Mutational Load Research Articles

A population-based study of familial coaggregation and shared genetic etiology of psychiatric and gastrointestinal disorders

BackgroundIt has been proposed that having a psychiatric disorder could increase the risk of developing a gastrointestinal disorder, and vice versa. The role of familial coaggregation and shared genetic loading between psychiatric and gastrointestinal disorders remains unclear.MethodsThis study used the Taiwan National Health Insurance Research Database; 4,504,612 individuals born 1970–1999 with parental information, 51,664 same-sex twins, and 3,322,959 persons with full-sibling(s) were enrolled. Genotyping was available for 106,796 unrelated participants from the Taiwan Biobank. A logistic regression model was used to examine the associations of individual history, affected relatives, and polygenic risk scores (PRS) for schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), and obsessive-compulsive disorder (OCD), with the risk of peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD), and vice versa.ResultsHere we show that parental psychiatric disorders are associated with gastrointestinal disorders. Full-siblings of psychiatric cases have an increased risk of gastrointestinal disorders except for SCZ/BPD and IBD; the magnitude of coaggregation is higher in same-sex twins than in full-siblings. The results of bidirectional analyses mostly remain unchanged. PRS for SCZ, MDD, and OCD are associated with IBS, PUD/GERD/IBS/IBD, and PUD/GERD/IBS, respectively. PRS for PUD, GERD, IBS, and IBD are associated with MDD, BPD/MDD, SCZ/BPD/MDD, and BPD, respectively.ConclusionsThere is familial coaggregation and shared genetic etiology between psychiatric and gastrointestinal comorbidity. Individuals with psychiatric disorder-affected relatives or with higher genetic risk for psychiatric disorders should be monitored for gastrointestinal disorders, and vice versa.

Experimental evidence of inbreeding depression for competitive ability and its population-level consequences in a mixed-mating plant.

Inbreeding depression is a key factor regulating the evolution of self-fertilization in plants. Despite predictions that inbreeding depression should evolve with selfing rates as deleterious alleles are increasingly exposed and removed by selection, evidence of purging the genetic load in wild populations is equivocal at best. This discordance could be explained, in part, if the load underlying inbreeding depression is subject to soft selection, i.e., the fitness of selfed individuals depends on the frequency and density of selfed vs. outcrossed individuals in the population. Somewhat counterintuitively, this means that populations with contrasting mutation load can have similar fitness. Soft selection against selfed individuals may be expected when there is inbreeding depression for competitive ability in density-regulated populations. We tested population-level predictions of inbreeding depression in competitive ability by creating a density series of potted plants consisting of either purely outcrossed, purely selfed, or mixed (50% outcrossed, 50% selfed) seed of the mixed-matingbiennial Sabatia angularis (Gentianaceae) representing ecological neighborhoods. Focusing on the growth and survival of juveniles, we show that mean plant size is independent of neighborhood composition when resources are limiting, but greatest in outcrossed neighborhoods at low densities. Across a range of densities, this manifests as stronger density-dependence in outcrossed populations compared to selfed or mixed ones. We also found significantly greater size inequalities among individuals in mixed neighborhoods, even at high densities where mean juvenile size converged, a key signature of asymmetric competition between outcrossed and selfed individuals. Our work illustrates how soft selection could shelter the genetic load underlying inbreeding depression and its demographic consequences.

Identification of telomere-related lncRNAs and immunological analysis in ovarian cancer.

Ovarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined. Relevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells. A six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets. According to the nomogram, the model could effectively predict prognosis. Furthermore, we detected the levels of regulatory T cells and M2 macrophages were comparatively higher in the high-risk TRLs group, but the levels of activated CD8 T cells and monocytes were the opposite. Finally, the low-risk group was more sensitive to anti-cancer drugs. The mRNA levels of PTPRD-AS1, SPAG5-AS1, FAM27E3, and AC018647.3 were significantly over-expressed in OC cell lines (SKOV3, A2780, CAOV3) in comparison to normal IOSE-80 cells. AC074286.1 were over-expressed in A2780 and CAOV3 cells and CHRM3-AS2 only in A2780 cells. PTPRD-AS1 knockdown decreased the proliferation, cloning, and migration of CAOV3 cells. Our study identified potential biomarkers for the six-TRLs model related to the prognosis of OC.

