diversity of human copy number variation and multicopy genes pdf

Diversity Of Human Copy Number Variation And Multicopy Genes Pdf

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Copy number variation CNV , which is characterized by large-scale losses or gains of DNA fragments, contributes significantly to genetic and phenotypic variation.

Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs

Variability in the susceptibility to infectious disease and its clinical manifestation can be determined by variation in the environment and by genetic variation in the pathogen and the host. Despite several successes based on candidate gene studies, defining the host variation affecting infectious disease has not been as successful as for other multifactorial diseases. In this review we focus on CNV, particularly on complex multiallelic CNV that is often not well characterised either directly by hybridisation methods or indirectly by analysis of genotypes and flanking single nucleotide variants.

We also highlight some understudied areas that might prove fruitful areas for further research. Infectious disease can be regarded as a complex multifactorial disease, with both genetic and environmental variation contributing to differing susceptibilities to infection, and differing effects of infection Chapman and Hill Like any other multifactorial disease, the variation in who is infected has been divided into a genetic component and an environmental component, with heritability estimates equivalent to other multifactorial diseases [for example, heritability of malaria in Kenya is 0.

Like any other multifactorial disease, both rare and common genetic variations are likely to play a role. Genomewide association studies have been of limited success in identifying alleles that affect infectious disease susceptibility. We might infer from this that most genetic susceptibility is not determined by common alleles effectively assayed by these studies. Another complicating factor is that, at present, most GWASs of infectious disease are either using relatively small cohorts or by combining cohorts from different countries, and correcting for population differences statistically.

The effect on the power to detect susceptibility variants, which may have different frequencies in regions with different patterns of LD in different populations, is unclear.

Analyses of the effect of rare variants on infectious disease susceptibility have not yet been published, but there is increasing evidence that CNV has an important role. CNV is simply different numbers of the same DNA sequence across different individuals and includes not only simple deletion and duplications but also more complex multiallelic variation, with copy numbers ranging from 0 to 14, for example, as has been described for the CCL3L1 gene Aklillu et al.

CNV can potentially affect phenotype in several different ways. Perhaps the simplest way is due to a gene dosage effect, where increased numbers of the same gene result in increased levels of mRNA and increased levels of protein.

However, CNV can also create novel fusion genes, alter the distance of a gene from a regulatory element, or alter the number of protein-coding exons within a gene Fig. CNVs are just another form of variation, and subject to the same rules of population genetics as other variants. However, it is useful to distinguish CNVs into two categories which are based on mutational origin: non-recurrent and recurrent CNVs.

Recurrent and non-recurrent CNVs are likely to have different mutation rates and different evolutionary trajectories. The different possible mechanisms of CNV affecting phenotype. The CNV affects an entire gene, altering the number of copies of the full gene and altering the total amount of mRNA and protein encoded by the gene. The CNV affects the distance between a regulatory element and the gene.

The regulatory element can be either an enhancer or a repressor, or affect tissue specificity. Example: HoxD in mouse Montavon et al. A deletion caused by unequal crossing over between the two copies of DNA sequence results in a fusion gene. If the genes on copy 1 and copy 2 are identical, this will have no effect, but if they have diverged in sequence or regulation the new fusion gene may have novel effects.

Example: butyrophilin-like genes Aigner et al. Variation in the number of tandem repeats of coding exons within a gene alters the number of functional protein domains, and final size of the protein. Example: complement receptor 1 Wong et al. Non-recurrent CNVs of any size can be generated by mechanisms such as non-homologous end-joining NHEJ or fork-stalling and template-switching FosTes , and, because they are often large, are more likely to affect genes and more likely to have an extremely deleterious phenotypic effect Arlt et al.

Large deletions, for example, will be rare in the population because negative selection acts to rapidly remove the deletion from the population. Recurrent infections are sometimes a symptom of multiple congenital abnormalities caused by a large chromosomal deletion.

For example, patients with 22q There are also examples of rare small deletion alleles that segregate within a family, collectively known as Mendelian infectious susceptibility disease syndromes. These regions of segmental duplication are non-randomly distributed in the genome and are particularly frequent in subtelomeric and pericentromeric regions, although they occur elsewhere in the genome Bailey et al. These regions are difficult to assemble and often are associated with gaps in the reference genome assembly.

