Mixed ancestry analysis of whole-genome sequencing reveals common, rare, and structural variants associated with posterior urethral valves

Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but the genetic architecture of this disorder remains largely unknown. To address this, we analyzed whole-genome sequencing (WGS) data from 132 unrelated PUV cases and 23,727 controls of mixed ancestry. We observed enrichment of rare structural variation intersecting with candidate cis-regulatory elements, particularly inversions predicted to affect chromatin looping (P=3.1x10-5). We also identified statistically significant associations with common variants at 12q24.21 (P=7.8x10-12; OR 0.4) and uncommon variants at 6p21.1 (P=2x10-8; OR 7.2), that were replicated in an independent European cohort. Bayesian fine mapping and functional annotation mapped these loci to the transcription factor TBX5 and planar cell polarity gene PTK7, respectively, providing insights into the biological pathways underlying PUV. These findings demonstrate that a well-controlled diverse ancestry WGS approach can reveal the genetic architecture of a complex disorder by increasing power for disease locus discovery and facilitating fine-mapping of causal variants.

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QTG-Seq Accelerates QTL Fine Mapping through QTL Partitioning and Whole-Genome Sequencing of Bulked Segregant Samples

Molecular Plant ◽

10.1016/j.molp.2018.12.018 ◽

2019 ◽

Vol 12 (3) ◽

pp. 426-437 ◽

Cited By ~ 14

Author(s):

Hongwei Zhang ◽

Xi Wang ◽

Qingchun Pan ◽

Pei Li ◽

Yunjun Liu ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Fine Mapping ◽

Whole Genome ◽

Qtl Fine Mapping

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Fine mapping of genomic regions associated with female fertility in Nellore beef cattle based on sequence variants from segregating sires

Journal of Animal Science and Biotechnology ◽

10.1186/s40104-019-0403-0 ◽

2019 ◽

Vol 10 (1) ◽

Author(s):

Gerson A. Oliveira Júnior ◽

Daniel J. A. Santos ◽

Aline S. M. Cesar ◽

Solomon A. Boison ◽

Ricardo V. Ventura ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Fine Mapping ◽

Reproductive Hormones ◽

Sequence Variants ◽

Whole Genome ◽

Biological Processes ◽

Snp Chip ◽

Mesh Terms ◽

Genomic Regions

Abstract Background Impaired fertility in cattle limits the efficiency of livestock production systems. Unraveling the genetic architecture of fertility traits would facilitate their improvement by selection. In this study, we characterized SNP chip haplotypes at QTL blocks then used whole-genome sequencing to fine map genomic regions associated with reproduction in a population of Nellore (Bos indicus) heifers. Methods The dataset comprised of 1337 heifers genotyped using a GeneSeek® Genomic Profiler panel (74677 SNPs), representing the daughters from 78 sires. After performing marker quality control, 64800 SNPs were retained. Haplotypes carried by each sire at six previously identified QTL on BTAs 5, 14 and 18 for heifer pregnancy and BTAs 8, 11 and 22 for antral follicle count were constructed using findhap software. The significance of the contrasts between the effects of every two paternally-inherited haplotype alleles were used to identify sires that were heterozygous at each QTL. Whole-genome sequencing data localized to the haplotypes from six sires and 20 other ancestors were used to identify sequence variants that were concordant with the haplotype contrasts. Enrichment analyses were applied to these variants using KEGG and MeSH libraries. Results A total of six (BTA 5), six (BTA 14) and five (BTA 18) sires were heterozygous for heifer pregnancy QTL whereas six (BTA 8), fourteen (BTA 11), and five (BTA 22) sires were heterozygous for number of antral follicles’ QTL. Due to inadequate representation of many haplotype alleles in the sequenced animals, fine mapping analysis could only be reliably performed for the QTL on BTA 5 and 14, which had 641 and 3733 concordant candidate sequence variants, respectively. The KEGG “Circadian rhythm” and “Neurotrophin signaling pathway” were significantly associated with the genes in the QTL on BTA 5 whereas 32 MeSH terms were associated with the QTL on BTA 14. Among the concordant sequence variants, 0.2% and 0.3% were classified as missense variants for BTAs 5 and 14, respectively, highlighting the genes MTERF2, RTMB, ENSBTAG00000037306 (miRNA), ENSBTAG00000040351, PRKDC, and RGS20. The potential causal mutations found in the present study were associated with biological processes such as oocyte maturation, embryo development, placenta development and response to reproductive hormones. Conclusions The identification of heterozygous sires by positionally phasing SNP chip data and contrasting haplotype effects for previously detected QTL can be used for fine mapping to identify potential causal mutations and candidate genes. Genomic variants on genes MTERF2, RTBC, miRNA ENSBTAG00000037306, ENSBTAG00000040351, PRKDC, and RGS20, which are known to have influence on reproductive biological processes, were detected.

