ReviewIsochores and the evolutionary genomics of vertebrates
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
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