Measures of selective constraint on genes have been used for many applications, including clinical interpretation of rare coding variants, disease gene discovery and studies of genome evolution. However, widely used metrics are severely underpowered at detecting constraints for the shortest ~25% of genes, potentially causing important pathogenic mutations to be overlooked. Here we developed a framework combining a population genetics model with machine learning on gene features to enable accurate inference of an interpretable constraint metric, s. Our estimates outperform existing metrics for prioritizing genes important for cell essentiality, human disease and other phenotypes, especially for short genes. Our estimates of selective constraint should have wide utility for characterizing genes relevant to human disease. Finally, our inference framework, GeneBayes, provides a flexible platform that can improve the estimation of many gene-level properties, such as rare variant burden or gene expression differences.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1038/s41588-024-01820-9 | DOI Listing |
Sci Adv
January 2025
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals.
View Article and Find Full Text PDFRev Paul Pediatr
January 2025
Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil.
Objective: 3p deletion syndrome is a rare monosomal disease that encompasses deletions throughout the short arm of chromosome 3. It is often in the distal region (3p25-pter), but variations in breakpoints and a complex clinical manifestation exist, with congenital heart defects being considered rare. We present the first case of hypoplastic left heart syndrome and minor dysmorphic features associated with 3p- syndrome.
View Article and Find Full Text PDFMol Biol Cell
January 2025
Department of Biology, Ball State University, Muncie, Indiana.
Degradation of aberrant, excess, and regulatory proteins at the endoplasmic reticulum (ER) is a conserved feature of eukaryotic cells, disruption of which contributes to disease. While remarkable progress has been made in recent years, mechanisms and genetic requirements for ER-Associated Degradation (ERAD) remain incompletely understood. We recently conducted a screen for genes required for turnover of a model ER translocon-associated substrate of the Hrd1 ubiquitin ligase in .
View Article and Find Full Text PDFIntroduction: Tat protein is a trans-activator of HIV-1 genome transcription, with additional functions including the ability to induce the chronic inflammatory process. Natural amino acid polymorphisms in Tat may affect its functional properties and the course of HIV infection. The aim of this work is to analyze the marks of Tat consensus sequences in non-A6 HIV-1 variants characteristic of the Russian Federation, as well as study natural polymorphisms in Tat CRF63_02A6 and subtype B variants circulating in Russia.
View Article and Find Full Text PDFMetab Brain Dis
January 2025
Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, P.R. China.
The immune system has emerged as a major factor in the pathogenesis of Alzheimer's disease (AD). PANoptosis is a newly defined programmed cell death mechanism related to many inflammatory diseases. This study aimed to identify the differentially expressed (DE) PANoptosis-related genes with characteristics of immune dysregulation (PRGIDs) in AD using bioinformatics analysis of bulk RNA-seq and single-nuclei RNA sequencing (snRNA-seq) data.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!
© LitMetric 2025. All rights reserved.