The number of individuals without CCL3L or CCL4L is always below 5% in all continental regions [52,53]. The duplicated region encoding human CCL3L–CCL4L genes has an ancestral correlate in non-human primates. The CCL3L–CCL4L copy numbers are much higher in non-human primates than in human populations [53–55]. Gonzalez et al. determined the gene copy numbers of the chimpanzee (Pan troglodytes) CCL3L DNA Methyltransferas inhibitor orthologues from 83 animals. The CCL3L copies range from 6 to 17 per diploid genome (median 9; mean 9·3) [53]. Similarly, Degenhardt et al. observed extensive variation in copy number of the CCL3L region among 57 samples of rhesus macaque (Macaca mulatta):

copy number estimates range from 5 to 31 copies per diploid genome (median 10; mean 11·1) [54]. Currently, the official symbols of the genes included in the CCL3L–CCL4L cluster are based on the public human genome sequence which contains, by chance, three CCL3L copies and two CCL4L copies. CCL3L and CCL4L have been numbered based on their position from the more centromeric

BVD-523 manufacturer to the more telomeric. Thus the official symbols for CCL3L genes are CCL3L1 (GeneID: 6349), CCL3L2 (GeneID: 390788) and CCL3L3 (GeneID: 414062). The official symbols for CCL4L genes are CCL4L1 (GeneID: 9560) and CCL4L2 (GeneID: 388372). However, we believe that the nomenclature criterion should consider whether the genes are really different rather than solely their copy number. Although CCL3L1 and CCL3L3 are separate genes, both have three identical exons and encode identical proteins [42,47], and therefore they are denoted together here as CCL3L1 (Fig. 1). CCL3L2 (known previously as LD78γ or GOS19-3) was identified initially as a pseudogene, as it contains two exons that are homologous to exons 2 and 3 of the CCL3L1 Exoribonuclease gene and appeared to contain a 5′ truncation compared with CCL3L1[46].

However, Shostakovich-Koretskaya et al. recently identified novel 5′ exons for CCL3L2 which give rise to two alternatively spliced transcripts by bioinformatics and mRNA profiling (Fig. 1c) [51]. These alternatively transcribed mRNA species contain chemokine-like domains but are not predicted to encode classical chemokines (data not shown [51]). Regarding CCL4L genes, CCL4L1 and CCL4L2 share 100% sequence identity in the coding regions. However, a fixed mutation at the intron–exon boundary of some CCL4L genes results in the production of aberrantly spliced transcripts [48]. We proposed the name of the originally described gene (corresponding to GeneID: 388372) as CCL4L1 and CCL4L2 (GeneID: 9560) as the gene that contains the mutation at the intron–exon boundary [38,48,52,56]. We use this nomenclature in this review (view Fig. 1) and we note that the same concept has been applied recently by others [51].