Importantly, such regions can also harbour extensive sequence variation in the form of paralogous sequence variants PSVs , which are differences between segmental duplications. Many of these segmental duplication-rich regions arose in the ancestor of great apes Locke et al. Recurrent NAHR between these paralogues can shuffle these variants as well as generate CNV, and both copy number and sequence variation can contribute to diversity within these CNVs, which tend to be multiallelic and are sometimes associated with other polymorphic rearrangements such as inversions.

In this review we will focus on common multiallelic CNV where alleles are present at polymorphic frequencies within populations. Studies of complex multiallelic CNVs have shown that the mutation rate is high, several orders of magnitude higher than for single nucleotide polymorphisms, usually because of recurrent NAHR Abu Bakar et al.

This has two consequences: first CNVs can accumulate variation under mutation-drift balance resulting in a particular DNA sequence having a high level of standing variation and, therefore, a substrate for subsequent selection.

Second, if the copy number allele is deleterious then, under mutation-selection balance, the strength of negative selection has to be stronger to remove a deleterious allele at a locus that has a higher mutation rate. If the negative selection is mild, or perhaps episodic, then a deleterious copy number allele might reach appreciable allele frequencies. This high mutation rate recurrently generating copy number alleles also can explain why multiallelic CNVs are not well tagged, or at least consistently tagged, by alleles at flanking SNPs.

For an overview see Locke et al. In this review we aim to give an overview of the evidence that human host CNV affects susceptibility to infectious disease. These suggest a mutation rate of 4. Two loci encoding receptors used by Plasmodium falciparum to gain entry into erythrocytes are also known to be copy number variable.

The region of CR1 critical for P. However, the crystal structure of the receptor is not known and it is perhaps likely that higher numbers of the large LHR domains will interfere with the interaction with P. Several SNPs within and surrounding CR1 , including those responsible for the Knops blood group alleles Moulds , have been tested for association with various malaria clinical phenotypes, with inconsistent results Thathy et al.

Genetic variation plays an important role in several clinical phenotypes related to infection by human immunodeficiency virus-1 HIV-1 , such as susceptibility to infection, time from infection to development of AIDS and viral load levels at clinical latency known as set point viral load Shea et al.

A large study on both horizontal transfer adult—adult and vertical transfer mother—child of HIV-1 suggested that higher copy number of CCL3L1 led to protection against HIV-1 infection, and a lower copy number led to susceptibility to HIV-1 infection Gonzalez et al.

First, and perhaps most importantly, is the importance of the most accurate and precise estimates of diploid copy number for each individual in a cohort. This is important because we generally expect genetic effects to be small, and they are likely to be much smaller than effects due to noise or systematic bias of an assay.

Noisy assays will generally lead to false negative results, because the small effect is swamped by random noise. Second, systematic bias in a study, either due to population stratification effects or technical biases for example, assaying controls and cases in separate experiments , will increase the false positive rate as such biases will be interpreted as a real genetic effect. The strengths and weakness of different assays for CCL3L1 copy number have been extensively discussed elsewhere Cantsilieris and White , and, importantly, these issues apply to all other multiallelic loci discussed in this review.

The thousands of droplets are effectively miniaturised PCR reactions, with the genomic DNA at limiting dilution such that most droplets will not contain a DNA molecule that can be amplified by the CNV or reference primers.

This approach uses carefully designed primers that amplify a region within the CNV of interest but also at a diploid reference control locus. Such primers are often targeted to diverged repeat elements, and the products amplified from the reference and CNV need to be distinguished by size, so that they can be detected by capillary electrophoresis and quantified. In practice, at least two PRTs are designed per CNV locus, and positive controls of known copy number used to normalise for variation between experiments.

In a Yoruba trio, a copy number allele comprised tandem copies of repeat units, some of which were larger and carrying the neighbouring TBC1D3 gene. An alternative assembly of this region in provided by the Genome Reference Consortium in GRC38 supports this observation. An important clinical phenotype of HIV infection is the response to antiretroviral drugs, particularly given the implementation of highly active antiretroviral therapy HAART to high-prevalence areas in Africa.

