Conditional frequency spectra as a tool for studying selection on complex traits in biobanks DOI Creative Commons
Roshni Patel, Clemens L. Weiß,

Huisheng Zhu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 17, 2024

Abstract Natural selection on complex traits is difficult to study in part due the ascertainment inherent genome-wide association studies (GWAS). The power detect a trait-associated variant GWAS function of frequency and effect size — but for under selection, determines strength against it, constraining its frequency. To account ascertainment, we propose studying joint distribution allele frequencies across populations, conditional cohort. Before considering these spectra, first characterized impact non-equilibrium demography dynamics forwards backwards time. We then used results understand spectra realistic human demography. Finally, investigated empirical variants associated with 106 traits, finding compelling evidence either stabilizing or purifying selection. Our provide insight into polygenic score portability other properties ascertained GWAS, highlighting utility spectra.

Language: Английский

A DNA language model based on multispecies alignment predicts the effects of genome-wide variants DOI
Gonzalo Benegas,

Carlos Albors,

Alan J. Aw

et al.

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

Published: Jan. 2, 2025

Language: Английский

Citations

5
The complete and fully-phased diploid genome of a male Han Chinese DOI Creative Commons
Chentao Yang, Yang Zhou, Yanni Song

et al.

Cell Research, Journal Year: 2023, Volume and Issue: 33(10), P. 745 - 761

Published: July 14, 2023

Since the release of complete human genome, priority genomic study has now been shifting towards closing gaps in ethnic diversity. Here, we present a fully phased and well-annotated diploid genome from Han Chinese male individual (CN1), which assemblies both haploids achieve telomere-to-telomere (T2T) level. Comparison this with CHM13 haploid T2T revealed significant variations centromere. Outside centromere, discovered 11,413 structural variations, including numerous novel ones. We also detected thousands CN1 alleles that have accumulated high substitution rates few under positive selection East Asian population. Further, found outperforms as reference mapping variant calling for population owing to distinct variants two references. SNP large cohort 8869 genomes using respectively showed bias profoundly impacts rare calling, nearly 2 million SNPs miss-called different genomes. Finally, applying reference, 5.80 Mb 4.21 putative introgression sequences Neanderthal Denisovan, respectively, many specific ones undetected reference. Our analyses reveal advances studies paleo-genomic studies. This will serve an alternative future on

Language: Английский

Citations

37
Explainable machine learning framework to predict personalized physiological aging DOI Creative Commons
David Bernard, Emmanuel Doumard, Isabelle Ader

et al.

Aging Cell, Journal Year: 2023, Volume and Issue: 22(8)

Published: June 10, 2023

Abstract Attaining personalized healthy aging requires accurate monitoring of physiological changes and identifying subclinical markers that predict accelerated or delayed aging. Classic biostatistical methods most rely on supervised variables to estimate do not capture the full complexity inter‐parameter interactions. Machine learning (ML) is promising, but its black box nature eludes direct understanding, substantially limiting physician confidence clinical usage. Using a broad population dataset from National Health Nutrition Examination Survey (NHANES) study including routine biological after selection XGBoost as appropriate algorithm, we created an innovative explainable ML framework determine Personalized age (PPA). PPA predicted both chronic disease mortality independently chronological age. Twenty‐six were sufficient PPA. SHapley Additive exPlanations (SHAP), implemented precise quantitative associated metric for each variable explaining (i.e., delayed) deviations age‐specific normative data. Among variables, glycated hemoglobin (HbA1c) displays major relative weight in estimation Finally, clustering profiles identical contextualized explanations reveal different trajectories opening opportunities specific follow‐up. These data show robust, ML‐based monitors health status. Our approach also provides complete applicable datasets allowing precision estimation.

Language: Английский

Citations

26
Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression DOI Creative Commons

Ruoyu Tian,

Tian Ge, Hyeokmoon Kweon

et al.

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

Published: Feb. 26, 2024

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on remains poorly understood. Here, we present whole-exome sequencing analyses with seven different definitions based survey, questionnaire, and electronic health records in 320,356 UK Biobank participants. We showed that burden damaging loss-of-function intolerant genes is significantly associated various definitions. compared common genetic architecture across correlation relationships between variants. In addition, demonstrated effects variant polygenic score are additive. The gene set revealed overlapping components developmental disorder, autism, schizophrenia. Our study provides insights into contribution variants, separately conjunction their neurodevelopmental disorders.

Language: Английский

Citations

13
Exome-wide analysis implicates rare protein-altering variants in human handedness DOI Creative Commons
Dick Schijven, Sourena Soheili‐Nezhad, Simon E. Fisher

et al.

