scholarly journals Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Trenell J. Mosley ◽  
H. Richard Johnston ◽  
David J. Cutler ◽  
Michael E. Zwick ◽  
Jennifer G. Mulle
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Copy Number Variants ◽  
Parental Origin ◽  
Recombination Rates ◽  
Pathogenic Cnvs ◽  
Parent Of Origin ◽  
Genomic Disorders ◽  
The Relationship ◽  
Male To Female

Abstract Background Structural rearrangements of the genome, which generally occur during meiosis and result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb), underlie genomic disorders. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood. Methods We performed a systematic, comprehensive literature search to curate parent of origin data for multiple pathogenic CNV loci. Using a regression framework, we assessed the relationship between parental CNV origin and the male to female recombination rate ratio. Results We demonstrate significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci (p = 1.07 × 10–14). Conclusions Our results suggest that parental origin of CNVs is largely influenced by sex-specific recombination rates and highlight the need to consider these differences when investigating mechanisms that cause structural variation.

scholarly journals Sex-specific recombination predicts parent of origin for recurrent genomic disorders

2020 ◽  
Author(s):  
Trenell Mosley ◽  
H. Richard Johnston ◽  
David J Cutler ◽  
Michael E Zwick ◽  
Jennifer G Mulle
Keyword(s):  
Large Scale ◽  
Structural Variation ◽  
De Novo ◽  
Copy Number Variants ◽  
Parental Origin ◽  
Structural Rearrangements ◽  
Recombination Rates ◽  
Pathogenic Cnvs ◽  
Parent Of Origin ◽  
Genomic Disorders

Abstract Genomic disorders are caused by structural rearrangements of the genome that generally occur during meiosis. Often the rearrangements result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb). Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood. Here we have curated parent of origin data for multiple pathogenic CNV loci and demonstrate a significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci. Our results suggest that parental-origin of CNVs is largely controlled by sex-specific recombination rates, and highlight the need to consider these differences when investigating mechanisms that cause structural variation.

scholarly journals Sex-specific recombination predicts parent of origin for recurrent genomic disorders

2020 ◽  
Author(s):  
Trenell Mosley ◽  
H. Richard Johnston ◽  
David J. Cutler ◽  
Michael E. Zwick ◽  
Jennifer G. Mulle
Keyword(s):  
Large Scale ◽  
Structural Variation ◽  
De Novo ◽  
Copy Number Variants ◽  
Parental Origin ◽  
Recombination Rates ◽  
Pathogenic Cnvs ◽  
Parent Of Origin ◽  
Genomic Disorders ◽  
Underlying Risk

SUMMARYGenomic disorders are caused by structural rearrangements of the genome that generally occur during meiosis1. Often the rearrangements result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb)2,3. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR)3,4. Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs5–9. However, the mechanism underlying these biases is not well understood. Here we have curated parent of origin data for multiple pathogenic CNV loci and demonstrate a significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci. Our results suggest that parental-origin of CNVs is largely controlled by sex-specific recombination rates and bring into light the need to consider these differences when seeking to determine the factors underlying risk for structural variation.

scholarly journals The Genomic Architecture of a Rapid Island Radiation: Recombination Rate Variation, Chromosome Structure, and Genome Assembly of the Hawaiian Cricket Laupala

2017 ◽  
Author(s):  
Thomas Blankers ◽  
Kevin P. Oh ◽  
Aureliano Bombarely ◽  
Kerry L. Shaw
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Chromosomal Rearrangements ◽  
Evolutionary Genetics ◽  
Rate Variation ◽  
Linkage Maps ◽  
Recombination Rates ◽  
Behavioral Isolation ◽  
Genomic Architecture ◽  
Suppressed Recombination

