Biology subjects

Dorajoo, R.

Publications and source records attributed to Dorajoo, R..

11 recordsLinked to original sources

bioRxiv2026

Fatty acid metabolic interactome atlas linked to cellular longevity

Fatty acid biosynthesis is a central metabolic process required for membrane formation, organelle maintenance, and cellular proliferation, yet its broader relationship with stress responses and cellular aging remains incompletely understood. Here, we combined human and yeast interactome analyses with transcriptomic profiling and chronological lifespan assays to investigate the systems-level organization of fatty acid metabolic pathways and their relationship to cellular longevity. Integrated interactome mapping of mammalian fatty acid metabolic regulators, including ACACA, FASN, SCD, ACSL, ELOVL, and SLC27 family proteins, together with conserved yeast orthologs including ACC1, FAS1/FAS2, ELO1-3, OLE1, FAA1-4, ACS1/ACS2, and FAT1 revealed strong enrichment of anabolic growth regulation, membrane organization, vesicle trafficking, proteostasis, and endoplasmic reticulum (ER)-associated stress pathways. In yeast, fatty acid metabolic networks segregated into distinct anabolic and membrane-associated functional modules. Pharmacological inhibition of fatty acid synthesis using cerulenin suppressed cellular proliferation while extending chronological lifespan and induced broad downregulation of translation-associated anabolic pathways together with activation of stress-associated and membrane lipid remodeling programs. ER-associated interactome analyses of DPAGT1 and ALG7 further identified strong enrichment of membrane trafficking and unfolded protein response (UPR)-associated pathways, while pharmacological ER stress induction using tunicamycin also promoted enhanced chronological longevity. Collectively, our findings support a conserved model in which perturbation of fatty acid metabolic pathways remodels anabolic growth and ER-associated stress responses to promote cellular longevity.

systems biology↗

bioRxiv2026

TORC1 integrates metabolic state transitions during aging

Target of rapamycin complex 1 (TORC1) coordinates nutrient availability with anabolic metabolism, yet how TORC1-linked metabolic states influence cellular aging remains unclear. Using genetic, transcriptomic, metabolomic, and pharmacological analyses in prototrophic Saccharomyces cerevisiae, we identify context-dependent metabolic state transitions that uncouple cellular proliferation from long-term survival during aging. Loss of the SEACIT complex, conserved with mammalian GATOR1, establishes a low-flux metabolic state characterized by coordinated remodeling of nitrogen, nucleotide, and central carbon metabolism during stationary phase. Pharmacological restraint of nucleotide, glycolytic, or sterol metabolism converges on similar adaptive metabolic programs, whereas perturbations that impair mitochondrial respiratory capacity destabilize these states and reduce survival. Integrative analyses in human cancer and primary cells further reveal that diverse metabolic perturbations converge on mTORC1 suppression but generate distinct mitochondrial and stress responses depending on nutrient availability. Together, these findings demonstrate that TORC1 integrates metabolic state transitions in which nutrient availability and mitochondrial function determine cellular survival during aging.

systems biology↗

bioRxiv2026

Copper modulates iron-dependent survival through distinct TORC1 and AMPK signaling pathways

Copper and iron are redox-active micronutrients with tightly coupled homeostasis, yet how copper modulates iron-dependent stress responses remains unclear. Using Saccharomyces cerevisiae under nutrient-limited conditions, we uncoupled proliferative growth from long-term survival to dissect metal-dependent adaptation. Copper selectively preserved survival without affecting growth, whereas iron showed similar effects. Iron chelation impaired growth and suppressed electron transport chain gene expression; copper partially rescued these defects but required iron for its pro-survival activity. Despite this interdependence, copper and iron engaged distinct signaling programs. Iron-dependent survival required a Target of Rapamycin complex 1 (TORC1)-permissive state and was attenuated by rapamycin, whereas copper remained active under TORC1 inhibition. In contrast, copper promoted survival through AMP-activated protein kinase (AMPK) and antioxidant pathways, while iron exhibited context-dependent AMPK reliance. Together, these findings identify copper and iron as state-dependent regulators of cellular survival.

