Biology subjects

Singh, N.

Publications and source records attributed to Singh, N..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Activation-dependent lentiviruses enable antigen-specific T cell expansion and transduction

Cancer immunotherapies rely on tumor-specific T cells, which arise endogenously in most patients with cancer, but can be low frequency and poorly functional. Methods to specifically identify, expand, and manipulate tumor-specific T cells at the rare frequencies found in peripheral blood would enable new immunotherapeutic strategies. Here, we demonstrate an approach to virally transduce polyclonal tumor-reactive T cells across any MHC haplotype and in the absence of knowing the cognate antigen. By generating lentiviral vectors that selectively transduce cells expressing 4-1BB (CD137), a marker of T cell activation, we can transduce antigen-specific T cells with user-defined genetic cargoes that can selectively expand and track individual clonotypes via single-cell sequencing. Anti-4-1BB lentiviruses (4-1BB LVs) encoding therapeutic cargoes can also enhance antigen-specific T cells to extend survival in a xenograft model of human melanoma and transduce tumor-infiltrating T cells from patients with ovarian cancer. Overall, the 4-1BB LV platform targets antigen-specific T cells in a manner agnostic to both the antigen and presenting MHC, with potential applications in adoptive cell therapy manufacturing and TCR identification. One Sentence SummaryEngineered lentiviral vectors targeting 4-1BB selectively activate, expand, and transduce antigen-specific T cells with immunomodulatory cargo.

immunology↗

bioRxiv2026

Glutamylated vimentin proteoform identified by a synthetic binder links to epithelial-mesenchymal plasticity

Cytoskeletal protein expression and filament dynamics change significantly during cell state transitions. However, post-translational modifications of cytoskeletal proteins during these transitions have rarely been described. Here, using a synthetic glutamylation-binder (SB2B49) selected against a bi-glutamylated peptide epitope, we identify a distinct pool of glutamylated vimentin filaments. We demonstrate that vimentin glutamylation is enzymatically added by tubulin tyrosine ligase-like (TTLLs) and removed by cytosolic carboxypeptidases (CCPs). Mass spectrometry and mutagenesis reveal that glutamylation occurs on specific vimentin residues. We find that glutamylated vimentin levels are dynamically modulated during epithelial-mesenchymal plasticity. During collective migration in scratch-wound assays, glutamylated vimentin filaments are transiently depleted at the wound edge, a process controlled by canonical glutamylation writer-erasers. Our findings reveal a new layer of vimentin regulation via glutamylation and establish the glutamylation-binder as a valuable tool for exploring the diversity of vimentin proteoforms and glutamylation modifications in both physiological and pathological contexts.

cell biology↗

bioRxiv2026

Genome-wide CRISPR knockout cell screening platform for the disease vector tick species Ixodes scapularis

The black legged tick, Ixodes scapularis, is a vector of the bacterium that causes Lyme disease and several other illnesses, including anaplasmosis, babesiosis, and tick-borne encephalitis. Although high-quality genome annotations are available for I. scapularis, functional understanding of I. scapularis genes is limited. To address this, we developed a platform for genome-wide CRISPR-Cas9 knockout screening in I. scapularis cells. To evaluate the platform, we performed a screen to identify genes associated with cellular fitness, and screens for resistance to treatment with copper chloride, Antimycin A, or Destruxin A (DA), a cyclic hexadepsipeptide produced by the pathogenic fungus Metarhizium anisopliae. In each case, the screens implicate specific sets of conserved and non-conserved I. scapularis genes in relevant cellular functions, providing the first experimental evidence of function for a large set of I. scapularis genes. Altogether, in this first-of-its-kind effort for the arthropod subclass Acari, we present an unbiased genome-wide CRISPR-Cas9 knockout cell screening platform, related resources, and datasets that will be broadly useful to efficiently uncover cellular functions of I. scapularis genes.

