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At least 19 recordsLinked to original sources
PubMed2004

Isochore structures in the genome of the plant Arabidopsis thaliana.

Arabidopsis thaliana is an important model system for the study of plant biology. We have analyzed the complete genome sequences of Arabidopsis by using a newly developed windowless method for the GC content computation, the cumulative GC profile. It is shown that the Arabidopsis genome is organized into a mosaic structure of isochores. All the centromeric regions are located in GC-rich isochores, called centromere-isochores, which are characterized by a high GC content but low gene and T-DNA insertion densities. This characteristic distinguishes centromere-isochores from the other class of GC-rich isochores, called GC-isochores, which have high gene and T-DNA insertion densities. Consequently, 15 isochores have been identified, i.e., 7 AT-isochores, 3 GC-isochores, and 5 centromere-isochores. The genes in centromere-isochores, which have the highest GC content, have much shorter intron lengths and lower intron numbers, compared to those of the other two types. There is also considerable difference in the numbers and lengths of transposable elements (TEs) between AT and GC-isochores, i.e., the TE number (length) of AT-isochores is 6.3 (7.3) times that of GC-isochores. It is generally believed that TEs are accumulated in the regions surrounding the centromeres. However, within these TE-rich regions, there are regions of extremely low TE numbers (TE deserts), which correspond to the positions of centromere-isochores. In addition, a heterochromatic knob is located at the boundary of an AT-isochore. Furthermore, we show that the differences in GC content among isochores are mainly due to the GC content variation of introns, the third codon positions and intergenic regions.

Analysis of Variance↗
PubMed2002

Isochore chromosome maps of the human genome.

The human genome is a mosaic of isochores, which are long DNA segments (z.Gt;300 kbp) relatively homogeneous in G+C. Human isochores were first identified by density-gradient ultracentrifugation of bulk DNA, and differ in important features, e.g. genes are found predominantly in the GC-richest isochores. Here, we use a reliable segmentation method to partition the longest contigs in the human genome draft sequence into long homogeneous genome regions (LHGRs), thereby revealing the isochore structure of the human genome. The advantages of the isochore maps presented here are: (1) sequence heterogeneities at different scales are shown in the same plot; (2) pair-wise compositional differences between adjacent regions are all statistically significant; (3) isochore boundaries are accurately defined to single base pair resolution; and (4) both gradual and abrupt isochore boundaries are simultaneously revealed. Taking advantage of the wide sample of genome sequence analyzed, we investigate the correspondence between LHGRs and true human isochores revealed through DNA centrifugation. LHGRs show many of the typical isochore features, mainly size distribution, G+C range, and proportions of the isochore classes. The relative density of genes, Alu and long interspersed nuclear element repeats and the different types of single nucleotide polymorphisms on LHGRs also coincide with expectations in true isochores. Potential applications of isochore maps range from the improvement of gene-finding algorithms to the prediction of linkage disequilibrium levels in association studies between marker genes and complex traits. The coordinates for the LHGRs identified in all the contigs longer than 2 Mb in the human genome sequence are available at the online resource on isochore mapping: http://bioinfo2.ugr.es/isochores.

Alu Elements↗
PubMed2001

Isochore chromosome maps of eukaryotic genomes.

