Copy number variation in chemokine superfamily: the complex scene of CCL3L-CCL4L genes in health and disease

Abstract

Genome copy number changes (copy number variations: CNVs) include inherited, de novo and somatically acquired deviations from a diploid state within a particular chromosomal segment. CNVs are frequent in higher eukaryotes and associated with a substantial portion of inherited and acquired risk for various human diseases. CNVs are distributed widely in the genomes of apparently healthy individuals and thus constitute significant amounts of population-based genomic variation. Human CNV loci are enriched for immune genes and one of the most striking examples of CNV in humans involves a genomic region containing the chemokine genes CCL3L and CCL4L. The CCL3L-CCL4L copy number variable region (CNVR) shows extensive architectural complexity, with smaller CNVs within the larger ones and with interindividual variation in breakpoints. Furthermore, the individual genes embedded in this CNVR account for an additional level of genetic and mRNA complexity: CCL4L1 and CCL4L2 have identical exonic sequences but produce a different pattern of mRNAs. CCL3L2 was considered previously as a CCL3L1 pseudogene, but is actually transcribed. Since 2005, CCL3L-CCL4L CNV has been associated extensively with various human immunodeficiency virus-related outcomes, but some recent studies called these associations into question. This controversy may be due in part to the differences in alternative methods for quantifying gene copy number and differentiating the individual genes. This review summarizes and discusses the current knowledge about CCL3L-CCL4L CNV and points out that elucidating their complete phenotypic impact requires dissecting the combinatorial genomic complexity posed by various proportions of distinct CCL3L and CCL4L genes among individuals.

Fig. 1

Genomic organization and mRNA products of human CCL3–CCL4 and CCL3L–CCL4L genes. (a) Map of the CC chemokine cluster in the 17q11.2–q12 region, based on the genomic sequence NT_010799. The orientation of each gene is shown by an arrow. (b) Genomic organization of human CCL3–CCL4 and CCL3L–CCL4L genes based on the genomic sequence NT_010799. Distances between genes are expressed in Kb. The nucleotide change [single nucleotide polymorphism (SNP) rs4796195] that leads to CCL4L1 (A allele) or CCL4L2 (G allele) is shown. (c) Transcription pattern of human CCL3–CCL4 and CCL3L–CCL4L genes. mRNAs derived from each individual gene are shown.

Fig. 2

Alignment of human CCL3–CCL4 and CCL3L–CCL4L derived proteins. Signal peptides are depicted in grey. Cysteines are depicted in red. Basic amino acids, which are involved in the binding of chemokines to the glycosaminoglycans are depicted in blue. The S/G swap shared between CCL3–CCL3L1 and CCL4–CCL4L1/L2 proteins is depicted in green.