The genetic architecture and evolution of the human skeletal form

Science, Journal Year: 2023, Volume and Issue: 381(6655)

Published: July 20, 2023

The human skeletal form underlies bipedalism, but the genetic basis of proportions (SPs) is not well characterized. We applied deep-learning models to 31,221 x-rays from UK Biobank extract a comprehensive set SPs, which were associated with 145 independent loci genome-wide. Structural equation modeling suggested that limb exhibited strong sharing width and torso proportions. Polygenic score analysis identified specific associations between osteoarthritis hip knee SPs. In contrast other traits, SP enriched in accelerated regions regulatory elements genes are differentially expressed humans great apes. Combined, our work identifies variants affect ties major evolutionary facet anatomical change pathogenesis.

Language: Английский

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Osteoarthritis

The Lancet, Journal Year: 2025, Volume and Issue: 405(10472), P. 71 - 85

Published: Jan. 1, 2025

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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A Litmus Test for Confounding in Polygenic Scores

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

Abstract Polygenic scores (PGSs) are being rapidly adopted for trait prediction in the clinic and beyond. PGSs often thought of as capturing direct genetic effect one’s genotype on their phenotype. However, because constructed from population-level associations, they influenced by factors other than effects, including stratification, assortative mating, dynastic effects (“SAD effects”). Our interpretation application may hinge relative impact SAD since be environmentally or culturally mediated. We developed a method that estimates proportion variance PGS (in given sample) is driven covariance. leverage comparison interest based standard GWAS with sibling GWAS—which largely immune to effects—to quantify contribution each type interest. method, Partitioning Genetic Scores Using Siblings (PGSUS, pron. “Pegasus”), breaks down components further axes ancestry, allowing nuanced effects. In particular, PGSUS can detect stratification along major ancestry well “isotropic” respect ancestry. Applying PGSUS, we found evidence using large meta-analyses height educational attainment range UK Biobank. some instances, appears stratified axis one sample but not another (for example, comparisons samples different countries, ancient DNA vs. contemporary samples). Finally, show approaches adjustment population structure GWASs have distinct advantages mitigation ancestry-axis-specific isotropic PGS. study illustrates how family-based designs combined population-based guide genomic predictors.

Language: Английский

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Tracing human trait evolution through integrative genomics and temporal annotations

Cell Genomics, Journal Year: 2025, Volume and Issue: unknown, P. 100767 - 100767

Published: Jan. 1, 2025

Understanding the evolution of human traits is a fundamental yet challenging question. In recent Cell Genomics article, Kun et al.1 integrate large-scale genomic and phenotypic data, including deep-learning-derived imaging phenotypes, with temporal annotations to estimate timing evolutionary changes that led differences in between modern humans primates or hominin ancestors.

Language: Английский

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Multi-omic spatial effects on high-resolution AI-derived retinal thickness

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 4, 2025

Abstract Retinal thickness is a marker of retinal health and more broadly, seen as promising biomarker for many systemic diseases. measurements are procured from optical coherence tomography (OCT) part routine clinical eyecare. We processed the UK Biobank OCT images using convolutional neural network to produce fine-scale across > 29,000 points in macula, retina responsible human central vision. The macula disproportionately affected by high disease burden disorders such age-related macular degeneration diabetic retinopathy, which both involve metabolic dysregulation. Analysis common genomic variants, metabolomic, blood immune biomarkers, PheCodes genetic scores grid, reveals multiple novel loci including four on X chromosome; thinning associated with sclerosis; associations correlated metabolites that cluster spatially retina. highlight parafoveal be particularly susceptible insults. These results demonstrate gains discovery power resolution achievable AI-leveraged analysis. Results accessible bespoke web interface gives full control pursue findings.

Language: Английский

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Optimized phenotyping of complex morphological traits: enhancing discovery of common and rare genetic variants

Briefings in Bioinformatics, Journal Year: 2025, Volume and Issue: 26(2)

Published: March 1, 2025

Abstract Genotype–phenotype (G-P) analyses for complex morphological traits typically utilize simple, predetermined anatomical measures or features derived via unsupervised dimension reduction techniques (e.g. principal component analysis (PCA) eigen-shapes). Despite the popularity of these approaches, they do not necessarily reveal axes phenotypic variation that are genetically relevant. Therefore, we introduce a framework to optimize phenotyping G-P analyses, such as genome-wide association studies (GWAS) common variants rare variant (RVAS) variants. Our strategy is two-fold: (i) construct multidimensional feature space spanning wide range variation, and (ii) within this space, use an optimization algorithm search directions combinations enriched. To test our approach, examine human facial shape in context GWAS RVAS. In GWAS, phenotypes exhibiting high heritability, estimated from either family data genomic relatedness measured unrelated individuals. RVAS, skewness phenotype distributions, aiming detect commingled distributions suggest single few loci with major effects. We compare approach eigen-shapes baseline involving 8246 individuals European ancestry gene-based tests subset 1906 After applying linkage disequilibrium score regression results, heritability-enriched yielded highest SNP followed by eigen-shapes, while commingling-based displayed lowest heritability. Heritability-enriched also exhibited higher discovery rates, identifying same number independent smaller effective traits. For resulted more genes passing exome-wide significance threshold than lead only associations. Overall, results demonstrate optimized allows extraction relevant can specifically enhance efforts variants, evidenced their increased power

Language: Английский

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Using deep-learning based segmentation to enable spatial evaluation of knee osteoarthritis (SEKO) in rodent models

Osteoarthritis and Cartilage, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Motion–Force Interaction Performance of Parallel Robotic Mechanisms

Published: March 24, 2025

ABSTRACT Parallel robotic mechanisms have emerged as a vital subfield in robotics science and engineering over the past few decades, receiving widespread attention undergoing significant advancements. Despite extensive research encompassing type synthesis, dimension optimization, control theory, design principles, manufacturing techniques, others, comprehensive reviews on motion–force‐related performance of parallel their applications to real‐world problems are still lacking. This review aims fill this gap by analyzing summarizing studies motion–force interaction mechanisms. Examining historical development theoretical paradigms, began relatively late compared with serial counterparts. Initially, approaches for were inherited or adopted from However, many cases demonstrated that possess unique characteristics, making it infeasible directly transfer theories developed Therefore, new methodologies needed properly analyze evaluate intrinsic properties mechanisms, where between motion force plays crucial role. paper offers an systematic existing journal literature analyzes evaluates also known motion/force transmission constraint performance, providing broad detailed bibliography will serve reference community. The work examines strategies, evaluation methods, indices, concerning offering foundation stimulate future innovation.

Language: Английский

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The genetic architecture of and evolutionary constraints on the human pelvic form

Science, Journal Year: 2025, Volume and Issue: 388(6743)

Published: April 10, 2025

Human pelvic evolution following the human-chimpanzee divergence is thought to result in an obstetrical dilemma, a mismatch between large infant brains and narrowed female birth canals, but empirical evidence has been equivocal. By using deep learning on 31,115 dual-energy x-ray absorptiometry scans from UK Biobank, we identified 180 loci associated with seven highly heritable phenotypes. Birth canal phenotypes showed sex-specific genetic architecture, aligning reproductive function. Larger canals were linked slower walking pace reduced back pain increased hip osteoarthritis risk, whereas narrower floor disorder risk obstructed labor risk. Lastly, correlation head widths provides of coevolution human pelvis brain, partially mitigating dilemma.

Language: Английский

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