Analytical DNA ultracentrifugation revealed that eukaryotic genomes are mosaics of isochores: long DNA segments (>>300 kb on average) relatively homogeneous in G+C. Important genome features are dependent on this isochore structure, e.g. genes are found predominantly in the GC-richest isochore classes. However, no reliable method is available to rigorously partition the genome sequence into relatively homogeneous regions of different composition, thereby revealing the isochore structure of chromosomes at the sequence level. Homogeneous regions are currently ascertained by plain statistics on moving windows of arbitrary length, or simply by eye on G+C plots. On the contrary, the entropic segmentation method is able to divide a DNA sequence into relatively homogeneous, statistically significant domains. An early version of this algorithm only produced domains having an average length far below the typical isochore size. Here we show that an improved segmentation method, specifically intended to determine the most statistically significant partition of the sequence at each scale, is able to identify the boundaries between long homogeneous genome regions displaying the typical features of isochores. The algorithm precisely locates classes II and III of the human major histocompatibility complex region, two well-characterized isochores at the sequence level, the boundary between them being the first isochore boundary experimentally characterized at the sequence level. The analysis is then extended to a collection of human large contigs. The relatively homogeneous regions we find show many of the features (G+C range, relative proportion of isochore classes, size distribution, and relationship with gene density) of the isochores identified through DNA centrifugation. Isochore chromosome maps, with many potential applications in genomics, are then drawn for all the completely sequenced eukaryotic genomes available.

Animals↗
PubMed2005

GC composition of the human genome: in search of isochores.

The isochore theory, proposed nearly three decades ago, depicts the mammalian genome as a mosaic of long, fairly homogeneous genomic regions that are characterized by their guanine and cytosine (GC) content. The human genome, for instance, was claimed to consist of five distinct isochore families: L1, L2, H1, H2, and H3, with GC contents of <37%, 37%-42%, 42%-47%, 47%-52%, and >52%, respectively. In this paper, we address the question of the validity of the isochore theory through a rigorous sequence-based analysis of the human genome. Toward this end, we adopt a set of six attributes that are generally claimed to characterize isochores and statistically test their veracity against the available draft sequence of the complete human genome. By the selection criteria used in this study: distinctiveness, homogeneity, and minimal length of 300 kb, we identify 1,857 genomic segments that warrant the label "isochore." These putative isochores are nonuniformly scattered throughout the genome and cover about 41% of the human genome. We found that a four-family model of putative isochores is the most parsimonious multi-Gaussian model that can be fitted to the empirical data. These families, however, are GC poor, with mean GC contents of 35%, 38%, 41%, and 48% and do not resemble the five isochore families in the literature. Moreover, due to large overlaps among the families, it is impossible to classify genomic segments into isochore families reliably, according to compositional properties alone. These findings undermine the utility of the isochore theory and seem to indicate that the theory may have reached the limits of its usefulness as a description of genomic compositional structures.

Base Composition↗
PubMed1997

Evolution of isochores in rodents.

The most deviant isochore pattern within mammals was found in rat and mouse; most other mammals possess a different kind of isochore organization called the "general pattern." However, isochore patterns remain largely unknown in rodents other than mouse and rat. To investigate the taxonomic distribution of isochore patterns in rodents, we sequenced the nuclear gene LCAT (lecithin:cholesterol acyltransferase) from 17 rodents species (bringing the total of LCAT sequences in rodent to 19) and compared their GC contents at third codon positions and in introns. We also analyzed an extensive sequence database from rodents other than rat and mouse. All murid LCAT sequences are much poorer in GC than all nonrodent LCAT sequences, and the hamster sequence database shows exactly the same isochore pattern as rat and mouse. Thus, all murids share the same special isochore pattern--GC homogenization. LCAT sequences are GC-poor in hystricomorphs too, but the guinea pig sequence database indicates that large changes in GC content occur without an overall modification of the isochore pattern. This novel mode of isochore evolution is called GC reordering. LCAT sequences also show that the evolution of isochores in sciurids and glirids is nonconservative in comparison with that in nonrodents. Thus, at least two novel patterns of isochore evolution were found. No rodent investigated to date shared the general mammalian pattern.

Animals↗
PubMed2005

Detection of nucleolar organizer and mitochondrial DNA insertion regions based on the isochore map of Arabidopsis thaliana.

