scholarly journals RBV: Read balance validator, a tool for prioritising copy number variations in germline conditions

2018 ◽  
Author(s):  
Whitney Whitford ◽  
Klaus Lehnert ◽  
Russell G. Snell ◽  
Jessie C. Jacobsen
Keyword(s):  
Copy Number ◽  
High Throughput Sequencing ◽  
Sequence Data ◽  
Relative Proportion ◽  
Copy Number Variants ◽  
Read Depth ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Software Packages ◽  
Bioinformatic Tool

AbstractBackgroundThe popularisation and decreased cost of genome resequencing has resulted in an increased use in molecular diagnostics. While there are a number of established and high quality bioinfomatic tools for identifying small genetic variants including single nucleotide variants and indels, currently there is no established standard for the detection of copy number variants (CNVs) from sequence data. The requirement for CNV detection from high throughput sequencing has resulted in the development of a large number of software packages. These tools typically utilise the sequence data characteristics: read depth, split reads, read pairs, and assembly-based techniques. However the additional source of information from read balance, defined as relative proportion of reads of each allele at each position, has been underutilised in the existing applications.ResultsWe present Read Balance Validator (RBV), a bioinformatic tool which uses read balance for prioritisation and validation of putative CNVs. The software simultaneously interrogates nominated regions for the presence of deletions or multiplications, and can differentiate larger CNVs from diploid regions. Additionally, the utility of RBV to test for inheritance of CNVs is demonstrated in this report.ConclusionsRBV is a CNV validation and prioritisation bioinformatic tool for both genome and exome sequencing available as a python package from https://github.com/whitneywhitford/RBV

scholarly journals RBV: Read balance validator, a tool for prioritising copy number variations in germline conditions

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Whitney Whitford ◽  
Klaus Lehnert ◽  
Russell G. Snell ◽  
Jessie C. Jacobsen
Keyword(s):  
Copy Number ◽  
High Throughput Sequencing ◽  
Sequence Data ◽  
Relative Proportion ◽  
Copy Number Variants ◽  
Read Depth ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Software Packages ◽  
Bioinformatic Tool

AbstractThe popularisation and decreased cost of genome resequencing has resulted in an increased use in molecular diagnostics. While there are a number of established and high quality bioinfomatic tools for identifying small genetic variants including single nucleotide variants and indels, currently there is no established standard for the detection of copy number variants (CNVs) from sequence data. The requirement for CNV detection from high throughput sequencing has resulted in the development of a large number of software packages. These tools typically utilise the sequence data characteristics: read depth, split reads, read pairs, and assembly-based techniques. However, the additional source of information from read balance (defined as relative proportion of reads of each allele at each position) has been underutilised in the existing applications. Here we present Read Balance Validator (RBV), a bioinformatic tool that uses read balance for prioritisation and validation of putative CNVs. The software simultaneously interrogates nominated regions for the presence of deletions or multiplications, and can differentiate larger CNVs from diploid regions. Additionally, the utility of RBV to test for inheritance of CNVs is demonstrated in this report. RBV is a CNV validation and prioritisation bioinformatic tool for both genome and exome sequencing available as a python package from https://github.com/whitneywhitford/RBV.

scholarly journals Adaptive archaic introgression of copy number variants and the discovery of previously unknown human genes

Science ◽  
2019 ◽  
Vol 366 (6463) ◽  
pp. eaax2083 ◽  
Author(s):  
PingHsun Hsieh ◽  
Mitchell R. Vollger ◽  
Vy Dang ◽  
David Porubsky ◽  
Carl Baker ◽  
...  
Keyword(s):  
Copy Number ◽  
Large Scale ◽  
Sequence Data ◽  
Local Population ◽  
Copy Number Variants ◽  
Human Populations ◽  
Single Nucleotide Variants ◽  
Human Genes ◽  
Long Read ◽  
Archaic Introgression

