Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes.

Background: The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Prior research shows that the deleterious effects and the subsequent molecular consequences of variants are often conserved among paralogous protein sequences within a gene family. Here, we systematically quantify on an exome-wide scale whether the existence of pathogenic variants in paralogous genes at a conserved position can serve as evidence for the pathogenicity of a new variant.

Advancing gene-editing platforms to improve the viability of rare-disease therapeutics: key insights from a 2024 Scientific Exchange hosted by ARM, ISCT, and Danaher.

Rare-disease therapeutics face viability challenges due to small patient populations and drug-development and regulatory frameworks that were not developed to address rapidly progressive or quickly fatal conditions. Because the majority of rare diseases are genetic in nature, gene-editing modalities offer substantial promise. This Scientific Exchange, co-hosted by the Alliance for Regenerative Medicine, the International Society for Cell and Gene Therapy, and Danaher Corporation in November 2024, set out to address the challenge of realizing the full promise of gene editing for rare-disease therapies by advancing platforms that leverage stable and reusable processes or components to develop multiple therapies.

Pan-cancer immune and stromal deconvolution predicts clinical outcomes and mutation profiles.

Traditional gene expression deconvolution methods assess a limited number of cell types, therefore do not capture the full complexity of the tumor microenvironment (TME). Here, we integrate nine deconvolution tools to assess 79 TME cell types in 10,592 tumors across 33 different cancer types, creating the most comprehensive analysis of the TME. In total, we found 41 patterns of immune infiltration and stroma profiles, identifying heterogeneous yet unique TME portraits for each cancer and several new findings.

Environmental factors capable of broadly interfering with nutritional lifespan extension paradigms.

Despite being principally prescribed to treat type 2 diabetes, biguanides, especially metformin and phenformin, have been shown to extend lifespan and healthspan in preclinical models. Although there have been conflicting results in studies involving rodents and humans, consistent evidence indicates metformin and phenformin's ability to significantly extend lifespan in . We find that variation in agar from lot-to-lot or from different manufacturers influences metformin's ability to extend lifespan in diverse species.

Malignant Transformation of Glioblastoma: One Step at a Time.

In this issue of Cancer Discovery, Kim and colleagues characterize the transcriptional and epigenomic changes associated with gradual transformation of murine subventricular zone neural stem cells into glioblastoma, identifying an intermediary precancerous stage. Analysis of human glioblastoma and tumor-free subventricular zone tissues hints at the presence of precancerous cells with transcriptional similarity to murine precancerous cells and distinct aneuploidy from the bulk tumor. See related article by Kim et al.

Loss of CFHR5 function reduces the risk for age-related macular degeneration.

Age-related macular degeneration (AMD) is a prevalent cause of vision loss in the elderly with limited therapeutic options. A single chromosomal region around the complement factor H gene (CFH) is reported to explain nearly 25% of genetic AMD risk. Here, we used association testing, statistical finemapping and conditional analyses in 12,495 AMD cases and 461,686 controls to deconvolute four major CFH haplotypes that convey protection from AMD.

Polygenic Risk Prediction for Normal-Tension Glaucoma.

Purpose: Normal-tension glaucoma (NTG) is a subtype of glaucoma characterized by optic nerve damage in the setting of normal intraocular pressure. Polygenic risk scores (PRSs) have shown potential to assist with risk prediction in glaucoma, but to date no comprehensive studies have evaluated the predictive ability of PRSs for NTG.

Methods: We utilized genome-wide association study (GWAS) summary data for NTG from a European cohort to estimate the variant weights and construct PRSs.

A Molecular Glue Approach to Control the Half-Life of CRISPR-Based Technologies.

Cas9 is a programmable nuclease that has furnished transformative technologies, including base editors and transcription modulators (e.g., CRISPRi/a), but several applications of these technologies, including therapeutics, mandatorily require precision control of their half-life.

Precision Grounding: Augmenting Large Language Models with Evidence-Based Databases for Trustworthy Genetic Variant Summarization.

Backgrounds: Accurate interpretation of genetic variants is critical for precision medicine. While large language models (LLMs) show promise for summarization, they are prone to hallucinations. In this study, we thus propose a novel approach named "precision grounding" that augments LLMs with a query tool that integrated evidence-based, variant-specific information to improve summarization accuracy.

A Critical Appraisal of Lipid Management in the Post-Statin Era: Comparison on Guidelines, Therapeutic Targets, and Screening in a Case-Based Framework of Lipid Management.

The role of low-density lipoprotein-cholesterol in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD) is well established. Lipid management remains the cornerstone of addressing ASCVD. In addition to statin therapy, there is a large and growing number of nonstatin therapies available to manage elevated cholesterol levels.

Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction.

Background: High intake of red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported 204 variants (G) associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways and constructed pathway-based Polygenic Risk Scores (pPRS) to model pPRS x environment (E) interactions.

Design of combination therapeutics from protein response to drugs in ovarian cancer cells.

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic malignancy and novel treatment approaches are needed. Here, we used unbiased quantitative protein mass spectrometry to assess the cellular response profile to drug perturbations in ovarian cancer cells for the rational design of potential combination therapies. Analysis of the perturbation profiles revealed proteins responding across several drug perturbations (called frequently responsive below) as well as drug-specific protein responses.

Results of the Protein Engineering Tournament: An Open Science Benchmark for Protein Modeling and Design.