genetics↗

bioRxiv2026

Chromatin dynamics identifies 78 genes at loci associated with elevated intraocular pressure and primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a chronic neurodegenerative disorder, and elevated intraocular pressure (IOP) represents the major, and only modifiable, risk factor for the disease. We modeled increased IOP by treating three primary human trabecular meshwork (TM) cell strains with dexamethasone, then generated a high-resolution map of promoter-centered chromatin contacts and regulatory modules to decipher how the genomic architecture and epigenetic state of disease-associated loci contribute to pathogenesis. We identify dynamic changes in chromatin compartments and looping, cis-regulatory elements and transcription factor hubs corresponding to altered transcriptional profile. By integrating GWAS-associated variants with dexamethasone-induced 3D chromatin landscape, we discovered 26 IOP- and 52 POAG- candidate causal genes, which belong to vesicle transport, TLR, MAPK and hippo-YAP signaling pathways. We also uncovered transcriptional regulatory role of 103 non-coding lead variants. Our studies provide a mechanistic framework of genetic complexity associated with ocular hypertension and POAG pathogenesis in addition to targets for therapies.

genomics↗

bioRxiv2026

CRY1 couples blue light dependent systemic acquired defense through NPR1 interaction and SnRK3.6-mediated translocation

Systemic acquired resistance (SAR) is a whole-plant immune response triggered by localized infection. Cryptochromes (CRY) that are blue light receptors, work together with phytochromes (PHY) to regulate light dependent responses in Arabidopsis. Although the effect of light on plant immunity is fairly well studied, the molecular mechanisms remain unclear. In this study, we show that CRY1 is essential for optimal SAR induction under blue light conditions in Arabidopsis thaliana. The cry1 mutants fail to activate SAR under blue light, as evidenced by reduced expression of defense genes, increased susceptibility to Pseudomonas syringae (PstDC3000), and impaired stomatal defense. While SAR is intact in both wild type and cry1 under white light, blue light selectively reveals critical role of CRY1 in SAR. Interestingly, npr1 mutants activate SAR under blue light, supporting the fact that blue light can trigger SAR through NPR1 independent pathways. Using biochemical and cell-based assays, we show that CRY1 directly interacts with NPR1 in nucleus in a blue-light-enhanced manner. Overexpression of CRY1 induces NPR1 levels and enhances SAR. Expression of each of them individually partly rescued SAR, but their co-expression fully reinstated it, implying that SAR relies on interaction between NPR1 and CRY1. Stomatal movement measurements further show that CRY1 and NPR1 act synergistically to promote stomatal closure to limit pathogen entry. We also identify SnRK3.6, a blue-light-inducible kinase, as a novel regulator of CRY1. SnRK3.6 physically interacts with and phosphorylates CRY1, facilitating its nuclear translocation. Our results revealed a novel role of CRY1-NPR1 complex formation and regulation of CRY1 by SnRK3.6 in inducing SAR.

molecular biology↗

bioRxiv2026

Positron Emission Tomography of CD47/SIRPα Axis and Image-Informed Therapeutic Design

CD47/SIRP immune axis is of substantial clinical interest for innate cancer immunotherapy. Development on this axis has largely focused on monoclonal antibody agents and combination therapy strategies. Clinical use is challenging due to dose limiting side effects and severe anemia. Better understanding of the whole-body dynamics of CD47/SIRP can be used to improve the developmental and therapeutic strategies targeting this axis. Herein, we developed anti-CD47 and anti-SIRP radiotracers with good yields and stability. CD47/SIRP biodistribution showed consistent whole-body results in healthy and colorectal cancer (CT26) allograft mice, demonstrating significant uptake in normal organs liver and spleen in addition to tumor accumulation of these agents. Enhancing immunogenicity via low-dose radiotherapy had no impact on over-all biodistribution but caused small, significant changes for anti-SIRP tumor uptake. Antibody PEGylation of the anti-SIRP tracer was further able to modify the whole-body distribution and reduce splenic uptake. These findings suggest that SIRP targeted agents may benefit from co-therapies and drug delivery systems to optimize tumor uptake. Our work highlights the importance of in vivo molecular imaging in addition to in vitro and ex vivo assays when evaluating therapeutic designs.

bioengineering↗

bioRxiv2026

PfApiAT2 is a proline transporter essential for the transmission of Plasmodium falciparum by the mosquito vector.

