Biology subjects

Adams, D. J.

Publications and source records attributed to Adams, D. J..

At least 19 recordsLinked to original sources

bioRxiv2026

iPSC-Derived Chondroprogenitors as a Promising Cell Source for Cartilage Engineering: A Comparison with MSCs in Unmodified and Peptide-Functionalized Alginate Hydrogels

Articular cartilage degeneration is a hallmark of degenerative joint diseases, yet its limited regenerative capacity poses significant challenges for tissue engineering. While mesenchymal stem cells (MSCs) are the most commonly employed cell type in cartilage tissue engineering, they exhibit donor variability, restricted expansion capacity, and tendencies toward fibrocartilage formation and hypertrophic differentiation. Human induced pluripotent stem cell-derived chondroprogenitors (iCPs) represent a promising alternative, offering scalable production of developmentally relevant cells with intrinsic chondrogenic commitment. However, their performance within three-dimensional biomaterial scaffolds remains largely unexplored. Here, we compared chondrogenic differentiation of iCPs and MSCs within alginate hydrogels of varying stiffness (0.37 - 4.55 kPa) exhibiting physiologically relevant stress relaxation properties. Intermediate stiffness (2% alginate, ~2.17 kPa) optimally supported chondrogenesis for both cell types. While MSCs differentiated as single cells, iCPs spontaneously self-organized into cartilaginous aggregates without requiring a separate pellet pre-culture step, showing significantly higher hyaline indices and reduced COL10 expression, despite initial low viability in hydrogels. To further enhance chondrogenesis, we functionalized 2% alginate gels with RGD and HAVDI peptides mimicking integrin- and cadherin-mediated signaling. HAVDI/RGD functionalization significantly enhanced hyaline cartilage marker expression in both cell types, with iCPs exhibiting superior matrix composition characterized by elevated aggrecan and SOX9 expression and reduced COL10 and MMP13 compared to MSCs. These findings establish iCPs as a promising cell source for cartilage tissue engineering and disease modeling, particularly within biomaterials integrating mechanical and bioactive cues that recapitulate the native cartilage microenvironment.

cell biology↗

bioRxiv2026

Function-driven geometry directs human pilosebaceous unit development

Single-cell technologies have generated cell censuses of tissues, however, how tissue geometry reflects functional needs remains poorly characterized. The human pilosebaceous unit offers a tractable model, a prenatally-formed complex mini-organ combining hair and sebum production with a stem cell reservoir. Using histomorphology, spatial transcriptomics, and single-cell multiomics on the same human prenatal scalp skin samples (8-19 post-conception weeks), integrated and analyzed using machine learning approaches, we built a spatiotemporal map of pilosebaceous unit development. We demonstrate that epithelial-mesenchymal interactions coordinate cellular fate and organogenesis, using an in vitro hair-bearing skin organoid model to validate this tissue-patterning. In addition, we show sebaceous gland developmental programmes are overcome during tumor formation. Our large-scale multi-modal analysis provides a unique framework for understanding form and function of tissues with applications in tissue engineering and pathology.

developmental biology↗

bioRxiv2026

Multi-scale modeling of human tissues from spatial transcriptomics with TERRA

Spatial transcriptomics maps gene expression at cellular resolution, revealing how cells organize into multicellular niches. Yet computational analyses remain dataset-specific, without a transferable representation of tissue organization that generalizes across datasets, tasks and tissues or predicts how tissues behave under perturbation. We present TERRA, a foundation model pretrained on 112 million human cells profiled by spatial transcriptomics. From a single pretrained backbone, TERRA yields embeddings at the scale of cells, the genes they express and the neighborhoods in which they reside, and supports spatial in silico perturbation, all applied zero-shot to unseen tissues. At the cell level, in newly generated spatial data for developing pancreas, TERRA identified an islet-associated capillary state which we posit represents a developmental precursor of the mature islet microvasculature. At the gene level, in untreated kidney sections, in silico knockout of immune-checkpoint targets predicted a gene program of immune-checkpoint-blockade-associated nephrotoxicity, which we validated in treatment-exposed tissue and recovered in blood. At the neighborhood level, TERRA mapped macrophages across tissues to identify recurring cross-organ niches, which we term archetypes, including a tumor-boundary niche associated with poor prognosis in kidney cancer. Together, TERRA captures the spatial and multicellular logic of human tissue and predicts, in silico, its response to perturbation, providing a multi-scale framework for tissue biology, therapeutic development and clinical application.

