Cell Genomics, Год журнала: 2024, Номер 4(12), С. 100721 - 100721
Опубликована: Дек. 1, 2024
Язык: Английский
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Март 21, 2024
Abstract Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies genomic syndromes in both clinical and population cohorts, mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion 89 duplication carriers among unrelated white British UK Biobank participants, we performed a phenome-wide association study between region’s copy number 117 complex traits diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by CNVs, with deletion-only, mirror, U-shape, duplication-only models being best fit for thirty, ten, four, two phenotypes, respectively, aligning stronger deleteriousness deletion. Upon individually adjusting CNV effects either body mass index (BMI), height, cognitive function, or socio-economic status as potential mediators, found that sixteen testable deletion-driven associations (61%) – primarily cardiovascular metabolic BMI-dependent, other mediators playing more subtle role. Bidirectional Mendelian randomization supported 13 out these 16 (81%) secondary consequences CNV’s impact on BMI. For 22 remained significantly associated upon individual adjustment matched-control analyses eleven including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, pulmonary capacity, pneumonia, acute kidney injury, under strict Bonferroni correction, eight additional nominally significant associations. These results paint picture BP4-5’s pattern involves direct multiple physiological systems indirect co-morbidities consequential BMI cognition, acting through trait-specific mechanisms.
Язык: Английский
Процитировано
2
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Авг. 28, 2024
SUMMARY Variable expressivity of disease-associated variants implies a role for secondary that modify clinical features. We assessed the effects modifier towards outcomes 2,252 individuals with primary variants. Among 132 families 16p12.1 deletion, distinct rare and common variant classes conferred risk specific developmental features, including short tandem repeats neurological defects SNVs microcephaly, while additional multiple genetic diagnoses. Within disease population cohorts 773 we found opposing features across ascertainments. Additional analysis 1,479 probands other variants, such as 16p11.2 deletion CHD8 1,084 without showed phenotypic associations differed by context were influenced synergistic interactions between Our study provides paradigm to dissect genomic architecture complex disorders personalized treatment.
Язык: Английский
Процитировано
2
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown
Опубликована: Ноя. 13, 2023
Abstract The proteome is fundamental to human biology and health but little known about ancestral diversity of its genetic determinants. In GWAS plasma levels 2,923 proteins in 3,974 Chinese adults, we identified pQTLs for 1,784 proteins, including 1,312 cis -pQTLs 1,264 proteins. Fine-mapping 3,475 credible sets independent pQTLs, 36% which were distinct from those European adults as assessed by three different methods. phenome-wide MR analyses, 59 disease associations strong LD (r 2 >0.95) with a -pQTL sentinel variant, 26 evidence colocalisation (PP.H4>0.9) 34 not previous similar studies. Evaluation current drug development 8 confirmed therapeutic targets, potential repurposing 19 novel targets (13 previously reported Europeans). findings demonstrate the importance extending proteogenomic studies non-European ancestry populations identify major diseases.
Язык: Английский
Процитировано
4
Molecular Cytogenetics, Год журнала: 2024, Номер 17(1)
Опубликована: Май 20, 2024
Abstract Background The incidence of spontaneous abortion (SA), which affects approximately 15–20% pregnancies, is the most common complication early pregnancy. Pathogenic copy number variations (CNVs) are recognized as potential genetic causes SA. However, CNVs variants uncertain significance (VOUS) have been identified in products conceptions (POCs), and their correlation with SA remains uncertain. Results Of 189 cases, trisomy 16 was numerical chromosome abnormality, followed by monosomy X. often occurred on chromosomes 4 8. Gene Ontology signaling pathway analysis revealed significant enrichment genes related to nervous system development, transmembrane transport, cell adhesion, structural components chromatin. Furthermore, within VOUS were screened integrating human placental expression profiles, PhyloP scores, Residual Variance Intolerance Score (RVIS) percentiles identify candidate associated abortion. Fourteen ( LZTR1 , TSHZ1 AMIGO2 H1-4 H2BC4 H2AC7 H3C8 H4C3 H3C6 P HKG2 PRR14 RNF40 SRCAP, ZNF629 ) identified. Variations may contribute embryonic lethality. Conclusions CNV sequencing (CNV-seq) an effective technique for detecting chromosomal abnormalities POCs identifying
Язык: Английский
Процитировано
1
Human Genetics and Genomics Advances, Год журнала: 2024, Номер 5(4), С. 100340 - 100340
Опубликована: Авг. 12, 2024
Язык: Английский
Процитировано
1
Life Science Alliance, Год журнала: 2024, Номер 8(3), С. e202402949 - e202402949
Опубликована: Дек. 10, 2024
Structural variants (SVs) over 50 base pairs play a significant role in phenotypic diversity and are associated with various diseases, but their analysis is complex resource-intensive. Numerous computational tools have been developed for SV prioritization, yet effectiveness biomedicine remains unclear. Here we benchmarked eight widely used prioritization tools, categorized into knowledge-driven (AnnotSV, ClassifyCNV) data-driven (CADD-SV, dbCNV, StrVCTVRE, SVScore, TADA, XCNV) groups accordance the ACMG guidelines. We assessed accuracy, robustness, usability across diverse genomic contexts, biological mechanisms efficiency using seven carefully curated independent datasets. Our results revealed that both of methods exhibit comparable predicting pathogenicity, although performance varies among emphasizing importance selecting appropriate tool based on specific research purposes. Furthermore, pinpointed potential improvement expanding these future applications. benchmarking framework provides crucial evaluation method offering practical guidance biomedical facilitating advancement better tools.