Plasmodium falciparum oocysts undergo an explosive biomass increase during development in Anopheles mosquitoes, a dramatic growth process likely promoted by as-yet unknown nutrients scavenged from the mosquito. We previously observed in blood-stage parasites, that the amino acid transporter PfApiAT2, although dispensable, regulates proline homeostasis and mediates resistance to halofuginone, a potent proline-tRNA synthetase inhibitor. Here, we demonstrate that PfApiAT2 is a proline-specific transporter essential for early oocyst development in Anopheles gambiae. Halofuginone-resistant pfapiat2-mutant parasites form stunted oocysts severely defective in sporozoite production. This phenotype is recapitulated in PfApiAT2-knockout parasites that undergo a complete block in sporogony, forming oocysts that stall and degenerate. Remarkably, this growth defect can be rescued by nutrient supplementation to the mosquito vector. By identifying an amino acid transporter essential for oocyst growth, our data unveil a vulnerability in P. falciparum transmission, revealing a critical nutritional dependency of the parasite on its mosquito vector.

microbiology↗

bioRxiv2026

PRSS56 acts as an intrinsic retinal signal driving postnatal ocular axial growth and myopia susceptibility

Myopia is a leading cause of visual impairment worldwide, and high myopia markedly increases the risk of irreversible vision loss. Although visual experience guides postnatal ocular elongation, the role of intrinsic retinal growth signals remains poorly defined. Here we identify the serine protease PRSS56 as a retinal factor that promotes ocular axial growth beyond early development. Using genetic mouse models, we show that conditional inactivation of Prss56 in Muller glia reduces axial length and causes hyperopia even under dark-rearing conditions, demonstrating that PRSS56 drives axial elongation independently of light-evoked visual input during emmetropization. Conversely, Muller glia-specific overexpression of Prss56 induces axial elongation in a proteolysis-dependent manner, supporting its role as an autonomous retinal growth signal. In concordance, human genetic analyses reveal that the common PRSS56 variant rs2853447 is associated with increased axial length in individuals with myopia and high myopia, but not in non-myopes, suggesting that this variant confers a selective growth advantage in individuals predisposed to ocular elongation. Functional genomic analyses further identify a myopia-associated variant, rs2741297, within a retinal enhancer in intron 4 of PRSS56 marked by open chromatin and transcription factor occupancy. Together, these findings establish PRSS56 as an intrinsic retinal growth factor that functions beyond early eye development and support a model in which genetic and environmental factors converge on retinal pathways to modulate myopia susceptibility.

genetics↗

bioRxiv2025

Innate antiviral readiness drives the expansion of protective T stem cell memory against influenza

The development of T-cell-based influenza vaccines relies on eliciting broad CD8+ T-cell immunity, wherein T stem cell-like memory (TSCM) cells serve as the ultimate long-lived reservoir for immune memory, thereby unlocking the potential for durable protection against viral drift and shift. However, the specific immunological cues that drive the robust expansion and functional preservation of this self-renewing, multipotent subset remain unknown. Here, utilizing multi-omic systems immunology in a pediatric cohort immunized with live attenuated influenza vaccine, we identified the determinants governing the expansion of influenza virus-reactive TSCM cells. We show that a pre-existing state of innate antiviral readiness, defined by a plasmacytoid dendritic cell-associated type I interferon signature, is the requisite condition for a robust TSCM expansion. Mechanistically, this baseline innate state enhances antigen priming and enforces a qualitative divergence in T-cell fate, driving responders toward a functionally poised, Th1-dominant phenotype while non-responders default to a dysfunctional, hyper-proliferative state. To determine the clinical relevance of this cellular subset, we analyzed an independent controlled human influenza challenge study. This validation revealed a critical functional division of labor in host defense: whereas pre-existing antibodies primarily mitigated symptom severity, the baseline frequency of influenza virus-reactive TSCM cells was the strongest predictor of rapid viral load clearance. These findings establish that the expansion of durable cellular memory is not stochastic but is predetermined by the innate cytokine environment, providing a predictive biomarker for patient stratification and a validated target for adjuvants designed to expand the TSCM reservoir deliberately.

immunology↗

bioRxiv2025

Effects of a novel proteasome inhibitor, UR238 on the tumor immune microenvironment and growth in epithelial ovarian cancer