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Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7

Nature Genetics ◽

10.1038/ng.3761 ◽

2017 ◽

Vol 49 (2) ◽

pp. 186-192 ◽

Cited By ~ 71

Author(s):

Yang Luo ◽

Katrina M de Lange ◽

Luke Jostins ◽

Loukas Moutsianas ◽

Joshua Randall ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Bowel Disease ◽

Genetic Architecture ◽

Whole Genome ◽

Inflammatory Bowel

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Linked-read whole-genome sequencing resolves common and private structural variants in multiple myeloma

10.1101/2021.12.09.471893 ◽

2021 ◽

Author(s):

Lucía Peña Pérez ◽

Nicolai Frengen ◽

Julia Hauenstein ◽

Charlotte Gran ◽

Charlotte Gustafsson ◽

...

Keyword(s):

Multiple Myeloma ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Cohort Analysis ◽

Genomic Medicine ◽

Molecular Classification ◽

Regulatory Elements ◽

Copy Number Variations ◽

Whole Genome ◽

Structural Variants

Multiple myeloma (MM) is an incurable and aggressive plasma cell malignancy characterized by a complex karyotype with multiple structural variants (SVs) and copy number variations (CNVs). Linked-read whole-genome sequencing (lrWGS) allows for refined detection and reconstruction of SVs by providing long-range genetic information from standard short-read sequencing. This makes lrWGS an attractive solution for capturing the full genomic complexity of MM. Here we show that high-quality lrWGS data can be generated from low numbers of FACS sorted cells without DNA purification. Using this protocol, we analyzed FACS sorted MM cells from 37 MM patients with lrWGS. We found high concordance between lrWGS and FISH for the detection of recurrent translocations and CNVs. Outside of the regions investigated by FISH, we identified >150 additional SVs and CNVs across the cohort. Analysis of the lrWGS data allowed for resolving the structure of diverse SVs affecting the MYC and t(11;14) loci causing the duplication of genes and gene regulatory elements. In addition, we identified private SVs causing the dysregulation of genes recurrently involved in translocations with the IGH locus and show that these can alter the molecular classification of the MM. Overall, we conclude that lrWGS allows for the detection of aberrations critical for MM prognostics and provides a feasible route for providing comprehensive genetics. Implementing lrWGS could provide more accurate clinical prognostics, facilitate genomic medicine initiatives, and greatly improve the stratification of patients included in clinical trials.

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Whole genome sequencing identifies common and rare structural variants contributing to hematologic traits in the NHLBI TOPMed program

10.1101/2021.12.16.21267871 ◽

2021 ◽

Author(s):

Marsha M. Wheeler ◽

Adrienne M Stilp ◽

Shuquan Rao ◽

Bjarni V Halldorsson ◽

Doruk V Beyter ◽

...

Keyword(s):

Blood Cell ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Association Studies ◽

Regulatory Elements ◽

Chromatin Domain ◽

Genome Wide Association Studies ◽

Whole Genome ◽

Structural Variants ◽

Genome Wide

Genome-wide association studies (GWAS) have identified thousands of single nucleotide variants and small indels that contribute to the genetic architecture of hematologic traits. While structural variants (SVs) are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of SVs to quantitative blood cell trait variation is unknown. Here we utilized SVs detected from whole genome sequencing (WGS) in ancestrally diverse participants of the NHLBI TOPMed program (N=50,675). Using single variant tests, we assessed the association of common and rare SVs with red cell-, white cell-, and platelet-related quantitative traits. The results show 33 independent SVs (23 common and 10 rare) reaching genome-wide significance. The majority of significant association signals (N=27) replicated in independent datasets from deCODE genetics and the UK BioBank. Moreover, most trait-associated SVs (N=24) are within 1Mb of previously-reported GWAS loci. SV analyses additionally discovered an association between a complex structural variant on 17p11.2 and white blood cell-related phenotypes. Based on functional annotation, the majority of significant SVs are located in non-coding regions (N=26) and predicted to impact regulatory elements and/or local chromatin domain boundaries in blood cells. We predict that several trait-associated SVs represent the causal variant. This is supported by genome-editing experiments which provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