Copy number variants (CNVs) are subject to stronger selective pressure than single-nucleotide variants, but their roles in archaic introgression and adaptation have not been systematically investigated. We show that stratified CNVs are significantly associated with signatures of positive selection in Melanesians and provide evidence for adaptive introgression of large CNVs at chromosomes 16p11.2 and 8p21.3 from Denisovans and Neanderthals, respectively. Using long-read sequence data, we reconstruct the structure and complex evolutionary history of these polymorphisms and show that both encode positively selected genes absent from most human populations. Our results collectively suggest that large CNVs originating in archaic hominins and introgressed into modern humans have played an important role in local population adaptation and represent an insufficiently studied source of large-scale genetic variation.

scholarly journals Detection of copy number variants in African goats using whole genome sequence data

2020 ◽  
Author(s):  
Wilson Nandolo ◽  
Gábor Mészáros ◽  
Maria Wurzinger ◽  
Liveness J. Banda ◽  
Timothy N. Gondwe ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Characterization ◽  
Sequence Data ◽  
Copy Number Variants ◽  
Copy Number Variations ◽  
Whole Genome Sequence ◽  
African Countries ◽  
Body Of Knowledge ◽  
Number Variation ◽  
Cellular Components

Abstract Background Copy number variations (CNV) are a significant source of variation in the genome and are therefore essential to the understanding of genetic characterization. The aim of this study was to develop a fine-scaled copy number variation map for African goats. We used sequence data from multiple breeds and from multiple African countries. Results A total of 253,553 CNV (244,876 deletions and 8,677 duplications) were identified, corresponding to an overall average of 1,393 CNV per animal. The mean CNV length was 3.3 kb, with a median of 1.3 kb. There was substantial differentiation between the populations for some CNV, suggestive of the effect of population-specific selective pressures. A total of 6,231 global CNV regions (CNVR) were found across all animals, representing 59.2 Mb (2.4%) of the goat genome. About 1.6% of the CNVR were present in all 34 breeds and 28.7% were present in all 5 geographical areas across Africa, where animals had been sampled. The CNVR had genes that were highly enriched in important biological functions, molecular functions, and cellular components including retrograde endocannabinoid signaling, glutamatergic synapse and circadian entrainment. Conclusions This study presents the first fine CNV map of African goat based on WGS data and adds to the growing body of knowledge on the genetic characterization of goats.

scholarly journals The transcription factor Maz is essential for normal eye development

2020 ◽  
Vol 13 (8) ◽  
pp. dmm044412
Author(s):  
Olga Medina-Martinez ◽  
Meade Haller ◽  
Jill A. Rosenfeld ◽  
Marisol A. O'Neill ◽  
Dolores J. Lamb ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Copy Number ◽  
Eye Development ◽  
Copy Number Variants ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Gene Encoding ◽  
Ocular Development ◽  
Ciliary Margin

ABSTRACTWnt/β-catenin signaling has an essential role in eye development. Faulty regulation of this pathway results in ocular malformations, owing to defects in cell-fate determination and differentiation. Herein, we show that disruption of Maz, the gene encoding Myc-associated zinc-finger transcription factor, produces developmental eye defects in mice and humans. Expression of key genes involved in the Wnt cascade, Sfrp2, Wnt2b and Fzd4, was significantly increased in mice with targeted inactivation of Maz, resulting in abnormal peripheral eye formation with reduced proliferation of the progenitor cells in the region. Paradoxically, the Wnt reporter TCF-Lef1 displayed a significant downregulation in Maz-deficient eyes. Molecular analysis indicates that Maz is necessary for the activation of the Wnt/β-catenin pathway and participates in the network controlling ciliary margin patterning. Copy-number variations and single-nucleotide variants of MAZ were identified in humans that result in abnormal ocular development. The data support MAZ as a key contributor to the eye comorbidities associated with chromosome 16p11.2 copy-number variants and as a transcriptional regulator of ocular development.

scholarly journals Detection of copy number variants in African goats using whole genome sequence data

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wilson Nandolo ◽  
◽  
Gábor Mészáros ◽  
Maria Wurzinger ◽  
Liveness J. Banda ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Characterization ◽  
Sequence Data ◽  
Copy Number Variants ◽  
Copy Number Variations ◽  
Whole Genome Sequence ◽  
African Countries ◽  
Body Of Knowledge ◽  
Number Variation ◽  
Cellular Components