cell biology↗

bioRxiv2026

Developing a multi-modal neuroimaging-based BrainAge model across childhood

BrainAge models hold promise as a clinical biomarker for developmental brain health, especially in childhood when there is the potential for early intervention. To distinguish between normative developmental variance and pathological divergence, BrainAge models should reflect the dynamic and diverse neurodevelopmental processes that occur in distinct developmental windows across childhood. We utilized multi-modal neuroimaging data from three pediatric cohorts covering ages 4 to 13 years (n = 1005, 2126 scans), split into Train and Test datasets. Twelve sex-stratified BrainAge models were built stratified by type and different combinations of neuroimaging features. Model types were "Full-Span" models covering the full age range, and "Phase-Specific" models split into early- and late-childhood. We first compared BrainAge estimates in the Test dataset amongst our candidate models, then benchmarked the best-performing model against published pre-trained models and DNA-based biological age measures. Our findings show that a BrainAge model that was phase-specific and consisted of both structural and functional features (cortical thickness, subcortical volumes, and functional network integration measures) showed good prediction of age and best distinguished between healthy and symptomatic subgroups. We present a proof-of-concept for developmental models supporting building BrainAge models of higher temporal resolution that align to different childhood developmental phases.

neuroscience↗

bioRxiv2026

Integrative Genomic Analyses Identify COL21A1 and ENPEP-FGF5 Regulatory Pathways for Blood Pressure Variation in East Asians

BackgroundHypertension is a highly heritable cardiovascular disorder and a major determinant of cardiometabolic disease, including diabetes. However, the regulatory genes and tissue-specific mechanisms underlying blood pressure variations remain incompletely understood. MethodsLeveraging a well-characterized prospective population-based cohort comprised of 27,308 participants from the Singapore Chinese Health Study (SCHS), we evaluated genome-wide genetic associations for five blood pressure traits: hypertension status, systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP) and pulse pressure (PP). Additionally, we conducted a transcriptome-wide association study (TWAS), integrating gene expression data from 49 tissues, followed by colocalization and fine-mapping to prioritize regulatory genes. Association of identified variants with incident diabetes was additionally evaluated in the longitudinal data. ResultsWe validated 10 blood pressure loci (P between 1.64 x 10-20 - 4.10 x 10-8) and identified an East-Asian specific splice donor variant at the COL21A1 gene associated with PP (rs149344559, P = 6.78 x 10-10). Integrative analyses prioritized FGF5 in kidney cortex and ENPEP in pituitary tissue as candidate regulatory genes. The blood pressure-lowering allele at ENPEP (T allele, rs1879056) was associated with reduced risk of incident diabetes. Mediation analysis demonstrated that approximately 21% of the genetic association with diabetes was mediated through MAP (Pindirect-effect = 2 x 10-16). ConclusionThis study refines genetic predispositions for blood pressure among East-Asians. We further delineate tissue-specific regulatory pathways underlying blood pressure variations and identify ENPEP-mediated dysfunctions linking blood pressure genetics to diabetes risk, underscoring integrated disease mechanisms.

genetics↗

bioRxiv2026

Mitochondrial competence determines responses to metabolic interventions during aging

