Genetic load and viability of a future restored northern white rhino population DOI Creative Commons
Aryn P. Wilder, Cynthia Steiner, Sarah A. Hendricks

et al.

Evolutionary Applications, Journal Year: 2024, Volume and Issue: 17(4)

Published: April 1, 2024

Abstract As biodiversity loss outpaces recovery, conservationists are increasingly turning to novel tools for preventing extinction, including cloning and in vitro gametogenesis of biobanked cells. However, restoration populations can be hindered by low genetic diversity deleterious load. The persistence the northern white rhino ( Ceratotherium simum cottoni ) now depends on cryopreserved cells 12 individuals. These banked genomes have higher than southern rhinos C. s. ), a sister subspecies that successfully recovered from severe bottleneck, but potential impact load is unknown. We estimated how demographic history has shaped genome‐wide nine 13 rhinos. bottleneck left with more fixed homozygous alleles longer runs homozygosity, whereas retained masked heterozygosity. To gauge fitness population restored cells, we simulated recovery using as benchmark viable population. Unlike traditional restoration, cell‐derived founders reintroduced subsequent generations boost lost relieve inbreeding. In simulations repeated reintroduction into population, cost remained lower borne Without reintroductions, rapid growth (>20–30% per generation) would needed maintain comparable fitness. Our results suggest inbreeding depression not necessarily barrier demonstrate relieves some constraints conventional limited founder pool. Established conservation methods protect healthy will remain paramount, emerging technologies hold promise bolster these combat extinction crisis.

Language: Английский

CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions DOI Creative Commons
Max Schubach, Thorben Maaß, Lusiné Nazaretyan

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(D1), P. D1143 - D1154

Published: Jan. 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.

Language: Английский

Citations

132
Leveraging base-pair mammalian constraint to understand genetic variation and human disease DOI
Patrick F. Sullivan, Jennifer R. S. Meadows, Steven Gazal

et al.

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

Citations

72
Three-dimensional genome rewiring in loci with human accelerated regions DOI
Kathleen C. Keough, Sean Whalen, Fumitaka Inoue

et al.

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

Published: April 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.

Language: Английский

Citations

61
The contribution of historical processes to contemporary extinction risk in placental mammals DOI
Aryn P. Wilder, Megan A. Supple, Ayshwarya Subramanian

et al.

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

Published: April 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 (

Language: Английский

Citations

58
Identification of constrained sequence elements across 239 primate genomes DOI Creative Commons
Lukas F. K. Kuderna, Jacob C. Ulirsch,

Sabrina Mohd Rashid

et al.

Nature, Journal Year: 2023, Volume and Issue: 625(7996), P. 735 - 742

Published: Nov. 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.

Language: Английский

Citations

44
Diversity and evolution of the vertebrate chemoreceptor gene repertoire DOI Creative Commons
Maxime Policarpo, Maude W. Baldwin, Didier Casañe

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 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.

Language: Английский

Citations

26
A model of human neural networks reveals NPTX2 pathology in ALS and FTLD DOI Creative Commons
Marián Hruška-Plocháň, Vera I. Wiersma, A Betz

et al.

Nature, Journal Year: 2024, Volume and Issue: 626(8001), P. 1073 - 1083

Published: Feb. 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

Language: Английский

Citations

17
New Opportunity: Materials Genome Strategy for Engineered Cementitious Composites (ECC) Design DOI
Wenguang Chen, Long Liang, Fangming Jiang

et al.

Cement and Concrete Composites, Journal Year: 2025, Volume and Issue: 159, P. 106009 - 106009

Published: Feb. 27, 2025

Language: Английский

Citations

2
Genetics: A Starting Point for the Prevention and the Treatment of Obesity DOI Open Access
Giuseppe Novelli,

Carmen Cassadonte,

Paolo Sbraccia

et al.

Nutrients, Journal Year: 2023, Volume and Issue: 15(12), P. 2782 - 2782

Published: June 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.

Language: Английский

Citations

23
Single-fly genome assemblies fill major phylogenomic gaps across the Drosophilidae Tree of Life DOI Creative Commons
Bernard Kim, Hannah R. Gellert, Samuel H. Church

et al.

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(7), P. e3002697 - e3002697

Published: July 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.

Language: Английский

Citations

16