Concurrent analysis of genome and transcriptome in one single cell

Thus far, multiple techniques for single cell analysis have been developed, yet we lack a relatively simple tool to assess DNA and RNA from the same cell at whole-transcriptome and whole-genome depths. Here we present an updated method for physical separation of cytoplasmic RNA from the nuclei, which allows for simultaneous studies of DNA and RNA from the same single cell. The method consists of three steps—(1) immobilization of a single cell on solid substrate, (2) hypotonic lysis of immobilized single cell, and (3) separation of cytosol containing aqueous phase and immobilized nucleus. We found that DNA and RNA extracted from single cell using our approach is suitable for downstream sequencing-based applications. We demonstrated that the coverage of transcriptome and genome sequencing data obtained after DNA/RNA separation is similar to that observed without separation. We also showed that the separation procedure does not create any noticeable bias in observed mutational load or mutation spectra. Thus, our method can serve as a tool for simultaneous complex analysis of the genome and transcriptome, providing necessary information on the relationship between somatic mutations and the regulation of gene expression.

Abstract B042: Dissection of the T cell infiltrate in mouse pancreatic tumors reveals a diverse tumor-reactive T cell repertoire targeting neoantigens and tumor-associated antigens

Abstract Although pancreatic cancer is generally refractory to immune checkpoint blockade (ICB), recent studies of tumor-infiltrating T cells in human tumor samples demonstrated the presence of in vivo expanded, tumor-reactive T cell receptor (TCR) clonotypes. Here, we explored the T cell repertoire in ICB-refractory murine pancreatic cancer models by combining single-cell transcriptomics with functional TCR characterization. Our initial studies in an orthotopic, transplantable model revealed a remarkable diversity of tumor-reactive TCR clonotypes that could be distinguished from bystander T cells based on gene expression signatures. We identified TCRs exclusively reactive against the tumor of origin, TCRs that also react against an independently derived pancreatic tumor line, and TCRs broadly reactive to tumor cells of diverse tissue origin (e.g. MC38), the latter category being predominant. Subsequent studies were performed in an autochthonous mouse model, in which single focal tumors were induced in the pancreas by means of in vivo electroporation of gene constructs encoding mutant Kras and inducing CRISPR/Cas9-mediated inactivation of tumor suppressor genes. We analyzed the T cell repertoire in tumors with different levels of mutational burden by also inactivating DNA damage repair genes. Interestingly, even in mismatch repair-deficient tumors that featured a high mutational load, the anti-tumor T cell response was primarily directed against recurrent tumor-associated antigens (TAAs) rather than ‘private’ mutanome-encoded neoantigens. Several TAA-reactive TCRs also mediated reactivity against non-transformed cells. Immunopeptidome analysis thus far revealed the identity of 5 cognate antigens targeted by the tumor-reactive TCR repertoire: a mutanome-encoded neoantigen, an epitope encoded by an ectopically expressed endogenous retroviral provirus, and three epitopes derived from TAAs: Lon Peptidase 2 (LONP2), ATPase Na+/K+ Transporting Subunit Beta 3 (ATP1B3) and SEC24B, a component of secretory vesicles. Notably, the overexpression of LONP2 and ATP1B3 was found associated with progression of human cancers, whereas silencing was shown to suppress tumor cell growth. Overexpression of SEC24B in cancers has not been reported, but this protein plays an essential role in the secretory pathway of acinar cells. In summary, in-depth analysis of the natural T cell response in murine pancreatic cancer models revealed a diverse tumor-reactive T cell repertoire that is predominantly directed against TAAs, some of which are also expressed in normal somatic cells. These findings underline the importance of uncovering the antigen-specificity of the natural tumor-reactive TCR repertoire, both in mouse models and human tumor samples, to assess its therapeutic potential and safety with regard to personalized immunotherapy. Citation Format: Stefan Zens, Hannes Kehm, Daniel Baumann, Aline Konrad, Zibo Meng, Arnoud H. de Ru, Julian Mochayedi, Francesca Lucato, Angelika B. Riemer, Isabel Poschke, Michael Volkmar, Peter A. van Veelen, Rienk Offringa. Dissection of the T cell infiltrate in mouse pancreatic tumors reveals a diverse tumor-reactive T cell repertoire targeting neoantigens and tumor-associated antigens [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B042.

