Evolutionary constraint and innovation across hundreds of placental mammals

Science, Journal Year: 2023, Volume and Issue: 380(6643)

Published: April 27, 2023

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes 240 species, we identify bases that, when mutated, are likely affect fitness and alter disease risk. At least 332 million (~10.7%) in human genome unusually conserved across species (evolutionarily constrained) relative neutrally evolving repeats, 4552 ultraconserved elements nearly perfectly conserved. Of 101 significantly constrained single bases, 80% outside protein-coding exons half have no functional annotations Encyclopedia of DNA Elements (ENCODE) resource. Changes genes regulatory associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast imperiled biodiversity offers distinctive power identifying genetic variants function organismal phenotypes.

Language: Английский

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

Science, Journal Year: 2023, Volume and Issue: 380(6643)

Published: April 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.

Language: Английский

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Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 1, 2023

Abstract Sequence-based machine learning models trained on genome-scale biochemical assays improve our ability to interpret genetic variants by providing functional predictions describing their impact the cis-regulatory code. Here, we introduce a new model, Borzoi, which learns predict cell- and tissue-specific RNA-seq coverage from DNA sequence. Using statistics derived Borzoi’s predicted coverage, isolate accurately score variant effects across multiple layers of regulation, including transcription, splicing, polyadenylation. Evaluated QTLs, Borzoi is competitive with, often outperforms, state-of-the-art individual regulatory functions. By applying attribution methods statistics, extract patterns driving RNA expression post-transcriptional regulation in normal tissues. The wide availability data species, conditions, profiling specific aspects emphasizes potential this approach decipher mapping sequence function.

Language: Английский

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Conserved and divergent gene regulatory programs of the mammalian neocortex

Nature, Journal Year: 2023, Volume and Issue: 624(7991), P. 390 - 402

Published: Dec. 13, 2023

Abstract Divergence of cis- regulatory elements drives species-specific traits 1 , but how this manifests in the evolution neocortex at molecular and cellular level remains unclear. Here we investigated gene programs primary motor cortex human, macaque, marmoset mouse using single-cell multiomics assays, generating expression, chromatin accessibility, DNA methylome chromosomal conformation profiles from a total over 200,000 cells. From these data, show evidence that divergence transcription factor expression corresponds to epigenome landscapes. We find conserved divergent features are reflected three-dimensional genome. Transposable contribute nearly 80% human-specific candidate cortical Through machine learning, develop sequence-based predictors different species demonstrate genomic syntax is highly preserved rodents primates. Finally, epigenetic conservation combined with sequence similarity helps uncover functional enhances our ability interpret genetic variants contributing neurological disease traits.

Language: Английский

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Spatiotemporal omics for biology and medicine

Cell, Journal Year: 2024, Volume and Issue: 187(17), P. 4488 - 4519

Published: Aug. 1, 2024

Language: Английский

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Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

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Enhancer-driven cell type comparison reveals similarities between the mammalian and bird pallium

Science, Journal Year: 2025, Volume and Issue: 387(6735)

Published: Jan. 2, 2025

Combinations of transcription factors govern the identity cell types, which is reflected by genomic enhancer codes. We used deep learning to characterize these codes and devised three metrics compare types in telencephalon across amniotes. To this end, we generated single-cell multiome spatially resolved transcriptomics data chicken telencephalon. Enhancer orthologous nonneuronal γ-aminobutyric acid–mediated (GABAergic) show a high degree similarity amniotes, whereas excitatory neurons mammalian neocortex avian pallium exhibit varying degrees similarity. mesopallial are most similar those deep-layer neurons. With study, present generally applicable approaches on basis regulatory sequences.

Language: Английский

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Evolutionary dynamics of genome size and content during the adaptive radiation of Heliconiini butterflies

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 12, 2023

Heliconius butterflies, a speciose genus of Müllerian mimics, represent classic example an adaptive radiation that includes range derived dietary, life history, physiological and neural traits. However, key lineages within the genus, across broader Heliconiini tribe, lack genomic resources, limiting our understanding how neutral processes shaped genome evolution during their radiation. Here, we generate highly contiguous assemblies for nine Heliconiini, 29 additional reference-assembled genomes, improve 10 existing assemblies. Altogether, provide dataset annotated genomes total 63 species, including 58 species tribe. We use this extensive to robust dated heliconiine phylogeny, describe major patterns introgression, explore architecture, basis innovations in enigmatic group, assessment putative regulatory regions at stem. Our work illustrates increased resolution provided by such dense sampling improves power test gene-phenotype hypotheses, precisely characterize evolve.

Language: Английский

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Vocal learning–associated convergent evolution in mammalian proteins and regulatory elements

Science, Journal Year: 2024, Volume and Issue: 383(6690)

Published: Feb. 29, 2024

Vocal production learning ("vocal learning") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (

Language: Английский

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Artificial Intelligence‐Based Approaches for AAV Vector Engineering

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

Abstract Adeno‐associated virus (AAV) has emerged as a leading vector for gene therapy due to its broad host range, low pathogenicity, and ability facilitate long‐term expression. However, AAV vectors face limitations, including immunogenicity insufficient targeting specificity. To enhance the efficacy of therapy, researchers have been modifying using various methods. Traditional experimental approaches optimizing are often time‐consuming, resource‐intensive, difficult replicate. The advancement artificial intelligence (AI), particularly machine learning, offers significant potential accelerate capsid optimization while reducing development time manufacturing costs. This review compares traditional AI‐based methods engineering highlights recent research in AI algorithms.

Language: Английский

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