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PubMed2025

The mutation landscape of Daphnia obtusa reveals evolutionary forces shaping genome stability.

Spontaneous mutations are the primary source of genetic variation and play a central role in shaping evolutionary processes. To investigate mutational dynamics in Daphnia obtusa, we generated a chromosome-level genome assembly spanning 129.4 Mb across 12 chromosomes, encompassing 15,321 predicted protein-coding genes. Leveraging whole-genome sequencing of eight mutation accumulation (MA) lines propagated for an average of 482 generations (spanning over 20 years), we estimated a spontaneous single nucleotide mutation (SNM) rate of 2.23 × 10-9 and an indel mutation rate of 2.75 × 10-10 per site per generation. The SNM spectrum was strongly biased toward C:G > T:A transitions. Comparative analyses with natural population data revealed that exonic mutations observed in the MA lines were significantly less likely to be present in standing variation than intronic or intergenic mutations, suggesting that purifying selection in natural populations acts to remove deleterious alleles. We also identified 48 de novo loss-of-heterozygosity (LOH) events, comprising 8 heterozygous deletions and 40 gene conversion events. The genome-wide gene conversion rate was estimated at 2.62 × 10-5 per heterozygous site per generation. These findings provide a comprehensive view of the mutation spectrum, selective pressures, and mechanisms underlying genome stability in D. obtusa.

Daphnia obtusa↗

PubMed2025

Suppression of LKB1-mutant lung adenocarcinoma by natural killer cells from females.

BACKGROUND: This study addressed the enigma of sex differences in smoking-related lung cancer, particularly focusing on the low LKB1 mutation frequency in female patients with lung adenocarcinoma. METHODS: Sex bias was studied with a genetically engineered mouse model and various tail-vein injection models. Immune cells were analyzed by antibody-depletion study, flow cytometry, and immunofluorescence. The relevance of our findings to human disease was validated by evaluating various lung adenocarcinoma datasets. All statistical tests are 2-sided. RESULTS: A statistically significant percentage of females are resistant to LKB1-mutant tumor formation in our models, reflecting this sex difference in humans. Natural killer (NK) cells were identified as a critical factor in this sex-biased response. This sex difference was observed primarily in LKB1-mutant lung adenocarcinoma, probably due to their low major histocompatibility complex class I level, making them the ideal target for NK cells through the missing-self recognition. Although females resistant to LKB1-mutant lung adenocarcinoma formation did not have enhancement of any specific NK subpopulation, our immunofluorescence analysis revealed high numbers of NKs in female lungs even with the presence of LKB1-mutant lung adenocarcinoma. Our gene set enrichment analysis of The Cancer Genome Atlas-lung adenocarcinoma dataset also showed that female LKB1-mutant lung adenocarcinoma patients have a stronger NK-mediated response after adjusting for other male-female differences using the LKB1 wild-type lung adenocarcinoma dataset. CONCLUSION: Females have a stronger NK-mediated response against LKB1-mutant lung adenocarcinoma, which was present in our mouse model and the human lung adenocarcinoma dataset. This study revealed a novel role of NK cells in suppressing LKB1-mutant lung adenocarcinoma in females, which should be assessed in the clinical setting in the future.

Killer Cells, Natural↗

PubMed1979

Evolution of methionine initiator and phenylalanine transfer RNAs.

Sequence data from methionine initiator and phenylalanine transfer RNAs were used to construct phylogenetic trees by the maximum parsimony method. Although eukaryotes, prokaryotes and chloroplasts appear related to a common ancestor, no firm conclusion can be drawn at this time about mitochondrial-coded transfer RNAs. tRNA evolution is not appropriately described by random hit models, since the various regions of the molecule differ sharply in their mutational fixation rates. "Hot" mutational spots are identified in the Tpsic, the amino acceptor and the upper anticodon stems; the D arm and the loop areas on the other hand are highly conserved. Crucial tertiary interactions are thus essentially preserved while most of the double helical domain undergoes base pair interchange. Transitions are about half as costly as transversions, suggesting that base pair interchanges proceed mostly through G-U and A-C intermediates. There is a preponderance of replacements starting from G and C but this bias appears to follow the high G + C content of the easily mutated base paired regions.