genomics↗

bioRxiv2026

Saturation-seq integrates single-cell saturation genome editing and RNA-seq to quantify NFE2L2 (NRF2) variant effects

Interpreting the functional consequences of variants remains one of the central unsolved problems in genomics and clinical genetics. Compounding this, most existing approaches rely on reductive, one-dimensional proxies such as cell growth to score variant effects, which can be a poor substitute for the rich, multidimensional phenotyping that is ultimately needed to understand how variants alter biology. This is especially true for variants known to act through gain-of-function/neomorphic mechanisms. We developed Saturation-seq, a high-throughput platform that combines saturation genome editing with single-cell DNA and RNA profiling to systematically map variant effects. Using CRISPR-based editing in a barcoded haploid cell line, we install hundreds of variants directly into endogenous genomic loci, testing them in multiplex and preserving the native coding and regulatory context. Single-cell amplicon and transcriptome sequencing enables direct linkage of each genomic edit to its transcriptional impact. We apply Saturation-seq to comprehensively characterize 230 variants in the recurrently mutated N-terminal region of NFE2L2 (NRF2), a master regulator of oxidative stress and an oncogene mutated in lung cancer. We define variant function with disruption scores computed from misregulation of known NRF2 targets in single-cell transcriptomes; scores separate pathogenic/benign truthset variants with >90% accuracy and enabled interpretation of TCGA and TRACERx patient tumor data, as well as a rare NFE2L2 germline variant linked to a developmental syndrome. Thus, we establish a broadly applicable high-resolution single-cell variant-to-function platform with a rich phenotypic readout.

genomics↗

bioRxiv2026

Bone response to intermittent parathyroid hormone (PTH) is both genetic and sex specific

Teriparatide (PTH 1-34) is an anabolic agent used to treat osteoporosis, yet clinical response varies widely among patients. To investigate genetic and sex-specific determinants of skeletal response, we administered intermittent PTH to male and female mice from eight genetically diverse inbred strains. Mice were treated for four weeks, and bone phenotypes were assessed via DXA, microCT, and mechanical testing. Response to PTH was highly strain- and sex-dependent, with some strains responding at the femur but not the spine, and vice versa. Heritability estimates for PTH-induced changes in areal bone mineral density (aBMD), cortical bone area at the femoral mid-diaphysis, femur strength, and trabecular bone volume fraction (BV/TV) ranged from moderate to high, with BV/TV showing the strongest genetic influence. Cortical bone response mechanisms differed by sex: males exhibited periosteal expansion, while females showed endosteal remodeling. These findings mirror clinical observations where non-response to PTH can be anatomic site specific. Further, our study suggests that genetic background and sex significantly influence bone response to PTH. Our data support the future use of genetically diverse mouse models to elucidate the genetic architecture of skeletal response to PTH.

genetics↗

bioRxiv2026

Calibrated high-throughput electrophysiology enables clinical interpretation of CACNA1G missense variants

ObjectiveAccurate classification of ion channel variants of uncertain significance (VUS) remains a persistent challenge in clinical genomics, limiting diagnostic resolution in neurological disorders. MethodsWe developed a calibrated electrophysiological framework to generate functional evidence for clinical interpretation of CACNA1G variants encoding the low-voltage-activated calcium channel Cav3.1. Functional metrics derived from automated patchclamp recordings were calibrated against benign/likely benign (B/LB) and pathogenic/likely pathogenic (P/LP) reference variants to enable conservative application of ACMG/AMP functional criteria within clinical variant interpretation workflows. ResultsCalibration using 25 B/LB and 16 P/LP CACNA1G variants showed that more than 80% of P/LP variants exhibited reduced current density (CD). Deactivation kinetics ({tau}Deact) provided complementary discriminatory information by identifying gating abnormalities in variants with preserved CD. Application of this dual-metric framework to five VUS identified in Australian patients revealed two variants (Cav3.1-R186Q and R1394Q) with abnormal functional profiles consistent with voltage-sensor perturbation, supporting reassessment as likely pathogenic under ACMG/AMP guidelines. The remaining VUS displayed functional properties overlapping the benign reference distribution. ConclusionThese findings establish a calibrated functional framework for generating electrophysiological evidence that supports clinical interpretation of CACNA1G missense variants under ACMG/AMP guidelines. When applied as external functional evidence, this approach improves resolution of CACNA1G-associated VUS while maintaining conservative standards for variant classification.