ABSTRACTPhenotypic evolution and speciation depend on recombination in many ways. Within populations, recombination can promote adaptation by bringing together favorable mutations and decoupling beneficial and deleterious alleles. As populations diverge, cross-over can give rise to maladapted recombinants and impede or reverse diversification. Suppressed recombination due to genomic rearrangements, modifier alleles, and intrinsic chromosomal properties may offer a shield against maladaptive gene flow eroding co-adapted gene complexes. Both theoretical and empirical results support this relationship. However, little is known about this relationship in the context of behavioral isolation, where co-evolving signals and preferences are the major hybridization barrier. Here we examine the genomic architecture of recently diverged, sexually isolated Hawaiian swordtail crickets (Laupala). We assemble a de novo genome and generate three dense linkage maps from interspecies crosses. In line with expectations based on the species’ recent divergence and successful interbreeding in the lab, the linkage maps are highly collinear and show no evidence for large-scale chromosomal rearrangements. The maps were then used to anchor the assembly to pseudomolecules and estimate recombination rates across the genome. We tested the hypothesis that loci involved in behavioral isolation (song and preference divergence) are in regions of low interspecific recombination. Contrary to our expectations, a genomic region where a male song QTL co-localizes with a female preference QTL was not associated with particularly low recombination rates. This study provides important novel genomic resources for an emerging evolutionary genetics model system and suggests that trait-preference co-evolution is not necessarily facilitated by locally suppressed recombination.

Genomic Syndromes in Schizophrenia

2013 ◽  
pp. 247-255
Author(s):  
George Kirov ◽  
Michael C. O’Donovan ◽  
Michael J. Owen
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Individual Risk ◽  
Genomic Deletions ◽  
Pathogenic Cnvs ◽  
Cognition And Learning

Several submicroscopic genomic deletions and duplications known as copy number variants (CNVs) have been reported to increase susceptibility to schizophrenia. Those for which the evidence is particularly strong include deletions at chromosomal segments 1q21.1, 3q29, 15q11.2, 15q13.3, 17q12 and 22q11.2, duplications at 15q11.2-q13.1, 16p13.1, and 16p11.2, and deletions atthe gene NRXN1. The effect of each on individual risk is relatively large, but it does not appear that any of them is alone sufficient to cause disorder in carriers. These CNVs often arise as new mutations(de novo). Analyses of genes enriched among schizophrenia implicated CNVs highlight the involvement in the disorder of post-synaptic processes relevant to glutamatergicsignalling, cognition and learning. CNVs that contribute to schizophrenia risk also contribute to other neurodevelopmental disorders, including intellectual disability, developmental delay and autism. As a result of selection, all known pathogenic CNVs are rare, and none makes a sizeable contribution to overall population risk of schizophrenia, although the study of these mutations is nevertheless providing important insights into the origins of the disorder.

scholarly journals Trio-Based Low-Pass Genome Sequencing Reveals Characteristics and Significance of Rare Copy Number Variants in Prenatal Diagnosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Matthew Hoi Kin Chau ◽  
Jicheng Qian ◽  
Zihan Chen ◽  
Ying Li ◽  
Yu Zheng ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Genome Sequencing ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Recurrence Risk ◽  
Rare Cnvs ◽  
Pathogenic Cnvs ◽  
Low Pass ◽  
Clinically Significant

Background: Low-pass genome sequencing (GS) detects clinically significant copy number variants (CNVs) in prenatal diagnosis. However, detection at improved resolutions leads to an increase in the number of CNVs identified, increasing the difficulty of clinical interpretation and management.Methods: Trio-based low-pass GS was performed in 315 pregnancies undergoing invasive testing. Rare CNVs detected in the fetuses were investigated. The characteristics of rare CNVs were described and compared to curated CNVs in other studies.Results: A total of 603 rare CNVs, namely, 597 constitutional and 6 mosaic CNVs, were detected in 272 fetuses (272/315, 86.3%), providing 1.9 rare CNVs per fetus (603/315). Most CNVs were smaller than 1 Mb (562/603, 93.2%), while 1% (6/603) were mosaic. Forty-six de novo (7.6%, 46/603) CNVs were detected in 11.4% (36/315) of the cases. Eighty-four CNVs (74 fetuses, 23.5%) involved disease-causing genes of which the mode of inheritance was crucial for interpretation and assessment of recurrence risk. Overall, 31 pathogenic/likely pathogenic CNVs were detected, among which 25.8% (8/31) were small (<100 kb; n = 3) or mosaic CNVs (n = 5).Conclusion: We examined the landscape of rare CNVs with parental inheritance assignment and demonstrated that they occur frequently in prenatal diagnosis. This information has clinical implications regarding genetic counseling and consideration for trio-based CNV analysis.

