The clinical context of copy number variation in the human genome

During the past five years, copy number variation (CNV) has emerged as a highly prevalent form of genomic variation, bridging the interval between long-recognised microscopic chromosomal alterations and single-nucleotide changes. These genomic segmental differences among humans reflect the dynamic nature of genomes, and account for both normal variations among us and variations that predispose to conditions of medical consequence. Here, we place CNVs into their historical and medical contexts, focusing on how these variations can be recognised, documented, characterised and interpreted in clinical diagnostics. We also discuss how they can cause disease or influence adaptation to an environment. Various clinical exemplars are drawn out to illustrate salient characteristics and residual enigmas of CNVs, particularly the complexity of the data and information associated with CNVs relative to that of single-nucleotide variation. The potential is immense for CNVs to explain and predict disorders and traits that have long resisted understanding. However, creative solutions are needed to manage the sudden and overwhelming burden of expectation for laboratories and clinicians to assay and interpret these complex genomic variations as awareness permeates medical practice. Challenges remain for understanding the relationship between genomic changes and the phenotypes that might be predicted and prevented by such knowledge.

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Structural genome analysis in cultivated potato taxa

Theoretical and Applied Genetics ◽

10.1007/s00122-019-03519-6 ◽

2019 ◽

Vol 133 (3) ◽

pp. 951-966 ◽

Cited By ~ 3

Author(s):

Maria Kyriakidou ◽

Sai Reddy Achakkagari ◽

José Héctor Gálvez López ◽

Xinyi Zhu ◽

Chen Yu Tang ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Agronomic Traits ◽

Genomic Variation ◽

Sequencing Data ◽

Structural Variations ◽

Structural Genomic ◽

Ploidy Levels ◽

Cultivated Potato ◽

Number Variation

Abstract Key message Twelve potato accessions were selected to represent two principal views on potato taxonomy. The genomes were sequenced and analyzed for structural variation (copy number variation) against three published potato genomes. Abstract The common potato (Solanum tuberosum L.) is an important staple crop with a highly heterozygous and complex tetraploid genome. The other taxa of cultivated potato contain varying ploidy levels (2X–5X), and structural variations are common in the genomes of these species, likely contributing to the diversification or agronomic traits during domestication. Increased understanding of the genomes and genomic variation will aid in the exploration of novel agronomic traits. Thus, sequencing data from twelve potato landraces, representing the four ploidy levels, were used to identify structural genomic variation compared to the two currently available reference genomes, a double monoploid potato genome and a diploid inbred clone of S. chacoense. The results of a copy number variation analysis showed that in the majority of the genomes, while the number of deletions is greater than the number of duplications, the number of duplicated genes is greater than the number of deleted ones. Specific regions in the twelve potato genomes have a high density of CNV events. Further, the auxin-induced SAUR genes (involved in abiotic stress), disease resistance genes and the 2-oxoglutarate/Fe(II)-dependent oxygenase superfamily proteins, among others, had increased copy numbers in these sequenced genomes relative to the references.

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Salivary AMY1 Copy Number Variation Modifies Age-Related Type 2 Diabetes Risk

Clinical Chemistry ◽

10.1093/clinchem/hvaa072 ◽

2020 ◽

Vol 66 (5) ◽

pp. 718-726

Author(s):

Yuwei Liu ◽

Caren E Smith ◽

Laurence D Parnell ◽

Yu-Chi Lee ◽

Ping An ◽

...

Keyword(s):

Type 2 Diabetes ◽

Copy Number Variation ◽

Metabolic Pathway ◽

Copy Number ◽

Lipid Lowering ◽

Pathway Enrichment Analysis ◽

Copy Numbers ◽

Number Variation ◽

The Relationship

Abstract Background Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain. Methods We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk. Results We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR. Conclusions We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.

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Copy Number Variation of the PIGY Gene in Sheep and Its Association Analysis with Growth Traits

Animals ◽

10.3390/ani10040688 ◽

2020 ◽

Vol 10 (4) ◽

pp. 688 ◽

Cited By ~ 3

Author(s):

Ziting Feng ◽

Xinyu Li ◽

Jie Cheng ◽

Rui Jiang ◽

Ruolan Huang ◽

...

Keyword(s):

