Pathogenic variants in human DNA damage repair genes mostly arose in recent human history.

Background: Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases.

Classification of MLH1 Missense VUS Using Protein Structure-Based Deep Learning-Ramachandran Plot-Molecular Dynamics Simulations Method.

Pathogenic variation in DNA mismatch repair (MMR) gene is associated with Lynch syndrome (LS), an autosomal dominant hereditary cancer. Of the 3798 germline variants collected in the ClinVar database, 38.7% (1469) were missense variants, of which 81.

Integration of deep learning with Ramachandran plot molecular dynamics simulation for genetic variant classification.

Functional classification of genetic variants is a key for their clinical applications in patient care. However, abundant variant data generated by the next-generation DNA sequencing technologies limit the use of experimental methods for their classification. Here, we developed a protein structure and deep learning (DL)-based system for genetic variant classification, DL-RP-MDS, which comprises two principles: 1) Extracting protein structural and thermodynamics information using the Ramachandran plot-molecular dynamics simulation (RP-MDS) method, 2) combining those data with an unsupervised learning model of auto-encoder and a neural network classifier to identify the statistical significance patterns of the structural changes.

Mr.Vc v2: An updated version of database with increased data of transcriptome and experimental validated interactions.

Mr.Vc is a database of curated transcriptome data and annotated information. The main objective is to facilitate the accessibility and reusability of the rapidly growing omics data and relevant annotation.

Ethnic-specificity, evolution origin and deleteriousness of Asian BRCA variation revealed by over 7500 BRCA variants derived from Asian population.

Pathogenic variation in BRCA1 and BRCA2 (BRCA) causes high risk of breast and ovarian cancer, and BRCA variation data are important markers for BRCA-related clinical cancer applications. However, comprehensive BRCA variation data are lacking from the Asian population despite its large population size, heterogenous genetic background and diversified living environment across the Asia continent. We performed a systematic study on BRCA variation in Asian population including extensive data mining, standardization, annotation and characterization.

Antibiotic-Induced Primary Biles Inhibit SARS-CoV-2 Endoribonuclease Nsp15 Activity in Mouse Gut.

The gut microbiome profile of COVID-19 patients was found to correlate with a viral load of SARS-CoV-2, COVID-19 severity, and dysfunctional immune responses, suggesting that gut microbiota may be involved in anti-infection. In order to investigate the role of gut microbiota in anti-infection against SARS-CoV-2, we established a high-throughput screening system for COVID-19 therapeutics by targeting the endoribonuclease (Nsp15). We also evaluated the activity inhibition of the target by substances of intestinal origin, using a mouse model in an attempt to explore the interactions between gut microbiota and SARS-CoV-2.

Distinct landscapes of deleterious variants in DNA damage repair system in ethnic human populations.

Deleterious variants in DNA damage repair (DDR) system can cause genome instability and increase cancer risk. In this study, we analyzed the deleterious variants in DDR system in 16 ethnic human populations. From the genetic variants in 169 DDR genes involved in nine DDR pathways collected from 158,612 individuals of different ethnic background, we identified 1,781 deleterious variants in 81 DDR genes in eight DDR pathways (https://genemutation.

Identification of deleterious variants of uncertain significance in BRCA2 BRC4 repeat through molecular dynamics simulations.

Large quantity of variants of uncertain significance (VUS) has been identified in cancer predisposition genes, but classification of VUS remains a big challenge. We proposed that the impact of VUS on protein structure stability can be used to identify these with deleterious effects by using molecular dynamics simulation (MDS)-based approach and developed a MDS-based method for missense VUS classification. In the current study, we applied the system to classify the missense VUS in BRCA2.

Human pathogenic variants were originated during recent human history.

and () play essential roles in maintaining genome stability. germline pathogenic variants increase cancer risk. However, the evolutionary origin of human pathogenic variants remains largely elusive.

Comprehensive Identification of Deleterious Missense VUS Variants Based on Their Impact on TP53 Structural Stability.

TP53 plays critical roles in maintaining genome stability. Deleterious genetic variants damage the function of TP53, causing genome instability and increased cancer risk. Of the large quantity of genetic variants identified in TP53, however, many remain functionally unclassified as variants of unknown significance (VUS) due to the lack of evidence.

CBS-derived H2S facilitates host colonization of Vibrio cholerae by promoting the iron-dependent catalase activity of KatB.

Sensing and resisting oxidative stress is critical for Vibrio cholerae to survive in either the aquatic environment or the gastrointestinal tract. Previous studies mainly focused on the mechanisms of oxidative stress response regulation that rely on enzymatic antioxidant systems, while functions of non-enzymatic antioxidants are rarely discussed in V. cholerae.

and Variation in Taiwanese General Population and the Cancer Cohort.

and () play essential roles in maintaining genome stability. Rapidly evolving human generates oncogenic variants causing high cancer risk. variation is ethnic-specific in reflecting adaptation and/or effects of genetic drift.

Prevalence and spectrum of DNA mismatch repair gene variation in the general Chinese population.

Background: Identifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including , , and play essential roles in maintaining microsatellite stability through DNA mismatch repair, and pathogenic variation in MMR genes causes microsatellite instability and is the genetic predisposition for cancer as represented by the Lynch syndrome. While the prevalence and spectrum of MMR variation has been extensively studied in cancer, it remains largely elusive in the general population.

Crosstalks Between Gut Microbiota and .

, the causative agent of cholera, could proliferate in aquatic environment and infect humans through contaminated food and water. Enormous microorganisms residing in human gastrointestinal tract establish a special microecological system, which immediately responds to the invasion of , through "colonization resistance" mechanisms, such as antimicrobial peptide production, nutrients competition, and intestinal barrier maintenances. Meanwhile, could quickly sense those signals and modulate the expression of relevant genes to circumvent those stresses during infection, leading to successful colonization on the surface of small intestinal epithelial cells.

Ethnic-specific variation within Asia population: evidence from over 78 000 cancer and 40 000 non-cancer cases of Indian, Chinese, Korean and Japanese populations.

Background: Germline mutation in 1 and () is genetic predisposition for breast and ovarian cancer. Identification of mutation carriers is a critical step to prevent and treat the cancer in the mutation carriers. Human variation has been well determined as ethnic-specific by studies in Ashkenazi Jewish, Polish and Icelandic populations in the 1990s.

Can population screening be applied in non-Ashkenazi Jewish populations? Experience in Macau population.

Background: Pathogenic mutation in genes causes high cancer risk. Identifying the mutation carriers plays key roles in preventing mutation-related cancer. Population screening has demonstrated its power for comprehensive identification of the mutation carriers.

Variants of DNA mismatch repair genes derived from 33,998 Chinese individuals with and without cancer reveal their highly ethnic-specific nature.

Purpose: DNA mismatch repair (MMR) genes play important roles in maintaining genome stability. Mutations in MMR genes disrupt their mismatch repair function, cause genome instability and lead to increased risk of cancer in the mutation carriers as represented by Lynch Syndrome. Studies have identified a large number of MMR variants, mostly in the Caucasian population, whereas data from non-Caucasian populations remain poorly illustrated.

Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.

BRCA1 and BRCA2 play essential roles in maintaining the genome stability. Pathogenic germline mutations in these two genes disrupt their function, lead to genome instability and increase the risk of developing breast and ovarian cancers. BRCA mutations have been extensively screened in Caucasian populations, and the resulting information are used globally as the standard reference in clinical diagnosis, treatment and prevention of BRCA-related cancers.