Dosage sensitivity is a major determinant of human copy number variant pathogenicity

Rice, Alan M.; McLysaght, Aoife

doi:10.1038/ncomms14366

Cited by 127 publications

(135 citation statements)

References 66 publications

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“…For example, Makino et al highlighted the importance of cross-species SV deserts in identifying disease-related SVs in humans (Makino et al 2013). Rice and McLysaght, as well as Makino et al used conservation, both at the sequence and copy number levels, as a proxy to show that SV pathogenicity can be predicted by dosage sensitivity (Rice and McLysaght 2017). In sum, by constructing an updated map of SV hotspots, and outlining their broad evolutionary implications, our study opens new avenues for research to better understand genome evolution and biomedical implications of complex variations.…”

Section: A Note On Background Selection and Svsmentioning

confidence: 82%

Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots

Lin

Gökçümen

2018

Preprint

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Genomic structural variants (SVs) are distributed nonrandomly across the human genome. These "hotspots" have been implicated in critical evolutionary innovations, as well as serious medical conditions. However, the evolutionary and biomedical features of these hotspots remain incompletely understood. In this study, we analyzed data from 2,504 genomes from the 1000 Genomes Project Consortium and constructed a refined map of 1,148 SV hotspots in human genomes. By studying the genomic architecture of these hotspots, we found that both nonallelic homologous recombination and non-homologous mechanisms act as mechanistic drivers of SV formation. We found that the majority of SV hotspots are within gene-poor regions and evolve under relaxed negative selection or neutrality. However, we found that a small subset of SV hotspots harbor genes that are enriched for anthropologically crucial functions, including blood oxygen transport, olfaction, synapse assembly, and antigen binding. We provide evidence that balancing selection may have maintained these SV hotspots, which include two independent hotspots on different chromosomes affecting alpha and beta hemoglobin gene clusters. Biomedically, we found that the SV hotspots coincide with breakpoints of clinically relevant, large de novo SVs, significantly more often than genome-wide expectations. As an example, we showed that the breakpoints of multiple large de novo SVs, which lead to idiopathic short stature, coincide with SV hotspots. As such, the mutational instability in SV hotpots likely enables chromosomal breaks that lead to pathogenic structural variation formations. Our study contributes to a better understanding of the mutational landscape of the genome and implicates both mechanistic and adaptive forces in the formation and maintenance of SV hotspots.

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Section: A Note On Background Selection and Svsmentioning

confidence: 82%

Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots

Lin

Gökçümen

2018

Preprint

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“…Since the vast majority of CNVs are unique and nonrecurrent, determining the clinical significance can be challenging . Benign CNVs are often small, intergenic, or encompass genes that can tolerate a change in copy number, whereas pathogenic CNVs are significantly enriched for genes involved in development and genes with constrained evolutionary patterns of duplication and loss . Professional guidelines have been developed for the interpretation and reporting of clinically relevant CNVs, and consider factors such as size (albeit with caution), genomic content, comparison with internal and external databases for population frequency information, and whether the CNV is inherited or de novo …”

Section: Clinical Significance Of Cnvsmentioning

confidence: 99%

“…10,11 Benign CNVs are often small, intergenic, or encompass genes that can tolerate a change in copy number, whereas pathogenic CNVs are significantly enriched for genes involved in development and genes with constrained evolutionary patterns of duplication and loss. 12 Professional guidelines have been developed for the interpretation and reporting of clinically relevant CNVs, and consider factors such as size (albeit with caution), genomic content, comparison with internal and external databases for population frequency information, and whether the CNV is inherited or de novo. 13 Chromosomal microarray (CMA) has been advocated as a firsttier cytogenetic diagnostic test for patients with unexplained developmental delay/ intellectual disability, autism spectrum disorders, or multiple congenital anomalies.…”

Section: Clinical Significance Of Cnvsmentioning

confidence: 99%

Genomic disorders 20 years on—mechanisms for clinical manifestations

2017

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Genomic disorders result from copy-number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) microarrays, and more recently, whole genome sequencing and whole-exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the association between CNVs and specific diseases or susceptibility to morbid traits have enhanced our understanding of the downstream effects. In this review, we discuss the hallmarks of genomic disorders as they were defined during the first decade of the field, including genomic instability and the mechanism for rearrangement defined as nonallelic homologous recombination (NAHR); recurrent vs nonrecurrent rearrangements; and gene dosage sensitivity. Moreover, we highlight the exciting advances of the second decade of this field, including a deeper understanding of genomic instability and the mechanisms underlying complex rearrangements, mechanisms for constitutional and somatic chromosomal rearrangements, structural intra-species polymorphisms and susceptibility to NAHR, the role of CNVs in the context of genome-wide copy number and single nucleotide variation, and the contribution of noncoding CNVs to human disease.

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“…gene dosage-effect;Desjardin et al, 2012. Although the alteration of gene-dosage balance is often prejudicial to fitness and have been mostly documented with diseases(Gamazon & Stranger 2015;Rice & McLysaght., 2017), in some cases, gene dosage-effect induce by CNVs can be positive and facilitate the adaptation of organisms to environmental changes. For example, CNVs have been highlighted as drivers of insecticide resistance in populations of Aedes mosquitoes by increasing the effectiveness of detoxification enzymes…”

mentioning

confidence: 99%

Copy number variants outperform SNPs to reveal genotype-temperature association in a marine species

Dorant

Cayuela

Wellband

et al. 2020

Preprint

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Copy number variants (CNVs) are a major component of genotypic and phenotypic variation in genomes. Yet, our knowledge on genotypic variation and evolution is often limited to single nucleotide polymorphism (SNPs) and the role of CNVs has been overlooked in non-model species, partly due to their challenging identification until recently. Here, we document the usefulness of reducedrepresentation sequencing data (RAD-seq) to detect and investigate copy number variants (CNVs) alongside SNPs in American lobster (Homarus americanus) populations. We conducted a comparative study to examine the potential role of SNPs and CNVs in local adaptation by sequencing 1141 lobsters from 21 sampling sites within the southern Gulf of St. Lawrence which experiences the highest yearly thermal variance of the Canadian marine coastal waters. Our results demonstrated that CNVs accounts for higher genetic differentiation than SNP markers. Contrary to SNPs for which no association was found, genetic-environment association revealed that 48 CNV candidates were significantly associated with the annual variance of sea surface temperature, leading to the genetic clustering of sampling locations despite their geographic separation. Altogether, we provide a strong empirical case that CNVs putatively contribute to local adaptation in marine species and unveil stronger spatial signal than SNPs.Our study provides the means to study CNVs in non-model species and underlines the importance to consider structural variants alongside SNPs to enhance our understanding of ecological and evolutionary processes shaping adaptive population structure.

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Dosage sensitivity is a major determinant of human copy number variant pathogenicity

Cited by 127 publications

References 66 publications

Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots

Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots

Genomic disorders 20 years on—mechanisms for clinical manifestations

Copy number variants outperform SNPs to reveal genotype-temperature association in a marine species

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