Animals↗

PubMed2026

First complete mitochondrial genome of Uzelothrips scabrosus (Thysanoptera: Uzelothripidae) provides insights into gene rearrangements and phylogenetic position within Terebrantia.

The family Uzelothripidae is represented by a single genus Uzelothrips and can be distinguished from others by the presence of whip-like antennae, a circular ventral sensorium on antennal segment III, a well-developed tentorium, and a membranous ovipositor. Here, we generated the first complete mitochondrial genome of Uzelothrips scabrosus (15,674 bp) using next-generation sequencing to explore the gene rearrangements and phylogenetic relationships. It consists of 13 protein-coding genes, 22 transfer RNAs, two ribosomal RNAs, and two putative control regions. The genome exhibits strong AT bias (71.35%) with negative AT and GC skew. Codon usage analyses indicate a strong bias towards A/U-ending codons and influenced by both natural selection and mutation pressure. All PCGs were under purifying selection, with cox1 being the most conserved and nad4L the most variable. The gene order of the family Uzelothripidae is highly rearranged compared to the ancestral insect gene order. Comparative analysis revealed that gene block B was the most widely conserved, whereas the remaining gene blocks exhibited family or lineage-specific conservation patterns, reflecting extensive mitochondrial gene rearrangements during the evolution of the Thysanoptera. Moreover, 228 synapomorphic and 68 autapomorphic gene boundaries were identified across thysanopteran mitogenomes. Phylogenies indicated that the family Uzelothripidae is in a sister relationship with Stenurothripidae, and the Uzelothripidae + Stenurothripidae clade is sister to Thripidae. This study provides the first mitogenomic insights into Uzelothripidae and highlights the need for broader taxon sampling and nuclear genomic data to resolve deep evolutionary relationships within Thysanoptera.

Comparative analysis↗

PubMed2026

Evidence for the prognostic value of TP53 mutations in circulating tumor DNA across solid malignancies: a systematic review and meta-analysis.

BACKGROUND: The purpose of this meta-analysis study is to provide evidence for the clinical utility of TP53 mutations in circulating tumor DNA (ctDNA) as a prognostic biomarker. METHODS: We searched the PubMed, Embase, Cochrane, and Web of Science databases (last update May 2025) for studies on TP53 mutations in ctDNA or cfDNA as prognosis overall survival and in solid tumors. A total of 21 studies that met the criteria were utilized and data was collected regarding the authors, year of publication, study design, site of the study, number of patients, detection, mutation sample size and outcome measures were collected. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the study, and meta-analysis was done by using STATA 16.0. Effect sizes were in the form of hazard ratios (HR) that had 95% confidence intervals (CI). The models used were fixed-effects and random-effects based on heterogeneity. Funnel plots, and Egger's test was used to measure publication bias, and sensitivity analysis conducted through a leave-one-out method. RESULTS: A total of 21 studies (2,685 TP53-mutated patients, one unreported) showed: Mutated patients had worse progression-free survival (PFS) (HR=2.10, p=0.000; 12 studies, heterogeneity resolved after excluding Yoshida 2023), shorter OS (HR=1.74, p=0.014; 9 studies), and reduced DFS (HR=1.73, p=0.007; 3 studies), but RFS (2 items) showed no statistically significant differences. Subgroup analyses revealed: Prospective studies showed stronger PFS (HR=2.14 vs retrospective 1.90) with Japanese subgroup HR=4.90; Lung/liver cancers had higher HRs than breast. Prospective OS HR=2.25 (lung 3.14, endometrial 0.75). Retrospective DFS HR=1.89 vs Japanese breast RFS HR=4.00. Heterogeneity originated from study design, region, and cancer type variations, with no significant publication bias (Egger's test p>0.05). CONCLUSION: Current evidence suggests that TP53 mutations detected in ctDNA are significantly associated with poor prognosis in various solid tumors, particularly lung cancer. The association is robust for PFS and OS, though high heterogeneity and biological complexity warrant cautious interpretation. These findings support the potential incorporation of ctDNA-based TP53 mutation status into clinical prognostic assessment systems as an adjunctive parameter; however, further standardization of detection protocols, functional annotation of mutation types (e.g., LOF vs. GOF), incorporation of VAF and clonality analysis, and validation in large prospective multicenter cohorts are needed before routine clinical implementation. PROSPERO REGISTRATION NUMBER: CRD420251021095.

