-
Genome Biology and Evolution Nov 2023Germline mutations are the ultimate source of genetic variation and the raw material for organismal evolution. Despite their significance, the frequency and genomic...
Germline mutations are the ultimate source of genetic variation and the raw material for organismal evolution. Despite their significance, the frequency and genomic locations of mutations, as well as potential sex bias, are yet to be widely investigated in most species. To address these gaps, we conducted whole-genome sequencing of 12 great reed warblers (Acrocephalus arundinaceus) in a pedigree spanning 3 generations to identify single-nucleotide de novo mutations (DNMs) and estimate the germline mutation rate. We detected 82 DNMs within the pedigree, primarily enriched at CpG sites but otherwise randomly located along the chromosomes. Furthermore, we observed a pronounced sex bias in DNM occurrence, with male warblers exhibiting three times more mutations than females. After correction for false negatives and adjusting for callable sites, we obtained a mutation rate of 7.16 × 10-9 mutations per site per generation (m/s/g) for the autosomes and 5.10 × 10-9 m/s/g for the Z chromosome. To demonstrate the utility of species-specific mutation rates, we applied our autosomal mutation rate in models reconstructing the demographic history of the great reed warbler. We uncovered signs of drastic population size reductions predating the last glacial period (LGP) and reduced gene flow between western and eastern populations during the LGP. In conclusion, our results provide one of the few direct estimates of the mutation rate in wild songbirds and evidence for male-driven mutations in accordance with theoretical expectations.
Topics: Animals; Female; Male; Songbirds; Germ-Line Mutation; Genome; Sex Chromosomes; Mutation; Mutation Rate
PubMed: 37793164
DOI: 10.1093/gbe/evad180 -
Clinical & Translational Immunology 2023Genomic biomarkers predicting immune checkpoint inhibitor (ICI) treatment outcomes for Asian metastatic melanoma have been rarely reported. This study presents data on...
OBJECTIVE
Genomic biomarkers predicting immune checkpoint inhibitor (ICI) treatment outcomes for Asian metastatic melanoma have been rarely reported. This study presents data on next-generation sequencing (NGS) and tumour microenvironment biomarkers in 33 cases.
METHODS
Thirty-three patients with advanced melanoma, who underwent ICI treatment at the Chang Gung Memorial Hospital in Taiwan, were recruited. The study evaluated clinical outcomes, including response rate, disease control rate, progression-free survival (PFS) rate and overall survival (OS) rate. Archived tissue samples from 33 cases were subjected to NGS by ACTOnco, and ACTTME was employed in 25 cases.
RESULTS
The most prevalent driver mutations were mutations (24.2%), followed by (15.2%), (12.1%), (9.1%) and (9.1%) mutations. Acral/mucosal melanomas exhibited distinct mutation patterns compared to non-acral melanomas. Tumour mutational burden estimated using ACTOnco was not associated with ICI efficacy. Notably, genetic alterations in the p53 pathway ( loss, gain/amplification and mutation) accounted for 36.4% and were significantly associated with unfavourable PFS (median PFS 2.7 months 3.9 months, 0.0394). Moreover, 26 genes were identified as differentially expressed genes that were upregulated in patients with clinical benefits compared to those without benefits. Four genes, , , and , were found to be associated with both PFS and OS.
CONCLUSION
Genetic alterations in the p53 pathway may be critical in Asian patients with melanoma undergoing ICI treatment. Further investigation is required to explore this mechanism and validate these findings.
PubMed: 37649975
DOI: 10.1002/cti2.1465 -
Nature Communications Jul 2023Citrus canker caused by Xanthomonas citri subsp. citri (Xcc) is a destructive citrus disease worldwide. Generating disease-resistant cultivars is the most effective,...
Citrus canker caused by Xanthomonas citri subsp. citri (Xcc) is a destructive citrus disease worldwide. Generating disease-resistant cultivars is the most effective, environmentally friendly and economic approach for disease control. However, citrus traditional breeding is lengthy and laborious. Here, we develop transgene-free canker-resistant Citrus sinensis lines in the T0 generation within 10 months through transformation of embryogenic protoplasts with Cas12a/crRNA ribonucleoprotein to edit the canker susceptibility gene CsLOB1. Among the 39 regenerated lines, 38 are biallelic/homozygous mutants, demonstrating a 97.4% biallelic/homozygous mutation rate. No off-target mutations are detected in the edited lines. Canker resistance of the cslob1-edited lines results from both abolishing canker symptoms and inhibiting Xcc growth. The transgene-free canker-resistant C. sinensis lines have received regulatory approval by USDA APHIS and are exempted from EPA regulation. This study provides a sustainable and efficient citrus canker control solution and presents an efficient transgene-free genome-editing strategy for citrus and other crops.
