scholarly journals Haplotype-resolved inversion landscape reveals hotspots of mutational recurrence associated with genomic disorders

2021 ◽  
Author(s):  
David Porubsky ◽  
Wolfram Höps ◽  
Hufsah Ashraf ◽  
PingHsun Hsieh ◽  
Bernardo Rodriguez-Martin ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Segmental Duplications ◽  
Common Variants ◽  
Base Pairs ◽  
Genomic Technologies ◽  
Human Genomes ◽  
Heterozygous Carriers ◽  
Critical Regions ◽  
Genomic Disorders

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1-retrotransposition; 80% of the larger inversions are balanced and affect twice as many base pairs as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or mobile elements. Since this suggests recurrence due to non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7*10-4 per locus and generation. Recurrent inversions exhibit a sex-chromosomal bias, and significantly co-localize to the critical regions of genomic disorders. We propose that inversion recurrence results in an elevated number of heterozygous carriers and structural SD diversity, which increases mutability in the population and predisposes to disease-causing CNVs.

Basic principles of genetic disease

ESC CardioMed ◽  
2018 ◽  
pp. 669-671
Author(s):  
Eric Schulze-Bahr
Keyword(s):  
Genetic Disease ◽  
Copy Number ◽  
Copy Number Variants ◽  
Single Nucleotide Variants ◽  
Individual Genome ◽  
Base Pairs ◽  
Single Nucleotide ◽  
Basic Principles ◽  
Bona Fide ◽  
Genomic Regions

The human genome consists of approximately 3 billion (3 × 109) base pairs of DNA (around 20,000 genes), organized as 23 chromosomes (diploid parental set), and a small mitochondrial genome (37 genes, including 13 proteins; 16,589 base pairs) of maternal origin. Most human genetic variation is natural, that is, common or rare (minor allele frequency >0.1%) and does not cause disease—apart from every true disease-causing (bona fide) mutation each individual genome harbours more than 3.5 million single nucleotide variants (including >10,000 non-synonymous changes causing amino acid substitutions) and 200–300 large structural or copy number variants (insertions/deletions, up to several thousands of base-pairs) that are non-disease-causing variations and scattered throughout coding and non-coding genomic regions.

Genetics of Schizophrenia and Bipolar Disorder

2017 ◽  
Author(s):  
Alexander Charney ◽  
Pamela Sklar
Keyword(s):  
Bipolar Disorder ◽  
Copy Number ◽  
Psychotic Disorders ◽  
Copy Number Variants ◽  
Nucleotide Polymorphisms ◽  
Common Variants ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. There is now convincing genetic evidence that indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, and there is evidence for polygenicity. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder.

scholarly journals Segmental duplications are hot spots of copy number variants affecting barley gene content

2020 ◽  
Vol 103 (3) ◽  
pp. 1073-1088
Author(s):  
Gianluca Bretani ◽  
Laura Rossini ◽  
Chiara Ferrandi ◽  
Joanne Russell ◽  
Robbie Waugh ◽  
...  
Keyword(s):  
Hot Spots ◽  
Copy Number ◽  
Copy Number Variants ◽  
Gene Content ◽  
Segmental Duplications

scholarly journals Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants

2012 ◽  
Vol 367 (14) ◽  
pp. 1321-1331 ◽  
Author(s):  
Santhosh Girirajan ◽  
Jill A. Rosenfeld ◽  
Bradley P. Coe ◽  
Sumit Parikh ◽  
Neil Friedman ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Phenotypic Heterogeneity ◽  
Genomic Disorders

Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants

2006 ◽  
Vol 38 (10) ◽  
pp. 1216-1220 ◽  
Author(s):  
Adnan Derti ◽  
Frederick P Roth ◽  
George M Church ◽  
C-ting Wu
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Segmental Duplications ◽  
Ultraconserved Elements

scholarly journals Combining callers improves the detection of copy number variants from whole-genome sequencing

2021 ◽  
Author(s):  
Marie Coutelier ◽  
Manuel Holtgrewe ◽  
Marten Jäger ◽  
Ricarda Flöttman ◽  
Martin A. Mensah ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Copy Number Variants ◽  
Computation Time ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Base Pairs ◽  
Whole Exome ◽  
Human Pathology

AbstractCopy Number Variants (CNVs) are deletions, duplications or insertions larger than 50 base pairs. They account for a large percentage of the normal genome variation and play major roles in human pathology. While array-based approaches have long been used to detect them in clinical practice, whole-genome sequencing (WGS) bears the promise to allow concomitant exploration of CNVs and smaller variants. However, accurately calling CNVs from WGS remains a difficult computational task, for which a consensus is still lacking. In this paper, we explore practical calling options to reach the best compromise between sensitivity and sensibility. We show that callers based on different signal (paired-end reads, split reads, coverage depth) yield complementary results. We suggest approaches combining four selected callers (Manta, Delly, ERDS, CNVnator) and a regenotyping tool (SV2), and show that this is applicable in everyday practice in terms of computation time and further interpretation. We demonstrate the superiority of these approaches over array-based Comparative Genomic Hybridization (aCGH), specifically regarding the lack of resolution in breakpoint definition and the detection of potentially relevant CNVs. Finally, we confirm our results on the NA12878 benchmark genome, as well as one clinically validated sample. In conclusion, we suggest that WGS constitutes a timely and economically valid alternative to the combination of aCGH and whole-exome sequencing.

scholarly journals Analysis of copy number variants and segmental duplications in the human genome: Evidence for a change in the process of formation in recent evolutionary history

2008 ◽  
Vol 18 (12) ◽  
pp. 1865-1874 ◽  
Author(s):  
P. M. Kim ◽  
H. Y.K. Lam ◽  
A. E. Urban ◽  
J. O. Korbel ◽  
J. Affourtit ◽  
...  
Keyword(s):  
Human Genome ◽  
Copy Number ◽  
Evolutionary History ◽  
Copy Number Variants ◽  
Segmental Duplications

The genomic architecture of segmental duplications and copy number variants in dogs

2009 ◽  
Vol 4 (2) ◽  
pp. 71-72
Author(s):  
Thomas J. Nicholas ◽  
Ze Cheng ◽  
Katrina L. Mealey ◽  
Evan E. Eichler ◽  
Joshua M. Akey
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Segmental Duplications ◽  
Genomic Architecture
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