Evolutionary constraint and innovation across hundreds of placental mammals

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

Опубликована: Апрель 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.

Язык: Английский

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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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Transposable elements as tissue-specific enhancers in cancers of endodermal lineage

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Сен. 1, 2023

Transposable elements (TE) are repetitive genomic that harbor binding sites for human transcription factors (TF). A regulatory role TEs has been suggested in embryonal development and diseases such as cancer but systematic investigation of their functions limited by widespread silencing the genome. Here, we utilize unbiased massively parallel reporter assay data using a whole genome library to identify with functional enhancer activity two types endodermal lineage, colorectal liver cancers. We show identified TE enhancers characterized features associated active enhancers, epigenetic marks TF binding. Importantly, distinct subfamilies function tissue-specific namely MER11- LTR12-elements colon cancers, respectively. These bound TFs each cell type, they have predicted associations differentially expressed genes. In conclusion, these demonstrate how different can paving way comprehensive understanding bona fide genomes.

Язык: Английский

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Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 5, 2023

Abstract Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal (TG) are specialized to detect transduce diverse environmental stimuli including touch, temperature, pain central nervous system. Recent advances single-cell RNA-sequencing (scRNA-seq) have provided new insights into diversity of ganglia cell types rodents, non-human primates, humans, but it remains difficult compare transcriptomically defined across studies species. Here, we built cross-species harmonized atlases DRG TG that describe 18 neuronal 11 non-neuronal 6 species 19 studies. We then demonstrate utility this reference atlas by using annotate newly profiled nuclei/cells from both human highly regenerative axolotl. observe transcriptomic profiles neuron subtypes broadly similar vertebrates, expression functionally important neuropeptides channels can vary notably. The resources data presented here guide future comparative transcriptomics, simplify type nomenclature differences studies, help prioritize targets for therapy development.

Язык: Английский

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DNAGPT: A Generalized Pre-trained Tool for Multiple DNA Sequence Analysis Tasks

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 12, 2023

Abstract Pre-trained large language models demonstrate potential in extracting information from DNA sequences, yet adapting to a variety of tasks and data modalities remains challenge. To address this, we propose DNAGPT, generalized pre-training model trained on over 200 billion base pairs all mammals. By enhancing the classic GPT with binary classification task (DNA sequence order), numerical regression (guanine-cytosine content prediction), comprehensive token language, DNAGPT can handle versatile analysis while processing both data. Our evaluation genomic signal region recognition, mRNA abundance regression, artificial genome generation demonstrates DNAGPT’s superior performance compared existing designed for specific downstream tasks, benefiting using newly structure.

Язык: Английский

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Selection on synonymous sites: the unwanted transcript hypothesis

Nature Reviews Genetics, Год журнала: 2024, Номер 25(6), С. 431 - 448

Опубликована: Янв. 31, 2024

Язык: Английский

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Jump-starting life: balancing transposable element co-option and genome integrity in the developing mammalian embryo

EMBO Reports, Год журнала: 2024, Номер 25(4), С. 1721 - 1733

Опубликована: Март 25, 2024

Abstract Remnants of transposable elements (TEs) are widely expressed throughout mammalian embryo development. Originally infesting our genomes as selfish and acting a source genome instability, several these have been co-opted part complex system regulation. Many TEs lost transposition ability their transcriptional potential has tampered result interactions with the host evolutionary time. It proposed that ultimately repurposed to function gene regulatory hubs scattered genomes. In early in particular, find perfect environment naïve chromatin escape repression by host. As consequence, it is thought hosts found ways co-opt TE sequences regulate large-scale changes transcription state this review, we discuss examples during development, for co-option regulation pressures on

Язык: Английский

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Evolution of plant cell-type-specificcis-regulatory elements

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 9, 2024

Abstract Cis -regulatory elements (CREs) are critical in regulating gene expression, and yet understanding of CRE evolution remains challenging. Here, we constructed a comprehensive single-cell atlas chromatin accessibility Oryza sativa , integrating data from 103,911 nuclei representing 126 discrete cell states across nine distinct organs. We used comparative genomics to compare cell-type resolved between O. 57,552 four additional grass species ( Zea mays, Sorghum bicolor, Panicum miliaceum Urochloa fusca ). Accessible regions (ACRs) had different levels conservation depending on the degree specificity. found complex relationship ACRs with conserved noncoding sequences, specificity, conservation, tissue-specific switching. Additionally, that epidermal were less compared other types, potentially indicating more rapid regulatory has occurred L1-derived layer these species. Finally, identified characterized subset overlapped repressive histone modification H3K27me3, implicating them as silencer-like CREs maintained by evolution. Collectively, this approach highlights dynamics plant cell-type-specific

Язык: Английский

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Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements

Science Advances, Год журнала: 2024, Номер 10(21)

Опубликована: Май 23, 2024

Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from PsychENCODE Consortium and other published sources to construct a comprehensive atlas candidate brain cis-regulatory elements. Using deep learning, model these elements' sequence syntax predict how binding sites for lineage-specific transcription factors contribute cell type-specific gene regulation various types glia neurons. The evolutionary history suggests that new regulatory information emerges primarily via smaller mutations within conserved mammalian elements rather than entirely human- or primate-specific sequences. However, elements, particularly those active during fetal development excitatory neurons astrocytes, implicated heritability brain-related human traits. Additionally, introduce PsychSCREEN, web-based platform offering interactive visualization PsychENCODE-generated diverse individuals healthy controls.

Язык: Английский

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Gene regulatory dynamics during craniofacial development in a carnivorous marsupial

Опубликована: Янв. 7, 2025

Marsupials and placental mammals exhibit significant differences in reproductive life history strategies. are born highly underdeveloped after an extremely short period of gestation, leading to prioritization the development structures critical for post-birth survival pouch. Critically, they must undergo accelerated oro-facial region compared placentals. Previously we described carnivorous Australian marsupial, fat-tailed dunnart Sminthopsis crassicaudata that has one shortest gestations any mammal. By combining genome comparisons mouse with functional data enhancer-associated chromatin modifications, H3K4me3 H3K27ac, investigated divergence craniofacial regulatory landscapes between these species. This is first description genome-wide face elements a 60,626 putative enhancers 12,295 promoters described. We also generated RNA-seq investigate expression dynamics genes near predicted active elements. While involved regulating facial were largely conserved dunnart, landscape varied significantly. Additionally, subset dunnart-specific associated expressed only relating cranial neural crest proliferation, embryonic myogenesis epidermis development. Comparative analyses tissue revealed mechanosensory system. Accelerated sensory system likely relates cues received by nasal-oral during postnatal journey Together suggest may be driven enhancer activity. Our study highlights power marsupial-placental comparative genomics understanding role driving temporal shifts

Язык: Английский

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