Evolutionary History of Copy-Number-Variable Locus for the Low-Affinity Fcγ Receptor: Mutation Rate, Autoimmune Disease, and the Legacy of Helminth Infection

Machado, Lee; Hardwick, Robert J.; Bowdrey, Jennifer; Bogle, Helen; Knowles, Timothy; Sironi, Manuela; Hollox, Edward J.

doi:10.1016/j.ajhg.2012.04.018

Cited by 40 publications

(86 citation statements)

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“…2008a). We might expect that higher copy number of an antiviral peptide would result in a lower 213 HIV viral load and improved immune reconstitution, but the opposite appears to be the case 214 (Hardwick et al 2012). We can reconcile this result with the fact that several beta-defensins, hBD-2 215 (encoded by DEFB4 gene) in particular, have chemoattractant activities to a variety of cells including 216 dendritic cells (Yang et al 1999) and Th-17 cells (Ghannam et al 2011).…”

Section: Host Copy Number Variation and Hiv 151mentioning

confidence: 70%

“…Furthermore, because of the particular structure of the CNV, the copy number of FCGR2C varies in 317 concert with FCGR3B and FCGR3A ( (Machado et al 2012), figure 4). Because CNV of FCGR3B is 318 associated with altered cell expression of FCGR2B and CNV of FCGR2C, it is difficult to determine the 319 cause of an observed association between FCGR3B copy number and disease.…”

Section: Host Copy Number Variation and Other Infectious Diseases 242mentioning

confidence: 99%

“…Gonzalez et al, although one result is reported several cohorts were tested and analysed using different approaches. High copy number associated with higher viral load (Hardwick et al 2012) F o r P e e r R e v i e w 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 F o r P e e r R e v i e w 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 3...…”

Section: Figurementioning

confidence: 99%

“…where the ancestral HNA1a and FCGR2C*Gln57 variants are associated with helminth diversity 385 across human populations (Machado et al 2012), and have been associated with susceptibility to 386 ideopathic pulmonary fibrosis (Bournazos et al 2010) and the haematological autoimmune disease 387 idiopathic thrombocytopenic purpura idiopathic respectively (Breunis et al 2008). There is some 388 suggestive evidence that FCGR2C*Gln57 is protective against tuberculosis co-infection in an HIV-389 infected Ethiopian cohort, but this may be confounded by FCGR3B copy number, and the causative 390 allele is unclear (Machado et al 2013).…”

Section: Host Cnv and Autoimmune Disease 346mentioning

confidence: 99%

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Human gene copy number variation and infectious disease

Hollox

Hoh

2014

Hum Genet

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16Variability in the susceptibility to infectious disease and its clinical manifestation can be determined 17 by variation in the environment and by genetic variation in the pathogen and the host. Despite 18 several successes based on candidate gene studies, defining the host variation affecting infectious 19 disease has not been as successful as other multifactorial diseases. Both single nucleotide variation 20 and copy number variation (CNV) in the host contribute to the host's susceptibility to infectious 21 disease. In this review we focus on CNV, particularly on complex multiallelic CNV that is often not 22 well characterised either directly by hybridisation methods or indirectly by analysis of genotypes and 23 flanking single nucleotide variants. We summarise the well-known examples, such as alpha-globin 24 deletion and susceptibility to severe malaria, as well as more recent controversies, such as the 25 extensive CNV of the chemokine gene CCL3L1 and HIV infection. We discuss the potential biological 26 mechanisms that could underly any genetic association and reflect on the extensive complexity and 27 functional variation generated by a combination of CNV and sequence variation, as illustrated by the 28 Fc gamma receptor genes FCGR3A, FCGR3B and FCGR2C. We also highlight some understudied areas 29 that might prove fruitful areas for further research. 30 31

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Section: Host Copy Number Variation and Hiv 151mentioning

confidence: 70%

Section: Host Copy Number Variation and Other Infectious Diseases 242mentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Host Cnv and Autoimmune Disease 346mentioning

confidence: 99%

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Human gene copy number variation and infectious disease

Hollox

Hoh

2014

Hum Genet

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“…Second, it has been put forward that highly variable gene families have evolved in response to changing pathogens and environments (e.g., Gokcumen et al 2011a). Third, it is possible that a balance exists between protection against pathogens and susceptibility to autoimmune disorders (e.g., Machado et al 2012). Therefore, it is likely that the SVs affecting immune system are maintained in human populations as a response to everchanging pathogenic pressures, under a balancing/diversifying selection scenario.…”

mentioning

confidence: 99%

Geographic Distribution and Adaptive Significance of Genomic Structural Variants: An Anthropological Genetics Perspective