High-grade serous ovarian cancer (HGSOC) is a deadly gynecologic malignancy, often diagnosed at an advanced stage and most patients will experience recurrence and resistance to platinum-based chemotherapy. While there are few targeted therapies available for HGSOC, there are no effective immunotherapies available to treat this disease. The ubiquitin-proteasome system (UPS) maintains cellular protein homeostasis by degrading misfolded or damaged proteins. In epithelial ovarian cancer (EOC) elevated expression of proteasome subunit PSMB4 correlates with epithelial ovarian cancer growth and poor prognosis. A proteasome inhibitor has yet to be approved for EOC treatment despite evidence of activity in phase-1/2 clinical trials. Limitations of past generation proteosome inhibitors include sub-optimal solid tumor/tissue penetration due to boronic acid functionality, and poor solubility. Here, we show that a novel proteasome inhibitor, UR238, suppresses viability of several EOC cell lines and reduces tumor burden in both murine xenograft and rat syngeneic models. In a rat EOC model, UR238 treatment reduced tumor burden, shifted the predominantly suppressive immune microenvironment to an inflammatory phenotype with reduced suppressive macrophages, and decreased PD-L1 expression on myeloid cells. Additionally, in a mouse model, UR238 also induced robust immune changes in HGSOC bearing mice without a corresponding reduction in tumor burden. Our data highlights the promise of UR238 for the treatment of ovarian cancers as a single-agent or in combination with immunotherapies, where modulating the immune composition of these tumors will be important in improving outcomes for ovarian cancer patients.

immunology↗

bioRxiv2025

Form and function of actin impacts actin health and aging.

The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans. Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs) - arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin) - led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Bulk and single-nucleus RNA-sequencing revealed that ABP knockdowns elicited a strongly "aged" transcriptome. Actin dysfunction broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely-tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting evolutionary conservation of actins role in healthy aging. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how actin integrity intersects with diverse aging pathways across tissues and scales. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics contribute to aging.

cell biology↗

bioRxiv2025

High Precision Peptide-MHC Class I CARs Enhance In Vivo Killing ofTargeted CD8 T Cells to Prevent Type 1 Diabetes in Novel RIP-mOVA Model

Progress has been made to address refractory T cell-mediated diseases with chimeric antigen receptor (CAR) T cell platforms, with the need more specifically target pathogenic cells being addressed by peptide-MHC (pMHC) CAR T cells. However, progress to date has largely been limited to peptide-MHC Class II (pMHC-II) CARs for the targeting of autoreactive CD4 T cells in multiple models. Here, we develop the first single molecule peptide-MHC Class I-{beta}2 microglobulin CAR platform to demonstrate the proof of concept for depletion of antigen-specific CD8 T cells and compare the in vitro and in vivo functionality to a traditional scFv-based CAR that also targets the TCR. We demonstrate that while the scFv CAR is more rapidly and robustly activated by target CD8 T cells in vitro, the greater precision offered by pMHC-I CARs results in greater efficacy in multiple in vivo models. Additionally, we developed a novel adjuvanted ovalbumin vaccination with adoptive transfer model to induce type 1 diabetes (T1D) in RIP-mOVA mice using a polyclonal, polyepitopic T cell population. We demonstrate that our pMHC-I platform depletes SIINFEKL-reactive T cells and that control of the immune response to the dominant SIINFEKL epitope can control a broader antigenic response.

immunology↗

bioRxiv2025

Programmable DNA-Silk fibroin hydrogel scaffold with temporal mechanical reinforcement for mesenchymal stem cells differentiation and accelerated wound healing in a full-thickness skin defect mice model

DNA-based hydrogels have attracted significant attention in biomedical applications due to their programmability, biocompatibility, and tunable functionalities. However, their clinical translation is hindered by high synthesis costs, limited mechanical strength, poor stability, and complex synthesis protocols. In this work, we present a novel DNA-silk fibroin hybrid hydrogel that overcomes these limitations by combining the unique biofunctionality of DNA with the superior mechanical and chemical properties of silk fibroin. Salmon-derived DNA, an abundant and low-cost source, was incorporated with silk fibroin to form hybrid networks via a simple, scalable process. Silk fibroin served as a robust scaffold, enhancing mechanical strength, controlling degradability, and improving structural stability, while the entangled DNA-silk network reduced rapid DNA degradation. The resulting hybrid hydrogel demonstrated temporal mechanical reinforcement and prolonged stability, with in vitro studies demonstrating that the developed hybrid hydrogel enhanced the chondrogenic and osteogenic differentiation of Infrapatellar Fat Pad Mesenchymal Stem Cells (IFP-MSCs). Additionally, hemostatic and in vivo studies demonstrated the potential of DNA-silk fibroin hydrogel as a promising biomaterial for rapid hemostasis and accelerated wound healing. Overall, the developed DNA-silk fibroin hybrid hydrogel offers strong potential for mesenchymal tissue engineering, hemostatic adjuvant and wound healing.