neuroscience↗

bioRxiv2026

In vivo screening reveals new regulators of Natural Killer cell development and functional response to acute cytomegalovirus infection

Natural killer (NK) cells are critical innate immune effectors in antiviral and antitumour responses. However, the factors governing NK cell development and function remain incompletely understood. To address this, we adopted an in vivo screening approach, generating a panel of mice deficient in genes differentially expressed across NK cell maturation stages or following viral infection. We performed a combinational screen comprising baseline immunophenotyping and mouse cytomegalovirus (MCMV) challenge. We identified novel regulators of NK cell development, including transcriptional regulators and proteins with putative trafficking functions. MCMV challenge studies additionally identified proteins that impacted antiviral immunity independently of NK cell phenotypes, including a novel regulator of NK cell degranulation, Synaptotagmin-like protein 3. Identified genes exhibited reduced tolerance to loss-of-function in large scale human sequencing studies and evidence for reduced NK cell numbers in a cohort of immunodeficiency patients. Together, these findings provide a resource of NK-expressed genes important for NK cell maturation and function, with relevance to human health. SummaryPring et al. conduct an in vivo screen in mice identifying novel regulators of natural killer (NK) cell development and/or antiviral functionality. Large-scale human sequencing and human immunodeficiency patients revealed evidence for the relevance of identified genes in human health.

immunology↗

bioRxiv2025

A Step-wise, Deterministic and Fatal Mouse Model of Myeloid Neoplasm with Spontaneous Acquisition of Patient-relevant RTK-RAS Mutations

Leukaemia arises through the stepwise transformation of healthy haematopoietic cells, yet the asymptomatic premalignant phase and its progression to overt disease remain poorly understood. To model this process, we engineered a patient-derived CEBPA mutation into Hoxb8-FL multipotent murine progenitors and transplanted them into syngeneic mice, capturing a clinically silent premalignant stage. All recipients developed overt disease after [~]12 months with 100% penetrance and all acquired secondary RTK-RAS mutations, often with identical amino acid changes to those in patients. Single-cell transcriptomics and phenotypic profiling showed that premalignant mutant cells adopt a plasmacytoid dendritic progenitor-like state in vitro which generates both myeloid and B-lymphoid lineages during premalignancy in vivo, with individual tumours restricted to one lineage. Specificity for RTK-RAS mutations coupled with ongoing differentiation is reminiscent of Juvenile Myelomonocytic Leukaemia, where cellular models are currently lacking, thus providing a tractable model of myeloid neoplasm for mechanistic studies and drug discovery.

cancer biology↗

bioRxiv2025

The mouse pangenome reveals the structural complexity of the murine protein coding landscape

We present the first mouse pangenome consisting of 17 high-quality inbred mouse strain genomes with complete annotation. This collection includes 12 widely used classical laboratory strains and 5 wild-derived strains. We have fully resolved previously incomplete genomic regions, including the major histocompatibility complex (MHC), the defensin cluster, T-cell receptor, and Ly49 complexes. Hundreds of non-reference genes identified in previous publications not found in GRCm39, like Defa1, Raet1a, and Klra20 (Ly49T), were localised in the new reference genomes. We conducted the first genome-wide scan of variable number tandem repeats (VNTRs) within the coding regions of mice, identifying over 400 genes with VNTR polymorphisms up to more than 600 repeat copies and repeat units reaching 990 nucleotides. Our strain-specific annotations enhance RNA-Seq analyses, as demonstrated in PWK/PhJ, where we observed a 5.1% improvement in read mapping and expression level differences in 2.1% of coding genes compared to using GRCm39.

genomics↗

bioRxiv2025

Contribution of CaV2.2 and GIRK1/2 channels to membrane excitability of rodent and human dorsal root ganglion neurons