APOBEC family reshapes the immune microenvironment and therapy sensitivity in clear cell renal cell carcinoma

Emerging evidence suggests that the APOBEC family is implicated in multiple cancers and might be utilized as a new target for cancer detection and treatment. However, the dysregulation and clinical implication of the APOBEC family in clear cell renal cell cancer (ccRCC) remain elusive. TCGA multiomics data facilitated a comprehensive exploration of the APOBEC family across cancers, including ccRCC. Remodeling analysis classified ccRCC patients into two distinct subgroups: APOBEC family pattern cancer subtype 1 (APCS1) and subtype 2 (APCS2). The study investigated differences in clinical parameters, tumor immune microenvironment, therapeutic responsiveness, and genomic mutation landscapes between these subtypes. An APOBEC family-related risk model was developed and validated for predicting ccRCC patient prognosis, demonstrating good sensitivity and specificity. Finally, the overview of APOBEC3B function was investigated in multiple cancers and verified in clinical samples. APCS1 and APCS2 demonstrated considerably distinct clinical features and biological processes in ccRCC. APCS1, an aggressive subtype, has advanced clinical stage and a poor prognosis. APCS1 exhibited an oncogenic and metabolically active phenotype. APCS1 also exhibited a greater tumor mutation load and immunocompromised condition, resulting in immunological dysfunction and immune checkpoint treatment resistance. The genomic copy number variation of APCS1, including arm gain and loss, was much more than that of APCS2, which may help explain the tired immune system. Furthermore, the two subtypes have distinct drug sensitivity patterns in clinical specimens and matching cell lines. Finally, we developed a predictive risk model based on subtype biomarkers that performed well for ccRCC patients and validated the clinical impact of APOBEC3B. Aberrant APOBEC family expression patterns might modify the tumor immune microenvironment by increasing the genome mutation frequency, thus inducing an immune-exhausted phenotype. APOBEC family-based molecular subtypes could strengthen the understanding of ccRCC characterization and guide clinical treatment. Targeting APOBEC3B may be regarded as a new therapeutic target for ccRCC.

Evolution of the correlated genomic variation landscape across a divergence continuum in the genus Castanopsis.

The heterogeneous landscape of genomic variation has been well documented in population genomic studies. However, disentangling the intricate interplay of evolutionary forces influencing the genetic variation landscape over time remains challenging. In this study, we assembled a chromosome-level genome for Castanopsis eyrei and sequenced the whole genomes of 276 individuals from 12 Castanopsis species, spanning a broad divergence continuum. We found highly correlated genomic variation landscapes across these species. Furthermore, variations in genetic diversity and differentiation along the genome were strongly associated with recombination rates and gene density. These results suggest that long-term linked selection and conserved genomic features have contributed to the formation of a common genomic variation landscape. By examining how correlations between population summary statistics change throughout the species divergence continuum, we determined that background selection alone does not fully explain the observed patterns of genomic variation; the effects of recurrent selective sweeps must be considered. We further revealed that extensive gene flow has significantly influenced patterns of genomic variation in Castanopsis species. The estimated admixture proportion correlated positively with recombination rate and negatively with gene density, supporting a scenario of selection against gene flow. Additionally, putative introgression regions exhibited strong signals of positive selection, an enrichment of functional genes, and reduced genetic burdens, indicating that adaptive introgression has played a role in shaping the genomes of hybridizing species. This study provides insights into how different evolutionary forces have interacted in driving the evolution of the genomic variation landscape.

Identification of novel candidate predisposing genes in familial nonmedullary thyroid carcinoma implicating DNA damage repair pathways.

The genetic basis of nonsyndromic familial nonmedullary thyroid carcinoma (FNMTC) is still poorly understood, as the susceptibility genes identified so far only account for a small percentage of the genetic burden. Recently, germline mutations in DNA repair-related genes have been reported in cases with thyroid cancer. In order to clarify the genetic basis of FNMTC, 94 genes involved in hereditary cancer predisposition, including DNA repair genes, were analyzed in 48 probands from FNMTC families, through targeted next-generation sequencing (NGS). Genetic variants were selected upon bioinformatics analysis and in silico studies. Structural modeling and network analysis were also performed. In silico results of NGS data unveiled likely pathogenic germline variants in 15 families with FNMTC, in genes encoding proteins involved in DNA repair (ATM, CHEK2, ERCC2, BRCA2, ERCC4, FANCA, FANCD2, FANCF, and PALB2) and in the DICER1, FLCN, PTCH1, BUB1B, and RHBDF2 genes. Structural modeling predicted that most missense variants resulted in the disruption of networks of interactions between residues, with implications for local secondary and tertiary structure elements. Functional annotation and network analyses showed that the involved DNA repair proteins functionally interact with each other, within the same DNA repair pathway and across different pathways. MAPK activation was a common event in tumor progression. This study supports that rare germline variants in DNA repair genes may be accountable for FNMTC susceptibility, with potential future utility in patients' clinical management, and reinforces the relevance of DICER1 in disease etiology.