bioengineering↗

bioRxiv2025

Junctional Heterogeneity Shapes Epithelial Morphospace

Tissues and organs develop a wide range of shapes, sizes and cellular organisations, linked to their physiological function. How developmental programmes generate this organisational diversity remains poorly understood. Inner ear sensory epithelia in birds, fish, and mammals provide a tractable system to address this question, as their constituent cells arise from a common developmental lineage, share molecular signatures, and have conserved physiological functions, yet assemble into distinct cellular organisations. These epithelia contain two principal cell types, mechanosensory hair cells (HCs) and supporting cells (SCs), organised into mosaics. Here, we developed a three-parameter morphospace that quantitatively captures epithelial organisation, enabling comparisons across species, structures and developmental stages. Combining this framework with genetic perturbation, biochemical analysis and live imaging reveals that the diverse mature organisations emerge from a common early organisational state constrained by Notch-Delta signalling. During subsequent development, the differential localisation of adhesion molecules (Cdh1,2 and Nectin) and contractility-associated proteins (NM2 and -actinin-4) at HC-SC and SC-SC junctions establishes junctional asymmetries. Across species, asymmetry drives stable circular HCs and actively remodelling SCs. The coexistence of these cell shape states drives selective intercalation, guiding each epithelium along a distinct trajectory through morphospace toward its mature organisation. These findings identify cell-shape dynamics as a developmental mechanism for generating organisational diversity in sensory, and potentially other, epithelia.

developmental biology↗

bioRxiv2025

FOLR1-targeted Actinium-225-based Alpha-particle Therapy Eliminates Ovarian Cancer

Despite the advancement in therapies, ovarian cancer treatment is challenging due to poor prognosis and high relapse associated with acquired resistance. Targeting overexpression of FOLR1 in ovarian cancers has proven to be an attractive strategy. The recent FDA approval of FOLR1 targeted antibody drug conjugate has shown promising results albeit resistance with repeated use appears inevitable. Emerging targeted alpha-particle therapies, particularly Actinium-225 (225Ac), for treating refractory cancers have opened avenues for improved therapeutic options. The success of alpha-particle therapy relies on tumor specific delivery of the alpha emitters. Herein we describe the first example of FOLR1-targeted 225Ac alpha-particle therapy for treatment of ovarian cancer. Longitudinal PET imaging demonstrated high tumor-specific uptake of FOLR1 in SKOV3 xenografts. FOLR1-targeted 225Ac demonstrated high therapeutic efficacy achieving marked tumor regression, 80% survival and 40% complete response. The therapy resulted in tumor specific double stranded DNA damage, and no obvious toxicity was observed in normal tissues. Estimated human dosimetry showed high absorbed dose for tumor and minimal absorbed dose for healthy tissues establishing its safety. In totality, FOLR1-targeted 225Ac alpha-particle therapy is an efficacious and safe treatment with high feasibility for clinical translation to fight against ovarian cancer.

bioengineering↗

bioRxiv2025

Synapse-related protein alterations and estradiol deficiency associate with early Parkinsonism in female A53T-α-synuclein transgenic mice fed on a high-fat diet

Substantial evidence highlights the detrimental impact of a fat-rich diet on cognitive and emotional behaviour. Epidemiological studies have linked the consumption of saturated fat with an increased risk of Parkinsons disease (PD), whereas a low-fat or ketogenic diet is reported to improve both motor and non-motor symptoms. Several animal model studies further support these associations. However, the impact of a high-fat diet (HFD) on sex-specific behavioural alterations and the underlying molecular mechanism in PD remains poorly studied. In the present study, we investigated the impact of HFD on PD progression in a sex-specific manner using the A53T transgenic mouse model of PD. Behavioural and pathophysiological analyses revealed a faster onset and progression of PD-like phenotype in female mice exposed to HFD compared with the male mice. Proteomics profiling of brain tissues demonstrated positive enrichment of immune system-related pathways in males, while females exhibited considerable downregulation of synapse-associated pathways under HFD conditions. The reduced estradiol level was identified as a potential factor contributing to synaptic dysfunction and the subsequent early onset of PD in female mice. These findings provide novel insights into the sex-specific consequences of HFD on PD pathogenesis and highlight the role of estrogen-linked synaptic vulnerability in mediating diet-induced PD onset.

