The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility

Abstract

Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1alphaP), a potent human immunodeficiency virus-1 (HIV-1)-suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.

Population structure in copy number variation and SNPs in the CCL4L chemokine gene

“…The similarity of the population CNV distribution between CCL4L and CCL3L performed in the same set of individuals is noteworthy. 21 To give a more general view of the worldwide distribution of CCL4L copy number, individuals were pooled into seven broad continental regions and the mean of CCL4L copy number was calculated. Sub-Saharan African populations display the highest number of CCL4L copies (mean ¼ 4.32 ± 0.63, including individuals with 8, 9 or 10 copies), whereas Europe present the lowest copy number (1.89 ± 0.40), including a 25% of individuals with only one CCL4L copy.…”

“…[25][26][27] Recently, the widespread presence of CNVs in the genomes of healthy individuals with no obvious genetic disorders has been described in a few populations, 1,2 but relatively few data has been reported regarding CNVs and disease resistance or susceptibility. 9,21 Regarding this point, the main aim of our work was to link the analysis of SNPs and CNVs within a worldwide framework to achieve a more powerful tool in the future determination of genetic basis of susceptibility or resistance to disease. It seems clear that genes with CNV require a nonconventional method to study their SNPs, and this is the reason why we established a clear and precise approach to solve this problem.…”

“…The knowledge of the intra-and interpopulation variation seems to be the key parameter in understanding the individual chemokine immune response, beyond the knowledge of the individual genetic composition. 21 The CNV analyzed in this study belongs to the multiallelic CNVs (see CNV classification in Redon et al 4 ) and extends across a 120 kb stretch in the q12 region of chromosome 17 that includes CCL4L and CCL3L genes. The high level of similarity between them, common gene strand orientations, comparable intergenic distances and amino-acid similarities strongly argue for nonallelic recombination as a mechanism responsible for the origin of one of these gene pairs.…”

“…19,20 However, two key points should be emphasized: (i) there are some individuals that lack the CCL3L-CCL4L tandem and (ii) there are haplotypes with different gene copy number (meaning that the gene copy number of both genes can be different in a single chromosome). 18 Evidence of a functional significance for the CCL3L CNV has been described by Gonzalez et al 21 demonstrating their influence on HIV susceptibility. According to Gonzalez et al, the strength of the immune response based on CCL3L activity depends on the relative gene copy number of the individual in relation to the mean copy number of the ethnic group to which the individual belongs.…”

The pursuit of genome-wide association studies: where are we now?

“…[162][163][164][165][166] In addition, one study has shown the correlations of about 30 SNPs (that found to be associated with various traits by GWAS) with CNVs at r 2 40.5, this provides preliminary evidence of the associations and possible roles of CNVs in human complex traits. 161 The amount of evidence is expected to increase in the near future, when we have a better understanding of the characteristics of non-SNP variants and a more comprehensive map of them constructed upon the completion of the 1000 Genomes Project, and when more efficient and accurate methods are available to detect the non-SNP variants for disease-association studies.…”