Pangenome Identification and Analysis of Terpene Synthase Gene Family Members in Gossypium.

Terpene synthases (TPSs), key gatekeepers in the biosynthesis of herbivore-induced terpenes, are pivotal in the diversity of terpene chemotypes across and within plant species. Here, we constructed a gene-based pangenome of the Gossypium genus by integrating the genomes of 17 diploid and 10 tetraploid species. Within this pangenome, 208 TPS syntelog groups (SGs) were identified, comprising 2 core SGs (TPS5 and TPS42) present in all 27 analyzed genomes, 6 softcore SGs (TPS11, TPS12, TPS13, TPS35, TPS37, and TPS47) found in 25 to 26 genomes, 131 dispensable SGs identified in 2 to 24 genomes, and 69 private SGs exclusive to a single genome. The mutational load analysis of these identified TPS genes across 216 cotton accessions revealed a great number of splicing variants and complex splicing patterns. The nonsynonymous/synonymous Ka/Ks value for all 52 analyzed TPS SGs was less than one, indicating that these genes were subject to purifying selection. Of 208 TPS SGs encompassing 1795 genes, 362 genes derived from 102 SGs were identified as atypical and truncated. The structural analysis of TPS genes revealed that gene truncation is a major mechanism contributing to the formation of atypical genes. An integrated analysis of three RNA-seq datasets from cotton plants subjected to herbivore infestation highlighted nine upregulated TPSs, which included six previously characterized TPSs in G. hirsutum (AD1_TPS10, AD1_TPS12, AD1_TPS40, AD1_TPS42, AD1_TPS89, and AD1_TPS104), two private TPSs (AD1_TPS100 and AD2_TPS125), and one atypical TPS (AD2_TPS41). Also, a TPS-associated coexpression module of eight genes involved in the terpenoid biosynthesis pathway was identified in the transcriptomic data of herbivore-infested G. hirsutum. These findings will help us understand the contributions of TPS family members to interspecific terpene chemotypes within Gossypium and offer valuable resources for breeding insect-resistant cotton cultivars.

Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia

Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients. In addition to two clock-like mutational processes, we identified UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component as drivers of mutagenesis. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Thiopurine exposure was the most prominent source of new mutations in relapse, affecting over half of the studied patients in first and/or later relapse and causing potential relapse-driving mutations in multiple patients. Our data demonstrate that multiple mutational processes frequently act in parallel as prominent secondary drivers with dynamic activity during ALL development and progression.

Sonification of Genomic Data to Represent Genetic Load in Zoo Populations.

Maintaining a diverse gene pool is important in the captive management of zoo populations, especially in endangered species such as the pink pigeon (Nesoenas mayeri). However, due to the limited number of breeding individuals and relaxed natural selection, the loss of variation and accumulation of harmful variants is inevitable. Inbreeding results in a loss of fitness (i.e., inbreeding depression), principally because related parents are more likely to transmit a copy of the same recessive deleterious genetic variant to their offspring. Genomics-informed captive breeding can manage harmful variants by artificial selection, reducing the genetic load by avoiding the inheritance of two copies of the same harmful variant. To explain this concept in an interactive way to zoo visitors, we developed a sonification game to represent the fitness impacts of harmful variants by detuning notes in a familiar musical melody (i.e., Beethoven's Für Elise). Conceptually, zoo visitors play a game aiming to create the most optimal pink pigeon offspring in terms of inbreeding depression. They select virtual crosses between pink pigeon individuals and listen for the detuning of the melody, which represents the realised load of the resultant offspring. Here we present the sonification algorithm and the results of an online survey to see whether participants could identify the most and least optimal offspring from three potential pink pigeon offspring. Of our 98 respondents, 85 (86.7%) correctly identified the least optimal offspring, 73 (74.5%) correctly identified the most optimal, and 62 (63.3%) identified both the most and least optimal offspring using only the sonification.