Chronic visceral pain is a key symptom of irritable bowel syndrome (IBS). Modulation of voltage-dependent calcium and potassium channels by G protein-coupled receptors (GPCRs) plays a key role in dampening nociceptive transmission. Baclofen and the analgesic peptide -conotoxin Vc1.1 both activate GABAB receptors (GABABR), resulting in the inhibition of CaV2.2 and CaV2.3 calcium channels to reduce colonic nociception. Recent studies have also shown that GABABR activation potentiates GIRK1/2 potassium channels in mammalian sensory afferent neurons. In this study, we investigated the expression of these ion channel targets in rodent and human dorsal root ganglion (DRG) neurons, including those innervating the colon. We also examined how CaV2.2 and GIRK channel antagonists, as well as a GIRK channel activator, affect the passive and active electrical properties of adult mouse DRG neurons. Additionally, we assessed the effects of -conotoxin Vc1.1 on neuronal excitability in the presence of the selective CaV2.2 antagonist {omega}-conotoxin CVIE and the GIRK channel activator ML297. We further evaluated the impact of the GIRK channel antagonist Tertiapin-Q on excitability in mouse colonic DRGs and colonic afferents and explored the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in regulating membrane excitability of colonic DRGs. Our findings demonstrate that both CaV2.2 inhibition and GIRK channel potentiation reduce excitability in mouse DRGs, likely mediating the analgesic effects of Vc1.1 and baclofen observed in vivo. However, our findings indicate that GIRK channel potentiation appears to play a limited role in modulating excitability in colon-innervating DRGs and colonic afferents. These findings suggest that neurons innervating different regions of the body employ distinct mechanisms to regulate neuronal excitability and nociceptive signaling. KEY POINTS SUMMARYO_LIGABABR1, CaV2.2, and GIRK1 are highly expressed in the thoracolumbar dorsal root ganglia (DRGs) of both mice and humans. C_LIO_LIIn mouse DRGs, CaV2.2 inhibition and GIRK channel potentiation contribute to reduced neuronal excitability. C_LIO_LIThe analgesic peptide, -conotoxin Vc1.1 reduces neuronal excitability by inhibiting CaV2.2 and potentiating GIRK channels. C_LIO_LIHowever, potentiation of GIRK channels does not significantly affect the excitability in colon-innervating DRG neurons or colonic afferents. C_LIO_LISensory neurons innervating different body regions utilize distinct mechanisms to regulate their excitability. C_LI

neuroscience↗

bioRxiv2024

PRLX-93936 and BMS-214662 are cytotoxic molecular glues that leverage TRIM21 to degrade nucleoporins

Although molecular glues have emerged as innovative tools within the field of chemically induced proximity, approaches for their discovery remain limited. Here we report a phenotypic screening approach in which small molecules whose cytotoxic mechanisms require ubiquitination show gain of viability following pharmacological inhibition of the E1 enzyme UAE. This approach revealed two previously clinically-evaluated cytotoxins of unknown mechanism, PRLX-93936 and BMS-214662, as molecular glues that directly target the E3 ubiquitin ligase TRIM21. These molecules induce TRIM21-mediated proteasomal degradation of multiple nucleoporin proteins, leading to inhibition of nuclear export and ultimately cell death. Loss of nucleoporins and nuclear export accounts for past observations in which BMS-214662 led to disrupted subcellular protein localization. Furthermore, the cytotoxicity of these agents correlates strongly with TRIM21 expression, suggesting clinical re-evaluation of these agents in patients with TRIM21-high cancers. Additionally, relative to recently-reported TRIM21-targeting glues, these two scaffolds display high cellular potency, creating new opportunities for targeted protein degradation via the design of additional glues and TRIMTACs.

pharmacology and toxicology↗

bioRxiv2024

Coagulative Granular Hydrogels with an Enzyme Catalyzed Fibrin Network for Endogenous Tissue Regeneration

Granular hydrogels, composed of densely packed microgels, are an emerging class of injectable microporous scaffolds that provide interstitial porosity for endogenous cell recruitment and tissue repair. However, weak bonding interactions between constituent microgels compromises the mechanical integrity of these biomaterials, limiting their scope and effectiveness for in vivo application where structural support is required. To address this challenge, we introduce a new bioinspired stabilization method and a novel class of regenerative biomaterial: coagulative granular hydrogels, assembled from thrombin-functionalized gelatin methacryloyl microgels. The surface-bound thrombin is enzymatically active and catalyzes the conversion of fibrinogen into a fibrin hydrogel that extends throughout the interstitial voids of the granular hydrogel. This secondary network acts as a biological glue to stabilize the granular hydrogel, yielding shear and compressive properties comparable to bulk hydrogel controls. Furthermore, the interstitial fibrin network provides a favorable microenvironment for the adhesion, proliferation, and invasion of endothelial cells, highlighting the potential of the biomaterial to support endogenous tissue repair. This innovative stabilization mechanism provides a responsive biomaterial system, and future studies will seek to explore how the biomaterial is annealed in vivo by the presence of blood plasma fibrinogen.

