Elsevier

Gene

Volume 241, Issue 1, 4 January 2000, Pages 3-17
Gene

Review
Isochores and the evolutionary genomics of vertebrates

https://doi.org/10.1016/S0378-1119(99)00485-0Get rights and content

Abstract

The nuclear genomes of vertebrates are mosaics of isochores, very long stretches (≫300 kb) of DNA that are homogeneous in base composition and are compositionally correlated with the coding sequences that they embed. Isochores can be partitioned in a small number of families that cover a range of GC levels (GC is the molar ratio of guanine+cytosine in DNA), which is narrow in cold-blooded vertebrates, but broad in warm-blooded vertebrates. This difference is essentially due to the fact that the GC-richest 10–15% of the genomes of the ancestors of mammals and birds underwent two independent compositional transitions characterized by strong increases in GC levels. The similarity of isochore patterns across mammalian orders, on the one hand, and across avian orders, on the other, indicates that these higher GC levels were then maintained, at least since the appearance of ancestors of warm-blooded vertebrates. After a brief review of our current knowledge on the organization of the vertebrate genome, evidence will be presented here in favor of the idea that the generation and maintenance of the GC-richest isochores in the genomes of warm-blooded vertebrates were due to natural selection.

Introduction

In this review, I will concentrate on investigations from our laboratory. I will first present a summary of our current knowledge on the sequence organization of the human genome which is typical of most mammalian genomes, and shares its basic properties with avian genomes), and of the genomes of cold-blooded vertebrates. I will then describe the compositional transitions which occurred when warm-blooded vertebrates emerged from reptiles and the maintenance of the new compositional patterns in mammals and birds, respectively. Finally I will discuss the general implications of these results.

This order of presentation, which reflects the chronological development of our work, is also a logical one. Indeed, the present organization of the human genome is the result of a long evolutionary process, which has taken close to 500 million years since the earliest vertebrates. Understanding this genome organization provides the best starting point for asking precise questions about its evolutionary origin.

Section snippets

Sequence organization of the mammalian genome

The experimental approach that we followed was based on the study of the most elementary property of the genome, its nucleotide composition, more precisely the frequencies of nucleotides in DNA molecules. This approach (reviewed by Bernardi et al., 1973), the only one that was possible before DNA sequencing became available, still is extremely useful. Indeed, it could be, and was, very easily moved from DNA molecules to DNA sequences.

Over 30 years ago, we found that DNA–silver complexes could be

Compositional correlations

An obvious question is whether there is any correlation between the compositional patterns of coding sequences (which represent as little as 3% of the genome in vertebrates) and the compositional patterns of DNA fragments (97% of which are formed by intergenic sequences and introns). Another question is whether there is any correlation within genes between the composition of the exons and that of the introns. The answer to both questions is yes.

Indeed, linear correlations hold between the GC

Gene distribution and gene spaces

The correlation between GC3 levels of coding sequences and GC levels of isochores (Fig. 3c) is especially important, because it allows the positioning of the distribution profile of coding sequences relative to that of DNA fragments, the CsCl profile. In turn, this allowed us to estimate the relative gene density by dividing the percentage of genes located in given GC intervals by the percentage of DNA located in the same intervals. Since it had been tacitly assumed that genes were uniformly

The major compositional transitions of the vertebrate genomes

The compositional pattern just described for the human genome is basically shared by all warm-blooded vertebrates (Bernardi et al., 1997, Mouchiroud and Bernardi, 1993, Sabeur et al., 1993). In contrast, cold-blooded vertebrates are endowed with genomes characterized by a much lower level of compositional heterogeneity and by the fact that, as a general rule, they do not reach the high GC levels attained by the genomes of warm-blooded vertebrates (Bernardi and Bernardi, 1990a, Bernardi and

The causes of compositional transitions in vertebrate genomes

An obvious question concerns the cause(s) (i) of the compositional genome transitions; and (ii) of the maintenance of the new compositional patterns. The original explanation for the compositional transition (Bernardi and Bernardi, 1986) was that natural selection was responsible. Natural selection, the differential multiplication of mutant types, occurs through the elimination of organisms with deleterious mutations (negative selection) and, very rarely, via the preferential propagation of

