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Undoubtedly, intratumor heterogeneity (ITH) is one of the causes of the intractability of cancers. Recently, technological innovation in genomics has promoted studies on ITH in solid tumors and on the pattern and level of diversity, which varies among malignancies. We profiled the genome in multiple regions of nine colorectal cancer (CRC) cases. The most impressive finding was that in the late phase, a parental clone branched into numerous subclones. We found that minor mutations were dominant in advanced CRC named neutral evolution; that is, driver gene aberrations were observed with high proportion in the early‐acquired phase, but low in the late‐acquired phase. Then, we validated that neutral evolution could cause ITH in advanced CRC by super‐computational analysis. According to the clinical findings, we explored a branching evolutionary process model in cancer evolution, which assumes that each tumor cell has cellular automaton. According to the model, we verified factors to foster ITH with neutral evolution in advanced CRC. In this review, we introduce recent advances in the field of ITH including the general component of ITH, clonal selective factors that consolidate the evolutionary process, and a representative clinical application of ITH.

ABSTRACT MUC16 ranks among the top three genes exhibiting the highest mutation frequencies in various cancer types. It encodes transmembrane mucins present in the epithelial linings of the ocular, respiratory, gastric and female reproductive systems, serving to protect and maintain mucosal surfaces. Overexpression of MUC16 contributes to the differentiation, proliferation, invasion and metastasis of cancer cells in ovarian, endometrial, pancreatic, colon, breast and non‐small‐cell lung cancers. In this study, we analysed the structural and functional effects of pathogenic and potentially harmful non‐synonymous single nucleotide polymorphisms (nsSNPs) of MUC16, employing a blend of computational algorithms. Initially, SNPs data for MUC16 were gathered from the Ensembl database and refined using computational tools (PROVEAN, SIFT, PolyPhen‐2, SNAP‐2, MutPred, I‐Mutant3.0 and MUpro) to isolate four final pathogenic SNP variants (L151P, Y144N, C111Y and D108Y). Through evolutionary conservation analysis, we determined that these mutational variants originate from a highly conserved and stable domain. Our findings particularly emphasise the Y144N variant as a potentially highly deleterious mutation situated in the SEA5 domain. This variant could significantly impact stability, overall flexibility, compactness, expansion, glycosylation ability and metastatic potential when compared to both the wild‐type and other mutant variants. In summary, these findings shed light on missense mutational variants, providing insights into the vast array of disease susceptibilities associated with MUC16's glycosylation process. This understanding could aid in the development of effective drugs for diseases linked with these mutations.

Recent clinical trials of non‐small cell lung cancer with immune checkpoint inhibitors revealed that patients with epidermal growth factor receptor (EGFR) mutations had more unfavorable outcomes compared with those with wild‐type EGFR. However, the underlying mechanism for the link between EGFR mutations and immune resistance remains unclear. We performed T cell receptor (TCR) repertoire analysis of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate the characteristics of TCR repertoires. We collected a total of 39 paired (normal and tumor) lung tissue samples (20 had EGFR mutations) and conducted TCR repertoire analysis as well as whole‐exome sequencing (WES) and transcriptome analysis. The TCR diversity index in EGFR‐mutant tumors was significantly higher than that in EGFR‐wild‐type tumors (median [range] 552 [162‐1,135] vs 230 [30‐764]; P < .01), suggesting higher T cell clonal expansion in EGFR‐wild‐type tumors than in EGFR‐mutant tumors. In WES, EGFR‐mutant tumors showed lower numbers of non‐synonymous mutations and predicted neoantigens than EGFR‐wild‐type tumors (P < .01, P = .03, respectively). The number of non‐synonymous mutations revealed a positive correlation with the sum of frequencies of the TCRβ clonotypes of 1% or higher in tumors (r = .52, P = .04). The present study demonstrates significant differences in TCR repertoires and the number of predicted neoantigens between EGFR‐mutant and wild‐type lung tumors. Our findings provide important information for understanding the molecular mechanism behind EGFR‐mutant patients showing unfavorable responses to immune checkpoint inhibitors. We report distinct characteristics of TCR repertoires in lung adenocarcinomas with and without EGFR mutations.

Zyxin functions as a regulator of the restructuring of the actin cytoskeleton during the process of repairing tissue damage, cell movement and attachment. It has also been identified as a potential gene involved in chicken coccidiosis. In order to gain a deeper understanding of these phenomena, we employed a collection of computer-based techniques and databases to examine the amino acid sequence, structural dynamics, molecular interactions, and activities of the gene. Our analysis revealed that Zyxin contains two non-synonymous SNPs (A > C at position 22 and G > A at position 137) at exon 1. Also, there existed a non-synonymous SNPs in Exon 3 (A>C and A>T both at position 861) of the gene with Synonymous SNPs observed only in exon 3 (A>G at position 812 and 854, T > C at position 863). The genetic diversity revealed in these chicken populations indicates the presence of genetic variation, with Naked neck chickens showing a considerably higher frequency of particular SNPs. Two non-synonymous single nucleotide polymorphisms (nsSNPs) were forecasted to exert a profound influence on the structure, stability, and activities of Zyxin, thereby heightening the vulnerability to coccidiosis.

