Elsevier

Gene

Volume 238, Issue 1, 30 September 1999, Pages 103-114
Gene

Review
Genome evolution and the evolution of exon-shuffling — a review

https://doi.org/10.1016/S0378-1119(99)00228-0Get rights and content

Abstract

Recent studies on the genomes of protists, plants, fungi and animals confirm that the increase in genome size and gene number in different eukaryotic lineages is paralleled by a general decrease in genome compactness and an increase in the number and size of introns. It may thus be predicted that exon-shuffling has become increasingly significant with the evolution of larger, less compact genomes. To test the validity of this prediction, we have analyzed the evolutionary distribution of modular proteins that have clearly evolved by intronic recombination. The results of this analysis indicate that modular multidomain proteins produced by exon-shuffling are restricted in their evolutionary distribution. Although such proteins are present in all major groups of metazoa from sponges to chordates, there is practically no evidence for the presence of related modular proteins in other groups of eukaryotes. The biological significance of this difference in the composition of the proteomes of animals, fungi, plants and protists is best appreciated when these modular proteins are classified with respect to their biological function. The majority of these proteins can be assigned to functional categories that are inextricably linked to multicellularity of animals, and are of absolute importance in permitting animals to function in an integrated fashion: constituents of the extracellular matrix, proteases involved in tissue remodelling processes, various proteins of body fluids, membrane-associated proteins mediating cell–cell and cell–matrix interactions, membrane associated receptor proteins regulating cell–cell communications, etc. Although some basic types of modular proteins seem to be shared by all major groups of metazoa, there are also groups of modular proteins that appear to be restricted to certain evolutionary lineages.

In summary, the results suggest that exon-shuffling acquired major significance at the time of metazoan radiation. It is interesting to note that the rise of exon-shuffling coincides with a spectacular burst of evolutionary creativity: the Big Bang of metazoan radiation. It seems probable that modular protein evolution by exon-shuffling has contributed significantly to this accelerated evolution of metazoa, since it facilitated the rapid construction of multidomain extracellular and cell surface proteins that are indispensable for multicellularity.

Introduction

Shortly after the discovery of split genes, it was realized that the existence of introns may have dramatic consequences on protein evolution (Gilbert, 1978). It was pointed out that recombination within introns could assort exons independently, and middle repetitious sequences in introns may create hotspots for recombination to shuffle the exonic sequences.

The presence of introns in most eukaryotic protein-coding genes and their absence from prokaryotes was explained by two types of hypotheses. The ‘introns early’ hypotheses assumed that introns and RNA splicing are the relics of the RNA world and the ‘genes in pieces’ organization of the eukaryotic genome is the original, ancestral form (Darnell, 1978, Darnell and Doolittle, 1986, Doolittle, 1978, Gilbert, 1986). According to this view, eukaryotes retained introns and the genetic plasticity of the primitive ancestors of all cells. On the other hand, bacteria gained increased efficiency by eliminating their introns. Supporters of the introns-early hypotheses assume that the introns of all protein-coding genes reflect the assembly of these genes from pieces; that exons do indeed correspond to building blocks (α-helices, β-sheets, etc.) from which all the genes were assembled by intronic recombination (Gilbert and Glynias, 1993).

In contrast with this, the ‘introns late’ theories suggest that the prokaryotic genes resemble the ancestral ones and that the introns were inserted later in genes of eukaryotes (Cavalier-Smith, 1985, Cech, 1985, Crick, 1979, Orgel and Crick, 1980, Sharp, 1985). In fact, it is now obvious that the exon–intron structure of eukaryotic protein-coding genes is not static: introns are continually inserted into (as well as removed from) genes. The actual mechanisms of insertion, propagation of some self-splicing introns have been analyzed in detail and the mechanisms responsible for the insertion of spliceosomal introns are also becoming clear (Belfort, 1991, Belfort, 1993, Dujon, 1989, Grivell, 1994, Lambowitz and Belfort, 1989, Lambowitz, 1993, Morl and Schmelzer, 1990, Mueller et al., 1993, Patthy, 1995, Perlman and Butow, 1989).

Since introns themselves are subject to evolution, it is clear that exon-shuffling has been evolving parallel with the evolution of introns. We have argued previously that the introns suitable for exon-shuffling appeared at a relatively late stage of evolution; therefore, exon-shuffling could not play a major role in the construction of ancient proteins (Patthy, 1987, Patthy, 1991a, Patthy, 1991b). The self-splicing introns of the RNA world that could be present at the time the first proteins were formed are practically unsuitable for exon-shuffling by intronic recombination: such self-splicing introns encode an essential function, therefore their sequence is not tolerant to intronic recombination (Patthy, 1987, Patthy, 1991a, Patthy, 1991b, Patthy, 1994). Exon-shuffling could become significant only with the appearance of spliceosomal introns: these introns play a negligible role in their own excision, therefore intronic recombination is less likely to produce recombinant introns that are deficient in splicing. Furthermore, the nonessential parts of spliceosomal introns could accommodate large segments of middle repetitious sequences, further increasing the chances of intronic recombination. Since spliceosomal introns evolved relatively recently from group II self-splicing introns (Cavalier-Smith, 1991, Cech, 1986, Copertino and Hallick, 1993, Jacquier, 1990, Saldanha et al., 1993, Sharp, 1994) and are restricted in their evolutionary distribution (Cavalier-Smith, 1991, Logsdon, 1991, Palmer and Logsdon, 1991) exon-shuffling could play a major role only in the construction of ‘younger’ proteins (Patthy, 1987, Patthy, 1991a, Patthy, 1991b, Patthy, 1994, Patthy, 1995, Patthy, 1996).