Humans↗

PubMed2026

Integrated signatures define mutational processes in prostate cancer.

Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology1. Here we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group and assess their clinical relevance. By integrating de novo extracted single-base substitution, insertion-deletion and copy-number signatures with six novel complex structural variant signatures, we identify eight integrated mutational footprints (IMFs) that collectively explain the mutational processes in 85% of primary prostate cancer genomes. IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress. Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis. These included reactive oxygen-species-driven mutagenesis and both canonical and non-canonical homologous recombination deficiency, the latter being enriched in patients of African ancestry. Extending to the metastatic setting, we found that IMFs predicted sensitivity to androgen receptor pathway inhibitors. Taken together, our study delineates the aetiologies and mutational processes that drive the genomic and clinical heterogeneity of prostate cancer, introduces IMFs as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.

Journal Article↗

PubMed2025

A model for background selection in non-equilibrium populations.

In many taxa, levels of genetic diversity are observed to vary along their genome. The framework of background selection models this variation in terms of linkage to constrained sites, and recent applications have been able to explain a large portion of the variation in human genomes. However, these studies have also yielded conflicting results, stemming from two key limitations. First, existing models are inaccurate in a critical region of parameter space (), where the local reduction in diversity is sharpest. Second, they assume a constant population size over time. Here, we develop predictions for diversity under background selection based on the Hill-Robertson system of two-locus statistics, which allows for population size changes. We treat the joint effect of multiple selected loci independently, but we show that interference among them is well captured through local rescaling of mutation, recombination and selection in an iterative procedure that converges quickly. We further accommodate existing background selection theory to non-equilibrium demography, bridging the gap between weak and strong selection. Simulations show that our predictions are accurate across the entire range of selection coefficients. We characterize the temporal dynamics of linked selection under population size changes and demonstrate that patterns of diversity can be misinterpreted by other models. Specifically, biases due to the incorrect assumption of equilibrium carry over to downstream inferences of the distribution of fitness effects and deleterious mutation rate. Jointly modeling demography and linked selection therefore improves our understanding of the genomic landscape of diversity, which will help refine inferences of linked selection in humans and other species.

Journal Article↗

PubMed2026

[State Changes and Stability Grading of Driver Genes in Non-small Cell Lung Cancer Based on Repeated NGS Testing].