Eukaryotic genomes are composed of isochores, i.e. long sequences relatively homogeneous in GC content. In this paper, the isochore structure of Arabidopsis thaliana genome has been studied using a windowless technique based on the Z curve method and intuitive curves are drawn for all the five chromosomes. Using these curves, we can calculate the GC content at any resolution, even at the base level. It is observed that all the five chromosomes are composed of several GC-rich and AT-rich regions alternatively. Usually, these regions, named 'isochore-like regions', have large fluctuations in the GC content. Five isochores with little fluctuations are also observed. Detailed analyses have been performed for these isochores. A GC-rich 'isochore-like region' and a GC-isochore in chromosome II and IV, respectively, are the nucleolar organizer regions (NORs), and genes located in the two regions prefer to use GC-ending codons. Another GC-isochore located in chromosome II is a mitochondrial DNA insertion region, the position and size of this region is precisely predicted by the current method. The amino acid usage and codon preference of genes in this organellar-to-nuclear transfer region show significant difference from other regions. Moreover, the centromeres are located in GC-rich 'isochore-like regions' in all the five chromosomes. The current method can provide a useful tool for analyzing whole genomic sequences of eukaryotes.

AT Rich Sequence↗
PubMed1993

Correlations between isochores and chromosomal bands in the human genome.

The human genome is made up of long DNA segments, the isochores, which are compositionally homogeneous and can be subdivided into a small number of families characterized by different G+C levels. Chromosome in situ suppression hybridization (in which excess unlabeled human DNA is added to suppress hybridization of repeated sequences present in the probe, enabling enhanced observation of single-copy sequences) of DNA fractions characterized by an increasing G+C level was carried out to determine the distribution of "single-copy" sequences corresponding to isochore families L1+L2, H1, H2, and H3 on metaphase chromosomes. This produced a banding pattern progressing from a relatively diffuse staining to an R-banding, to a T-banding. More specifically, our results showed that (i) T-bands are formed by the G+C-richest isochores of the H3 family and by part of the G+C-rich isochores of the H1 and H2 families (with a predominance of the latter); (ii) R'-bands (namely, R-bands exclusive of T-bands) are formed to almost equal extents by G+C-rich isochores of the H1 families (with a minor contribution of the H2 and H3 families) and by G+C-poor isochores of the L1+L2 families; (iii) G-bands essentially consist of G+C-poor isochores from the L1+L2 families, with a minor contribution of isochores from the H1 family. These results not only clarify the correlations between DNA base composition and chromosomal bands but also provide information on the distribution of genes in chromosomes, gene concentration increasing with the G+C levels of isochores.

Base Composition↗
PubMed2005

The biased distribution of Alus in human isochores might be driven by recombination.

Alu retrotransposons do not show a homogeneous distribution over the human genome but have a higher density in GC-rich (H) than in AT-rich (L) isochores. However, since they preferentially insert into the L isochores, the question arises: What is the evolutionary mechanism that shifts the Alu density maximum from L to H isochores? To disclose the role played by each of the potential mechanisms involved in such biased distribution, we carried out a genome-wide analysis of the density of the Alus as a function of their evolutionary age, isochore membership, and intron vs. intergene location. Since Alus depend on the retrotransposase encoded by the LINE1 elements, we also studied the distribution of LINE1 to provide a complete evolutionary scenario. We consecutively check, and discard, the contributions of the Alu/LINE1 competition for retrotransposase, compositional matching pressure, and Alu overrepresentation in introns. In analyzing the role played by unequal recombination, we scan the genome for Alu trimers, a direct product of Alu-Alu recombination. Through computer simulations, we show that such trimers are much more frequent than expected, the observed/expected ratio being higher in L than in H isochores. This result, together with the known higher selective disadvantage of recombination products in H isochores, points to Alu-Alu recombination as the main agent provoking the density shift of Alus toward the GC-rich parts of the genome. Two independent pieces of evidence-the lower evolutionary divergence shown by recently inserted Alu subfamilies and the higher frequency of old stand-alone Alus in L isochores-support such a conclusion. Other evolutionary factors, such as population bottlenecks during primate speciation, may have accelerated the fast accumulation of Alus in GC-rich isochores.

