Abstract
The evolutionary mode of a multi-gene family can change over time, depending on the functional differentiation and local genomic environment of family members. In this study, we demonstrate such a change in the melanoma antigen (MAGE) gene family on the mammalian X chromosome. The MAGE gene family is composed of ten subfamilies that can be categorized into two types. Type I genes are of relatively recent origin, and they encode epitopes for human leukocyte antigen (HLA) in cancer cells. Type II genes are relatively ancient and some of their products are known to be involved in apoptosis or cell proliferation. The evolutionary history of the MAGE gene family can be divided into four phases. In phase I, a single-copy state of an ancestral gene and the evolutionarily conserved mode had lasted until the emergence of eutherian mammals. In phase II, eight subfamily ancestors, with the exception for MAGE-C and MAGE-D subfamilies, were formed via retrotransposition independently. This would coincide with a transposition burst of LINE elements at the eutherian radiation. However, MAGE-C was generated by gene duplication of MAGE-A. Phase III is characterized by extensive gene duplication within each subfamily and in particular the formation of palindromes in the MAGE-A subfamily, which occurred in an ancestor of the Catarrhini. Phase IV is characterized by the decay of a palindrome in most Catarrhini, with the exception of humans. Although the palindrome is truncated by frequent deletions in apes and Old World monkeys, it is retained in humans. Here, we argue that this human-specific retention stems from negative selection acting on MAGE-A genes encoding epitopes of cancer cells, which preserves their ability to bind to highly divergent HLA molecules. These findings are interpreted with consideration of the biological factors shaping recent human MAGE-A genes.
Highlights
The evolutionary mode of a gene family, namely the process of birth and death of genes and the extents of sequence divergence, depends on the functional divergence of duplicated genes and on the local structure of the genome where the family resides [1,2].Here, local structure of the genome refers to tandem or inverted repeats (IRs)
We argue that this human-specific retention stems from negative selection acting on melanoma antigen (MAGE)-A genes encoding epitopes of cancer cells, which preserves their ability to bind to highly divergent human leukocyte antigen (HLA) molecules
To identify MAGE homologs in lampreys, lancelets, tunicates, and sea urchins, a BLAST search was performed for their genome and EST sequences, using MAGE-D genes as queries
Summary
Local structure of the genome refers to tandem or inverted repeats (IRs). Warburton et al (2004) found a preponderance of large, IRs with a high degree of similarity between repeats on the X and Y chromosomes (,30% of IRs in the human genome are on the X and Y chromosomes) [3]. Many IRs on the X and Y contain genes expressed predominantly in the testis [3]. Warburton and his colleagues suggested that these IRs play an important role in human genome evolution. In this study, we attempt to examine the tempo and mode of gene family evolution in IRs, with a specific focus on the melanoma antigen (MAGE)
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