Abstract Background Copy number variations (CNV) are a significant source of variation in the genome and are therefore essential to the understanding of genetic characterization. The aim of this study was to develop a fine-scaled copy number variation map for African goats. We used sequence data from multiple breeds and from multiple African countries. Results A total of 253,553 CNV (244,876 deletions and 8677 duplications) were identified, corresponding to an overall average of 1393 CNV per animal. The mean CNV length was 3.3 kb, with a median of 1.3 kb. There was substantial differentiation between the populations for some CNV, suggestive of the effect of population-specific selective pressures. A total of 6231 global CNV regions (CNVR) were found across all animals, representing 59.2 Mb (2.4%) of the goat genome. About 1.6% of the CNVR were present in all 34 breeds and 28.7% were present in all 5 geographical areas across Africa, where animals had been sampled. The CNVR had genes that were highly enriched in important biological functions, molecular functions, and cellular components including retrograde endocannabinoid signaling, glutamatergic synapse and circadian entrainment. Conclusions This study presents the first fine CNV map of African goat based on WGS data and adds to the growing body of knowledge on the genetic characterization of goats.

scholarly journals Genome Scan for Variable Genes Involved in Environmental Adaptations of Nubian Ibex

2021 ◽  
Author(s):  
Vivien J. Chebii ◽  
Emmanuel A. Mpolya ◽  
Samuel O. Oyola ◽  
Antoinette Kotze ◽  
Jean-Baka Domelevo Entfellner ◽  
...  
Keyword(s):  
Copy Number ◽  
Viral Infections ◽  
Sequence Data ◽  
Transmembrane Protein ◽  
Plant Secondary Metabolites ◽  
Read Depth ◽  
Copy Number Variations ◽  
Structural Genomic ◽  
Ambient Temperatures ◽  
Variable Genes

AbstractThe Nubian ibex (Capra nubiana) is a wild goat species that inhabits the Sahara and Arabian deserts and is adapted to extreme ambient temperatures, intense solar radiation, and scarcity of food and water resources. To investigate desert adaptation, we explored the possible role of copy number variations (CNVs) in the evolution of Capra species with a specific focus on the environment of Capra nubiana. CNVs are structural genomic variations that have been implicated in phenotypic differences between species and could play a role in species adaptation. CNVs were inferred from Capra nubiana sequence data relative to the domestic goat reference genome using read-depth approach. We identified 191 CNVs overlapping with protein-coding genes mainly involved in biological processes such as innate immune response, xenobiotic metabolisms, and energy metabolisms. We found copy number variable genes involved in defense response to viral infections (Cluster of Differentiation 48, UL16 binding protein 3, Natural Killer Group 2D ligand 1-like, and Interferon-induced transmembrane protein 3), possibly suggesting their roles in Nubian ibex adaptations to viral infections. Additionally, we found copy number variable xenobiotic metabolism genes (carboxylesterase 1, Cytochrome P450 2D6, Glutathione S-transferase Mu 4, and UDP Glucuronosyltransferase-2B7), which are probably an adaptation of Nubian ibex to desert diets that are rich in plant secondary metabolites. Collectively, this study's results advance our understanding of CNVs and their possible roles in the adaptation of Nubian ibex to its environment. The copy number variable genes identified in Nubian ibex could be considered as subjects for further functional characterizations.

scholarly journals Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Nayoung Han ◽  
Jung Mi Oh ◽  
In-Wha Kim
Keyword(s):  
Copy Number ◽  
Genome Wide Association Study ◽  
Copy Number Gain ◽  
Copy Number Variations ◽  
Gene Gain ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Genome Wide ◽  
Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

Application of Copy Number Variation Sequencing in Genetic Analysis of Miscarriages in Early and Middle Pregnancy

