Molecular characterization of matrix metalloproteinase gene family across primates

Abstract

Deregulation of matrix metalloproteinases (MMPs) contributes considerably to cancers, psychiatric disorders, macular degeneration and bone diseases. The use of humans in the development of MMPs as prognostic biomarkers and therapeutic targets is complicated by many factors, while primate models can be useful alternatives for this purpose. Here, we performed genome-enabled identification of putative MMPs across primate species, and comprehensively investigated the genes. Phylogenetic topology of the MMP family showed each type formulates a distinct clade, and was further clustered to classes, largely agreeing with classification based on biochemical properties and domain organization. Across primates, the excess of candidate sites of positive selection was detected for MMP-19, in addition to 1-3 sites in MMP-8, MMP-10 and MMP-26. MMP-26 showed Ka/Ks value above 1 between human and chimpanzee copies. We observed two copies of MMP-19 in the old-world monkey genomes, suggesting gene duplication at the early stage of or prior to the emergence of the lineage. Furin-activatable MMPs demonstrate the most variable properties regarding Domain organization and gene structure. During human aging, MMP-11 showed gradually decreased expression in testis, so as MMP-2, MMP-14, MMP15 and MMP-28 in ovary, while MMP-7 and MMP-21 showed elevated expression, implying their distinct roles in different reproductive organs. Co-expression clusters were formed among human MMPs both within and across classes, and expression correlation was observed in MMP genes across primates. Our results illuminate the utilization of MMPs for the discovery of prognostic biomarkers and therapeutic targets for aging-related diseases and carry new messages on MMP classification.

Keywords: co-expression; gene structure; genomic organization; matrix metalloproteinase; primate.

Figure 1

Taxonomy of the primate species for investigation of MMPs. At the tip of each clade shows the common name followed by the Latin name of the organism. Tips shown in red represent species with comparative gene expression analyses performed. Shown at nodes are four major primate groups. Numbers in brackets are counting of MMPs identified for each organism.

Figure 2

Unrooted phylogenetic tree of 261 primate MMP peptides. Looped in brown ovals are four major groups supported with biochemistry evidence, and enclosed in red circles are sub-groups based on biochemical properties under certain groups. Phylogenetic analyses were performed by using PhyML v3.3.3 with 1000 bootstraps.

Figure 3

Phylogenetic tree of primate MMP-19s. Shaded are two independent clades as a result of duplication of old-world monkey MMP-19s. Labeled at nodes are bootstrap support values. Phylogenetic analyses were performed by using PhyML v3.3.3 with 1000 bootstraps.

Figure 4

Domain organization of human MMPs. Pfam domains were identified by using HMMER 3.3 against Pfam database, and signal peptides were obtained by querying SignalP-5.0 server. Pfam domains and signal peptides are shown as colored boxes.

Figure 5

Statistics of primate MMP gene structure. (A) Box plots of molecular weights of MMP peptides. (B) Box plots of gene lengths. (C) Box plots of CDS/gene ratio. (D) Box plots of exon counting. While MMP-23s are classified in furin-activatable MMPs, they demonstrate very different characteristics than other MMPs, and thus were investigated separately.

Figure 6

Localization of human MMP genes. A cluster is shown in the 11th chromosome. The localization of the genes was retrieved from GFF3 files.

Figure 7

Co-synteny of the MMP genes across human, chimpanzee, olive baboon and mouse lemur. Co-synteny clusters are shown as grey curves, and MMPs in the co-synteny clusters are shown in red.

Figure 8

Expression of human MMP genes. (A) Heatmap of human MMP gene expression in 11 tissues. (B) Longitudinal expression of human MMPs in testis (not normalized). (C) Longitudinal expression of human MMPs in testis (normalized). (D) Longitudinal expression of human MMPs in ovary (not normalized). (E) Longitudinal expression of human MMPs in ovary (normalized). The MMP genes are clustered based on expression patterns.

Figure 9

Co-expression of MMPs. (A) Expression correlation between human MMP genes. (B) Expression correlation of each MMP gene between human and four other primate species. Spearman’s correlation coefficients are depicted as heatmap, with each circle denoting a pair.

Figure 10

Summary and prospect of the findings in this article.