scholarly journals Presence of pathogenic copy number variants (CNVs) is correlated with socioeconomic status

2019 ◽  
Vol 57 (1) ◽  
pp. 70-72 ◽  
Author(s):  
George J Burghel ◽  
Unzela Khan ◽  
Wei-Yu Lin ◽  
William Whittaker ◽  
Siddharth Banka
Keyword(s):  
Socioeconomic Status ◽  
General Population ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Multiple Deprivation ◽  
Pathogenic Cnvs ◽  
Biological Determinants ◽  
Autosomal Copy ◽  
Index Of Multiple Deprivation

Socioeconomic status (SES) is a major determinant of health. We studied the Index of Multiple Deprivation Rank of 473 families with individuals with pathogenic autosomal copy number variants (CNVs) and known inheritance status. The IMDR distribution of families with pathogenic CNVs was significantly different from the general population. Families with inherited CNVs were significantly more likely to be living in areas of higher deprivation when compared with families that had individuals with de novo CNVs. These results provide unique insights into biological determinants of SES. As CNVs are relatively frequent in the general population, these results have important medical and policy consequences.

scholarly journals Chromosomal Microarray Analysis in Children with Unexplained Developmental Delay/Intellectual Disability

2018 ◽  
Vol 08 (01) ◽  
pp. 001-009
Author(s):  
Pinar Arican ◽  
Berk Ozyilmaz ◽  
Dilek Cavusoglu ◽  
Pinar Gencpinar ◽  
Kadri Erdogan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
De Novo ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Genetic Syndromes ◽  
Pathogenic Cnvs ◽  
Spectrum Disorders

AbstractChromosomal microarray (CMA) analysis for discovery of copy number variants (CNVs) is now recommended as a first-line diagnostic tool in patients with unexplained developmental delay/intellectual disability (DD/ID) and autism spectrum disorders. In this study, we present the results of CMA analysis in patients with DD/ID. Of 210 patients, pathogenic CNVs were detected in 26 (12%) and variants of uncertain clinical significance in 36 (17%) children. The diagnosis of well-recognized genetic syndromes was achieved in 12 patients. CMA analysis revealed pathogenic de novo CNVs, such as 11p13 duplication with new clinical features. Our results support the utility of CMA as a routine diagnostic test for unexplained DD/ID.

scholarly journals Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

2016 ◽  
Vol 371 (1710) ◽  
pp. 20150406 ◽  
Author(s):  
Jason R. Cowan ◽  
Muhammad Tariq ◽  
Chad Shaw ◽  
Mitchell Rao ◽  
John W. Belmont ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Copy Number ◽  
Congenital Heart ◽  
Heart Defects ◽  
Copy Number Variants ◽  
Loss Of Function ◽  
Pathogenic Cnvs ◽  
Number Variation ◽  
Left Right Asymmetry ◽  
Genomic Disorders

Genomic disorders and rare copy number abnormalities are identified in 15–25% of patients with syndromic conditions, but their prevalence in individuals with isolated birth defects is less clear. A spectrum of congenital heart defects (CHDs) is seen in heterotaxy, a highly heritable and genetically heterogeneous multiple congenital anomaly syndrome resulting from failure to properly establish left–right (L-R) organ asymmetry during early embryonic development. To identify novel genetic causes of heterotaxy, we analysed copy number variants (CNVs) in 225 patients with heterotaxy and heterotaxy-spectrum CHDs using array-based genotyping methods. Clinically relevant CNVs were identified in approximately 20% of patients and encompassed both known and putative heterotaxy genes. Patients were carefully phenotyped, revealing a significant association of abdominal situs inversus with pathogenic or likely pathogenic CNVs, while d-transposition of the great arteries was more frequently associated with common CNVs. Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in ZIC3, a gene known to cause X-linked heterotaxy. Morpholino loss-of-function experiments in Xenopus support a role for one of these novel candidates, the platelet isoform of phosphofructokinase-1 ( PFKP ) in heterotaxy. Collectively, our results confirm a high CNV yield for array-based testing in patients with heterotaxy, and support use of CNV analysis for identification of novel biological processes relevant to human laterality. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

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