HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of Copy Number Variant, Copy Number Variation Region, and Runs of Homozygosity.
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ABSTRACT:
SUBMITTER: Zhou J
PROVIDER: S-EPMC8484803 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundExome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.MethodsIn a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.ResultsThe QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.ConclusionsOur clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.
| S-EPMC6525387 | biostudies-literature
Project description:Discovery of copy number variations (CNVs), a major category of structural variations, have dramatically changed our understanding of differences between individuals and provide an alternate paradigm for the genetic basis of human diseases. CNVs include both copy gain and copy loss events and their detection genome-wide is now possible using high-throughput, low-cost next generation sequencing (NGS) methods. However, accurate detection of CNVs from NGS data is not straightforward due to non-uniform coverage of reads resulting from various systemic biases. We have developed an integrated platform, iCopyDAV, to handle some of these issues in CNV detection in whole genome NGS data. It has a modular framework comprising five major modules: data pre-treatment, segmentation, variant calling, annotation and visualization. An important feature of iCopyDAV is the functional annotation module that enables the user to identify and prioritize CNVs encompassing various functional elements, genomic features and disease-associations. Parallelization of the segmentation algorithms makes the iCopyDAV platform even accessible on a desktop. Here we show the effect of sequencing coverage, read length, bin size, data pre-treatment and segmentation approaches on accurate detection of the complete spectrum of CNVs. Performance of iCopyDAV is evaluated on both simulated data and real data for different sequencing depths. It is an open-source integrated pipeline available at https://github.com/vogetihrsh/icopydav and as Docker's image at http://bioinf.iiit.ac.in/icopydav/.
| S-EPMC5886540 | biostudies-literature
Project description:OBJECTIVES:Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and runs of homozygosity (ROH) are associated with an increased risk for disease phenotypes, including schizophrenia and other psychiatric disorders. The effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt (SA) were quantified in an Arab Bedouin Kindred. METHODS:We carried out genetic analyses of 439 individuals from an Arab kindred with high rates of depression and suicidal behavior. We obtained complete ascertainment of SAs and first-degree relatives of individuals who have attempted or died by suicide. RESULTS:We found extensive regions of ROH. On average, 5% of the genome is covered by ROH for these individuals, two-fold higher than ROH rates for individuals from populations of European ancestry. Inbreeding and total length of ROH were not associated with risk for depression or attempt. For CNVs, an increased number of duplications more than 500?kb was associated with an increased risk for attempt (odds ratio: 2.9; P=0.01; 95% confidence interval: 1.3-6.6). Although not significant after correction for multiple testing, the risk for SA appears to increase with copy number for a CNV on chromosome 9p24.1. This possibility is intriguing because the CNV covers GLDC, which encodes glycine dehydrogenase that binds to glycine, a co-agonist at N-methyl-D-aspartate glutamate receptors, and is involved in glutamatergic neurotransmission. CONCLUSION:Our findings add to the growing evidence of genetic risk factors that act pleiotropically to increase the risk for several neuropsychiatric disorders, including depression and SA, irrespective of ancestry.
| S-EPMC5572483 | biostudies-literature
Project description:Runs of homozygosity (ROH) islands are stretches of homozygous sequence in the genome of a large proportion of individuals in a population. Algorithms for the detection of ROH depend on the similarity of haplotypes. Coverage gaps and copy number variants (CNV) may result in incorrect identification of such similarity, leading to the detection of ROH islands where none exists. Misidentified hemizygous regions will also appear as homozygous based on sequence variation alone. Our aim was to identify ROH islands influenced by marker coverage gaps or CNV, using Illumina BovineHD BeadChip (777 K) single nucleotide polymorphism (SNP) data for Austrian Brown Swiss, Tyrol Grey and Pinzgauer cattle.ROH were detected using clustering, and ROH islands were determined from population inbreeding levels for each marker. CNV were detected using a multivariate copy number analysis method and a hidden Markov model. SNP coverage gaps were defined as genomic regions with intermarker distances on average longer than 9.24 kb. ROH islands that overlapped CNV regions (CNVR) or SNP coverage gaps were considered as potential artefacts. Permutation tests were used to determine if overlaps between CNVR with copy losses and ROH islands were due to chance. Diversity of the haplotypes in the ROH islands was assessed by haplotype analyses.In Brown Swiss, Tyrol Grey and Pinzgauer, we identified 13, 22, and 24 ROH islands covering 26.6, 389.0 and 35.8 Mb, respectively, and we detected 30, 50 and 71 CNVR derived from CNV by using both algorithms, respectively. Overlaps between ROH islands, CNVR or coverage gaps occurred for 7, 14 and 16 ROH islands, respectively. About 37, 44 and 52% of the ROH islands coverage in Brown Swiss, Tyrol Grey and Pinzgauer, respectively, were affected by copy loss. Intersections between ROH islands and CNVR were small, but significantly larger compared to ROH islands at random locations across the genome, implying an association between ROH islands and CNVR. Haplotype diversity for reliable ROH islands was lower than for ROH islands that intersected with copy loss CNVR.Our findings show that a significant proportion of the ROH islands in the bovine genome are artefacts due to CNV or SNP coverage gaps.