The maintenance of the compositional patterns of warm-blooded vertebrates

The maintenance of the compositional pattern of mammalian genes was initially investigated by an intergenic analysis comparing the average composition of synonymous and non-synonymous positions of orthologous genes. It was found that the frequencies of synonymous substitutions were correlated with the frequencies of non-synonymous substitutions (a point already reported by other authors) and gene-specific (Mouchiroud et al., 1995), suggesting that synonymous and non-synonymous rates are under

Alternative explanations: mutational bias

Several alternative explanations have been proposed to account for the compositional transitions and their maintenance. These comprise biases in DNA repair (Filipski, 1987), mutational bias (Sueoka, 1988), changes in nucleotide pools during DNA replication (Wolfe et al., 1989) and recombination (Eyre-Walker, 1993). Since biases in DNA repair, changes in nucleotide pools and recombination have already been ruled out as valid explanations (see Bernardi et al., 1993, Bernardi et al., 1988,

Objections to selection

While a mutational bias can be ruled out as the cause of the formation and maintenance of GC-rich isochores in warm-blooded vertebrates (a point further stressed by results concerning the murid pattern; see below), objections have been raised against the selectionist interpretation. They can, however, be answered.

(i) The low GC levels of some thermophilic bacteria do not contradict, as claimed (Galtier and Lobry, 1997), the selectionist interpretation discussed above. Indeed, different

Conclusions

In conclusion, recent results from our laboratories support the original working hypothesis (Bernardi and Bernardi, 1986) that natural selection underlies the regional compositional changes accompanying the transition from cold- to warm-blooded vertebrates and maintain the novel, high GC levels attained (Alvarez-Valin et al., 1998, Alvarez-Valin et al., 2000, Cacciò et al., 1994, Chiusano et al., 1999, Zoubak et al., 1995). They considerably refine the original idea and have led to some new

Acknowledgments

The author thanks the European Union for a Scholarship from the Senior Research Grant Programme in Japan and Professor Takashi Gojobori for his warm hospitality at the Center for Information Biology, National Institute of Genetics, Mishima 411, Japan, as well as Drs. Takashi Gojobori, Toshimichi Ikemura and Tomoko Ohta for discussions. Thanks are also due to all the co-authors of the primary publications, to Fernando Alvarez-Valin, Marcos Antezana, Giacomo Bernardi, Nicolas Carels, Maria Luisa

References (103)

  • J. Filipski

    Correlation between molecular clock ticking, codon usage fidelity of DNA repair, chromosome banding and chromatin compactness in germline cells

    FEBS Lett.

    (1987)
  • J. Filipski et al.

    An analysis of the bovine genome by Cs2SO4Ag+ density gradient centrifugation

    J. Mol. Biol.

    (1973)
  • E. Freese

    On the evolution of base composition of DNA

    J. Theor. Biol.

    (1962)
  • T. Fukagawa

    Characterization of the boundary region of long-range G+C% mosaic domains in the human MHC locus: pseudoautosomal boundary-like sequence near the boundary

    Genomics

    (1995)
  • X. Gu et al.

    Higher rates of amino acid substitution in rodents than in humans

    Mol. Phylogenet. Evol.

    (1992)
  • T. Ikemura et al.

    Global variation in G+C content along vertebrate genome DNA

    J. Mol. Biol.

    (1988)
  • T. Ikemura et al.

    Giant G+C% mosaic structures of the human genome found by arrangement of genebank human DNA sequences according to genetic positions

    Genomics

    (1990)
  • K. Jabbari et al.

    CpG doublets, CpG islands and Alu repeats in long human DNA sequences from different isochore families

    Gene

    (1998)
  • K. Jabbari et al.

    Evolutionary changes in CpG and methylation levels in the genome of vertebrates

    Gene

    (1997)
  • B.S. Kerem et al.

    Mapping of DNAase I sensitive regions of mitotic chromosomes

    Cell

    (1984)
  • J. Kyte et al.

