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Evolution of the Exon–Intron Structure and Alternative Splicing of the MAGE-A Family of Cancer/Testis Antigens

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Abstract

Cancer/testis antigens (CT-antigens) are proteins that are predominantly expressed in cancer and testis and thus are possible targets for immunotherapy. Most of them form large multigene families. The evolution of the MAGE-A family of CT-antigens is characterized by four processes: (1) gene duplications; (2) duplications of the initial exon; (3) point mutations and short insertions/deletions inactivating splicing sites or creating new sites; and (4) deletions removing sites and creating chimeric exons. All this concerns the genomic regions upstream of the coding region, creating a wide diversity of isoforms with different 5′-untranslated regions. Many of these isoforms are gene-specific and have emerged due to point mutations in alternative and constitutive splicing sites. There are also examples of chimeric mRNAs, likely produced by splicing of read-through transcripts. Since there is consistent use of homologous sites for different genes and no random, indiscriminant use of preexisting cryptic sites, it is likely that most observed isoforms are functional, and do not result from relaxed control in transformed cells.

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Acknowledgments

We are grateful to Andrew Simpson for the suggestion to analyze alternative splicing of CT antigens, to Andrey Mironov for useful discussion, and to Ali Osmay Güre for critical reading of the manuscript. We appreciate unpublished data on expression of alternatively spliced isoforms kindly provided by Matthew Scanlan and Ali Osmay Güre. This study was partially supported by grants from the Ludwig Institute of Cancer Research (CRDF RBO-1268), Howard Hughes Medical Institute (55000309), Russian Fund of Basic Research (04-04-49440), and Program in Molecular and Cellular Biology of the Russian Academy of Sciences.

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Authors and Affiliations

  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya 16/10, Moscow, 117997, Russia

    Irena I. Artamonova

  2. Institute for Problems of Information Transmission RAS, Bolshoi Karetny per. 19, Moscow, 127994, Russia

    Mikhail S. Gelfand

  3. State Scientific Center GosNIIGenetika, 1st Dorozhny proezd 1, Moscow, 117545, Russia

    Mikhail S. Gelfand

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  1. Irena I. Artamonova
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  2. Mikhail S. Gelfand
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Correspondence to Mikhail S. Gelfand.

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Artamonova, I.I., Gelfand, M.S. Evolution of the Exon–Intron Structure and Alternative Splicing of the MAGE-A Family of Cancer/Testis Antigens. J Mol Evol 59, 620–631 (2004). https://doi.org/10.1007/s00239-004-2654-3

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