The genetic architecture of the load linked to dominant and recessive self-incompatibility alleles in Arabidopsis halleri and Arabidopsis lyrata

The long-term balancing selection acting on mating types or sex-determining genes is expected to lead to the accumulation of deleterious mutations in the tightly linked chromosomal segments that are locally ‘sheltered’ from purifying selection. However, the factors determining the extent of this accumulation are poorly understood. Here, we took advantage of variations in the intensity of balancing selection along a dominance hierarchy formed by alleles at the sporophytic self-incompatibility system of the Brassicaceae to compare the pace at which linked deleterious mutations accumulate among them. We first experimentally measured the phenotypic manifestation of the linked load at three different levels of the dominance hierarchy. We then sequenced and phased polymorphisms in the chromosomal regions linked to 126 distinct copies of S-alleles in two populations of Arabidopsis halleri and three populations of Arabidopsis lyrata. We find that linkage to the S-locus locally distorts phylogenies over about 10–30 kb along the chromosome. The more intense balancing selection on dominant S-alleles results in greater fixation of linked deleterious mutations, while recessive S-alleles accumulate more linked deleterious mutations that are segregating. Hence, the structure rather than the overall magnitude of the linked genetic load differs between dominant and recessive S-alleles. Our results have consequences for the long-term evolution of new S-alleles, the evolution of dominance modifiers between them, and raise the question of why the non-recombining regions of some sex and mating type chromosomes expand over evolutionary times while others, such as the S-locus of the Brassicaceae, remain restricted to small chromosomal regions.

The genetic architecture of the load linked to dominant and recessive self-incompatibility alleles in Arabidopsis halleri and Arabidopsis lyrata.

The long-term balancing selection acting on mating types or sex-determining genes is expected to lead to the accumulation of deleterious mutations in the tightly linked chromosomal segments that are locally 'sheltered' from purifying selection. However, the factors determining the extent of this accumulation are poorly understood. Here, we took advantage of variations in the intensity of balancing selection along a dominance hierarchy formed by alleles at the sporophytic self-incompatibility system of the Brassicaceae to compare the pace at which linked deleterious mutations accumulate among them. We first experimentally measured the phenotypic manifestation of the linked load at three different levels of the dominance hierarchy. We then sequenced and phased polymorphisms in the chromosomal regions linked to 126 distinct copies of S-alleles in two populations of Arabidopsis halleri and three populations of Arabidopsis lyrata. We find that linkage to the S-locus locally distorts phylogenies over about 10-30 kb along the chromosome. The more intense balancing selection on dominant S-alleles results in greater fixation of linked deleterious mutations, while recessive S-alleles accumulate more linked deleterious mutations that are segregating. Hence, the structure rather than the overall magnitude of the linked genetic load differs between dominant and recessive S-alleles. Our results have consequences for the long-term evolution of new S-alleles, the evolution of dominance modifiers between them, and raise the question of why the non-recombining regions of some sex and mating type chromosomes expand over evolutionary times while others, such as the S-locus of the Brassicaceae, remain restricted to small chromosomal regions.

Healthy first-degree relatives from multiplex families versus simplex families have a higher subclinical intestinal inflammation, a distinct fecal microbial signature, and harbor a higher risk of developing Crohn’s disease

BACKGROUND & AIMSUnaffected first-degree relatives (FDRs) from families with two or more affected FDRs with Crohn’s disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex versus simplex families and to investigate the risk of future CD onset accounting for potential confounders. METHODSWe assessed the Crohn’s and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy FDRs of patients with CD. Genome-wide CD-polygenic risk scores (CD-PRS), urinary fractional excretion of lactulose-to-mannitol ratio (LMR), fecal calprotectin (FCP), and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between CD multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future CD onset. RESULTSThere were 4051 participants from simplex families and 334 from CD multiplex families. CD multiplex status was significantly associated with higher baseline FCP (p=0.026) but not with baseline CD-PRS or LMR. Three bacterial genera were found to be differentially abundant between both groups. CD multiplex status at recruitment was independently associated with an increased risk of developing CD (adjusted hazard ratio 3.65, 95% confidence interval 2.18 – 6.11, p < 0.001). CONCLUSIONWithin FDRs of patients with CD, participants from multiplex families had a 3-fold increased risk of CD onset, a higher FCP, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in FDRs from multiplex families.