    A simple method for displaying hydropathic character of a protein

    J. Mol. Biol.

    (1982)
  • F. Larsen et al.

    CpG islands as gene markers in the human genome

    Genomics

    (1992)
  • G. Macaya et al.

    An approach to the organization of eukaryotic genomes at a macromolecular level

    J. Mol. Biol.

    (1976)
  • D. Mouchiroud et al.

    The distribution of genes in the human genome

    Gene

    (1991)
  • G. Pilia et al.

    Isochores and CpG islands in YAC contigs in human X26.1-qter

    Genomics

    (1993)
  • A.V. Rynditch et al.

    The regional integration of retroviral sequences into the mosaic genomes of mammals

    Gene

    (1998)
  • S. Saccone et al.

    Identification of the gene-richest bands in human chromosomes

    Gene

    (1996)
  • R. Stephens et al.

    Gene organisation, sequence variation and isochore structure at the centromeric boundary of the human MHC

    J. Mol. Biol.

    (1999)
  • H. Taguchi et al.

    A chaperonin from a thermophilie bacterium Thermus thermophylus, that controls refolding of several thermophilic enzymes

    J. Biol. Chem.

    (1991)
  • J. Tazi et al.

    Alternative chromatin structure at CpG islands

    Cell

    (1990)
  • J.P. Thiery et al.

    An analysis of eukaryotic genomes by density gradient centrifugation

    J. Mol. Biol.

    (1976)
  • A. Wada et al.

    Local stability of DNA and RNA secondary structure and its relation to biological function

    Prog. Biophys. Mol. Biol.

    (1986)
  • B. Aı̈ssani et al.

    The compositional properties of human genes

    J. Mol. Evol.

    (1991)
  • H. Akashi

    Synonymous codon usage in Drosophila melanogaster: natural selection and translation accuracy

    Genetics

    (1994)
  • F. Alvarez-Valin et al.

    Synonymous and nonsynonymous substitutions in mammalian genes: intragenic correlation

    J. Mol. Evol.

    (1998)
  • F. Alvarez-Valin et al.

    Non-random spatial distribution of synonymous substitutions in the leishmanial GP63 gene

    Genetics

    (2000)
  • G. Bernardi

    Chromatography of nucleic acids on hydroxyapatite

    Nature (Lond.)

    (1965)
  • G. Bernardi

    The isochore organization of the human genome

    Annu. Rev. Genet.

    (1989)
  • G. Bernardi

    Le génome des vertébrés: organisation, fonction et evolution

    Biofutur

    (1990)
  • G. Bernardi

    Genome organization and species formation in vertebrates

    J. Mol. Evol.

    (1993)
  • G. Bernardi

    The vertebrate genome: isochores and evolution

    Mol. Biol. Evol.

    (1993)
  • G. Bernardi

    The human genome: organization and evolutionary history

    Annu. Rev. Genet.

    (1995)
  • G. Bernardi et al.

    Compositional constraints and genome evolution

    J. Mol. Evol.

    (1986)
  • G. Bernardi et al.

    Compositional patterns in the nuclear genomes of cold-blooded vertebrates

    J. Mol. Evol.

    (1990)
  • G. Bernardi et al.

    Compositional transitions in the nuclear genomes of cold-blooded vertebrates

    J. Mol. Evol.

    (1990)
  • G. Bernardi et al.

    Compositional properties of nuclear genes from cold-blooded vertebrates

    J. Mol. Evol.

    (1991)
  • G. Bernardi et al.

    Deoxyribonucleases: specificity and use in nucleotide sequence studies

    Nature New Biol.

    (1973)
  • G. Bernardi et al.

    The major compositional transitions in the vertebrate genome

    J. Mol. Evol.

    (1997)
  • G. Bernardi et al.

    Silent substitutions in mammalian genomes and their evolutionary implications

    J. Mol. Evol.

    (1993)
  • G. Bernardi et al.

    Compositional patterns in vertebrate genomes: conservation and change in evolution

    J. Mol. Evol.

    (1988)
  • Cited by (457)

    View all citing articles on Scopus
    View full text