Cellular responses to metabolic interventions vary across physiological contexts, but the basis for this variability remains unclear. Here, we show that mitochondrial competence determines whether cells can engage adaptive metabolic states that support survival during aging. Using 4-methylbenzoic acid (4-MBA), identified as a lifespan-extending compound, as a perturbation probe, we find that modulation of Target of Rapamycin Complex 1 (TORC1) signaling induces a shift from anabolic growth to maintenance-associated metabolism; however, signaling output alone does not predict outcomes. Instead, survival closely correlates with mitochondrial function, with its disruption abolishing adaptive responses. Genetic and biochemical analyses define a mitochondrial regulatory circuit that constrains signaling dynamics and governs state transitions. This regulatory logic is conserved across mammalian systems and operates under oxidative stress, replicative aging, and Hutchinson-Gilford progeria syndrome (HGPS), extending to proliferative cancer cells. These findings establish mitochondrial competence as a key determinant of cellular responsiveness and provide a framework for understanding context-dependent effects of metabolic interventions during aging.

cell biology↗

bioRxiv2025

Telomerase reverse transcriptase is required for resistance to mycobacterial infection

Age is an important risk factor for infections such as tuberculosis (TB). Telomerase is expressed in immune cells yet leukocyte telomere length declines during ageing suggesting an age-dependent loss of telomerase activity in the immune system. Leukocyte telomere length has been correlated with worse outcomes in TB patients, however the mechanisms linking telomere biology to TB susceptibility and response to therapy are unexplored. Here we use the zebrafish-Mycobacterium marinum model to investigate the role of telomerase in TB resistance. We find depletion and inhibition of Tert, the catalytic subunit of telomerase, increases bacterial burden in zebrafish embryos. The Tert depletion infection susceptibility phenotype could not be rescued by p53 or STING depletion suggesting a non-canonical role for Tert in controlling mycobacterial infection. Consistent with a previously described role for Tert in developmental hematopoiesis, we find Tert is necessary for demand-driven emergency myelopoiesis to support containment of extended mycobacterial infection. Our findings establish a previously undescribed role for host telomerase in supporting infection demand-driven hematopoiesis to control infection.

immunology↗

bioRxiv2025

Polygenic Risk Scores Across Genomic Platforms for Reliable Breast Cancer Risk Stratification

PurposeWe evaluated differences in a 313-variant breast cancer polygenic risk score (PRS313) across genomic platforms and their impact on risk stratification. MethodsWe compared PRS313 derived from genotyping arrays (Global Screening Array [GSA], OncoArray-500K [OncoArray], Global Diversity Array [GDA], custom Axiom_PrecipV1 array [ThermoFisher]) and low-coverage genome sequencing (lc-WGS) in 2 cell lines and 92 individuals. Probes were designed for all variants on ThermoFisher (success rate: 259/313). Sanger sequencing was performed to profile indels. Concordance of high-risk classification (PRSscore>0.6) across platforms was assessed using Kappa statistics. ResultsPRS313-lc-WGS was identical in the 4 cell line repeats. In saliva samples, indel concordance with Sanger sequencing varied widely (Kappa: 0.007-1.000). PRS313-ThermoFisher was predictable from other platforms using linear models, despite systematic differences. Greater agreement was observed between arrays with high imputation overlap (e.g., GDA[~]GSA slope=0.986). Pre-calibration agreement in high-risk classification was moderate (Fleiss Kappa=0.552) and improved post-calibration (Kappa=0.650). Arrays with similar designs showed higher pre-calibration agreement (Kappa=0.745). Calibration narrowed high-risk proportions from 4-45% to 15-21% -28% were high-risk by any platform, while 8% were high-risk across all five. ConclusionPlatform-specific biases affect PRS interpretation. Calibration enhances consistency in identifying high-risk individuals. STATEMENT OF SIGNIFICANCEThis study compares the performance of a validated 313-variant breast cancer polygenic risk score across platforms, revealing systematic biases in risk stratification and raising concerns about including inconsistent indels in the model.