Therefore, the role and possible mechanism of CCL3L1 in immune reconstitution remains unclear. Furthermore, the role of copy number variation at genes involved in the metabolism of drugs [for example CYP2D6 , Bertilsson et al. We might expect that higher copy number of an antiviral peptide would result in a lower HIV viral load and improved immune reconstitution, but the opposite appears to be the case Hardwick et al.

This might allow HIV-1 to establish infection foci more effectively in individuals with higher copy number, and, therefore, higher levels of hBD-2 protein. This casts doubt on the role of hBD2 as an antiviral molecule in vivo. The best-established role of CNV in HIV-1 infection remains that of killer-cell immunoglobulin-like receptor gene family KIRs , members of which are expressed by natural killer cells and encoded by a gene cluster on chromosome 19 Middleton and Gonzelez They bind to the major histocompatibility complex MHC class I ligands on the surface of target cells and mediate either an inhibitory or activatory response by NK cells depending on the exact nature of the KIR.

Within the B haplotype, there is further extensive variation in gene content and copy number, the functional consequences of which remain unclear. This is an interesting example of epistasis, where the effect of one allele is dependent on the presence of another allele at a physically unlinked locus.

It may be the case that similar epistatic effects between copy number variable ligands and receptors exist. HIV and malaria are the infectious diseases about which most research has been done and most is known. However, other studies of host CNV and infectious disease have shown interesting results, and we discuss some below.

Haptoglobin HP , a gene encoding an abundant acute-phase glycoprotein in the plasma, is one of the earliest blood serum proteins identified with copy number variation CNV , carrying two alleles namely Hp1 and Hp2, spanning a 1. All three genes are observed in extant Old World Monkeys and apes, except humans, who have lost the HPP gene after divergence from chimpanzees. In humans, HPR shows CNV between 2 and 4 copies per diploid genome, although an early study suggested rare copy numbers as high as 7 per diploid genome.

Haptoglobin protein Hp binds to the free haemoglobin Hb released by lysis of erythrocytes as a result of acute infection. The Hp—Hb complex is then cleared by binding to the macrophage scavenger receptor CD, followed by endocytosis.

Like Hp, haptoglobin-related protein Hpr binds with free heme, but the Hpr-Hb complex binds to ApoL1 instead and forms part of the trypanolytic lytic factor TLF providing innate immunity against trypanosomes Nielsen and Moestrup ; Vanhollebeke et al.

It is, therefore, conceivable that both HP and HPR gene copy number variations have experienced selection pressure in response to pathogens Iskow et al. The Hp2 allele has been suggested to protect against severe malaria Atkinson et al. There is suggestive evidence that duplication of the HPR gene is protective against human African trypanosomiasis HAT , and the population distribution of the HPR duplication mirrors the distribution of Trypanosoma brucei gambiense , which causes HAT.

The copy number of these genes has increased in the human lineage and shows copy number variation between individuals Sudmant et al. All three genes are within the pericentromeric region of chromosome 1, and the human-specific copy number increase is likely to be associated with a pericentromeric inversion that distinguishes human chromosome 1 from chimpanzee chromosome 1 Maresco et al.

However, although shown to be a human-specific CNV, with multiple copies, because the genes are within a complex pericentromeric region of chromosome 1 characterisation of the variation is challenging and the nature of the CNV, and its relationship with disease, remains unknown. The segmental duplication is copy number variable, with deletions and duplications at appreciable frequency in different populations Aitman et al.

There is a gene dosage effect for FCGR3B , where expression levels on the cell surface reflect gene copy number Willcocks et al. Sequence variation within paralogues adds another layer of complexity. Genetic structure of low-affinity Fc gamma receptor region.

This has been the substrate for further complex copy number and sequence variation at this locus, examples indicated by different numbers.

All these have been observed and published cited in the text , with the exception of the structure of the known duplicated alleles examples 6 and 7 which is predicted as the reciprocal of the deletion structure following NAHR. Such associations are difficult to disentangle, particularly because of the unclear relationship between copy number variation between flanking SNPs and CNVs.

