CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions

Nucleic Acids Research, Год журнала: 2024, Номер 52(D1), С. D1143 - D1154

Опубликована: Янв. 5, 2024

Machine Learning-based scoring and classification of genetic variants aids the assessment clinical findings is employed to prioritize in diverse studies analyses. Combined Annotation-Dependent Depletion (CADD) one first methods for genome-wide prioritization across different molecular functions has been continuously developed improved since its original publication. Here, we present our most recent release, CADD v1.7. We explored integrated new annotation features, among them state-of-the-art protein language model scores (Meta ESM-1v), regulatory variant effect predictions (from sequence-based convolutional neural networks) sequence conservation (Zoonomia). evaluated version on data sets derived from ClinVar, ExAC/gnomAD 1000 Genomes variants. For coding effects, tested 31 Deep Mutational Scanning (DMS) ProteinGym and, prediction, used saturation mutagenesis reporter assay promoter enhancer sequences. The inclusion features further overall performance CADD. As with previous releases, all sets, v1.7 scores, scripts on-site an easy-to-use webserver are readily provided via https://cadd.bihealth.org/ or https://cadd.gs.washington.edu/ community.

Язык: Английский

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Leveraging base-pair mammalian constraint to understand genetic variation and human disease

Science, Год журнала: 2023, Номер 380(6643)

Опубликована: Апрель 27, 2023

Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability discern which positions functionally important. Evolutionary constraint is a powerful predictor function, agnostic cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% the genome as significantly constrained and likely functional. We compared annotation, association studies, copy-number variation, clinical genetics findings, cancer data. Constrained enriched for variants that explain common heritability more than other functional annotations. Our results improve variant annotation also highlight regulatory landscape still needs be further explored linked disease.

Язык: Английский

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Three-dimensional genome rewiring in loci with human accelerated regions

Science, Год журнала: 2023, Номер 380(6643)

Опубликована: Апрель 27, 2023

Human accelerated regions (HARs) are conserved genomic loci that evolved at an rate in the human lineage and may underlie human-specific traits. We generated HARs chimpanzee with automated pipeline alignment of 241 mammalian genomes. Combining deep learning chromatin capture experiments neural progenitor cells, we discovered a significant enrichment topologically associating domains containing variants change three-dimensional (3D) genome organization. Differential gene expression between humans chimpanzees these suggests rewiring regulatory interactions neurodevelopmental genes. Thus, comparative genomics together models 3D folding revealed enhancer hijacking as explanation for rapid evolution HARs.

Язык: Английский

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The contribution of historical processes to contemporary extinction risk in placental mammals

Science, Год журнала: 2023, Номер 380(6643)

Опубликована: Апрель 27, 2023

Species persistence can be influenced by the amount, type, and distribution of diversity across genome, suggesting a potential relationship between historical demography resilience. In this study, we surveyed genetic variation single genomes 240 mammals that compose Zoonomia alignment to evaluate how effective population size (

Язык: Английский

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Identification of constrained sequence elements across 239 primate genomes

Nature, Год журнала: 2023, Номер 625(7996), С. 735 - 742

Опубликована: Ноя. 29, 2023

Abstract Noncoding DNA is central to our understanding of human gene regulation and complex diseases 1,2 , measuring the evolutionary sequence constraint can establish functional relevance putative regulatory elements in genome 3–9 . Identifying genomic that have become constrained specifically primates has been hampered by faster evolution noncoding compared protein-coding 10 relatively short timescales separating primate species 11 previously limited availability whole-genome sequences 12 Here we construct a alignment 239 species, representing nearly half all extant order. Using this resource, identified are under selective across other mammals at 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites 267,410 transcription factor binding but not placental validate their cis -regulatory effects on expression. These enriched for genetic variants affect expression traits diseases. Our results highlight important role recent differentiating primates, including humans, from mammals.