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Whole-genome sequencing of 175 Mongolians uncovers population-specific genetic architecture and gene flow throughout North and East Asia

Nature Genetics ◽

10.1038/s41588-018-0250-5 ◽

2018 ◽

Vol 50 (12) ◽

pp. 1696-1704 ◽

Cited By ~ 17

Author(s):

Haihua Bai ◽

Xiaosen Guo ◽

Narisu Narisu ◽

Tianming Lan ◽

Qizhu Wu ◽

...

Keyword(s):

Gene Flow ◽

East Asia ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genetic Architecture ◽

Whole Genome

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Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes

Human Molecular Genetics ◽

10.1093/hmg/ddu560 ◽

2014 ◽

Vol 24 (5) ◽

pp. 1504-1512 ◽

Cited By ~ 6

Author(s):

Andrew R. Wood ◽

Marcus A. Tuke ◽

Mike Nalls ◽

Dena Hernandez ◽

J. Raphael Gibbs ◽

...

Keyword(s):

Gene Expression ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genetic Architecture ◽

Whole Genome ◽

Common Gene

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Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma

Gut ◽

10.1136/gutjnl-2018-317612 ◽

2019 ◽

Vol 69 (6) ◽

pp. 1039-1052 ◽

Cited By ~ 3

Author(s):

Wen Fong Ooi ◽

Amrita M Nargund ◽

Kevin Junliang Lim ◽

Shenli Zhang ◽

Manjie Xing ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Therapy Resistance ◽

Regulatory Elements ◽

Genomic Rearrangements ◽

Common Mechanism ◽

Whole Genome ◽

Structural Variations ◽

Chromosome Conformation ◽

Chip Sequencing

ObjectiveGenomic structural variations (SVs) causing rewiring of cis-regulatory elements remain largely unexplored in gastric cancer (GC). To identify SVs affecting enhancer elements in GC (enhancer-based SVs), we integrated epigenomic enhancer profiles revealed by paired-end H3K27ac ChIP-sequencing from primary GCs with tumour whole-genome sequencing (WGS) data (PeNChIP-seq/WGS).DesignWe applied PeNChIP-seq to 11 primary GCs and matched normal tissues combined with WGS profiles of >200 GCs. Epigenome profiles were analysed alongside matched RNA-seq data to identify tumour-associated enhancer-based SVs with altered cancer transcription. Functional validation of candidate enhancer-based SVs was performed using CRISPR/Cas9 genome editing, chromosome conformation capture assays (4C-seq, Capture-C) and Hi-C analysis of primary GCs.ResultsPeNChIP-seq/WGS revealed ~150 enhancer-based SVs in GC. The majority (63%) of SVs linked to target gene deregulation were associated with increased tumour expression. Enhancer-based SVs targeting CCNE1, a key driver of therapy resistance, occurred in 8% of patients frequently juxtaposing diverse distal enhancers to CCNE1 proximal regions. CCNE1-rearranged GCs were associated with high CCNE1 expression, disrupted CCNE1 topologically associating domain (TAD) boundaries, and novel TAD interactions in CCNE1-rearranged primary tumours. We also observed IGF2 enhancer-based SVs, previously noted in colorectal cancer, highlighting a common non-coding genetic driver alteration in gastric and colorectal malignancies.ConclusionIntegrated paired-end NanoChIP-seq and WGS of gastric tumours reveals tumour-associated regulatory SV in regions associated with both simple and complex genomic rearrangements. Genomic rearrangements may thus exploit enhancer-hijacking as a common mechanism to drive oncogene expression in GC.

