Age-dependent gain of alternative splice forms and biased duplication explain the relation between splicing and duplication.

We analyze here the relation between alternative splicing and gene duplication in light of recent genomic data, with a focus on the human genome. We show that the previously reported negative correlation between level of alternative splicing and family size no longer holds true. We clarify this pattern and show that it is sufficiently explained by two factors. First, genes progressively gain new splice variants with time. The gain is consistent with a selectively relaxed regime, until purifying selection slows it down as aging genes accumulate a large number of variants. Second, we show that duplication does not lead to a loss of splice forms, but rather that genes with low levels of alternative splicing tend to duplicate more frequently. This leads us to reconsider the role of alternative splicing in duplicate retention.

[1]  Huanming Yang,et al.  Origin and evolution of new exons in rodents. , 2005, Genome research.

[2]  B. Graveley.  Alternative splicing: increasing diversity in the proteomic world. , 2001, Trends in genetics : TIG.

[3]  Adi Doron-Faigenboim,et al.  The “Alternative” Choice of Constitutive Exons throughout Evolution , 2007, PLoS genetics.

[4]  Eugene V. Koonin,et al.  Constraints and plasticity in genome and molecular-phenome evolution , 2010, Nature Reviews Genetics.

[5]  V. Ingram.  The evolution of a protein. , 1962, Federation proceedings.

[6]  L. Wagner,et al.  21. UniGene: A Unified View of the Transcriptome , 2003 .

[7]  P. Bork,et al.  Alternative splicing and genome complexity , 2002, Nature Genetics.

[8]  Joel Dudley,et al.  TimeTree: a public knowledge-base of divergence times among organisms , 2006, Bioinform..

[9]  Nicholas H. Putnam,et al.  The amphioxus genome and the evolution of the chordate karyotype , 2008, Nature.

[10]  J. Clemente,et al.  The evolutionary relationship between gene duplication and alternative splicing. , 2008, Gene.

[11]  M. Albà,et al.  Inverse relationship between evolutionary rate and age of mammalian genes. , 2005, Molecular biology and evolution.

[12]  X. Gu,et al.  Evolution of alternative splicing after gene duplication. , 2005, Genome research.

[13]  T. Chakraborty,et al.  Comparative Genomics and Evolution of Virulence , 2008 .

[14]  M. Lynch,et al.  The evolutionary fate and consequences of duplicate genes. , 2000, Science.

[15]  J. Garcia-Fernández,et al.  Widespread evolutionary conservation of alternatively spliced exons in Caenorhabditis. , 2008, Molecular biology and evolution.

[16]  A. N. Spiridonov,et al.  Distinct Patterns of Expression and Evolution of Intronless and Intron-Containing Mammalian Genes , 2010, Molecular biology and evolution.

[17]  Andrew M. Jenkinson,et al.  Ensembl 2009 , 2008, Nucleic Acids Res..

[18]  M J Thomsom,et al.  An alternative. , 1970, The American journal of psychiatry.

[19]  Peer Bork,et al.  Alternative splicing and evolution. , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[20]  C. Chothia,et al.  Evolution of the Protein Repertoire , 2003, Science.

[21]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[22]  G. Ast,et al.  Different levels of alternative splicing among eukaryotes , 2006, Nucleic acids research.

[23]  Tomaso Poggio,et al.  Identification and analysis of alternative splicing events conserved in human and mouse. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Sébastien Moretti,et al.  Bgee: Integrating and Comparing Heterogeneous Transcriptome Data Among Species , 2008, DILS.

[25]  M. Albà,et al.  On homology searches by protein Blast and the characterization of the age of genes , 2007, BMC Evolutionary Biology.

[26]  Sarah A. Teichmann,et al.  The (In)dependence of Alternative Splicing and Gene Duplication , 2007, PLoS Comput. Biol..

[27]  Damian Smedley,et al.  BioMart – biological queries made easy , 2009, BMC Genomics.

[28]  Ziheng Yang,et al.  PAML: a program package for phylogenetic analysis by maximum likelihood , 1997, Comput. Appl. Biosci..

[29]  Albert J. Vilella,et al.  EnsemblCompara GeneTrees: Complete, duplication-aware phylogenetic trees in vertebrates. , 2009, Genome research.

[30]  Doron Lancet,et al.  Alternative splicing and gene duplication are inversely correlated evolutionary mechanisms , 2005, Nature Genetics.

[31]  María Martín,et al.  The Universal Protein Resource (UniProt) in 2010 , 2010 .

[32]  G. Ast,et al.  Alternative splicing and evolution: diversification, exon definition and function , 2010, Nature Reviews Genetics.

[33]  Yoshiharu Sato,et al.  H-DBAS: human-transcriptome database for alternative splicing: update 2010 , 2009, Nucleic Acids Res..

[34]  M. Robinson‐Rechavi,et al.  How confident can we be that orthologs are similar, but paralogs differ? , 2009, Trends in genetics : TIG.

[35]  F. Kondrashov,et al.  The evolution of gene duplications: classifying and distinguishing between models , 2010, Nature Reviews Genetics.

[36]  David Haussler,et al.  The UCSC Genome Browser database: update 2010 , 2009, Nucleic Acids Res..

[37]  Baris E. Suzek,et al.  The Universal Protein Resource (UniProt) in 2010 , 2009, Nucleic Acids Res..

[38]  K. H. Wolfe,et al.  Not born equal: increased rate asymmetry in relocated and retrotransposed rodent gene duplicates. , 2006, Molecular biology and evolution.

[39]  Eugene V Koonin,et al.  The universal distribution of evolutionary rates of genes and distinct characteristics of eukaryotic genes of different apparent ages , 2009, Proceedings of the National Academy of Sciences.

[40]  D. Graur,et al.  The "inverse relationship between evolutionary rate and age of mammalian genes" is an artifact of increased genetic distance with rate of evolution and time of divergence. , 2006, Molecular biology and evolution.

[41]  Mary Goldman,et al.  The UCSC Genome Browser database: update 2011 , 2010, Nucleic Acids Res..

[42]  J. Civetta.  The inverse relationship between cost and survival. , 1973, The Journal of surgical research.

[43]  M. Gelfand,et al.  Comparative Genomics and Evolution of Alternative Splicing: The Pessimists′ Science , 2007 .