| S-EPMC6106898 | biostudies-other
Project description:Litter size and teat number are economically important traits in the porcine industry. However, the genetic mechanisms influencing these traits remain unknown. In this study, we analyzed the genetic basis of litter size and teat number in Bama Xiang pigs and evaluated the genomic inbreeding coefficients of this breed. We conducted a genome-wide association study to identify runs of homozygosity (ROH), and copy number variation (CNV) using the novel Illumina PorcineSNP50 BeadChip array in Bama Xiang pigs and annotated the related genes in significant single nucleotide polymorphisms and common copy number variation region (CCNVR). We calculated the ROH-based genomic inbreeding coefficients (F ROH) and the Spearman coefficient between F ROH and reproduction traits. We completed a mixed linear model association analysis to identify the effect of high-frequency copy number variation (HCNVR; over 5%) on Bama Xiang pig reproductive traits using TASSEL software. Across eight chromosomes, we identified 29 significant single nucleotide polymorphisms, and 12 genes were considered important candidates for litter-size traits based on their vital roles in sperm structure, spermatogenesis, sperm function, ovarian or follicular function, and male/female infertility. We identified 9,322 ROHs; the litter-size traits had a significant negative correlation to F ROH. A total of 3,317 CNVs, 24 CCNVR, and 50 HCNVR were identified using cnvPartition and PennCNV. Eleven genes related to reproduction were identified in CCNVRs, including seven genes related to the testis and sperm function in CCNVR1 (chr1 from 311585283 to 315307620). Two candidate genes (NEURL1 and SH3PXD2A) related to reproduction traits were identified in HCNVR34. The result suggests that these genes may improve the litter size of Bama Xiang by marker-assisted selection. However, attention should be paid to deter inbreeding in Bama Xiang pigs to conserve their genetic diversity.
| S-EPMC9195146 | biostudies-literature
Project description:In this study, we chose 17 worldwide sheep populations of eight breeds, which were intensively selected for different purposes (meat, milk, or wool), or locally-adapted breeds, in order to identify and characterize factors impacting the detection of runs of homozygosity (ROH) and heterozygosity-rich regions (HRRs) in sheep. We also applied a business intelligence (BI) tool to integrate and visualize outputs from complementary analyses. We observed a prevalence of short ROH, and a clear distinction between the ROH profiles across populations. The visualizations showed a fragmentation of medium and long ROH segments. Furthermore, we tested different scenarios for the detection of HRR and evaluated the impact of the detection parameters used. Our findings suggest that HRRs are small and frequent in the sheep genome; however, further studies with higher density SNP chips and different detection methods are suggested for future research. We also defined ROH and HRR islands and identified common regions across the populations, where genes related to a variety of traits were reported, such as body size, muscle development, and brain functions. These results indicate that such regions are associated with many traits, and thus were under selective pressure in sheep breeds raised for different purposes. Interestingly, many candidate genes detected within the HRR islands were associated with brain integrity. We also observed a strong association of high linkage disequilibrium pattern with ROH compared with HRR, despite the fact that many regions in linkage disequilibrium were not located in ROH regions.