genetics↗

bioRxiv2023

Disruption of Aldehyde Dehydrogenase 2 protects against 1 bacterial infection

The ALDH2*2 (rs671) variant present in >500 million individuals reduces ALDH2 function, impairing aldehyde detoxification. While aldehyde accumulation in these individuals is associated with numerous negative health consequences, a previous study showed a cohort of ALDH2*2 carriers are less likely to develop active pulmonary tuberculosis. Here, we present additional human data that support this finding and show ALDH2-deficiency in mice provides a fitness advantage during bacterial infections. We found aldehydes normally detoxified by ALDH2 killed the bacterial pathogens Mycobacterium tuberculosis and Francisella tularensis. Infected macrophages from Aldh2-/-mice had higher levels of formaldehyde and 4-hydroxynonenal, which enhanced their microbicidal capacity. Aldh2-/- mice were more resistant to infection with Mycobacterium tuberculosis and Francisella tularensis than parental mice and displayed elevated inflammatory cytokine and chemokine levels, accompanied by an increased accumulation of inflammatory monocytes and macrophages. These findings support a model in which host-derived aldehydes are robust innate immune effectors, limiting bacterial infection through both direct microbicidal activity and immune modulation. Collectively, this work may explain why the ALDH2*2 allele was selected for in humans.

microbiology↗

bioRxiv2022

RAPTOR: A Five-Safes approach to a secure, cloud native and serverless genomics data repository

Genomic researchers are increasingly utilizing commercial cloud platforms (CCPs) to manage their data and analytics needs. Commercial clouds allow researchers to grow their storage and analytics capacity on demand, keeping pace with expanding project data footprints and enabling researchers to avoid large capital expenditures while paying only for IT capacity consumed by their project. Cloud computing also allows researchers to overcome common network and storage bottlenecks encountered when combining or re-analysing large datasets. However, cloud computing presents a new set of challenges. Without adequate security controls, the risk of unauthorised access may be higher for data stored on the cloud. In addition, regulators are increasingly mandating data access patterns and specific security protocols on the storage and use of genomic data to safeguard rights of the study participants. While CCPs provide tools for security and regulatory compliance, utilising these tools to build the necessary controls required for cloud solutions is not trivial as such skill sets are not commonly found in a genomics lab. The Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud native genomics data repository and analytics platform focusing on security and regulatory compliance. Using a "five-safes" framework (Safe Purpose, Safe People, Safe Settings, Safe Data and Safe Output), RAPTOR provides security and governance controls to data contributors and users leveraging cloud computing for sharing and analysis of large genomic datasets without the risk of security breaches or running afoul of regulations. RAPTOR can also enable data federation with other genomic data repositories using GA4GH community-defined standards, allowing researchers to boost the statistical power of their work and overcome geographic and ancestry limitations of data sets

genomics↗

bioRxiv2017

A study of Kibbutzim in Israel reveals risk factors for cardiometabolictraits and subtle population structure

Genetic studies in isolated populations have provided increased power for identifying loci associated with complex diseases and traits. We present here the Kibbutzim Family Study (KFS), initiated for investigating environmental and genetic determinants of cardiometabolic traits in extended Israeli families living in communes characterized by long-term social stability and homogeneous environment. Extensive information on cardiometabolic traits, as well as genome-wide genetic data, was collected on 901 individuals, making this study, to the best of our knowledge, the largest of its kind in Israel. We have thoroughly characterized the KFS genetic structure, observing that most participants were of Ashkenazi Jewish (AJ) origin, and confirming a recent severe bottleneck in their recent history (point estimates: effective size {approx}450 individuals, 23 generations ago). Focusing on genetic variants enriched in KFS compared with non-Finnish Europeans, we demonstrated that AJ-specific variants are largely involved in cancer-related pathways. Using linear mixed models, we conducted an association study of these enriched variants with 16 cardiometabolic traits. We found 24 variants to be significantly associated with cardiometabolic traits. The strongest association, which we also replicated, was between a variant upstream of the MSRA gene, {approx}200-fold enriched in KFS, and weight (P=3.6{middle dot}10-8). In summary, the KFS is a valuable resource for the study of the population genetics of Israel as well as the genetics of cardiometabolic traits in a homogeneous environment.

genetics↗