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

Published: April 2, 2024

Abstract Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) microtubule-associated proteins. Here we examine whether left-handedness also influenced by rare coding (frequencies ≤ 1%), using exome data from 38,043 left-handed 313,271 right-handed individuals the UK Biobank. The beta-tubulin TUBB4B shows exome-wide significant association, with rate 2.7 times higher left-handers than right-handers. are heterozygous missense changes, but two frameshifts found only left-handers. Other been linked to sensorineural and/or ciliopathic disorders, not here. Among previously implicated autism schizophrenia screening, DSCAM FOXP1 show evidence for variant left-handedness. heritability due was 0.91%. This study reveals role rare, protein-altering left-handedness, providing further involvement microtubules disorder-relevant genes.

Language: Английский

Citations

13
Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults DOI Creative Commons
Yang Liu,

Ya‐Nan Ou,

Bang‐Sheng Wu

et al.

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

Published: July 15, 2024

Abstract The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes 35 IMDs, among which 124 were novel genes. Several genes, including FLG is associated with atopic dermatitis and asthma, showed converging evidence from both rare common variants. 91 exerted significant effects on longitudinal outcomes (interquartile range Hazard Ratio: 1.12-5.89). Mendelian randomization five causal four approved drug targets ( CDSN , DDR1 LTA IL18BP ). Proteomic analysis indicated that mutations specific might also affect protein expression other IMDs. For example, DXO (celiac disease-related gene) PSMB9 (alopecia areata-related could modulate (autoimmune hypothyroidism-, psoriasis-, asthma-, Graves’ expression. Identified predominantly impact immune biochemical processes, can be clustered into pathways immune-related, urate metabolism, antigen processing. Our findings are the key pathogenesis provided new insights tailored innovative therapies.

Language: Английский

Citations

8
The promise of explainable deep learning for omics data analysis: Adding new discovery tools to AI DOI Creative Commons
Mariangela Santorsola, Francesco Lescai

New Biotechnology, Journal Year: 2023, Volume and Issue: 77, P. 1 - 11

Published: June 16, 2023

Deep learning has already revolutionised the way a wide range of data is processed in many areas daily life. The ability to learn abstractions and relationships from heterogeneous provided impressively accurate prediction classification tools handle increasingly big datasets. This significant impact on growing wealth omics datasets, with unprecedented opportunity for better understanding complexity living organisms. While this revolution transforming these are analyzed, explainable deep emerging as an additional tool potential change biological interpreted. Explainability addresses critical issues such transparency, so important when computational introduced especially clinical environments. Moreover, it empowers artificial intelligence capability provide new insights into input data, thus adding element discovery powerful resources. In review, we overview transformative effects having multiple sectors, ranging genome engineering genomics, radiomics drug design trials. We offer perspective life scientists, understand tools, motivation implement them their research, by suggesting resources they can use move first steps field.

Language: Английский

Citations

20
Exome sequencing identifies genes associated with sleep-related traits DOI

Chen-Jie Fei,

Ze-Yu Li,

Jing Ning

et al.

Nature Human Behaviour, Journal Year: 2024, Volume and Issue: 8(3), P. 576 - 589

Published: Jan. 4, 2024

Language: Английский

Citations

6
Genomic findings and their implications for the evolutionary social sciences DOI Creative Commons
Brendan P. Zietsch

Evolution and Human Behavior, Journal Year: 2024, Volume and Issue: 45(4), P. 106596 - 106596

Published: July 1, 2024

What past selection pressures have shaped human traits and their variation covariation across individuals? These are key questions in the evolutionary social sciences. Recent advances field of genomics yielded a wealth evidence that sheds light on these questions, yet findings implications seem to be little known In this paper I aim bring together while explaining conceptual technical background is often assumed knowledge for reading primary reports. First, outline methodologies enabled relevant findings, such as genomewide association studies DNA-based heritability estimation. describe how reveal genetic architecture traits, then information turn enables inferences about selection. The show pervasive complex has been by negative (purifying) selection, implying extant maintained mutation-selection-drift balance. On other hand, there no balancing substantively strong it not. Finally, discuss issues dimensional structure personality plausibility psychological life history theory.

Language: Английский

Citations

6
Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes DOI Creative Commons
Joseph Glessner, Mylarappa Ningappa,

Kim A. Ngo

et al.

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(6), P. 1385 - 1395

Published: Aug. 11, 2023

Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) determine genetic basis BA.

Language: Английский

Citations

16