A distinct C modification that occurs in prokaryotes, methylation at N4, is not known to increase mutation rate. Here I report that a bacterial restriction-modification system, found in some Salmonella, increases the rate of C[->]A mutation by a factor of 500 at sites that it methylates at N4. This rate increase is much greater than that caused by C5 methylation. Although fewer than one in 1600 positions analyzed are methylation sites, over 10% of all mutations occur at these sites. Like other examples of extremely high mutation rate, whether naturally-occurring or the result of laboratory mutation, this phenomenon may shed light on the mechanism of mutation in general.

molecular biology↗