During dengue infection, the host immune response triggers a mechanism called antibody-dependent enhancement ADE , whereby a heterotypic antibody one from previous infection of a different dengue serotype binds to the virus from the secondary infection but does not neutralize it.

Many of the immunity genes that show CNV have been investigated in the context of susceptibility to autoimmune diseases Olsson and Holmdahl ; Schaschl et al.

Diversity of Human Copy Number Variation and Multicopy Genes

Protocol DOI: Copy number variation CNV , where a segment of DNA differs in copy number between different individuals, is an extensive and often underappreciated source of genetic variation within species. However, reliably determining copy number of a particular. However, reliably determining copy number of a particular DNA sequence for a large number of samples can be challenging. Here, I describe and review the paralogue ratio test PRT in detail.

The Y chromosome harbors nine multi-copy ampliconic gene families expressed exclusively in testis. Recent studies demonstrated high variation in Y ampliconic gene copy number among humans. However, how this variation affects expression levels in human testis remains understudied. Here we developed a novel computational tool Ampliconic Copy Number Estimator AmpliCoNE that utilizes read sequencing depth information to estimate Y ampliconic gene copy number per family. We applied this tool to whole-genome sequencing data of men with matched testis expression data whose samples are part of the Genotype-Tissue Expression GTEx project.

Distribution and Functionality of Copy Number Variation across European Cattle Populations

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Analysis of Copy Number Variation Using the Paralogue Ratio Test (PRT)

Variability in the susceptibility to infectious disease and its clinical manifestation can be determined by variation in the environment and by genetic variation in the pathogen and the host. Despite several successes based on candidate gene studies, defining the host variation affecting infectious disease has not been as successful as for other multifactorial diseases. In this review we focus on CNV, particularly on complex multiallelic CNV that is often not well characterised either directly by hybridisation methods or indirectly by analysis of genotypes and flanking single nucleotide variants. We also highlight some understudied areas that might prove fruitful areas for further research. Infectious disease can be regarded as a complex multifactorial disease, with both genetic and environmental variation contributing to differing susceptibilities to infection, and differing effects of infection Chapman and Hill

Derek M. Bickhart, Lingyang Xu, Jana L. Hutchison, John B. Cole, Daniel J. Null, Steven G.

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Previously, we identified long repeat sequences that are frequently associated with genome rearrangements, including copy number variation CNV , in many diverse isolates of the human fungal pathogen Candida albicans Todd et al. Here, we describe the rapid acquisition of novel, high copy number CNVs during adaptation to azole antifungal drugs. Single-cell karyotype analysis indicates that these CNVs appear to arise via a dicentric chromosome intermediate and breakage-fusion-bridge cycles that are repaired using multiple distinct long inverted repeat sequences. Subsequent removal of the antifungal drug can lead to a dramatic loss of the CNV and reversion to the progenitor genotype and drug susceptibility phenotype. These findings support a novel mechanism for the rapid acquisition of antifungal drug resistance and provide genomic evidence for the heterogeneity frequently observed in clinical settings. The evolution of antifungal drug resistance is an urgent threat to human health worldwide, particularly for hospitalized and immune-compromised individuals Perea and Patterson, ; Pfaller, ; Vandeputte et al. Only three classes of antifungal drugs are currently available and resistance to all three classes occurred for the first time in the emerging fungal pathogen Candida auris Chen and Sorrell, ; Ghannoum and Rice, ; Lockhart et al.

Metrics details. Copy number variations CNVs are an important type of structural variations in the genome that usually affect gene expression levels by gene dosage effect. Understanding CNVs as part of genome evolution may provide insights into the genetic basis of important agricultural traits and contribute to the crop breeding in the future. While available methods to detect CNVs utilizing next-generation sequencing technology have helped shed light on prevalence and effects of CNVs, the complexity of crop genomes poses a major challenge and requires development of additional tools. Here, we generated genomic and transcriptomic data of 93 rice Oryza sativa L. Moreover, the offspring copy mainly contributed to the expression levels and seemed more likely to become a pseudogene, whereas the parent copy tended to maintain the function of ancestral gene.

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