Copy Number Variation ◽

Association Analysis ◽

Copy Number ◽

Growth Traits ◽

Gansu Province ◽

Genomic Variation ◽

Association Analyses ◽

Qinghai Province ◽

Real Time Quantitative Pcr ◽

Number Variation

Copy number variation (CNV) is a type of genomic variation with an important effect on animal phenotype. We found that the PIGY gene contains a 3600 bp copy number variation (CNV) region located in chromosome 6 of sheep (Oar_v4.0 36,121,601–36,125,200 bp). This region overlaps with multiple quantitative trait loci related to phenotypes like muscle density and carcass weight. Therefore, in this study, the copy number variation of the PIGY gene was screened in three Chinese sheep breeds, namely, Chaka sheep (CKS, May of 2018, Wulan County, Qinghai Province, China), Hu sheep (HS, May of 2015, Mengjin County, Henan Province, China), and small-tailed Han sheep (STHS, May of 2016, Yongjing, Gansu Province, China). Association analyses were performed on the presence of CNV and sheep body size traits. We used real-time quantitative PCR (qPCR) to detect the CNV for association analysis. According to the results, the loss-type CNV was more common than other types in the three breeds (global average: loss = 61.5%, normal = 17.5%, and gain = 21.0%). The association analysis also showed significant effects of the PIGY gene CNV on body weight, chest circumference, and circumference of the cannon bone of sheep. Sheep with gain-type CNV had better growth traits than those with other types. The results indicate a clear relationship between the PIGY gene CNV and growth traits of sheep, suggesting the use of CNV as a new molecular breeding marker.

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Copy number variation is highly correlated with differential gene expression: a pan-cancer study

BMC Medical Genetics ◽

10.1186/s12881-019-0909-5 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 18

Author(s):

Xin Shao ◽

Ning Lv ◽

Jie Liao ◽

Jinbo Long ◽

Rui Xue ◽

...

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Copy Number Variation ◽

Differential Gene Expression ◽

Copy Number ◽

Close Correlation ◽

Number Variation ◽

Cancer Types ◽

Differential Gene ◽

The Relationship

Abstract Background Cancer is a heterogeneous disease with many genetic variations. Lines of evidence have shown copy number variations (CNVs) of certain genes are involved in development and progression of many cancers through the alterations of their gene expression levels on individual or several cancer types. However, it is not quite clear whether the correlation will be a general phenomenon across multiple cancer types. Methods In this study we applied a bioinformatics approach integrating CNV and differential gene expression mathematically across 1025 cell lines and 9159 patient samples to detect their potential relationship. Results Our results showed there is a close correlation between CNV and differential gene expression and the copy number displayed a positive linear influence on gene expression for the majority of genes, indicating that genetic variation generated a direct effect on gene transcriptional level. Another independent dataset is utilized to revalidate the relationship between copy number and expression level. Further analysis show genes with general positive linear influence on gene expression are clustered in certain disease-related pathways, which suggests the involvement of CNV in pathophysiology of diseases. Conclusions This study shows the close correlation between CNV and differential gene expression revealing the qualitative relationship between genetic variation and its downstream effect, especially for oncogenes and tumor suppressor genes. It is of a critical importance to elucidate the relationship between copy number variation and gene expression for prevention, diagnosis and treatment of cancer.

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CNV Workshop: an integrated platform for high-throughput copy number variation discovery and clinical diagnostics

BMC Bioinformatics ◽

10.1186/1471-2105-11-74 ◽

2010 ◽

Vol 11 (1) ◽

pp. 74 ◽

Cited By ~ 43

Author(s):

Xiaowu Gai ◽

Juan C Perin ◽

Kevin Murphy ◽

Ryan O'Hara ◽

Monica D'arcy ◽

...

Keyword(s):

Copy Number Variation ◽

High Throughput ◽

Copy Number ◽

Clinical Diagnostics ◽

Integrated Platform ◽

Number Variation

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Population genetics of immune-related multilocus copy number variation in Native Americans

Journal of The Royal Society Interface ◽

10.1098/rsif.2017.0057 ◽

2017 ◽

Vol 14 (128) ◽

pp. 20170057 ◽

Cited By ~ 3

Author(s):

Luciana W. Zuccherato ◽

Silvana Schneider ◽

Eduardo Tarazona-Santos ◽

Robert J. Hardwick ◽

Douglas E. Berg ◽

...

Keyword(s):

Population Genetics ◽

Population Structure ◽

Native American ◽

Native Americans ◽

Copy Number Variation ◽

Copy Number ◽

Genomic Variation ◽

Population Subdivision ◽

Nucleotide Polymorphisms ◽

Number Variation

While multiallelic copy number variation (mCNV) loci are a major component of genomic variation, quantifying the individual copy number of a locus and defining genotypes is challenging. Few methods exist to study how mCNV genetic diversity is apportioned within and between populations (i.e. to define the population genetic structure of mCNV). These inferences are critical in populations with a small effective size, such as Amerindians, that may not fit the Hardy–Weinberg model due to inbreeding, assortative mating, population subdivision, natural selection or a combination of these evolutionary factors. We propose a likelihood-based method that simultaneously infers mCNV allele frequencies and the population structure parameter f , which quantifies the departure of homozygosity from the Hardy–Weinberg expectation. This method is implemented in the freely available software CNVice, which also infers individual genotypes using information from both the population and from trios, if available. We studied the population genetics of five immune-related mCNV loci associated with complex diseases (beta-defensins, CCL3L1/CCL4L1 , FCGR3A , FCGR3B and FCGR2C ) in 12 traditional Native American populations and found that the population structure parameters inferred for these mCNVs are comparable to but lower than those for single nucleotide polymorphisms studied in the same populations.

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