Discovery of five conserved beta -defensin gene clusters using a computational search strategy - PubMed (original) (raw)

Discovery of five conserved beta -defensin gene clusters using a computational search strategy

Brian C Schutte et al. Proc Natl Acad Sci U S A. 2002.

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Abstract

The innate immune system includes antimicrobial peptides that protect multicellular organisms from a diverse spectrum of microorganisms. beta-Defensins comprise one important family of mammalian antimicrobial peptides. The annotation of the human genome fails to reveal the expected diversity, and a recent query of the draft sequence with the blast search engine found only one new beta-defensin gene (DEFB3). To define better the beta-defensin gene family, we adopted a genomics approach that uses hmmer, a computational search tool based on hidden Markov models, in combination with blast. This strategy identified 28 new human and 43 new mouse beta-defensin genes in five syntenic chromosomal regions. Within each syntenic cluster, the gene sequences and organization were similar, suggesting each cluster pair arose from a common ancestor and was retained because of conserved functions. Preliminary analysis indicates that at least 26 of the predicted genes are transcribed. These results demonstrate the value of a genomewide search strategy to identify genes with conserved structural motifs. Discovery of these genes represents a new starting point for exploring the role of beta-defensins in innate immunity.

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Figures

Figure 1

Figure 1

Multiple sequence alignment of human β-defensin proteins. The amino acid sequences were predicted from genomic sequence (Table 1). The chromosomal location of each gene is indicated, except where mapping was ambiguous (A). The sequences were aligned as described in Materials and Methods followed by minor manual manipulations to maximize sequence alignment and clustering of genes by chromosome. We classified β-defensin genes as known (K), if evidence exists that they are transcribed and that their protein product demonstrates antimicrobial activity; related (R), if evidence exists that they are transcribed but their protein product has not been tested for antimicrobial activity; predicted (P), if no evidence exists that they are transcribed; and pseudogenes (S), if the DNA sequence is highly similar to a β-defensin gene, but the predicted amino acid sequence lacks an ORF across the six-cysteine motif. The consensus sequence shows cysteine residues (yellow highlight), positively charged residues (blue +) and other residues (red) if they are represented in greater than 50% of all predicted β-defensin proteins.

Figure 2

Figure 2

Dendrogram of predicted β-defensin proteins. The length of each branch is inversely related to their similarity. The tree was constructed with the partial amino acid sequences predicted from the indicated human (●) and mouse (○) known, related, and predicted genes (Table 1). The genomic location for each gene is indicated. In some cases, the location of the genes was ambiguous (A) or unknown (U).

Figure 3

Figure 3

Genomic structure of five conserved β-defensin gene clusters. Vertical bars represent assembled genomic DNA sequence contigs (see Table 1 for GenBank and Celera accession nos.) from the indicated human (Hs) and mouse (Mm) chromosome. Slanted lines represent gaps in the genomic sequence of known (single) or unknown (double) length. The telomere (Tel) and centromere (Cen) orientation of human DNA sequence contigs was deduced from the position of genetic markers. The orientation of the mouse DNA sequence contigs was deduced from the alignment of human and mouse gene homologs. The direction of transcription is indicated for known and related genes (▴) and predicted genes and pseudogenes (▵) or is unknown (▫). Thin lines connect human and mouse genes with highest sequence similarity (Fig. 2).

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