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Annotation of immunoglobulin and T-cell receptor genes

VDJ recombination

The Immunoglobulin (Ig) and T-cell receptor (Tcr) genes are present in germ-line genomic DNA. They comprise the four segment types, variable (V), diversity (D), joining (J) and constant (C), which are rearranged and brought together by VDJ recombination to form functional Ig and Tcr genes during B-cell and T-cell maturation. This results in genetically different B-cells and T-cells, which encode different proteins to recognise specific antigens as part of the acquired immune system.

The protein and nucleotide databases contain many sequences of mature Ig/Tcr genes. Inferring gene structures by aligning these to the genome using the standard Ensembl annotation process pipeline gives unsatisfactory results, for two main reasons:

  • The non-coding DNA that separates pairs of gene segments brought together by V-D-J recombination is not an intron, and the gene boundaries display different sequence signals to splice sites. Spliced alignment programs such as GeneWise therefore require retuning in order to predict the gene structure correctly.

  • Some genes comprise multiple exons. Delineating a "spliced" alignment of a mature Ig/Tcr sequence to the genome into its constituent segments is therefore not straightforward.

Annotation of Ig/Tcr genes

For this reason, Ig/Tcr gene segments have been annotated differently to other Ensembl genes. Ensembl makes use of the IMGT database, which provides annotation of individual gene segments on reference sequences. Ensembl use a combination of manual annotation by Havana and automatic annotation by extracting individual gene sequences and aligning them to the genome using the Exonerate alignment tool for Ig/Tcr genes.

To reflect their role in the VDJ recombination process, segments are annotated as belonging to one of four classes: V, D, J and C. At present, Ensembl Ig/Tcr gene annotations are only available for human and mouse.

References

Lefranc M.-P., Giudicelli V., Kaas Q., Duprat E., Jabado-Michaloud J., Scaviner D., Ginestoux C., Clément O., Chaume D. and Lefranc G. IMGT, the international ImMunoGeneTics information system. Nucl. Acids Res. 2005 33:D593-D597

Slater G.S. and Birney E. Automated generation of heuristics for biological sequence comparison. BMC Bioinformatics 2005 6:31

Ewan Birney, Michele Clamp and Richard Durbin GeneWise and Genomewise Genome Research 2004 14(5):988-995.