BACKGROUND: Next-generation sequencing (NGS)-based driver gene testing has become a routine component of molecular subtyping and precision therapy for non-small cell lung cancer (NSCLC). Dynamic genomic monitoring facilitates early detection of resistance-related molecular alterations and informs timely therapeutic adjustments. However, standardized criteria for evaluating the stability of serial NGS testing are currently lacking, and the applicability of NGS using formalin-fixed paraffin-embedded (FFPE) specimens for dynamic monitoring remains poorly defined. This study aims to establish a stability grading system for driver gene status alterations based on repeated NGS testing, and to provide evidence-based support for clinical repeat biopsy strategies. METHODS: Data from 1232 patients with NSCLC who underwent two or more NGS tests on FFPE tissue specimens at Beijing Chest Hospital between June 2019 and April 2026 were collected retrospectively. Patients with an interval of ≥4 months between the initial and last tests were included to ensure the representativeness of temporal analysis, resulting in a main analysis cohort of 942 patients. The Kappa consistency test was used to evaluate the state stability of nine core driver genes [epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), mesenchymal‑epithelial transition factor (MET), rearranged during transfection (RET), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), erb‑b2 receptor tyrosine kinase 2 (ERBB2), and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA)] and to construct a five‑level grading system. Paired variant allele frequency (VAF) differences were compared using the Wilcoxon signed‑rank test. Independent influencing factors for mutation accumulation were identified by binary Logistic regression. RESULTS: The state stability of the nine genes was classified into five levels: EGFR showed high stability (Kappa=0.838), ROS1/ALK/KRAS good stability, BRAF/PIK3CA/RET moderate stability, and ERBB2 low stability, and MET showed high instability. MET exhibited the highest rate of state change (9.3%) with a raw observed agreement of 90.7%. Its Kappa value (0.172) was influenced by the low prevalence (3.7%) compression effect and should therefore be interpreted alongside the observed agreement (90.7%) and the prevalence-adjusted and bias-adjusted Kappa (PABAK). The VAF of PIK3CA increased significantly (P=0.005). T790M positivity increased from 5.8% to 10.8%, and 30 new C797S mutations were detected at the last test (13 with T790M, 17 without). The overall rate of new driver gene variants in the main cohort was 18.0%. Binary Logistic regression showed that a lower number of initial mutated genes was the only independent predictor of new variants [odds ratio (OR)=0.399, P<0.001], while sex and detection interval showed no independent association. CONCLUSIONS: A five level stability grading system for state changes of driver genes in NSCLC based on repeated NGS testing has been established. MET showed the most frequent state changes, which should be interpreted in conjunction with the prevalence effect. The VAF increase of PIK3CA is an observational finding, and its clinical significance requires further prospective validation. A lower initial mutation burden may reflect tumor clonal complexity and was associated with a higher likelihood of subsequent acquisition of new variants. FFPE based NGS is applicable for repeated testing at clinical treatment decision nodes.

Humans↗

PubMed2024

A framework for automated scalable designation of viral pathogen lineages from genomic data.

Pathogen lineage nomenclature systems are a key component of effective communication and collaboration for researchers and public health workers. Since February 2021, the Pango dynamic lineage nomenclature for SARS-CoV-2 has been sustained by crowdsourced lineage proposals as new isolates were sequenced. This approach is vulnerable to time-critical delays as well as regional and personal bias. Here we developed a simple heuristic approach for dividing phylogenetic trees into lineages, including the prioritization of key mutations or genes. Our implementation is efficient on extremely large phylogenetic trees consisting of millions of sequences and produces similar results to existing manually curated lineage designations when applied to SARS-CoV-2 and other viruses including chikungunya virus, Venezuelan equine encephalitis virus complex and Zika virus. This method offers a simple, automated and consistent approach to pathogen nomenclature that can assist researchers in developing and maintaining phylogeny-based classifications in the face of ever-increasing genomic datasets.

Animals↗

PubMed2026

Association of ctDNA RAS mutational status and clinical benefits in first-line metastatic colorectal cancer therapy with chemotherapy plus anti-EGFR (overall response rate and progression-free survival): a brief report of systematic review and meta-analysis.

