In fact, a few published studies already tackle this approach: Shostakovich-Koretskaya et al.  determined the influence of the combinatorial content of distinct
CCL3L and CCL4L genes on HIV/AIDS susceptibility. They developed two separate assays to quantify the total copy number of all CCL3L or CCL4L genes, and separate assays each for the individual components of CCL3L (CCL3L1 and CCL3L2) and CCL4L (CCL4L1 and CCL4L2). This study confirms and amplifies the results of previous studies which showed that a low dose of CCL3L genes is associated with an increased risk of acquiring HIV and progressing rapidly to AIDS. Their results also demonstrate that a low CCL4L Ixazomib cost gene dose has similar associations. Furthermore, they show that the balance between the copy numbers of the genes that transcribe classical (CCL3L1 and CCL4L1) versus aberrantly spliced (CCL3L2 and CCL4L2) mRNA species influences HIV/AIDS susceptibility: a higher gene content of CCL4L2 or a lower content of CCL3L1 and CCL4L1 increased the risk of transmission and an accelerated disease course. A similar
negative influence of CCL4L2 on HIV acquisition was shown previously . We also have shown that CNV in the CCL4L gene is associated with susceptibility to acute rejection in lung transplantation . After specifically quantifying the CCL4L1 and CCL4L2 copies, we demonstrated that the correlation between CCL4L copy number and risk of acute lung transplant rejection was explained mainly by the number of copies of the CCL4L1 gene. These two studies GSI-IX imply that the assessment of global CCL4L dose requires capturing the sum of two genes (CCL4L1 and CCL4L2) with inversely related copy
number frequencies [51,52] and differential effects. Thus, the true phenotypic impact of CCL4L1 and CCL4L2 cannot be made exclusively using the CCL3L copy number as a proxy for CCL4L or by evaluation of the composite CCL4L. This might explain, in part, why previous studies may not have found an association between eltoprazine CCL4L copy number and HIV disease . Similarly, accounting for this genomic complexity, including CCL3L2 copy number may be crucial for full interpretation of association studies. In summary, for future studies involving CCL3L–CCL4L CNVR and, in general, from a broader perspective of relevance to the CNV field, to determine normal phenotypic variation or disease susceptibility it seems to be crucial to define precisely the genomic structure, taking into account the specific combination of the distinct genes within a CNVR. The use of incomplete data will be always a source of controversy, providing misleading information. Only a complete analysis will clarify the importance of CCL3L–CCL4L CNVR in disease.