Язык: Английский
Процитировано
1
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Дек. 22, 2024
Abstract Copy number variants (CNVs) are prevalent in both diploid and haploid genomes, with the latter containing a single copy of each gene. Studying CNVs genomes from or few cells is significantly advancing our knowledge human disorders disease susceptibility. Low-input including low-cell single-cell sequencing data for organisms generally displays shallow highly non-uniform read counts resulting whole genome amplification steps that introduce biases. In addition, typically possess relatively short require higher degree DNA compared to organisms. However, most CNV detection methods specifically developed without specific consideration effects on genomes. Challenges also reside reference samples normal controls which used provide baseline signals defining losses gains. traditional methods, references usually pre-specified assumed be disease-free. use pre-defined can bias results if common present. Here, we present development comprehensive statistical framework normalization single- called HapCNV. The prominent advancement construction novel genomic location pseudo-reference selects unbiased using preliminary cell clustering method. This approach effectively preserves CNVs. Using simulations, demonstrated HapCNV outperformed existing by generating more accurate detection, especially Superior performance was validated detecting known real P. falciparum parasite dataset. conclusion, provides useful low-input datasets, easy applicability diploids.
Язык: Английский
Процитировано
1
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Март 2, 2024
Abstract Copy number variants (CNVs), which are duplicated or deleted genomic segments larger than 1000 base pairs 1 , have been implicated in a variety of neuropsychiatric and cognitive phenotypes 2-4 . In the first large-scale examination genome-wide CNV frequencies across ancestry groups, we found that deleterious CNVs less prevalent non-European groups they European both UK Biobank (UKBB) US replication cohort (SPARK). We also identified specific recurrent consistently differ frequency UKBB SPARK. These ancestry-related differences prevalence present an unselected community population family enriched with individuals diagnosed autism spectrum disorder (ASD) strongly suggest genetic should be considered when probing associations between health outcomes.
Язык: Английский
Процитировано
0
Research Square (Research Square), Год журнала: 2024, Номер unknown
Опубликована: Май 13, 2024
Язык: Английский
Процитировано
0
Опубликована: Окт. 29, 2024
Abstract Copy number variants (CNVs) are pivotal in driving phenotypic variation that facilitates species adaptation. They significant contributors to various disorders, making ancient genomes crucial for uncovering the genetic origins of disease susceptibility across populations. However, detecting CNVs DNA samples poses substantial challenges due several factors. Ancient (aDNA) is often highly degraded, and this degradation further complicated by contamination from microbial closely related species, introducing additional noise into sequencing data. Finally, typically low coverage aDNA renders accurate CNV detection particularly difficult. Conventional calling algorithms, optimized high long reads, underperform such conditions. To address these limitations, we introduce LYCEUM, a deep learning-based caller specifically designed low-coverage aDNA. LYCEUM performs transfer learning model detect another noisy data domain, whole exome then it fine-tuning with few which semi-ground truth calls available. Our findings demonstrate accurately identifies even downsampled genomes, maintaining robust performance range levels. Thus, offers researchers reliable solution challenging genomic datasets. available at https://github.com/ciceklab/LYCEUM
Язык: Английский
Процитировано
0