bioengineering↗

bioRxiv2024

Activation of Wnt/β-catenin signalling by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary gland basal cell adenoma

Wnt signalling must be just right to promote tumour growth. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Due to their rarity, the genetic profiles of BCA and BCAC have not been extensively explored. Using whole-exome and transcriptome sequencing of BCA and BCAC cohorts, we identify a novel recurrent FBXW11 missense mutation (p.F517S) in BCA, that was mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-function (GoF) mutation. These driver events collectively accounted for 94% of BCAs. In vitro, mutant FBXW11 had a dominant negative affect, characterised by defective binding to {beta}-catenin and the accumulation of {beta}-catenin in cells. This was consistent with the nuclear expression of {beta}-catenin observed in BCA cases harbouring the FBXW11 p.F517S mutation and activation of the Wnt/{beta}-catenin pathway. The genomic profiles of BCAC were distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-{kappa}B signalling pathway genes. A single BCAC, which may represent a malignant transformation of BCA, harboured the recurrent FBXW11 mutation. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

cancer biology↗

bioRxiv2024

Simulating CD8 T Cell Exhaustion: A Comprehensive Approach

Immunotherapy has revolutionised the treatment of multiple cancer types, however, these treatments only work for a proportion of patients and biomarkers to predict response are lacking. One correlate of response is the reinvigoration of a subset of CD8 T cells that have an exhausted phenotype and impaired functionality. In order to develop new therapies, reproducible models are required to identify candidate target genes that enables the reversal of key hallmarks of T cell exhaustion. Here we describe the development of an in vitro model by chronically stimulating T cells with their cognate antigen and performed an in depth temporal phenotypic characterisation. This model recapitulates many of the critical hallmarks of exhaustion, including increased expression of canonical exhaustion surface markers, impaired proliferation, reduced cytokine production, decreased release of cytotoxic granules, and metabolic alterations, including dysfunctional mitochondria. These exhaustion hallmarks were validated using an in vivo model and a gene signature identified which robustly define the shared in vitro and in vivo exhausted state. Critically, this signature is also observed in tumour infiltrating T cells from multiple human tumour types, validating the translational potential of this model for discovering and triaging new therapies.

immunology↗

bioRxiv2024

Distinct molecular and functional properties of human induced-proprioceptor and low-threshold mechanoreceptor neurons

Sensing mechanical stimuli is crucial for the function of internal and external tissues, such as the skin and muscles. Much of our understanding of mechanosensory physiology relies on rodent studies, which may not directly translate to humans. To address the knowledge gap in human mechanosensation, we developed distinct populations of human mechanosensory neuronal subtypes from human pluripotent stem cells (hPSC). By inducing co-expression of NGN2/RUNX3 or NGN2/SHOX2 in hPSC-derived migrating neural crest cells we directed their specification to proprioceptor and low-threshold mechanoreceptor neuronal subtypes, respectively. The induced neurons exhibited transcriptional profiles consistent with mechanosensory neurons and displayed functional responses to mechanical stimuli, such as stretch and submicrometer probe indentation to the soma. Notably, each subtype displayed unique mechanical thresholds and desensitization properties akin to proprioceptors and low-threshold mechanoreceptors and both induced neuronal subtypes fired action potentials in response to minute mechanical stimuli, predominantly relying on PIEZO2 for mechanosensory function. Collectively, this study provides a foundational model for exploring human neuronal mechanosensory biology.

neuroscience↗

bioRxiv2024

Parkinson's Disease-Linked Kir4.2 Mutation R28C Leads to Loss of Ion Channel Function