In the present review I wish to emphasize that the significance of exon-shuffling increased parallel with the evolution of less compact genomes. The basis of this correlation is that the number and size of introns and the proportion of repetitive sequences in introns increases parallel with the decrease of genome compactness, therefore the chances of exon-shuffling by intronic recombination also increase. Analysis of the evolutionary distribution of proteins that were clearly assembled from modules by intronic recombination suggests that exon-shuffling became significant at the time of the appearance of the first multicellular animals, and that the rise of exon-shuffling could in fact contribute to the explosive nature of metazoan radiation.

Section snippets

Introns and evolution of genome compactness

In the past few years, the complete sequences of the genomes of several Eubacteria (Escherichia coli, Bacillus subtilis, Haemophilus influenzae, Borrelia burgdorferi, Mycoplasma pneumoniae, Mycoplasma genitalium, etc.), Archaea (Methanococcus jannaschii, Archaeoglobus fulgidus, etc.), a unicellular eukaryote (Saccharomyces cerevisiae), and a multicellular animal (Caenorhabditis elegans) have been determined, and significant progress has also been made on the genome of a protozoan parasite (

References (89)

  • K.R. Cho et al.

    The DCC gene: structural analysis and mutations in colorectal carcinomas

    Genomics

    (1994)
  • D.W. Copertino et al.

    Group II and group III introns of twintrons: potential relationships with nuclear pre-mRNA introns

    Trends Biochem. Sci.

    (1993)
  • B. Dujon

    Group I introns as mobile genetic elements: facts and mechanistic speculations

    Gene

    (1989)
  • G. Elgar et al.

    Small is beautiful: comparative genomics with the pufferfish (Fugu rubripes)

    Trends Genet.

    (1996)
  • W. Gilbert et al.

    On the ancient nature of introns

    Gene

    (1993)
  • L.A. Grivell

    Invasive introns

    Curr. Biol.

    (1994)
  • A. Jacquier

    Self-splicing group II and nuclear pre-mRNA introns: how similar are they?

    Trends Biochem. Sci.

    (1990)
  • T. Kallunki et al.

    Structure of the human laminin B2 chain gene reveals extensive divergence from the laminin B1 chain gene

    J. Biol. Chem.

    (1991)
  • AM. Lambowitz et al.

    Infectious introns

    Cell

    (1989)
  • A.C.R. Martin et al.

    Protein folds and functions

    Structure

    (1998)
  • J.H. McVey et al.

    Characterization of the mouse SPARC/Osteonectin gene

    J. Biol. Chem.

    (1988)
  • M. Morl et al.

    Integration of group II intron bl1 into a foreign RNA by reversal of the self-splicing reaction in vitro

    Cell

    (1990)
  • D. Mouchiroud et al.

    The distribution of genes in the human genome

    Gene

    (1991)
  • T. Oohashi et al.

    Isolation and structure of the COL4A6 gene encoding the human α6(IV) collagen chain and comparison with other type IV collagen genes

    J. Biol. Chem.

    (1995)
  • J.D. Palmer et al.

    The recent origins of introns

    Curr. Opin. Genet. Dev.

    (1991)
  • L. Patthy

    Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules

    Cell

    (1985)
  • L. Patthy

    Intron-dependent evolution: preferred types of exons and introns

    FEBS Lett.

    (1987)
  • L. Patthy

    Detecting distant homologies of mosaic proteins. Analysis of the sequences of thrombomodulin, thrombospondin, complement components C9, C8α and C8β, vitronectin and plasma cell membrane glycoprotein PC-1

    J. Mol. Biol.

    (1988)
  • L. Patthy

    Modular exchange principles in proteins

    Curr. Opin. Struct. Biol.

    (1991)
  • L. Patthy

    Modular design of proteases of coagulation, fibrinolysis and complement activation: implications for protein engineering and structure function studies

    Methods Enzymol.

    (1993)
  • L. Patthy

    Exons and introns

    Curr. Opin. Struct. Biol.

    (1994)
  • L. Patthy

    Exon shuffling and other ways of module exchange

    Matrix Biol.

    (1996)
  • G.M. Rubin

    The Drosophila Genome Project: a progress report

    Trends Genet.

    (1998)
  • M.P. Sarras et al.

    Cloning and biological function of laminin in Hydra vulgaris

    Dev. Biol.

    (1994)
  • P.A. Sharp

    On the origin of RNA splicing and introns

    Cell

    (1985)
  • P.A. Sharp

    Split genes and RNA splicing

    Cell

    (1994)
  • F. Steiner et al.

    M band proteins myomesin and skelemin are encoded by the same gene: analysis of its organization and expression

    Genomics

    (1999)
  • K. Takahara et al.

    Structural organization and genetic localization of the human bone morphogenetic protein 1/mamalian tolloid gene

    Genomics

    (1995)
  • R. Vuolteenaho et al.

    Structure of the human laminin B1 chain gene

    J. Biol. Chem.

    (1990)
  • G.S.H. Yeo et al.

    Cloning and sequencing of complement component C9 and its linkage to DOC-2 in the pufferfish Fugu rubripes

    Gene

    (1997)
  • X. Zhang et al.

    Structure of the human laminin a2-chain gene (LAMA2) which is affected in congenital muscular dystrophy

    J. Biol. Chem.

    (1996)
  • M. Belfort

    An expanding universe of introns

    Science

    (1993)
  • F.R. Blattner et al.

    The complete genome sequence of Escherichia coli K-12

    Science

    (1997)
  • M. Blaxter

    Caenorhabditis elegans is a nematode

    Science

    (1998)
  • Cited by (0)

    Presented at the Symposium on Evolutionary Genomics, Puntarenas, Costa Rica, 11–15 January 1999.

    View full text