Effects of mode of reproduction on genetic polymorphism and divergence in wild yams (Dioscoreaceae: Dioscorea)

Evolutionary transitions from sexual to asexual reproduction should have significant influences on genetic divergence and polymorphism at the genome level. Plant lineages with diverse reproductive systems provide opportunities to investigate this question using comparative approaches and studies of molecular evolution. We investigated evidence for differences among the transcriptomes of 19 Dioscorea species (wild yams) with diverse reproductive systems. These included sexual species, those that propagate primarily by bulbils, and those with mixed sexual and asexual reproductive modes. We examined how transitions between these reproductive systems affected between-species divergence and within-species polymorphism. Primarily asexual species exhibited a reduced efficacy of natural selection and accumulation of deleterious mutations for both divergence and polymorphism. In contrast, species with mixed reproductive strategies involving both seed and clonal reproduction showed no evidence of an increased fixation of harmful mutations at the divergence level, while an accumulation of genetic load present in polymorphism was evident. Our study indicates that the genetic consequences of evolutionary transitions from sexual to predominantly clonal reproduction is likely to depend on both the duration and extent of asexuality occurring in populations.

Identification of E3 ubiquitin ligase-associated prognostic genes and construction of a prediction model for uterine cervical cancer based on bioinformatics analysis

E3 ligases are engaged in a variety of physiological processes within cells and use ubiquitin-labeled substrates to control their activity and stability. Although some research has indicated that E3 ligases or particular substrates have an impact on the treatment that cervical cancer patients get after their diagnosis, The exact purpose of these enzymes in the occurrence and evolution of cancer of the cervical region (CC) is not clear. In order to extract and analyze relevant mRNA gene expression data as well as clinical patient data, we used open databases. A reliable risk prediction model was developed by applying the least absolute shrinkage and selection operator (LASSO) technique in conjunction with Cox regression analysis. Column-line plots were combined to analyze the predictive model, and the GSE44001 dataset served as an external validation.Four gene models:proteasome (prosome, macropain) 26S subunit, non-ATPase, 14(PSMD14),proteasome (prosome, macropain) subunit, alpha type, 4(PSMA4,),zinc finger and BTB domain containing 16(ZBTB16),and ankyrin repeat domain 9(ANKRD9). Gene expression levels in both healthy and cancerous tissues have been confirmed by the HPA database. Next, the investigation focused on immunological state and tumor mutation load. The high-risk group and Cluster B had distinct levels of immune cell infiltration and a worse prognosis. Additionally, KEGG and GO analyses of differentially expressed genes (DEGs) between the high- and low-risk groups were performed, as well as tumor microenvironment (TME) investigations. Targeting E3 ligases may be an efficient strategy to treat cervical cancer (CC), according to a novel and comprehensive E3 ubiquitination ligase-associated gene model that has been presented.

Impact of Gut Microbiota on Aging and Frailty: A Narrative Review of the Literature.

Aging is a natural, complex, and individual process that focuses on the progressive decay of the body and a decrease in cell function that begins in approximately the sixth decade of life and ends with death. Current scientific evidence shows that the aging process is mostly related to genetic load and varies because of the environment. Therefore, aging can be adjusted through the intervention of factors that control homeostasis in genetic, biochemical, and immunological processes, including those involving the gut microbiota. Indeed, the diversity of the gut microbiota decreases during aging, based on the presence of modifications in the hormonal, immunological, and operational processes of the gastrointestinal tract. These modifications lead to a state of dysbiosis. However, altering bacterial communities remains complicated due to the great diversity of factors that influence their modification. Alterations caused by the aging process are known to foster dysbiosis and correspond to conditions that determine the degree of frailty in senior citizens. Consequently, the microbial structure can be used as a biomarker for geriatric care in the promotion of healthy aging.

Beyond population size: whole-genome data reveal bottleneck legacies in the peninsular Italian wolf.