2020 ◽  
Vol 160 (11-12) ◽  
pp. 634-642
Author(s):  
Shiqiang Luo ◽  
Xingyuan Chen ◽  
Tizhen Yan ◽  
Jiaolian Ya ◽  
Zehui Xu ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
High Throughput ◽  
Copy Number ◽  
High Throughput Sequencing ◽  
Chromosomal Abnormalities ◽  
Pregnancy Termination ◽  
Mendelian Inheritance ◽  
Copy Number Variations ◽  
Abnormal Chromosome ◽  
Number Variation

High-throughput sequencing based on copy number variation (CNV-seq) is commonly used to detect chromosomal abnormalities. This study identifies chromosomal abnormalities in aborted embryos/fetuses in early and middle pregnancy and explores the application value of CNV-seq in determining the causes of pregnancy termination. High-throughput sequencing was used to detect chromosome copy number variations (CNVs) in 116 aborted embryos in early and middle pregnancy. The detection data were compared with the Database of Genomic Variants (DGV), the Database of Chromosomal Imbalance and Phenotype in Humans using Ensemble Resources (DECIPHER), and the Online Mendelian Inheritance in Man (OMIM) database to determine the CNV type and the clinical significance. High-throughput sequencing results were successfully obtained in 109 out of 116 specimens, with a detection success rate of 93.97%. In brief, there were 64 cases with abnormal chromosome numbers and 23 cases with CNVs, in which 10 were pathogenic mutations and 13 were variants of uncertain significance. An abnormal chromosome number is the most important reason for embryo termination in early and middle pregnancy, followed by pathogenic chromosome CNVs. CNV-seq can quickly and accurately detect chromosome abnormalities and identify microdeletion and microduplication CNVs that cannot be detected by conventional chromosome analysis, which is convenient and efficient for genetic etiology diagnosis in miscarriage.

scholarly journals An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Leandro de Araújo Lima ◽  
Ana Cecília Feio-dos-Santos ◽  
Sintia Iole Belangero ◽  
Ary Gadelha ◽  
Rodrigo Affonseca Bressan ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Integrative Approach ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Hyperactivity Disorder ◽  
New Genes

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

scholarly journals Genotype-Phenotype correlation in Dravet Syndrome with SCN1A mutation increase efficiency of molecular diagnosis

2012 ◽  
Vol 18 (2) ◽  
pp. 60-62
Author(s):  
MC Gonsales ◽  
P Preto ◽  
MA Montenegro ◽  
MM Guerreiro ◽  
I Lopes-Cendes
Keyword(s):  
Protein Function ◽  
Copy Number ◽  
Mutation Screening ◽  
Copy Number Variants ◽  
Febrile Seizures ◽  
Copy Number Variations ◽  
Dravet Syndrome ◽  
Missense Mutations ◽  
The Impact ◽  
Doose Syndrome

OBJECTIVES: The purpose of this study was to advance the knowledge on the clinical use of SCN1A testing for severe epilepsies within the spectrum of generalized epilepsy with febrile seizures plus by performing genetic screening in patients with Dravet and Doose syndromes and establishing genotype-phenotype correlations. METHODS: Mutation screening in SCN1A was performed in 15 patients with Dravet syndrome and 13 with Doose syndrome. Eight prediction algorithms were used to analyze the impact of the mutations in putative protein function. Furthermore, all SCN1A mutations previously published were compiled and analyzed. In addition, Multiplex Ligation-Dependent Probe Amplification (MLPA) technique was used to detect possible copy number variations within SCN1A. RESULTS: Twelve mutations were identified in patients with Dravet syndrome, while patients with Doose syndrome showed no mutations. Our results show that the most common type of mutation found is missense, and that they are mostly located in the pore region and the N- and C-terminal of the protein. No copy number variants in SCN1A were identified in our cohort. CONCLUSIONS: SCN1A testing is clinically useful for patients with Dravet syndrome, but not for those with Doose syndrome, since both syndromes do not seem to share the same genetic basis. Our results indicate that indeed missense mutations can cause severe phenotypes depending on its location and the type of amino-acid substitution. Moreover, our strategy for predicting deleterious effect of mutations using multiple computation algorithms was efficient for most of the mutations identified.

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