Язык: Английский

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Diversity and evolution of the vertebrate chemoreceptor gene repertoire

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 15, 2024

Abstract Chemoreception – the ability to smell and taste is an essential sensory modality of most animals. The number type chemical stimuli that animals can perceive depends primarily on diversity chemoreceptors they possess express. In vertebrates, six families G protein-coupled receptors form core their chemosensory system, olfactory/pheromone receptor gene OR , TAAR V1R V2R T1R T2R . Here, we study vertebrate chemoreceptor repertoire its evolutionary history. Through examination 1,527 genomes, uncover substantial differences in composition across vertebrates. We show are co-evolving, highly dynamic, characterized by lineage-specific expansions (for example, tetrapods; teleosts; mammals; amphibians) losses. Overall, amphibians, followed mammals, clades with largest repertoires. While marine tetrapods feature a convergent reduction numbers, genes correlates habitat mammals birds migratory behavior birds, diet aquatic environment fish.

Язык: Английский

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A model of human neural networks reveals NPTX2 pathology in ALS and FTLD

Nature, Год журнала: 2024, Номер 626(8001), С. 1073 - 1083

Опубликована: Фев. 14, 2024

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed TDP-43 proteinopathies

Язык: Английский

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New Opportunity: Materials Genome Strategy for Engineered Cementitious Composites (ECC) Design

Cement and Concrete Composites, Год журнала: 2025, Номер 159, С. 106009 - 106009

Опубликована: Фев. 27, 2025

Язык: Английский

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Genetics: A Starting Point for the Prevention and the Treatment of Obesity

Nutrients, Год журнала: 2023, Номер 15(12), С. 2782 - 2782

Опубликована: Июнь 17, 2023

Obesity is a common, serious, and costly disease. More than 1 billion people worldwide are obese—650 million adults, 340 adolescents, 39 children. The WHO estimates that, by 2025, approximately 167 people—adults children—will become less healthy because they overweight or obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes, certain types of cancer. These among the leading causes preventable, premature death. estimated annual medical cost obesity in United States was nearly $173 2019 dollars. considered result complex interaction between genes environment. Both environment change different populations. In fact, prevalence changes as eating habits, lifestyle, expression coding for factors involved regulation body weight, food intake, satiety. Expression these involves epigenetic processes, such DNA methylation, histone modification, non-coding micro-RNA synthesis, well variations gene sequence, which results functional alterations. Evolutionary non-evolutionary (i.e., genetic drift, migration, founder’s effect) have shaped predisposition protection from modern human Understanding knowing pathogenesis will lead to prevention treatment strategies not only obesity, but also other related diseases.

Язык: Английский

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Single-fly genome assemblies fill major phylogenomic gaps across the Drosophilidae Tree of Life

PLoS Biology, Год журнала: 2024, Номер 22(7), С. e3002697 - e3002697

Опубликована: Июль 18, 2024

Long-read sequencing is driving rapid progress in genome assembly across all major groups of life, including species the family Drosophilidae, a longtime model system for genetics, genomics, and evolution. We previously developed cost-effective hybrid Oxford Nanopore (ONT) long-read Illumina short-read approach used it to assemble 101 drosophilid genomes from laboratory cultures, greatly increasing number assemblies this taxonomic group. The next challenge address culture bias taxon sampling by that cannot easily be reared lab. Here, we build upon our previous methods perform amplification-free ONT single wild flies obtained either directly field or ethanol-preserved specimens museum collections, improving representation lesser studied taxa whole-genome data. Using Novaseq X Plus P2 sequencers with R10.4.1 chemistry, set new benchmark inexpensive at US $150 per while assembling as little 35 ng genomic DNA fly. present 183 179 resource systematics, phylogenetics, comparative genomics. Of these genomes, 62 are pooled lab strains 121 adult flies. Despite sample limitations working small insects, most single-fly diploid comparable contiguity (>1 Mb contig N50), completeness (>98% complete dipteran BUSCOs), accuracy (>QV40 genome-wide R10.4.1) inbred lines. well-resolved multi-locus phylogeny 360 4 outgroup encompassing publicly available (as August 2023) Finally, Progressive Cactus whole-genome, reference-free alignment built subset 298 suitably high-quality genomes. alignment, along updated protocols computational pipelines, released an open tool studying evolution scale entire insect family.

Язык: Английский

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