Biology subjects

Uddin, M. M.

Publications and source records attributed to Uddin, M. M..

5 recordsLinked to original sources

bioRxiv2025

Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood

One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from [~]750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of "cryptic" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT, TCL1A, and SMC4) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT, clonal hematopoiesis, and observed mtDNA mutation accrual.

genetics↗

bioRxiv2025

Computational investigation unveils pathogenic LIG3 non-synonymous mutations and therapeutic targets in acute myeloid leukemia

Single nucleotide polymorphisms (SNPs) in DNA repair genes can impair protein structure and function, contributing to disease development, including cancer. Non-synonymous SNPs (nsSNPs) in the LIG3 gene are linked to genomic instability and increased cancer risk, particularly acute myeloid leukemia (AML). This study aims to identify the most deleterious nsSNPs in the LIG3 gene and potential therapeutic targets for DNA repair restoration in AML. We employed in-silico computational methods to analyze LIG3 nsSNPs, using PredictSNP and Mutation3D to assess pathogenicity. Subsequently, molecular docking and dynamics simulations were conducted to evaluate ligand-binding affinities and protein stability. Out of the 12,191 mapped SNPs, 132 were nsSNPs located in the coding region. Among these, 18 nsSNPs were identified as detrimental including 12 destabilizing and 6 stabilizing nsSNPs. Nine cancer-associated nsSNPs, including L381R and R528C, were predicted due to their structural and functional impacts. Further analysis revealed key phosphorylation and methylation sites, such as 529S and 224R. Molecular dynamics simulations highlighted stable interactions of compounds AHP-MPC and DM-BFC with wild-type and R528C mutant LIG3 proteins, while R671G and V781M mutants showed instability. Protein-protein interaction networks and functional enrichment linked LIG3 to DNA repair pathways. Kaplan-Meier analysis associated high LIG3 expression with improved survival in breast cancer and AML, suggesting its role as a prognostic biomarker. This study emphasizes the mutation-specific effects of LIG3 nsSNPs on protein stability and ligand interactions. We recommend identifying DM-BFC to advance personalized medicine approaches for targeting deleterious variants, following in vitro and in vivo validation for AML treatment.

cancer biology↗

bioRxiv2023

Human Plasma Proteomic Profile of Clonal Hematopoiesis

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.

genetics↗

bioRxiv2021

Clonal hematopoiesis is driven by aberrant activation of TCL1A

A diverse set of driver genes, such as regulators of DNA methylation, RNA splicing, and chromatin remodeling, have been associated with pre-malignant clonal expansion of hematopoietic stem cells (HSCs). The factors mediating expansion of these mutant clones remain largely unknown, partially due to a paucity of large cohorts with longitudinal blood sampling. To circumvent this limitation, we developed and validated a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate). Applying PACER to 5,071 persons with clonal hematopoiesis accurately recapitulated the known fitness effects due to different driver mutations. A genome-wide association study of PACER revealed that a common inherited polymorphism in the TCL1A promoter was associated with slower clonal expansion. Those carrying two copies of this protective allele had up to 80% reduced odds of having driver mutations in TET2, ASXL1, SF3B1, SRSF2, and JAK2, but not DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 by CRISPR editing led to aberrant expression of TCL1A and expansion of HSCs in vitro. These effects were abrogated in HSCs from donors carrying the protective TCL1A allele. Our results indicate that the fitness advantage of multiple common driver genes in clonal hematopoiesis is mediated through TCL1A activation. PACER is an approach that can be widely applied to uncover genetic and environmental determinants of pre-malignant clonal expansion in blood and other tissues.

genetics↗

bioRxiv2020

Mental Health Status of Adolescents During the COVID-19 Pandemic: A Cross-sectional Survey among the Bangladeshi Graduate Students at Dhaka City

ObjectivesTo identify the level of Mental Health Status of Adolescents During the COVID-19 Pandemic among the Bangladeshi Graduate Student at Dhaka MethodA cross-sectional survey was conducted with 330 students from different public and Private Universities in Dhaka, Bangladesh between April 01, 2020 and July 31, 2020 amid the COVID-19 lockdown period in Bangladesh. A standard, self-administered online questionnaire consisting of questions on socio-demographic variables, mental health status, as well as stress management sent to the respondents through social networking platforms. Data were analyzed using descriptive statistics, t-test, one-way ANOVA and correlation tests. ResultsThe mean score of mental health status was 2.08 based on four points scale. They felt problem in decision making (3.04), in doing the things well (2.92), in enjoying normal day to day life (2.88), in playing a useful part in life (2.85), in doing their task (2.75), living in perfectly well and in good health (2.70). The respondents also developed a suicidal tendency (2.55), felt nervous in strung-up (2.24), took longer time to do things (2.14), felt tightness and pressure in head (2.12), and found themselves pressurized by various stuff (2.05). This study also found a significant positive relationship between mental health status and age, living with parents, and parents attitude. Finally, this study revealed that the respondents managed their stress by chatting with their friends, parents and siblings, and by sleeping. ConclusionMental health status of adolescents was found moderate in this study. This study suggests further large-scale study including different socio-economic settings in order to figure out the real scenario of adolescents mental health status of the country during the pandemic.

scientific communication and education↗