Parkinsons disease (PD) is a complex, progressive neurodegenerative disorder driven by multiple pathogenetic factors, including oxidative stress, mitochondria dysfunction, neuroinflammation, and ion imbalance. Recent evidence highlights the significant role of potassium channels in the pathophysiology of PD. We recently identified a PD-linked genetic mutation in the KCNJ15 gene (KCNJ15p.R28C), encoding the inwardly rectifying potassium channel Kir4.2, within a four-generation family with familial PD. However, the role of the Kir4.2 channel in neurodegenerative diseases remains largely unexplored. This study aimed to elucidate the impact of the KCNJ15p.R28C (Kir4.2R28C) mutation on the biophysical and biochemical properties of Kir4.2. Employing Kir4.2-overexpressing HEK293T cells as a model, we investigated how the mutation affects the channels functional properties, total protein expression, intracellular processing in the endoplasmic reticulum and lysosomes, and plasma membrane trafficking. Patch clamp studies revealed that the Kir4.2R28C mutation results in loss of channel function with significant dominant-negative effects. This dysfunction is partially attributed to the substantial reduction in overall mutant channel protein expression compared to the wild-type (Kir4.2WT). We observed that both Kir4.2WT and Kir4.2R28C proteins undergo glycosylation during the post-translational modification process, albeit with differing protein turnover efficiencies. Furthermore, the Kir4.2R28C mutant exhibits reduced stability and compromised plasma membrane trafficking capacity compared to Kir4.2WT. These findings suggest that the Kir4.2R28C mutant has unique biomolecular and biophysical characteristics distinct from the Kir4.2WT channel, which potentially elucidates its role in the pathogenesis of PD. Key Points[tpltrtarr] Inwardly rectifying potassium channels are increasingly recognized for their critical role in the complex pathogenesis of Parkinsons disease (PD) [tpltrtarr]We previously identified a genetic mutation, Kir4.2R28C, in the inwardly rectifying potassium channel Kir4.2, which strongly segregates with familial PD in a multi- generational pedigree. [tpltrtarr]This study confirms Kir4.2R28C as a loss-of-function mutation with significant dominant- negative effects, impairing channel activity even in heterozygous conditions. [tpltrtarr]The Kir4.2R28C mutation significantly reduces overall protein levels, impairs protein stability and disrupts plasma membrane trafficking in in vitro cell models.

cell biology↗

bioRxiv2024

IFI207, a young and fast-evolving protein, controls retroviral replication via the STING pathway

Mammalian AIM-2-like receptor (ALR) proteins bind nucleic acids and initiate production of type I interferons or inflammasome assembly, thereby contributing to host innate immunity. In mice, the Alr locus is highly polymorphic at the sequence and copy number level and we show here, is one of the most dynamic regions of the genome. One rapidly evolving gene within this region, Ifi207, was introduced to the Mus genome by gene conversion or an unequal recombination event a few million years ago. Ifi207 has a large, distinctive repeat region that differs in sequence and length among Mus species and even closely related inbred Mus musculus strains. We show that IFI207 controls MLV infection in vivo and that it plays a role in the STING-mediated response to cGAMP, dsDNA, DMXXA and MLV. IFI207 binds to STING and inclusion of its repeat region appears to stabilize STING protein. The Alr locus and Ifi207 provide a clear example of the evolutionary innovation of gene function, possibly as a result of host-pathogen co-evolution. IMPORTANCEThe Red Queen hypothesis predicts that the arms race between pathogens and the host may accelerate evolution of both sides, and therefore cause higher diversity in virulence factors and immune-related proteins, respectively (1). The Alr gene family in mice has undergone rapid evolution in the last few million years and includes the creation of two novel members, MndaL and Ifi207. Ifi207 in particular became highly divergent, with significant genetic changes between highly related inbred mice. IFI207 protein acts in the STING pathway and contributes to anti-retroviral resistance via a novel mechanism. The data show that under the pressure of host-pathogen coevolution in a dynamic locus, gene conversion and recombination between gene family members creates new genes with novel and essential functions that play diverse roles in biological processes.

immunology↗

bioRxiv2023

A Weights-based variant ranking pipeline for familial complex disorders

Identifying genetic susceptibility factors for complex disorders remains a challenging task. We have developed a weights-based pipeline to prioritize variants and genes in collections of small and large pedigrees where genetic heterogeneity is likely, but biological commonalities are plausible. The Weights-based vAriant Ranking in Pedigrees (WARP) pipeline prioritizes variants using 5 weights: disease incidence rate, number of cases in a family, genome fraction shared amongst cases in a family, allele frequency and variant deleteriousness. Weights, except for the population allele frequency weight, are normalized between 0 to 1. Weights are combined multiplicatively to produce family-specific-variant weights that are then averaged across all families in which the variant is observed to generate a multifamily weight. Sorting multifamily weights in descending order creates a ranked list of variants and genes for further investigation. WARP was validated using familial melanoma sequence data from the European Genome-phenome Archive. The pipeline identified variation in known germline melanoma genes POT1, MITF and BAP1 in 4 out of 13 families (31%). Analysis of the other 9 families identified several interesting genes, some of which might have a role in melanoma. WARP provides an approach to identify disease predisposing genes in studies with small and large pedigrees.

genomics↗