Human gene copy number variation and infectious disease

Abstract

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

Increased Levels of Macrophage Inflammatory Proteins Result in Resistance to R5-Tropic HIV-1 in a Subset of Elite Controllers

“…Previous studies obtained mixed results regarding the association between the CCL3L1 and CCL4L1 copy numbers and HIV/ AIDS susceptibility and disease progression (reviewed by Hollox and Hoh [55]). For example, some reports demonstrated an association between high CCL3L1 copy numbers and a reduced prevalence of HIV seropositivity, slower progression to AIDS, and improved recovery of CD4 ϩ T cells (45,(56)(57)(58), whereas other studies and follow-up correspondences failed to detect an association even within the same data set (59)(60)(61).…”

Evolution of the rapidly mutating human salivary agglutinin gene ( DMBT1 ) and population subsistence strategy

“…Whether selection or a relaxation of functional constraint is responsible for this bias in genome-wide distribution remains unresolved, although there are strong arguments for the role of gene duplication in evolution (18). There is convincing evidence that CNV in humans can affect the host's susceptibility to infectious diseases, including the well established effect of α-globin deletion on malaria susceptibility (19). Furthermore, it has been suggested that the frequency of high copy number alleles of the salivary amylase gene AMY1 has increased by natural selection in populations that eat a carbohydrate-rich diet (20).…”

Copy number variation of the REXO1L1 gene cluster; euchromatic deletion variant or susceptibility factor?

“…As gains of RP11-96G1 were far more frequent than losses in the healthy populations analysed by Redon et al, 8 D'Apice et al 2 may have found a rare benign euchromatic deletion variant of 8q21.2 rather than a novel microdeletion. If not due to dosage, any possible effects of a deletion would require alternative mechanisms such as enhancer adoption by genes flanking the REXO1L1 cluster 7 or the release of other genes from epigenetic control. 6 …”

“…7 As immunological reaction against the human REXO1L1 gene product is a marker of HCV infection, a role for REXO1L1 copy number in HCV infection was suggested. 1 D'Apice et al 2 found increased genetic instability and apoptosis in their patient fibroblasts after treatment with DNA-damaging agents and, as REXO1L1 is a 3′-5' exonuclease member of the DEDD superfamily which might control HBV and RNA virus infections, speculated that low REXO1L1 copy number might predispose and high numbers protect against viral infection.…”

“…As other large-scale CNVs have been associated with inflammatory diseases 7,9 it is conceivable that low REXO1L1 copy number might predispose to inflammatory gastrointestinal conditions that include celiac, Crohn's and irritable bowel syndrome. The higher frequency of RP11-96G1 gains than losses 8 and the 0.7 skew against lower copy numbers among controls 1 suggest that there may be factors that select against low REXO1L1 cluster copy number.…”