Monitoring RAS mutations in circulating tumor DNA (ctDNA) is increasingly relevant in metastatic colorectal cancer (mCRC). In patients with tissue RAS wild-type (WT) tumors treated with first-line chemotherapy plus anti-epidermal growth factor receptor therapy (1LChT + anti-EGFR), some studies suggest that RAS WT ctDNA is associated with better outcomes, whereas others reported no differences according to ctDNA RAS mutational status. These inconsistencies may be related to small sample sizes, methodological heterogeneity, differences in assay sensitivity and tumor heterogeneity. We performed a systematic review in patients with tissue RAS WT treated with 1LChT + anti-EGFR. PubMed, Web of Science, and Scopus were searched up to April 2026. Risk of bias was assessed using the QUIPS tool, and random-effect models were applied. Fourteen studies met the inclusion criteria (ten non-interventional studies and four clinical trials). Compared with ctDNA RAS mutated tumors, ctDNA RAS WT tumors showed significantly higher overall response rates [ORR: pooled odds ratio (OR) 2.1, 95% confidence interval (CI): 1.3-3.4; P=0.002] and longer progression-free survival [PFS: pooled hazard ratio (HR) 1.6, 95% CI: 1.3-1.9; P<0.001] [non-interventional studies (NIS) + clinical trials (CT) data]. The pooled prevalence of ctDNA RAS mutations was 10.5% (95% CI: 6.2-14.8%). These findings support ctDNA RAS status as a potential biomarker of benefit from anti-EGFR-based therapy in mCRC, although methodological standardization and prospective validation remain necessary.

Circulating tumor DNA (ctDNA)↗

PubMed2018

Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations.