Topics: Citrus sinensis; RNA, Guide, CRISPR-Cas Systems; CRISPR-Cas Systems; Disease Resistance; Plant Breeding; Citrus; Xanthomonas; Plant Diseases
PubMed: 37402755
DOI: 10.1038/s41467-023-39714-9 -
Evolution Letters Dec 2023The effect of parental age on germline mutation rate across generations is not fully understood. While some studies report a positive linear relationship of mutation...
The effect of parental age on germline mutation rate across generations is not fully understood. While some studies report a positive linear relationship of mutation rate with increasing age, others suggest that mutation rate varies with age but not in a linear fashion. We investigated the effect of parental age on germline mutations by generating replicated mutation accumulation lines in at three parental ages ("Young T1" [Day 1], "Peak T2" [Day 2], and "Old T5" [Day 5] parents). We conducted whole-genome resequencing and variant calling to compare differences in mutation rates after three generations of mutation accumulation. We found that Peak T2 lines had an overall reduced mutation rate compared to Young T1 and Old T5 lines, but this pattern of the effect varied depending on the variant impact. Specifically, we found no high-impact variants in Peak T2 lines, and modifiers and up- and downstream gene variants were less frequent in these lines. These results suggest that animals at the peak of reproduction have better DNA maintenance and repair compared to young and old animals. We propose that start to reproduce before they optimize their DNA maintenance and repair, trading the benefits of earlier onset of reproduction against offspring mutation load. The increase in offspring mutation load with age likely represents germline senescence.
PubMed: 38045724
DOI: 10.1093/evlett/qrad052 -
Journal of the Royal Society, Interface Nov 2023Mutation accumulation in tumour evolution is one major cause of intra-tumour heterogeneity (ITH), which often leads to drug resistance during treatment. Previous studies...
Mutation accumulation in tumour evolution is one major cause of intra-tumour heterogeneity (ITH), which often leads to drug resistance during treatment. Previous studies with multi-region sequencing have shown that mutation divergence among samples within the patient is common, and the importance of spatial sampling to obtain a complete picture in tumour measurements. However, quantitative comparisons of the relationship between mutation heterogeneity and tumour expansion modes, sampling distances as well as the sampling methods are still few. Here, we investigate how mutations diverge over space by varying the sampling distance and tumour expansion modes using individual-based simulations. We measure ITH by the Jaccard index between samples and quantify how ITH increases with sampling distance, the pattern of which holds in various sampling methods and sizes. We also compare the inferred mutation rates based on the distributions of variant allele frequencies under different tumour expansion modes and sampling sizes. In exponentially fast expanding tumours, a mutation rate can always be inferred for any sampling size. However, the accuracy compared with the true value decreases when the sampling size decreases, where small sampling sizes result in a high estimate of the mutation rate. In addition, such an inference becomes unreliable when the tumour expansion is slow, such as in surface growth.
Topics: Humans; Neoplasms; Mutation
PubMed: 37989227
DOI: 10.1098/rsif.2023.0542 -
BioRxiv : the Preprint Server For... Dec 2023The prominence of positive selection, in which beneficial mutations are favored by natural selection and rapidly increase in frequency, is a subject of intense debate....
The prominence of positive selection, in which beneficial mutations are favored by natural selection and rapidly increase in frequency, is a subject of intense debate. Positive selection can result in selective sweeps, in which the haplotype(s) bearing the adaptive allele "sweep" through the population, thereby removing much of the genetic diversity from the region surrounding the target of selection. Two models of selective sweeps have been proposed: classical sweeps, or "hard sweeps", in which a single copy of the adaptive allele sweeps to fixation, and "soft sweeps", in which multiple distinct copies of the adaptive allele leave descendants after the sweep. Soft sweeps can be the outcome of recurrent mutation to the adaptive allele, or the presence of standing genetic variation consisting of multiple copies of the adaptive allele prior to the onset of selection. Importantly, soft sweeps will be common when populations can rapidly adapt to novel selective pressures, either because of a high mutation rate or because adaptive alleles are already present. The prevalence of soft sweeps is especially controversial, and it has been noted that selection on standing variation or recurrent mutations may not always produce soft sweeps. Here, we show that the inverse is true: selection on single-origin mutations may often result in an outcome that is indistinguishable from a soft sweep. This is made possible by allelic gene conversion, which "softens" hard sweeps by copying the adaptive allele onto multiple genetic backgrounds, a process we refer to as a "pseudo-soft" sweep. We carried out a simulation study examining the impact of gene conversion on sweeps from a single variant in models of human, , and populations. The fraction of simulations in which gene conversion had produced multiple haplotypes with the adaptive allele upon fixation was appreciable. Indeed, under realistic demographic histories and gene conversion rates, even if selection always acts on a single-origin mutation, sweeps involving multiple haplotypes are more likely than hard sweeps in large populations, especially when selection is not extremely strong. Thus, even when the mutation rate is low or there is no standing variation, hard sweeps are expected to be the exception rather than the rule in large populations. These results also imply that the presence of signatures of soft sweeps does not necessarily mean that adaptation has been especially rapid or is not mutation limited.