Eaaswarkhanth¹,

Pavlidis²,

Gökçümen³

2014

Human Biology

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Anthropological geneticists have successfully used single nucleotide and short tandem repeat variations across human genomes to reconstruct human history.These markers have also been used extensively to identify adaptive and 2 phenotypic variation. The recent advent of high-throughput genomic technologies revealed an overlooked type of genomic variation, namely structural variants (SVs). In fact, some SVs may contribute to human adaptation in substantial and previously unexplored ways. SVs include deletions, insertions, duplications, inversions and translocations of genomic segments that vary among individuals from the same species. SVs are much less numerous than single nucleotide variants, but account for at least seven times more variable base pairs than do single nucleotide variants when two human genomes are compared. Moreover, recent studies have shown that SVs have higher mutation rates than single nucleotide variants when the affected base pairs are considered, especially in certain parts of the genome. The null hypothesis for the evolution of SVs, like single nucleotide variants, is neutrality. Hence, drift is the primary force that shapes the current allelic distribution of most SVs. However, due to their size, a larger proportion of SVs appear to evolve under non-neutral forces (mostly purifying selection) than single nucleotide variants. In fact, as exemplified by several groundbreaking studies, SVs contribute to anthropologically relevant phenotypic variation and local adaption among humans.In this review, we argue that with the advent of affordable genomic technologies, anthropological scrutiny of genomic structural variation emerges as a fertile area of inquiry to better understand human phenotypic variation. To motivate potential studies, we discuss scenarios through which SVs affect 3 phenotypic variation among humans within an anthropological context. We further provide a methodological workflow in which we analyzed 1000 Genomes deletion variants and identified 16 exonic deletions that are specific to the African continent. We analyzed two of these deletion variants affecting the keratinassociated protein (KAP) cluster in a locus-specific manner. Our analysis revealed that these deletions may indeed affect phenotype and likely evolved under geography-specific positive selection. We outline all the major software and datasets for these analyses and also provide the basic R and perl codes we used for this example workflow analysis. Overall, we hope that this review will encourage and facilitate incorporation of genomic structural variation in anthropological research programs. 4 Beyond Neutral Markers in Anthropological GeneticsAnthropological geneticists have been utilizing genetic markers since the early 20th Century. One of the first major studies that incorporated modern genetic methodologies into anthropological questions explored the spread of early farming in Europe from the Near East (Menozzi et al. 1978). Later, more refined attempts of reconstructing the origin and dispersal of ...

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Association of FCGR3A and FCGR3B Copy Number Variations With Systemic Lupus Erythematosus and Rheumatoid Arthritis in Taiwanese Patients

Chen

Wang

Chang

et al. 2014

Arthritis & Rheumatology

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ObjectiveTo determine whether copy number variations (CNVs) in FCGR3A and FCGR3B are associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese individuals.MethodsFCGR3A and FCGR3B CNV genotypes were determined in 846 patients with SLE, 948 patients with RA, and 1,420 healthy control subjects, using custom TaqMan CNV assays. The FCGR3A and FCGR3B CNV genotypes were compared between healthy control subjects and patients and among patients stratified according to clinical characteristics.ResultsA low (<2) FCGR3A copy number was significantly associated with SLE (for <2 copies versus 2 copies, P = 5.06 × 10−4, false discovery rate–corrected P [PFDR] = 0.001, odds ratio [OR] 3.26, 95% confidence interval [95% CI] 1.68−6.35) and RA (for <2 copies versus 2 copies, P = 5.83 × 10−4, PFDR = 0.0012, OR 2.82, 95% CI 1.56−5.1). A low FCGR3B copy number was also significantly associated with SLE (for <2 copies versus 2 copies, P = 0.0032, PFDR = 0.0032, OR 1.59, 95% CI 1.17−2.18). Notably, a high (>2) FCGR3A copy number was also associated with SLE (for >2 copies versus 2 copies, P = 0.003, PFDR = 0.0061, OR 1.6, 95% CI 1.17−2.18). Additionally, the FCGR3A low copy number genotype was significantly enriched in subsets of patients with SLE (those with ulcer, arthritis, rash, discoid rash, photosensitivity, nephritis, leukopenia, thrombocytopenia, depressed complement levels, and autoantibody positivity) and patients with RA (those positive for rheumatoid factor) compared with healthy control subjects. The FCGR3B low copy number genotype was also significantly enriched in SLE patients with ulcer, rash, discoid rash, photosensitivity, ascites, nephritis, complement level depression, and anti–double-stranded DNA antibody positivity compared with control subjects. However, FCGR3B CNVs were not associated with RA susceptibility (for <2 copy numbers versus 2 copy numbers, P = 0.3584, OR 1.15, 95% CI 0.85–1.55) and clinical characteristics.ConclusionIn Taiwanese individuals, a low FCGR3A copy number is a common risk factor for SLE and RA, while a low FCGR3B copy number confers a risk of SLE but not RA.

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Evolutionary History of Copy-Number-Variable Locus for the Low-Affinity Fcγ Receptor: Mutation Rate, Autoimmune Disease, and the Legacy of Helminth Infection

Cited by 40 publications

References 53 publications

Human gene copy number variation and infectious disease

Human gene copy number variation and infectious disease

Geographic Distribution and Adaptive Significance of Genomic Structural Variants: An Anthropological Genetics Perspective

Association of FCGR3A and FCGR3B Copy Number Variations With Systemic Lupus Erythematosus and Rheumatoid Arthritis in Taiwanese Patients

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