BACKGROUND: The presence of deleterious mutations in breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2) significantly increases the risk of developing some cancers, such as breast and high-grade serous cancer (HGSC) of ovarian, tubal and peritoneal origin. Risk-reducing salpingo-oophorectomy (RRSO) is usually recommended to BRCA1 or BRCA2 carriers after completion of childbearing. Despite prior systematic reviews and meta-analyses on the role of RRSO in reducing the mortality and incidence of breast, HGSC and other cancers, RRSO is still an area of debate and it is unclear whether RRSO differs in effectiveness by type of mutation carried. OBJECTIVES: To assess the benefits and harms of RRSO in women with BRCA1 or BRCA2 mutations. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 7) in The Cochrane Library, MEDLINE Ovid, Embase Ovid and trial registries, with no language restrictions up to July 2017. We handsearched abstracts of scientific meetings and other relevant publications. SELECTION CRITERIA: We included non-randomised trials (NRS), prospective and retrospective cohort studies, and case series that used statistical adjustment for baseline case mix using multivariable analyses comparing RRSO versus no RRSO in women without a previous or coexisting breast, ovarian or fallopian tube malignancy, in women with or without hysterectomy, and in women with a risk-reducing mastectomy (RRM) before, with or after RRSO. DATA COLLECTION AND ANALYSIS: We extracted data and performed meta-analyses of hazard ratios (HR) for time-to-event variables and risk ratios (RR) for dichotomous outcomes, with 95% confidence intervals (CI). To assess bias in the studies, we used the ROBINS-I 'Risk of bias' assessment tool. We quantified inconsistency between studies by estimating the I2 statistic. We used random-effects models to calculate pooled effect estimates. MAIN RESULTS: We included 10 cohort studies, comprising 8087 participants (2936 (36%) surgical participants and 5151 (64%) control participants who were BRCA1 or BRCA2 mutation carriers. All the studies compared RRSO with or without RRM versus no RRSO (surveillance). The certainty of evidence by GRADE assessment was very low due to serious risk of bias. Nine studies, including 7927 women, were included in the meta-analyses. The median follow-up period ranged from 0.5 to 27.4 years. MAIN OUTCOMES: overall survival was longer with RRSO compared with no RRSO (HR 0.32, 95% CI 0.19 to 0.54; P < 0.001; 3 studies, 2548 women; very low-certainty evidence). HGSC cancer mortality (HR 0.06, 95% CI 0.02 to 0.17; I² = 69%; P < 0.0001; 3 studies, 2534 women; very low-certainty evidence) and breast cancer mortality (HR 0.58, 95% CI 0.39 to 0.88; I² = 65%; P = 0.009; 7 studies, 7198 women; very low-certainty evidence) were lower with RRSO compared with no RRSO. None of the studies reported bone fracture incidence. There was a difference in favour of RRSO compared with no RRSO in terms of ovarian cancer risk perception quality of life (MD 15.40, 95% CI 8.76 to 22.04; P < 0.00001; 1 study; very low-certainty evidence). None of the studies reported adverse events.Subgroup analyses for main outcomes: meta-analysis showed an increase in overall survival among women who had RRSO versus women without RRSO who were BRCA1 mutation carriers (HR 0.30, 95% CI 0.17 to 0.52; P < 0001; I² = 23%; 3 studies; very low-certainty evidence) and BRCA2 mutation carriers (HR 0.44, 95% CI 0.23 to 0.85; P = 0.01; I² = 0%; 2 studies; very low-certainty evidence). The meta-analysis showed a decrease in HGSC cancer mortality among women with RRSO versus no RRSO who were BRCA1 mutation carriers (HR 0.10, 95% CI 0.02 to 0.41; I² = 54%; P = 0.001; 2 studies; very low-certainty evidence), but uncertain for BRCA2 mutation carriers due to low frequency of HGSC cancer deaths in BRCA2 mutation carriers. There was a decrease in breast cancer mortality among women with RRSO versus no RRSO who were BRCA1 mutation carriers (HR 0.45, 95% CI 0.30 to 0.67; I² = 0%; P < 0.0001; 4 studies; very low-certainty evidence), but not for BRCA2 mutation carriers (HR 0.88, 95% CI 0.42 to 1.87; I² = 63%; P = 0.75; 3 studies; very low-certainty evidence). One study showed a difference in favour of RRSO versus no RRSO in improving quality of life for ovarian cancer risk perception in women who were BRCA1 mutation carriers (MD 10.70, 95% CI 2.45 to 18.95; P = 0.01; 98 women; very low-certainty evidence) and BRCA2 mutation carriers (MD 13.00, 95% CI 3.59 to 22.41; P = 0.007; very low-certainty evidence). Data from one study showed a difference in favour of RRSO and RRM versus no RRSO in increasing overall survival (HR 0.14, 95% CI 0.02 to 0.98; P = 0.0001; I² = 0%; low-certainty evidence), but no difference for breast cancer mortality (HR 0.78, 95% CI 0.51 to 1.19; P = 0.25; very low-certainty evidence). The risk estimates for breast cancer mortality according to age at RRSO (50 years of age or less versus more than 50 years) was not protective and did not differ for BRCA1 (HR 0.85, 95% CI 0.64 to 1.11; I² = 16%; P = 0.23; very low-certainty evidence) and BRCA2 carriers (HR 0.88, 95% CI 0.42 to 1.87; I² = 63%; P = 0.75; very low-certainty evidence). AUTHORS' CONCLUSIONS: There is very low-certainty evidence that RRSO may increase overall survival and lower HGSC and breast cancer mortality for BRCA1 and BRCA2 carriers. Very low-certainty evidence suggests that RRSO reduces the risk of death from HGSC and breast cancer in women with BRCA1 mutations. Evidence for the effect of RRSO on HGSC and breast cancer in BRCA2 carriers was very uncertain due to low numbers. These results should be interpreted with caution due to questionable study designs, risk of bias profiles, and very low-certainty evidence. We cannot draw any conclusions regarding bone fracture incidence, quality of life, or severe adverse events for RRSO, or for effects of RRSO based on type and age at risk-reducing surgery. Further research on these outcomes is warranted to explore differential effects for BRCA1 or BRCA2 mutations.

Adult↗

PubMed2022

Comparison on Major Gene Mutations Related to Rifampicin and Isoniazid Resistance between Beijing and Non-Beijing Strains of Mycobacterium tuberculosis: A Systematic Review and Bayesian Meta-Analysis.