| S-EPMC8472390 | biostudies-literature
Project description:MotivationGenome-wide association studies (GWAS) generate relationships between hundreds of thousands of single nucleotide polymorphisms (SNPs) and complex phenotypes. The contribution of the traditionally overlooked copy number variations (CNVs) to complex traits is also being actively studied. To facilitate the interpretation of the data and the designing of follow-up experimental validations, we have developed a database that enables the sensible prioritization of these variants by combining several approaches, involving not only publicly available physical and functional annotations but also multilocus linkage disequilibrium (LD) annotations as well as annotations of expression quantitative trait loci (eQTLs).ResultsFor each SNP, the SCAN database provides: (i) summary information from eQTL mapping of HapMap SNPs to gene expression (evaluated by the Affymetrix exon array) in the full set of HapMap CEU (Caucasians from UT, USA) and YRI (Yoruba people from Ibadan, Nigeria) samples; (ii) LD information, in the case of a HapMap SNP, including what genes have variation in strong LD (pairwise or multilocus LD) with the variant and how well the SNP is covered by different high-throughput platforms; (iii) summary information available from public databases (e.g. physical and functional annotations); and (iv) summary information from other GWAS. For each gene, SCAN provides annotations on: (i) eQTLs for the gene (both local and distant SNPs) and (ii) the coverage of all variants in the HapMap at that gene on each high-throughput platform. For each genomic region, SCAN provides annotations on: (i) physical and functional annotations of all SNPs, genes and known CNVs within the region and (ii) all genes regulated by the eQTLs within the region.Availabilityhttp://www.scandb.org.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC2852202 | biostudies-literature
Project description:Recent advances in molecular genetic analysis using next-generation sequencing (NGS) have drastically accelerated the identification of disease-causing gene mutations. Most next-generation sequencing analyses of inherited diseases have mainly focused on single-nucleotide variants and short indels, although, recently, structure variations including copy number variations have come to be considered an important cause of many different diseases. However, only a limited number of tools are available for multiplex PCR-based target genome enrichment. In this paper, we reported a simple and efficient copy number variation visualization method for Ion AmpliSeq™ target resequencing data. Unlike the hybridization capture-based target genome enrichment system, Ion AmpliSeq™ reads are multiplex PCR products, and each read generated by the same amplicon is quite uniform in length and position. Based on this feature, the depth of coverage information for each amplicon included in the barcode/amplicon coverage matrix file was used for copy number detection analysis. We also performed copy number analysis to investigate the utility of this method through the use of positive controls and a large Japanese hearing loss cohort. Using this method, we successfully confirmed previously reported copy number loss cases involving the STRC gene and copy number gain in trisomy 21 cases. We also performed copy number analysis of a large Japanese hearing loss cohort (2,475 patients) and identified many gene copy number variants. The most prevalent copy number variation was STRC gene copy number loss, with 129 patients carrying this copy number variation. Our copy number visualization method for Ion AmpliSeq™ data can be utilized in efficient copy number analysis for the comparison of a large number of samples. This method is simple and requires only easy calculations using standard spread sheet software.
| S-EPMC6081219 | biostudies-literature
Project description:BackgroundResults of microbial ecology studies using 16S rRNA sequence information can be deceiving due to differences in rRNA operon copy number and genome size of the detected organisms. It therefore will be useful for investigators to have a better understanding of how these two parameters differ in various organism types. In this study, the number of ribosomal operons and genome size were separately mapped onto a Bacterial phylogenetic tree.ResultsA representative Bacterial tree was constructed using 31 marker genes found in 578 bacterial genome sequences. Organism names are displayed on the trees using graduations of color such that similar colors indicate similar numbers of operons or genome size. The resulting images provide an intuitive understanding of how copy number and genome size vary in different Bacterial phyla.ConclusionOnce the phylogenetic position of a novel organism is known the number of rRNA operons, and to a lesser extent the genome size, can be estimated by examination of the colored maps. Further detail can then be obtained for members of relevant taxa from the rrnDB database.
| S-EPMC2761929 | biostudies-literature
Project description:Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of thyroid cancer (TC). Most cancer predisposition genes identified through GWASs function in a co-dominant manner, and studies have not found evidence for recessively functioning disease loci in TC. Our study examines whether homozygosity is associated with an increased risk of TC and searches for novel recessively acting disease loci.Data from a previously conducted GWAS were used for the estimation of the proportion of phenotypic variance explained by all common SNPs, the detection of runs of homozygosity (ROH) and the determination of inbreeding to unravel their influence on TC.Inbreeding coefficients were significantly higher among cases than controls. Association on a SNP-by-SNP basis was controlled by using the false discovery rate at a level of q*?< 0.05, with 34 SNPs representing true differences in homozygosity between cases and controls. The average size, the number and total length of ROHs per person were significantly higher in cases than in controls. A total of 16 recurrent ROHs of rather short length were identified although their association with TC risk was not significant at a genome-wide level. Several recurrent ROHs harbor genes associated with risk of TC. All of the ROHs showed significant evidence for natural selection (iHS, Fst, Fay and Wu's H).Our results support the existence of recessive alleles in TC susceptibility. Although regions of homozygosity were rather small, it might be possible that variants within these ROHs affect TC risk and may function in a recessive manner.
| S-EPMC4794977 | biostudies-literature