Objective: This study aims to explore mutation based on single nucleotide polymorphism (SNP) in the Cholecystokinin B receptor (CCKBR) gene of Pelung chickens. Materials and Methods: We collected DNA samples from 48 Pelung roosters that had won the crowing competition. The CCKBR target encompasses exon 3, intron 3, exon 4, and a part of intron 4, a long 601 bp. This target was replicated using PCR with specific primers that were designed by Primer-BLAST from NCBI. We generated the nucleotide sequence from the PCR product’s sequencing results. The SNP analysis was done by BioEdit and MEGA. Genotyping and haplotyp¬ing were done based on nonsynonymous single nucleotide polymorphisms (SNPs) on exons 3 and 4. We calculated allele and genotype frequency, heterozygosity, and Hardy-Weinberg Equilibrium (HWE) using POPGENE 32 programs. Results: This study found three nonsynonymous single nucleotide polymorphisms. The nsSNP in exon 3 alters the coding for the 210th amino acid from serine to asparagine (g.1290 G > A/S210N), while the SNPs in exon 4 alter the coding for the 232nd amino acid from valine to phenylalanine (g.1423G > T/V232F) and the 243rd amino acid that changes the amino acid valine to glycine (g.1457T > G/V243G). The frequency of the mutated alleles is lower than the unmutated alleles. However, the mutation at position g.1457T > G/V243G produces a higher frequency than the unmutated allele. The allele and genotype frequency were not in HWE. It was caused by intensive selection in Pelung chickens, especially for growing capacity. Conclusion: Nonsynonymous mutation on CCKBR may cause variations in the crowing and other traits such as the growth of Pelung chickens. Further studies are needed to explore the CCKBR gene, including the relationship of the gene with the vigor and/or stress level of Pelung chickens.

Human mitochondrial DNA (mtDNA) is a relevant marker in evolutionary and population genetics, including ancient DNA (aDNA) research, due to inherent characteristics. However, aDNA is prone to damage and sequencing artefacts, potentially confounding evolutionary interpretations. To assess evolutionary patterns in ancient and modern mtDNA, we built a phylogeny comprising 63,965 modern and 3757 ancient public mitogenomes, classified mutations by genomic region and functional effect, and analysed distribution, frequency, and predicted pathogenicity of private and pre-terminal mutations, investigating purifying selection. We compared mutation class ratios (non-synonymous, rRNA, tRNA, nonsense vs. synonymous) across ancient and modern terminal branches and pre-terminal nodes. The predicted pathogenicity of non-synonymous mutations was evaluated across major European haplogroups using three tools. Ancient variants exhibited higher ratios of potentially deleterious mutations and significantly elevated pathogenicity scores compared to modern and pre-terminal branches, highlighting a mutation load likely inflated by damage-related artefacts. Remarkably, nonsense mutations—largely incompatible with life—were over 70 times more frequent in aDNA. The correlation between mutation ratios and predicted deleteriousness across haplogroups suggests a pattern incompatible with biological persistence or relaxed selection alone. These findings highlight the importance of rigorous quality control for ancient data in evolutionary inference, molecular clock calibration, and pathogenic variant identification.

A-to-I RNA editing is an important post-transcriptional modification that converts adenosine (A) to inosine (I) in RNA molecules via hydrolytic deamination. Although editing of mRNAs catalyzed by adenosine deaminases acting on RNA (ADARs) is an evolutionarily conserved mechanism in metazoans, organisms outside the animal kingdom lacking ADAR orthologs were thought to lack A-to-I mRNA editing. However, recent discoveries of genome-wide A-to-I mRNA editing during the sexual stage of the wheat scab fungus Fusarium graminearum, model filamentous fungus Neurospora crassa, Sordaria macrospora, and an early diverging filamentous ascomycete Pyronema confluens indicated that A-to-I mRNA editing is likely an evolutionarily conserved feature in filamentous ascomycetes. More importantly, A-to-I mRNA editing has been demonstrated to play crucial roles in different sexual developmental processes and display distinct tissue- or development-specific regulation. Contrary to that in animals, the majority of fungal RNA editing events are non-synonymous editing, which were shown to be generally advantageous and favored by positive selection. Many non-synonymous editing sites are conserved among different fungi and have potential functional and evolutionary importance. Here, we review the recent findings about the occurrence, regulation, function, and evolution of A-to-I mRNA editing in fungi.