neuroscience↗

bioRxiv2025

Structural specialization of mossy fiber boutons is necessary for their unique computational functions

Sparsely active granule cells in the dentate gyrus (DG) project onto CA3 pyramidal neurons through mossy fibers (MF), forming a feedforward network that ensures even similar inputs activate distinct and minimally overlapping populations of CA3 neurons. This process, known as pattern separation, is a key computational feature at this synapse. However, such sparse activity and connectivity increase the risk of information loss, as multiple presynaptic inputs are typically required to elicit a postsynaptic action potential. Interestingly, MF synapses exhibit robust short-term plasticity (STP), enabling a dynamic increase in release probability during brief bursts of presynaptic activity. This mechanism ensures that a short, high-frequency burst from a single granule cell can reliably generate a spike in its postsynaptic CA3 target. Unlike other hippocampal synapses, MF boutons are large, with multiple active zones, each coupled to a cluster of voltage-dependent calcium channels (VDCCs). MF boutons also possess a large readily releasable pool of vesicles. The functional consequences of this unusual synaptic design remain largely unexplored. In fact, the MF synapse is often depicted as a synapse with multiple sites, each behaving as an independent transmission line, analogous to several CA3 boutons contacting a single CA1 dendrite. We developed a physiologically realistic spatial model of the MF bouton to investigate how its peculiar structural and functional properties affect synaptic signaling and plasticity. Contrary to earlier assumptions, our computational model revealed, release sites are not independent transmission units. Crosstalk between calcium domains is necessary for the observed strong STP and for the timely activation of CA3 neurons. VDCCs in the MF bouton are only loosely coupled to active zones, and the distance between active zones is relatively large. In addition to the synaptic design and the known role of calbindin-D28k and synaptotagmin-7 in STP, we find that loose coupling of VDCCs to active zones and large inter-AZ distances are crucial. These features keep the basal release probability low, and their combined action is required to generate the facilitation that triggers postsynaptic action potentials in response to bursts filtering out non-informative dentate activity, and provides a strong rationale for the mossy fibers synaptic architecture.

neuroscience↗

bioRxiv2025

MAP-PRS: Multi-Ancestry Portfolio-Based Polygenic Risk Scores

Polygenic Risk Scores (PRS) are emerging tools for predicting an individuals genetic risk for complex diseases. However, their usefulness in clinical practice remains limited because most existing models are based on data from people of European ancestry, leading to reduced accuracy and stability in other populations. This imbalance restricts the equitable use of PRS in precision medicine. To overcome these limitations, we introduce Multi-Ancestry Portfolio-Based Polygenic Risk Scores (MAP-PRS)--a new framework that combines mathematical modeling and data science principles to improve both fairness and reliability in genetic risk prediction across populations. MAP-PRS treats each ancestry-specific PRS as part of a "portfolio," similar to how investments are managed in finance, balancing two key aspects: predictive return (how well the score predicts disease) and risk complexity (how uncertain or ancestry-specific the prediction is). By jointly optimizing these factors, MAP-PRS identifies the best combination of ancestry-informed PRS models that maximize predictive accuracy while minimizing bias and instability. This approach also uses advanced computational tools--such as Bayesian modeling, machine learning, and generative neural networks--to refine risk estimates, incorporate environmental and lifestyle factors, and increase representation from under-studied populations. In doing so, MAP-PRS supports more inclusive, equitable, and interpretable precision medicine. As an initial demonstration, MAP-PRS has been applied to predict Type 2 Diabetes (T2D) risk in European ancestry populations, establishing a foundation for broader, multi-ancestry implementation. Future extensions will include additional diseases, such as cervical cancer and HPV susceptibility, endometrioid ovarian cancer, and Alzheimers disease--bringing us closer to clinically actionable and globally equitable genetic risk prediction.

genetics↗