Preserving genetic diversity and adaptive potential while avoiding inbreeding depression is crucial for the long-term conservation of natural populations. Despite demographic increases, traces of past bottleneck events at the genomic level should be carefully considered for population management. From this perspective, the peninsular Italian wolf is a paradigmatic case. After being on the brink of extinction in the late 1960s, peninsular Italian wolves rebounded and recolonized most of the peninsula aided by conservation measures, including habitat and legal protection. Notwithstanding their demographic recovery, a comprehensive understanding of the genomic consequences of the historical bottleneck in Italian wolves is still lacking. To fill this gap, we sequenced whole genomes of thirteen individuals sampled in the core historical range of the species in Central Italy to conduct population genomic analyses, including a comparison with wolves from two highly-inbred wolf populations (i.e., Scandinavia and Isle Royale). We found that peninsular Italian wolves, despite their recent recovery, still exhibit relatively low genetic diversity, a small effective population size, signatures of inbreeding, and a non-negligible genetic load. Our findings indicate that the peninsular Italian wolf population is still susceptible to bottleneck legacies, which could lead to local inbreeding depression in case of population reduction or fragmentations. This study emphasizes the importance of considering key genetic parameters to design appropriate long-term conservation management plans.

Large-scale genome sequencing of giant pandas improves the understanding of population structure and future conservation initiatives

The extinction risk of the giant panda has been demoted from "endangered" to "vulnerable" on the International Union for Conservation of Nature Red List, but its habitat is more fragmented than ever before, resulting in 33 isolated giant panda populations according to the fourth national survey released by the Chinese government. Further comprehensive investigations of the genetic background and in-depth assessments of the conservation status of wild populations are still necessary and urgently needed. Here, we sequenced the genomes of 612 giant pandas with an average depth of ~26× and generated a high-resolution map of genomic variation with more than 20 million variants covering wild individuals from six mountain ranges and captive representatives in China. We identified distinct genetic clusters within the Minshan population by performing a fine-grained genetic structure. The estimation of inbreeding and genetic load associated with historical population dynamics suggested that future conservation efforts should pay special attention to the Qinling and Liangshan populations. Releasing captive individuals with a genetic background similar to the recipient population appears to be an advantageous genetic rescue strategy for recovering the wild giant panda populations, as this approach introduces fewer deleterious mutations into the wild population than mating with differentiated lineages. These findings emphasize the superiority of large-scale population genomics to provide precise guidelines for future conservation of the giant panda.

PLCG2, A Regulator of Lung Adenocarcinoma Proliferation and Migration Associated with Immune Infiltration.

Results from the TCGA database showed that phosphatidylinositol-specific phospholipase Cγ2 (PLCG2) expression level in Lung Adenocarcinoma (LUAD) was notably decreased compared to adjacent tissues, so we unveiled its role of LUAD. This study aims to explore the expression and clinical significance of Phosphatidyl-inositol-specific phospholipase Cγ2 (PLCG2) in lung adenocarcinoma (LUAD) cells and its role in cell proliferation and metastasis. Differential PLCG2 mRNA and protein levels between LUAD tissues and adjacent tissues were analyzed from the TCGA database, TIMER, and UALCAN database. Differentially expressed genes were screened for patients in the high and low PLCG2 mRNA expression groups by the R package as well as GSEA. The expression level of PLCG2 in LUAD cells was detected using qRT-PCR and CCK8, clone formation, Transwell, and Western blot assays. PLCG2 was lowly expressed in LUAD and did not significantly correlate with the prognosis of LUAD. PLCG2 expression levels varied significantly in terms of patients' gender, age, T, N, and pathological stage. GO/KEGG enrichment analysis showed that co-expression of PLCG2 was mainly associated with the immune response- regulating cell-surface receptors, and so on. GSEA analysis showed enrichment pathways of PLCG2-related differential gees were primarily associated with the olfactory transduction pathway, ribosome, etc. R software analysis revealed a significant correlation between PLCG2 expression and six types of immune-infiltrat-ing cells, positively correlated with immune checkpoint-related genes and negatively regulated by tumor mutational load. Overexpressing PLCG2 showed reduced LUAD cell proliferation, clone formation, cell migration and invasion, and epithelial-mesenchymal transition-associated proteins, compared with the control group. PLCG2 is lowly expressed in LUAD tissues and is involved in immune infiltration of LUAD, inhibiting LUAD cell proliferation and metastasis.