Objective: The Beijing strain of Mycobacterium tuberculosis (MTB) is controversially presented as the predominant genotype and is more drug resistant to rifampicin and isoniazid compared to the non-Beijing strain. We aimed to compare the major gene mutations related to rifampicin and isoniazid drug resistance between Beijing and non-Beijing genotypes, and to extract the best evidence using the evidence-based methods for improving the service of TB control programs based on genetics of MTB. Method: Literature was searched in Google Scholar, PubMed and CNKI Database. Data analysis was conducted in R software. The conventional and Bayesian random-effects models were employed for meta-analysis, combining the examinations of publication bias and sensitivity. Results: Of the 8785 strains in the pooled studies, 5225 were identified as Beijing strains and 3560 as non-Beijing strains. The maximum and minimum strain sizes were 876 and 55, respectively. The mutations prevalence of rpoB, katG, inhA and oxyR-ahpC in Beijing strains was 52.40% (2738/5225), 57.88% (2781/4805), 12.75% (454/3562) and 6.26% (108/1724), respectively, and that in non-Beijing strains was 26.12% (930/3560), 28.65% (834/2911), 10.67% (157/1472) and 7.21% (33/458), separately. The pooled posterior value of OR for the mutations of rpoB was 2.72 ((95% confidence interval (CI): 1.90, 3.94) times higher in Beijing than in non-Beijing strains. That value for katG was 3.22 (95% CI: 2.12, 4.90) times. The estimate for inhA was 1.41 (95% CI: 0.97, 2.08) times higher in the non-Beijing than in Beijing strains. That for oxyR-ahpC was 1.46 (95% CI: 0.87, 2.48) times. The principal patterns of the variants for the mutations of the four genes were rpoB S531L, katG S315T, inhA-15C > T and oxyR-ahpC intergenic region. Conclusion: The mutations in rpoB and katG genes in Beijing are significantly more common than that in non-Beijing strains of MTB. We do not have sufficient evidence to support that the prevalence of mutations of inhA and oxyR-ahpC is higher in non-Beijing than in Beijing strains, which provides a reference basis for clinical medication selection.

Isoniazid↗

PubMed2024

Transgenerational increases in DNA methylation in Arabidopsis plants defective in active DNA demethylation.

Spontaneous gain or loss of DNA methylation occurs in plant and animal genomes, and DNA methylation changes can lead to meiotically stable epialleles that generate heritable phenotypic diversity. However, it is unclear whether transgenerational epigenetic stability may be regulated by any cellular factors. Here, we examined spontaneously occurring variations in DNA methylation in wild-type and ros1 mutant Arabidopsis plants that were propagated for ten generations from single-seed descent. We found that the ros1 mutant, which is defective in active DNA demethylation, showed an increased transgenerational epimutation rate. The ros1 mutation led to more spontaneously gained methylation than lost methylation at individual cytosines, compared to the wild type which had similar numbers of spontaneously gained and lost methylation cytosines. Consistently, transgenerational differentially methylated regions were also biased toward hypermethylation in the ros1 mutant. Our results reveal a genetic contribution of the ROS1 DNA demethylase to transgenerational epigenetic stability and suggest that ROS1 may have an unexpected surveillance function in preventing transgenerational DNA methylation increases.

Arabidopsis↗

PubMed1979

Water, protein folding, and the genetic code.

The absolute affinities of amino acid side chains for solvent water closely match their relative distributions between the surface and the interior of native proteins and are associated with a remarkable bias in the genetic code.

Amino Acids↗

PubMed1979

Mutants in yeast affecting ethidium bromide induced rho- formation and their effects on transmission and recombination of mitochondrial genes.

A series of mutants called ebi, less inducible by ethidium bromide than the parental strain for the rho+ leads to rho- mutation have been isolated after E.M.S. mutagenesis. Some of the ebi mutants also show an important accumulation of rho- cells, in the absence of ethidium bromide. Ebi mutations are nuclearly inherited as shown by meiotic segregation. The effects of these mutants on the transmission and recombination of mitochondrial genes among the diploid progeny of crosses have been studied. Some of the ebi mutants show a non coordinated transmission of the oli1 mitochondrial marker with respect to other mitochondrial markers unexpected for homosexual crosses. This bias which is independent from omega will be discussed in relation to the segregation and recombination. No significant decrease of the frequency of recombinants has been detected.