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One substance to rule them all and in the darkness bind them: whole-genome sequencing illuminates multifaceted targets of humic adaptation in Eurasian perch

10.22541/au.163457003.30026863/v1 ◽

2021 ◽

Author(s):

Mikhail Ozerov ◽

Kristina Noreikiene ◽

Siim Kahar ◽

Magnus Huss ◽

Ari Huusko ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Extreme Environments ◽

Gene Families ◽

Regulatory Elements ◽

Phenotypic Traits ◽

Whole Genome ◽

Humic Lakes ◽

Whole Genome Analysis ◽

Eurasian Perch

Extreme environments are inhospitable to the majority of species, but some organisms are able to survive in such hostile conditions due to evolutionary adaptations. For example, modern bony fishes have colonized various aquatic environments, including perpetually dark, hypoxic, hypersaline and toxic habitats. Eurasian perch (Perca fluviatilis) is among the few fish species of northern latitudes that is able to live in extremely acidic humic lakes. Such lakes represent almost “nocturnal” environments; they contain high levels of dissolved organic matter, which in addition to creating a challenging visual environment, also affects a large number of other habitat parameters and biotic interactions. To reveal the genomic targets of humic-associated selection, we performed whole-genome sequencing of perch originating from 16 humic and 16 clear-water lakes in northern Europe. We identified over 800,000 SNPs, of which >10,000 were identified as potential candidates under selection (associated with >3,000 genes) using multiple outlier approaches. Our findings suggest that adaptation to the humic environment involves hundreds of regions scattered across the genome. Putative signals of adaptation were detected in genes and gene families with diverse functions, including organism development and ion transportation. The observed excess of variants under selection in regulatory regions highlights the importance of adaptive evolution via regulatory elements, rather than via protein sequence modification. Our study demonstrates the power of whole-genome analysis to illuminate multifaceted nature of humic adaptation and highlights the next challenge moving from high-throughput outlier identification towards functional validation of causal mutations underlying phenotypic traits of ecological and evolutionary importance.

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Characterization of intermediate-sized insertions using whole genome sequencing data and analysis of their functional impacts on gene expression

10.21203/rs.3.rs-203007/v1 ◽

2021 ◽

Author(s):

Saeideh Ashouri ◽

Jing Hao Wong ◽

Hidewaki Nakagawa ◽

Mihoko Shimada ◽

Katsushi Tokunaga ◽

...

Keyword(s):

Gene Expression ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Gene Expression Regulation ◽

Regulatory Elements ◽

Expression Regulation ◽

Ctcf Binding ◽

Whole Genome Sequencing Data ◽

Whole Genome ◽

Sequencing Data

Abstract Intermediate-sized insertions are one of the structural variants contributing to genome diversity. However, due to technical difficulties in identifying them, their importance in disease pathogenicity and gene expression regulation remains unclear. We used whole-genome sequencing data of 174 Japanese samples to characterize intermediate-sized insertions using a highly-accurate insertion calling method (IMSindel software and joint-call recovery) and obtained a catalogue of 4,254 insertions. We constructed an imputation panel comprising of insertions and SNVs from all samples, and conducted imputation of intermediate-sized insertions for 82 publicly-available Japanese samples. Imputation accuracy, evaluated using Nanopore long-read sequencing data, was 97%. Subsequent eQTL analysis predicted 128 (~ 3.0%) insertions as causative for gene expression level changes. Enrichment analysis of causal insertions for genome regulatory elements showed significant associations with CTCF-binding sites, super-enhancers, and promoters. Among 17 causal insertions found in the same causal set with GWAS hits, there were insertions associated with changes in expression of cancer-related genes such as BRCA1, ZNF222, and ABCB10. Analysis of insertions sequences revealed that 461 insertions were short tandem duplications frequently found in early replicating regions of genome. Furthermore, comparison of functional importance of intermediate-sized insertions with that of intermediate-sized deletions detected in the same sample set in our previous study showed that insertions were more frequent in genic regions, and proportion of functional candidates was smaller in insertions. Here, we characterize a high-confidence set of intermediate-sized insertions and indicate their importance in gene expression regulation. Our results emphasize the importance of considering intermediate-sized insertions in trait association studies.

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