Combining Ramachandran plot and molecular dynamics simulation for structural-based variant classification: Using TP53 variants as model

Tam, Benjamin; Sinha, Siddharth; Wang, San Ming

doi:10.1016/j.csbj.2020.11.041

Cited by 44 publications

(34 citation statements)

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“…Ramachandran Plot Molecular Dynamic Simulation (RPMDS) method was used following the procedures described in detail. 34 Briefly, the N terminus of MLH1 crystal structure (PDB:4P7A, 2.30 A, residues 1–340) was used as the template. Altered amino acid residues caused by missense variants were incorporated into the wild-type MLH1 structure to generate mutant structures by using the Chimera software.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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BackgroundIdentifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including MLH1, MSH2, MSH6 and PMS2 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. Lack of the knowledge prevents effective prevention for MMR variation–caused cancer. In the current study, we addressed the issue by using the Chinese population as a model.MethodsWe performed extensive data mining to collect MMR variant data from 18 844 ethnic Chinese individuals and comprehensive analyses for the collected MMR variants to determine its prevalence, spectrum and features of the MMR data in the Chinese population.ResultsWe identified 17 687 distinct MMR variants. We observed substantial differences of MMR variation between the general Chinese population and Chinese patients with cancer, identified highly Chinese-specific MMR variation through comparing MMR data between Chinese and non-Chinese populations, predicted the enrichment of deleterious variants in the unclassified Chinese-specific MMR variants, determined MMR pathogenic prevalence of 0.18% in the general Chinese population and determined that MMR variation in the general Chinese population is evolutionarily neutral.ConclusionOur study provides a comprehensive view of MMR variation in the general Chinese population, a resource for biological study of human MMR variation, and a reference for MMR-related cancer applications.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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“…We first used the data generated from the wild-type (WT) alleles, known pathogenic and benign variants, as the trained data to set the cut-off value for the deleterious variants, by following the process described in detail in our previous publication [ 13 ]. Briefly, the density deviation of the 80 known pathogenic variants was plotted against the normal and lognormal distribution curves for Anderson-Darling and Kolmogorov-Smirnov goodness-of-fit tests [ 16 , 17 ] ( Figure 1 A,B).…”

Section: Resultsmentioning

confidence: 99%

“…The Ramachandran plot for each variant was generated from the MDS trajectory following the procedures [ 13 ]. Briefly, the torsional angle position by MDS was retained for each residue in the protein throughout the simulation.…”

Section: Methodsmentioning

confidence: 99%

“…Protein structure has been widely used to study gene function [ 10 , 11 ] and has also been used to study the relationship between TP53 variation and TP53 function [ 12 ]. We recently developed a protein-structure-based method, named Ramachandran Plot Molecular Dynamics Simulation (RPMDS), to study the effects of genetic variation on gene function [ 13 ]. In this method, the Ramachandran plot measures the influences of missense variants on TP53 secondary structure, and molecular dynamics simulation (MDS) simulates the dynamic effects of the variation on TP53 structural stability.…”

Section: Introductionmentioning

confidence: 99%

“…By referring to the information from the known pathogenic, known benign/likely benign variants (herein referred as benign variants), and wild type alleles, RPMDS provides a quantitative measurement for the impact of missense variants on TP53 structural stability and uses the information to identify the deleterious missense variants. Testing of the RPMDS method in a group of TP53 missense VUS showed satisfactory results [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

Tam

Sinha

Qin

et al. 2021

IJMS

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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. This is reflected by the presence of 749 (42%) VUS of the 1785 germline variants collected in the ClinVar database. In this study, we addressed the deleteriousness of TP53 missense VUS. Utilizing the protein structure-based Ramachandran Plot-Molecular Dynamics Simulation (RPMDS) method that we developed, we measured the effects of missense VUS on TP53 structural stability. Of the 340 missense VUS tested, we observed deleterious evidence for 193 VUS, as reflected by the TP53 structural changes caused by the VUS-substituted residues. We compared the results from RPMDS with those from other in silico methods and observed higher specificity of RPMDS in classification of TP53 missense VUS than these methods. Data from our current study address a long-standing challenge in classifying the missense VUS in TP53, one of the most important tumor suppressor genes.

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

Qin

Zhang

Tam

et al. 2022

Intl Journal of Cancer

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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. We identified 7587 BRCA variants from 685 592 Asian individuals in 40 Asia countries and regions, including 1762 clinically actionable pathogenic variants and 4915 functionally unknown variants (https://genemutation.fhs.um.edu.mo/Asian-BRCA/). We observed the highly ethnic-specific nature of Asian BRCA variants between Asian and non-Asian populations and within Asian populations, highlighting that the current European descendant population-based BRCA data is inadequate to reflect BRCA variation in the Asian population. We also provided archeological evidence for the evolutionary origin and arising time of Asian BRCA variation. We further provided structural-based evidence for the deleterious variants enriched within the functionally unknown Asian BRCA variants. The data from our study provide a current view of BRCA variation in the Asian population and a rich resource to guide clinical applications of BRCA-related cancer for the Asian population.

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Combining Ramachandran plot and molecular dynamics simulation for structural-based variant classification: Using TP53 variants as model

Abstract: Graphical abstract

Cited by 44 publications

References 45 publications

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

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

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

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

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