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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Genetics of human brain development

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 25(1), P. 26 - 45

Published: July 28, 2023

Language: Английский

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Three-dimensional genome rewiring in loci with human accelerated regions

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

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Massively parallel characterization of regulatory elements in the developing human cortex

Science, Journal Year: 2024, Volume and Issue: 384(6698)

Published: May 23, 2024

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays primary human cells from mid-gestation cortex cerebral organoids, we interrogated the cis-regulatory activity 102,767 open chromatin regions, including thousands sequences with cell type-specific accessibility variants associated brain regulation. In cells, identified 46,802 active enhancer 164 that alter activity. Activity was comparable organoids suggesting provide an adequate model for developing cortex. deep learning decoded sequence basis upstream regulators This work establishes a comprehensive catalog functional development.

Language: Английский

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A molecular and cellular perspective on human brain evolution and tempo

Nature, Journal Year: 2024, Volume and Issue: 630(8017), P. 596 - 608

Published: June 19, 2024

Language: Английский

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The trait-specific timing of accelerated genomic change in the human lineage

Cell Genomics, Journal Year: 2025, Volume and Issue: 5(1), P. 100740 - 100740

Published: Jan. 1, 2025

Humans exhibit distinct characteristics compared to our primate and ancient hominin ancestors. To investigate genomic bursts in the evolution of these traits, we use two complementary approaches examine enrichment among genome-wide association study loci spanning diseases AI-based image-derived brain, heart, skeletal tissue phenotypes with regions reflecting four evolutionary divergence points. These cover epigenetic differences humans rhesus macaques, human accelerated (HARs), selective sweeps, Neanderthal-introgressed alleles. Skeletal traits such as pelvic width limb proportions showed annotations that mirror morphological changes fossil record. Additionally, observe associated longitudinal fasciculus human-gained elements since visual cortex HARs, thalamus proper alleles, implying cognitive functions language processing, decision-making, sensory signaling, motor control are enriched at different depths.

Language: Английский

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Human neuronal maturation comes of age: cellular mechanisms and species differences

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 25(1), P. 7 - 29

Published: Nov. 23, 2023

Language: Английский

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Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(8), P. 100609 - 100609

Published: July 16, 2024

Little is known about the role of non-coding regions in etiology autism spectrum disorder (ASD). We examined three classes regions: human accelerated (HARs), which show signatures positive selection humans; experimentally validated neural VISTA enhancers (VEs); and conserved predicted to act as (CNEs). Targeted whole-genome analysis >16,600 samples >4,900 ASD probands revealed that likely recessive, rare, inherited variants HARs, VEs, CNEs substantially contribute risk whose parents share ancestry, enriches for recessive contributions, but modestly contribute, if at all, simplex family structures. identified multiple patient HARs near IL1RAPL1 VEs OTX1 SIM1 showed they change enhancer activity. Our results implicate both human-evolved evolutionarily suggest potential mechanisms how regulatory changes can modulate social behavior.

Language: Английский

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Understanding the Emergence of Schizophrenia in the Light of Human Evolution: New Perspectives in Genetics

Genes Brain & Behavior, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 13, 2025

Schizophrenia is a frequent and disabling disease. The persistence of the disorder despite its harmful consequences represents an evolutionary paradox. Based on recent discoveries in genetics, scientists have formulated "price-to-pay" hypothesis: schizophrenia would be intimately related to human evolution, particularly brain development human-specific higher cognitive functions. objective present work question scientific literature about relationship between evolution from genetic point view. In last two decades, research investigated association few markers: Human accelerated regions, segmental duplications, highly repetitive DNA such as Olduvai domain. Other studies focused action natural selection schizophrenia-associated variants, also thanks complete sequencing archaic hominins' genomes (Neanderthal, Denisova). Results suggested that connection may exist; nonetheless, much still needed, it possible definitive answer paradox will never found.

Language: Английский

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Comparative characterization of human accelerated regions in neurons

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

Published: Feb. 26, 2025

Language: Английский

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