PubMed: 38106127
DOI: 10.1101/2023.12.05.570141 -
Molecular Biology and Evolution Jul 2023Social networks can influence the ecology of gut bacteria, shaping the species composition of the gut microbiome in humans and other animals. Gut commensals evolve and...
Social networks can influence the ecology of gut bacteria, shaping the species composition of the gut microbiome in humans and other animals. Gut commensals evolve and can adapt at a rapid pace when colonizing healthy hosts. Here, we aimed at assessing the impact of host-to-host bacterial transmission on Escherichia coli evolution in the mammalian gut. Using an in vivo experimental evolution approach in mice, we found a transmission rate of 7% (±3% 2× standard error [2SE]) of E. coli cells per day between hosts inhabiting the same household. Consistent with the predictions of a simple population genetics model of mutation-selection-migration, the level of shared events resulting from within host evolution is greatly enhanced in cohoused mice, showing that hosts undergoing the same diet and habit are not only expected to have similar microbiome species compositions but also similar microbiome evolutionary dynamics. Furthermore, we estimated the rate of mutation accumulation of E. coli to be 3.0 × 10-3 (±0.8 × 10-3 2SE) mutations/genome/generation, irrespective of the social context of the regime. Our results reveal the impact of bacterial migration across hosts in shaping the adaptive evolution of new strains colonizing gut microbiomes.
Topics: Humans; Animals; Mice; Biological Evolution; Escherichia coli; Microbiota; Gastrointestinal Microbiome; Mutation; Mammals; Bacteria
PubMed: 37402639
DOI: 10.1093/molbev/msad153 -
Theoretical Population Biology Dec 2023Recombination is a powerful evolutionary process that shapes the genetic diversity observed in the populations of many species. Reconstructing genealogies in the...
Recombination is a powerful evolutionary process that shapes the genetic diversity observed in the populations of many species. Reconstructing genealogies in the presence of recombination from sequencing data is a very challenging problem, as this relies on mutations having occurred on the correct lineages in order to detect the recombination and resolve the ordering of coalescence events in the local trees. We investigate the probability of reconstructing the true topology of ancestral recombination graphs (ARGs) under the coalescent with recombination and gene conversion. We explore how sample size and mutation rate affect the inherent uncertainty in reconstructed ARGs, which sheds light on the theoretical limitations of ARG reconstruction methods. We illustrate our results using estimates of evolutionary rates for several organisms; in particular, we find that for parameter values that are realistic for SARS-CoV-2, the probability of reconstructing genealogies that are close to the truth is low.
Topics: Algorithms; Recombination, Genetic; Models, Genetic; Mutation; Biological Evolution; Phylogeny
PubMed: 37544486
DOI: 10.1016/j.tpb.2023.07.004 -
Trends in Genetics : TIG Aug 2023The germline mutation rate (GMR) sets the pace at which mutations, the raw material of evolution, are introduced into the genome. By sequencing a dataset of...
The germline mutation rate (GMR) sets the pace at which mutations, the raw material of evolution, are introduced into the genome. By sequencing a dataset of unprecedently broad phylogenetic scope, Bergeron et al. estimated species-specific GMR, offering numerous insights into how this parameter shapes and is shaped by life-history traits.
Topics: Phylogeny; Evolution, Molecular; Germ-Line Mutation; Mutation Rate; Mutation
PubMed: 37244758
DOI: 10.1016/j.tig.2023.05.001 -
Vaccine Oct 2023The SARS-CoV-2 pandemic has a huge impact on public health and global economy, meaning an enormous scientific, political, and social challenge. Studying how infection or... (Review)
Review
The SARS-CoV-2 pandemic has a huge impact on public health and global economy, meaning an enormous scientific, political, and social challenge. Studying how infection or vaccination triggers both cellular and humoral responses is essential to know the grade and length of protection generated in the population. Nowadays, scientists and authorities around the world are increasingly concerned about the arrival of new variants, which have a greater spread, due to the high mutation rate of this virus. The aim of this review is to summarize the different techniques available for the study of the immune responses after exposure or vaccination against SARS-CoV-2, showing their advantages and limitations, and proposing suitable combinations of different techniques to achieve extensive information in these studies. We wish that the information provided here will helps other scientists in their studies of the immune response against SARS-CoV-2 after vaccination with new vaccine candidates or infection with upcoming variants.
Topics: Humans; SARS-CoV-2; COVID-19; Pandemics; Physicians; Public Health; Vaccination; Antibodies, Viral
PubMed: 37770298
DOI: 10.1016/j.vaccine.2023.09.033