Dry direct-seeding of rice is rapidly increasing in China, but variable planting depth associated with machine sowing can lead to low seedling emergence rates. Phenotype analysis of 621 rice accessions showed that mesocotyl length (ML) was induced by deep soil covering and was important in deep-sowing tolerance in the field. Here, we performed and compared GWAS using three types of SNPs (non-synonymous SNP, non-synonymous SNPs and SNPs within promoters and 3 million randomly selected SNPs from the entire set of SNPs) and found that Non-Syn GWAS (GWAS using non-synonyomous SNP) decreased computation time and eliminated confounding by other loci relative to GWAS using randomly selected SNPs. Thirteen QTLs were finally detected, and two new major-effect genes, named and , were identified by an integrated analysis. There were 2 and 7 non-synonymous SNPs in and , respectively, from which 3 and 4 haplotypes were detected in cultivated rice. Combinations of superior haplotypes of and increased ML by up to 4 cm, representing high emergence rate (85%) in the field with 10 cm of soil cover. The studies provide key loci and naturally occurring alleles of ML that can be used in improving tolerance to dry direct-seeding.

Background Single nucleotide polymorphisms (SNPs) have emerged as the marker of choice in breeding and genetics, particularly in non-model organisms such as black pepper ( Piper nigrum L.), a globally recognized spice crop. This study presents a comprehensive catalog of SNPs in the black pepper genome using data from 30 samples obtained from RNA sequencing and restriction site-associated DNA sequencing, retrieved from the Sequence Read Archive, and their consequences at the sequence level. Results Three SNP calling and filtering pipelines, namely BCFtools, Genome Analysis Toolkit (GATK)-soft filtering, and GATK-hard filtering, were employed. Results revealed 498,128, 396,003, and 312,153 SNPs respectively identified by these pipelines, with 260,026 SNPs commonly detected across all methods. Analysis of SNP distribution across the 45 scaffolds of the black pepper genome showed varying densities, with pseudo-chromosomes Pn25 (0.86 SNPs/kb), Pn8 (0.74 SNPs/kb), and Pn7 (0.72 SNPs/kb) exhibiting the highest densities. Conversely, scaffolds Pn27 to Pn43 exhibited minimal SNP distribution, except Pn45. Approximately 34.80% of SNPs exhibited stronger genetic linkage ( r 2   >  0.7). Moreover, SNPs predominately mapped to downstream (≈ 32.54%), upstream (≈ 22.52%), and exonic (≈ 16.20%) regions of genes. Transition substitution accounted for the majority (≈ 57.42%) of identified SNPs, resulting in an average transition-to-transversion ratio of 1.36. Notably, 56.09% of SNPs were non-synonymous, with a significant proportion (≈ 53.59%) being missense mutations. Additionally, 12,491 SNPs with high or moderate impacts were identified, particularly in genes associated with secondary metabolism and alkaloid biosynthesis pathways. Furthermore, the expression of 675 genes was potentially influenced by local (cis-acting) SNPs, while 554 genes were affected by distal (trans-acting) SNPs. Conclusion The findings of the present study underscore the utility of identified SNPs and their targets, especially those impacting important pathways, for future genetic investigations and crop improvement efforts in black pepper. The characterization of SNPs in genes related to secondary metabolism and alkaloid biosynthesis highlights their potential for targeted breeding aimed at enhancing the yield, quality, and resilience of this economically important crop in diverse environmental conditions.

Background Deep mutational scanning (DMS) studies exploit the mutational landscape of sequence variation by systematically and comprehensively assaying the effect of single amino acid variants (SAVs; also referred to as missense mutations, or non-synonymous Single Nucleotide Variants – missense SNVs or nsSNVs) for particular proteins. We assembled SAV annotations from 22 different DMS experiments and normalized the effect scores to evaluate variant effect prediction methods. Three trained on traditional variant effect data (PolyPhen-2, SIFT, SNAP2), a regression method optimized on DMS data (Envision), and a naïve prediction using conservation information from homologs. Results On a set of 32,981 SAVs, all methods captured some aspects of the experimental effect scores, albeit not the same. Traditional methods such as SNAP2 correlated slightly more with measurements and better classified binary states (effect or neutral). Envision appeared to better estimate the precise degree of effect. Most surprising was that the simple naïve conservation approach using PSI-BLAST in many cases outperformed other methods. All methods captured beneficial effects (gain-of-function) significantly worse than deleterious (loss-of-function). For the few proteins with multiple independent experimental measurements, experiments differed substantially, but agreed more with each other than with predictions. Conclusions DMS provides a new powerful experimental means of understanding the dynamics of the protein sequence space. As always, promising new beginnings have to overcome challenges. While our results demonstrated that DMS will be crucial to improve variant effect prediction methods, data diversity hindered simplification and generalization.