The grand challenge of protein engineering is the development of computational models to characterize and generate protein sequences for arbitrary functions. Progress is limited by lack of (1) benchmarking opportunities, (2) large protein function datasets, and (3) access to experimental protein characterization. We introduce the Protein Engineering Tournament-a fully-remote competition designed to foster the development and evaluation of computational approaches in protein engineering.

TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation.

After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery.

Optimizing participant and community engagement in cancer genomic sequencing research.

Purpose: We describe strategies implemented across research centers of the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network to optimize engagement of participants and communities in cancer genomics research. We also present consensus definitions of engagement and engagement optimization, informed by our shared experiences in the Network.

Methods: Key informant interviews and a document review identified engagement and optimization strategies across PE-CGS research centers.

Evolutionary-scale enzymology enables exploration of a rugged catalytic landscape.

Quantitatively mapping enzyme sequence-catalysis landscapes remains a critical challenge in understanding enzyme function, evolution, and design. In this study, we leveraged emerging microfluidic technology to measure catalytic constants- and -for hundreds of diverse orthologs and mutants of adenylate kinase (ADK). We dissected this sequence-catalysis landscape's topology, navigability, and mechanistic underpinnings, revealing catalytically heterogeneous neighborhoods organized by domain architecture.

Neutrophil gene downregulation is associated with postoperative organ dysfunction following pediatric cardiac surgery with cardiopulmonary bypass.

Introduction: Pediatric cardiac surgery with cardiopulmonary bypass (CPB) carries substantial risks of postoperative organ dysfunction and mortality, making the identification of biomarkers for postoperative organ dysfunction crucial for enhancing patient outcomes. As neutrophils play a major role in the perioperative setting and act as double-edge swords to the host, we examined neutrophil transcriptomic profiles in pediatric patients undergoing cardiac surgery with CPB.

Methods: We enrolled into this study from May 31, 2022, to February 22, 2023.

Mechanoepigenetics in musculoskeletal disease.

This review explores the intricate interplay between genetic variants, mechanical forces, and the epigenetic landscape (defined as 'mechanoepigenetics'), particularly in the context of musculoskeletal (MSK) diseases such as osteoarthritis. Whilst our understanding of Mendelian monogenic disease has progressed with exome sequencing and the generation of novel gene therapies, common complex diseases characterized by difficult-to-pinpoint non-coding genetic variants have posed significant challenges. The recent implementation of techniques such as ChIP-seq, ATAC-seq, and chromatin capture (Hi-C) has been pivotal in understanding how enhancers, promoters, and repressors interact with target genes to control gene expression.

VEGF signaling promotes blastema growth and proliferation of vascular and non-vascular cells during axolotl limb regeneration.

Salamanders are capable of regenerating whole limbs throughout life, a feat that is unmatched by other tetrapods. Limb regeneration is dependent upon the formation of a blastema containing progenitor cells which give rise to most tissues of the regenerated limb. Many signaling pathways, including FGF, BMP and Wnt, are required for regeneration, but the role of VEGF signaling during salamander limb regeneration is not well understood, particularly outside of angiogenesis.

Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease.

Background: Obstructive sleep apnoea (OSA) is a common chronic condition, with obesity its strongest risk factor. Polygenic scores (PGSs) summarise the genetic liability to phenotype and can provide insights into relationships between phenotypes. Recently, large datasets that include genetic data and OSA status became available, providing an opportunity to utilise PGS approaches to study the genetic relationship between OSA and other phenotypes, while differentiating OSA-specific from obesity-specific genetic factors.

Global multi-ancestry genetic study elucidates genes and biological pathways associated with thyroid cancer and benign thyroid diseases.

Thyroid diseases are common and highly heritable. Under the Global Biobank Meta-analysis Initiative, we performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer, benign nodular goiter, Graves' disease, lymphocytic thyroiditis, and primary hypothyroidism. We analyzed genetic association data from ~2.

In situ profiling of plasma cell clonality with image-based single-cell transcriptomics.

Image-based single-cell transcriptomics can identify diverse cell types within intact tissues. However, in adaptive immunity, V(D)J recombination generates unique immune receptors within cells of the same type, leading to important functional variation that is not yet defined by these methods. Here we introduce B-cell-receptor multiplexed error robust fluorescence in situ hybridization (BCR-MERFISH), which distinguishes plasma cell clones based on V-gene usage in combination with transcriptome profiling.

Multi-tissue expression and splicing data prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes.

Genome-wide association studies have suggested numerous colorectal cancer (CRC) susceptibility genes, but their causality and therapeutic potential remain unclear. To prioritise causal associations between gene expression/splicing and CRC risk (52,775 cases; 45,940 controls), we perform a transcriptome-wide association study (TWAS) across six tissues with Mendelian randomisation and colocalisation, integrating sex- and anatomical subsite-specific analyses. Here we reveal 37 genes with robust causal links to CRC risk, ten of which have not previously been reported by TWAS.

Comparing the Metagenomic Performance of Stools Collected from Custom Cards and 95% Ethanol in Epidemiologic Studies.

Background: Stool cards have been used for microbiome assessment in epidemiologic studies.

Methods: We compared shotgun metagenomic sequencing from 32 participants who self-collected stool samples from the same bowel movement using a custom stool card versus a collection tube with 95% ethanol fixative in the Nurses' Health Study II. We evaluated the agreement between methods at both the whole-community and individual species levels.