Crosses, Genetic↗

PubMed2026

Genomic and molecular landscape of early onset colorectal cancer: Emerging insights and clinical implications-A systematic review.

BACKGROUND: Early onset colorectal cancer, defined as colorectal malignancy occurring before age 50, has been rising globally. Increasing molecular evidence suggests that early onset colorectal cancer is not merely a premature form of late-onset colorectal cancer but a distinct biologic entity with unique genomic and transcriptomic profiles. METHODS: A systematic PubMed search using the terms "early onset colorectal cancer," "genomic," and "molecular" identified 270 records. Eighteen original studies met the inclusion criteria and were supplemented by references from selected articles. Extracted data encompassed clinicopathologic characteristics, genomic and epigenetic alterations, and dysregulated signaling pathways distinguishing early onset colorectal cancer from late-onset colorectal cancer. RESULTS: Evidence from approximately 19,888 patients with early onset colorectal cancer was synthesized across genomic, transcriptomic, and clinical data sets. Early onset colorectal cancer showed a predominance in distal and rectal sites, a slight male bias, and a higher prevalence among Hispanic and Asian populations. Compared with late-onset colorectal cancer, early onset colorectal cancer exhibited lower B-Raf proto-oncogene, serine/threonine kinase V600E mutation and CpG island methylator phenotype-high methylation frequencies but higher rates of tumor protein p53, Kirsten rat sarcoma viral oncogene homolog, and DNA-repair gene alterations. Distinct comutation patterns (F-box and WD repeat domain containing 7-neurogenic locus notch homolog protein 3-phosphoinositide-3-kinase regulatory subunit 1 and adenomatous polyposis coli-tumor protein p53) and overexpression of immediate-early response genes (Proto-Oncogene c-Fos, EGR1, DUSP1, and CYR61) defined its transcriptional landscape. Perturbations of Wingless/Integrated signaling pathway, mitogen-activated protein kinase, phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin, and DNA-repair pathways, along with global long interspersed nuclear element-1 hypomethylation, indicated heightened genomic instability. CONCLUSION: Early onset colorectal cancer develops through tumor protein p53-driven genomic instability and defective DNA repair rather than the canonical CpG island methylator phenotype-B-Raf proto-oncogene, serine/threonine kinase axis. Recognition of these molecular distinctions is essential for age-specific risk assessment, screening, and precision therapeutics. Further integrative studies are needed to elucidate environmental and genetic contributors and identify novel biomarkers and treatment targets.

Humans↗

PubMed2025

Reference-Free Variant Calling with Local Graph Construction with ska lo (SKA).

The study of genomic variants is increasingly important for public health surveillance of pathogens. Traditional variant-calling methods from whole-genome sequencing data rely on reference-based alignment, which can introduce biases and require significant computational resources. Alignment- and reference-free approaches offer an alternative by leveraging k-mer-based methods, but existing implementations often suffer from sensitivity limitations, particularly in high mutation density genomic regions. Here, we present ska lo, a graph-based algorithm that aims to identify within-strain variants in pathogen whole-genome sequencing data by traversing a colored De Bruijn graph and building variant groups (i.e. sets of variant combinations). Through in silico benchmarking and real-world dataset analyses, we demonstrate that ska lo achieves high sensitivity in single-nucleotide polymorphism (SNP) calls while also enabling the detection of insertions and deletions, as well as SNP positioning on a reference genome for recombination analyses. These findings highlight ska lo as a simple, fast, and effective tool for pathogen genomic epidemiology, extending the range of reference-free variant-calling approaches. ska lo is freely available as part of the SKA program (https://github.com/bacpop/ska.rust).

Polymorphism, Single Nucleotide↗

PubMed2025

CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.

Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text]). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

Chromosomal Instability↗