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Evolutionary origin and genomic organization of micro-RNA genes in immunoglobulin lambda variable region gene family.

ABSTRACT: The genomic organizations and functions of many miRNA genes have been described in recent years, but the origin and evolution of miRNAs in the exons of protein-coding genes are not well understood. The overlap of miR-650 genes with the protein-coding region of immunoglobulin lambda variable (IGVL) region genes has given a unique opportunity to witness a birth of miRNA gene. Both sequence comparisons and structure predictions indicate that the miR-650 genes are present in multiple copies and overlap in the same transcription orientation with the leader exon of primate IGVL genes of a specific phylogenetic clan (clan II). By reconstructing the phylogeny of the clan II IGVL genes, the stages in which the mutations accumulated in the leader exon and gave rise to a stable hairpin structure of miR-650 could be documented. The copy number variation of miR-650 genes among different species is the result of the duplication or deletion of the IGVL genes. To my knowledge, this is the first report of a genomic association between miRNA and the protein-coding genes of a multigene family. Analysis of the upstream region of the leader exon suggests that the IGVL and the mir-650 genes use the same promoter region for their transcription. However, in contrast to the general expectation about the expression of miRNAs that overlap with other genes in the same transcriptional orientation, this analysis provides evidence that the miR-650 gene is apparently transcribed independently of the IGVL gene with which it overlaps because they are expressed in different cell types.

SUBMITTER: Das S

PROVIDER: S-EPMC2727374 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Evolutionary origin and genomic organization of micro-RNA genes in immunoglobulin lambda variable region gene family.

Das Sabyasachi S

Molecular biology and evolution 20090226 5

The genomic organizations and functions of many miRNA genes have been described in recent years, but the origin and evolution of miRNAs in the exons of protein-coding genes are not well understood. The overlap of miR-650 genes with the protein-coding region of immunoglobulin lambda variable (IGVL) region genes has given a unique opportunity to witness a birth of miRNA gene. Both sequence comparisons and structure predictions indicate that the miR-650 genes are present in multiple copies and over ...[more]

PMID: 19246621

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Project description:In systemic autoimmunity, autoantibodies directed against nuclear antigens (Ags) often arise by somatic hypermutation (SHM) that converts AGT and AGC (AGY) Ser codons into Arg codons. This can occur by three different single-base changes. Curiously, AGY Ser codons are far more abundant in complementarity-determining regions (CDRs) of IgV-region genes than expected for random codon use or from species-specific codon frequency data. CDR AGY codons are also more abundant than TCN Ser codons. We show that these trends hold even in cartilaginous fishes. Because AGC is a preferred target for SHM by activation-induced cytidine deaminase, we asked whether the AGY abundance was solely due to a selection pressure to conserve high mutability in CDRs regardless of codon context but found that this was not the case. Instead, AGY triplets were selectively enriched in the Ser codon reading frame. Motivated by reports implicating a functional role for poly/autoreactive specificities in antiviral antibodies, we also analyzed mutations at AGY in antibodies directed against a number of different viruses and found that mutations producing Arg codons in antiviral antibodies were indeed frequent. Unexpectedly, however, we also found that AGY codons mutated often to encode nearly all of the amino acids that are reported to provide the most frequent contacts with Ag. In many cases, mutations producing codons for these alternative amino acids in antiviral antibodies were more frequent than those producing Arg codons. Mutations producing each of these key amino acids required only single-base changes in AGY. AGY is the only codon group in which two-thirds of random mutations generate codons for these key residues. Finally, by directly analyzing X-ray structures of immune complexes from the RCSB protein database, we found that Ag-contact residues generated via SHM occurred more often at AGY than at any other codon group. Thus, preservation of AGY codons in antibody genes appears to have been driven by their exceptional functional versatility, despite potential autoreactive consequences.

Dataset Information

Evolutionary origin and genomic organization of micro-RNA genes in immunoglobulin lambda variable region gene family.

Publications

Evolutionary origin and genomic organization of micro-RNA genes in immunoglobulin lambda variable region gene family.

Similar Datasets

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