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Effect of gene structure changes on the rate of protein sequence evolution

Effect of gene structure changes on the rate of protein sequence evolution
BRIAN CUSACK

2006

Department of Genetics, Trinity College, University of Dublin, Dublin 2, IRELAND.

ABSTRACT

The elaborate architecture of the genes of multicellular eukaryotes is likely to underpin the unique complexity of eukaryotic gene functions. The structure of eukaryotic genes differs from that of prokaryotes and represents an assemblage of coding exons, introns that are spliced out of precursor mRNAs, extended UTRs and complex regulatory regions. It is likely that these features provided a platform for the evolution of the complex traits that typify metazoans including alternative splicing and complex gene regulation.

Here I performed genome-wide studies of the association between the rate of protein sequence evolution and the modification of gene structures that can result from the processes of gene duplication and alternative splicing. By considering recent gene duplicates in rodents I investigated genomic relocation following duplication and gene structure alteration by retrotransposition as possible determinants of evolutionary rate differences between duplicates. I found evidence that retrotransposition frequently results in asymmetric evolution of gene duplicates and that functional retrogenes consistently accelerate relative to their paralogs. Although the act of relocating a gene duplicate by transposition explains part of this effect my results show that the mechanism of retrotransposition makes an independent contribution to this acceleration. This is likely to reflect the fact that duplicates created by retrotransposition violate the assumption common to most theoretical models that gene duplicates are born equal. My results further suggest that the rate acceleration of functional retrogenes is likely to be mediated by changes in their expression.

Alternative splicing is a parallel route to the generation of functional diversity that is also associated with changes in the exon-intron structure of genes. The effect of changes in alternative splicing on evolutionary rate can be assessed by comparing evolutionary pattterns in genes where alternative splicing is species-specific to genes where it is conserved. I show that the existence of species-specific alternative exons in human and mouse orthologs is a result of recent gain of these exons. The gene structure alterations associated with these gains have resulted in an acceleration in the rate of sequence evolution of constant regions of the encoded protein. Moreover, this effect is shown to strongly correlate with the frequency of incorporation of these new exons. I argue that this correlation reflects a causative relationship between these variables and demonstrates the impact on constitutive parts of proteins of the acquisition of functional alternative splice forms.

Finally I present evidence from a single gene study supporting the intuition that alternative splicing and gene duplication can be parallel and complementary routes to the generation of functional diversity. I describe a gene fusion event that created a bifunctional gene coding for two proteins by alternative splicing. This chimeric gene persists in the mangrove genome but has duplicated in poplar and undergone subfunctionalisation to re-form its constituent genes through the complementary degeneration of its exons. This example is a clear illustration of the partitioning of alternative splice forms by subfunctionalisation at the level of gene structure. I also discuss evidence that accelerated protein sequence evolution occurred simultaneously with the gene structure changes corresponding to the initial gene fusion and the subsequent gene fission following duplication.

These results support the assertion that modifications of eukaryotic gene structure are frequently accompanied by an increase in the rate of protein sequence evolution.