An insight into the phylogenetic history of HOX linked gene families in vertebrates

Abstract

Background: The human chromosomes 2q, 7, 12q and 17q show extensive intra-genomic homology, containing duplicate, triplicate and quadruplicate paralogous regions centered on the HOX gene clusters. The fact that two or more representatives of different gene families are linked with HOX clusters is taken as evidence that these paralogous gene sets might have arisen from a single chromosomal segment through block or whole chromosome duplication events. This would imply that the constituent genes including the HOX clusters reflect the architecture of a single ancestral block (before vertebrate origin) where all of these genes were linked in a single copy.

Results: In the present study we have employed the currently available set of protein data for a wide variety of vertebrate and invertebrate genomes to analyze the phylogenetic history of 11 multigene families with three or more of their representatives linked to human HOX clusters. A topology comparison approach revealed four discrete co-duplicated groups: group 1 involves the genes from GLI, HH, INHB, IGFBP (cluster-1), and SLC4A families; group 2 involves ERBB, ZNFN1A, and IGFBP (cluster-2) gene families; group 3 involves the HOX clusters and the SP gene family; group 4 involves the integrin beta chain and myosine light chain families. The distinct genes within each co-duplicated group share the same evolutionary history and are duplicated in concert with each other, while the constituent genes of two different co-duplicated groups may not share their evolutionary history and may not have duplicated simultaneously.

Conclusion: We conclude that co-duplicated groups may themselves be remnants of ancient small-scale duplications (involving chromosomal segments or gene-clusters) which occurred at different time points during chordate evolution. Whereas the recent combination of genes from distinct co-duplicated groups on different chromosomal regions (human chromosomes 2q, 7, 12q, and 17q) is probably the outcome of subsequent rearrangement of genomic segments, including syntenic groups of genes.

Figure 1

Gene families with members on at least three of the human HOX-bearing chromsomes 2, 7, 12 and 17. Restricted location of members of many of these gene familes near the HOX clusters suggests that these paralogons may have duplicated simultaneously by block/whole chromosome duplication. SLC4, solute carrier family 4; INHB, inhibins; GLI, glioma-associated oncogene homolog belonging to kruppel family; ITGB, integrin β chains; SP, transcription factor Sp; HOX, homeobox; COL, collagens; MYL, myosin light chains; EGFR/ERBB, epidermal growth factor receptor/erythroblastoma; ZNFN1A, zinc finger protein, subfamily 1A; IGFBP, insulin-like growth factor-binding protein; HH, hedgehog. None of the features of this Figure are drawn to scale.

Figure 2

Neighbor-Joining tree of the COL family members. Uncorrected p-distance was used. Complete-deletion option was used. Numbers on branches represent bootstrap values (based on 1000 replications) supporting that branch; only the values ≥50% are presented here. Scale bar shows amino acid substitution per site.

Figure 3

Neighbor-Joining tree of the ERBB family. Symbols and parameters are the same as described in Figure 2.

Figure 4

Neighbor-Joining tree of the IGFBP family. Symbols and parameters are the same as described in Figure 2.

Figure 5

Neighbor-Joining tree of the Integrin β chain family. Symbols and parameters are the same as described in Figure 2.

Figure 6

Neighbor-Joining tree of the (A) Myosin light chain family (B) SP family (C) ZNFN1A family (D) SLC4A family. Symbols and parameters are the same as described in Figure 2.

Figure 7

Neighbor-Joining tree of the (A) GLI family (B) Hedgehog family and (C) Inhibin family. Symbols and parameters are the same as described in Figure 2.

Figure 8

Members of HOX linked gene families that have arisen early in vertebrate history. Order of branching within phylogenetic trees was used to estimate the time windows (double headed arrows on the right) of gene duplication events relative to major cladogenetic events. For each family the lower limit of time window was defined from fish-tetrapod split and the upper limit from the branching order of available closest invertebrate ancestral sequence (Protostomes: Drosophila, Apis mellifera; Echinoderm: Sea Urchin; Cephalochordates: Amphioxus; Urchordate: Ciona intestinalis, Ciona savignyi). The INHBE, INHBC and SLC4A8, SLC4A10 genes arose after the fish-tetrapods split. Previously Proposed timing [3-6] of extensive gene duplications during early chordate evolution is given on the left of the diagram.

Figure 9

Consistencies in phylogenies of families having members on at least three of the HOX-bearing chromosomes (A) schematic topology of GLI, INHB, IGFBP, HH and SLC4A families (B) schematic topology of ERBB, ZNFN1A and IGFBP family members (C) schematic topology of HOX clusters and SP gene family (D) schematic topology of integrin beta chain and myosin light chain gene families. In each case the percentage bootstrap support of the internal branches is given in parentheses. The connecting bars on the left depict the close physical linkage of relevant genes.