Algorithms↗
PubMed2002

Are isochore sequences homogeneous?

Three statistical/mathematical analyses are carried out on isochore sequences: spectral analysis, analysis of variance, and segmentation analysis. Spectral analysis shows that there are GC content fluctuations at different length scales in isochore sequences. The analysis of variance shows that the null hypothesis (the mean value of a group of GC contents remains the same along the sequence) may or may not be rejected for an isochore sequence, depending on the subwindow sizes at which GC contents are sampled, and the window size within which group members are defined. The segmentation analysis shows that there are stronger indications of GC content changes at isochore borders than within an isochore. These analyses support the notion of isochore sequences, but reject the assumption that isochore sequences are homogeneous at the base level. An isochore sequence may pass a homogeneity test when GC content fluctuations at smaller length scales are ignored or averaged out.

Analysis of Variance↗
PubMed2003

An isochore map of the human genome based on the Z curve method.

The distribution of the G+C content in the human genome has been studied by using a windowless technique derived from the Z curve method. The most important findings presented in this paper are twofold. First, abrupt variations of the G+C content along human chromosome sequences are the main variation patterns of G+C content. It is found that at some sites, the G+C content undergoes abrupt changes from a G+C-rich region to a G+C-poor region alternatively and vice versa. Second, it is shown that long domains with relatively homogeneous G+C content along each chromosome do exist. These domains are thought to be isochores, which usually have sharp boundaries. Consequently, 56 isochores longer than 3 Mb have been identified in chromosomes 1-22, X and Y. Boundaries, size and G+C content of each isochore identified are listed in detail. As an example to demonstrate the power of the method, the boundary between the Classes III and II isochores of the MHC sequence has been determined and found to be at 2,477,936, which is in good agreement with the experimental evidence. A homogeneity index is introduced to measure the homogeneity of G+C content in isochores. We emphasize that the homogeneity of G+C content is relative. The isochores in which the G+C content keeps absolutely constant do not exist. Isochore structures appear to be a basic organization of the human genome. Due to the relevance to many important biological functions, the clarification of isochore structures will provide much insight into the understanding of the human genome.

Algorithms↗
PubMed2006

Isochores exhibit evidence of genes interacting with the large-scale genomic environment.

The genomes of mammals and birds can be partitioned into megabase-long regions, termed isochores, with consistently high, or low, average C + G content. Isochores with high CG contain a mixture of CG-rich and AT-rich genes, while high-AT isochores contain predominantly AT-rich genes. The two gene populations in the high-CG isochores are functionally distinguishable by statistical analysis of their gene ontology categories. However, the aggregate of the two populations in CG isochores is not statistically distinct from AT-rich genes in AT isochores. Genes tend to be located at local extrema of composition within the isochores, indicating that the CG-enriching mechanism acted differently when near to genes. On the other hand, maximum-likelihood reconstruction of molecular phylogenetic trees shows that branch lengths (evolutionary distances) for third codon positions in CG-rich genes are not substantially larger than those for AT-rich genes. In the context of neutral mutation theory this argues against any strong positive selection. Disparate features of isochores might be explained by a model in which about half of all genes functionally require AT richness, while, in warm-blooded organisms, about half the genome (in large coherent blocks) acquired a strong bias for mutations to CG. Using mutations in CG-rich genes as convenient indicators, we show that approximately 20% of amino acids in proteins are broadly substitutable, without regard to chemical similarity.

Animals↗
PubMed1995

Statistical analysis of vertebrate sequences reveals that long genes are scarce in GC-rich isochores.

We compared the exon/intron organization of vertebrate genes belonging to different isochore classes, as predicted by their GC content at third codon position. Two main features have emerged from the analysis of sequences published in GenBank: (1) genes coding for long proteins (i.e., > or = 500 aa) are almost two times more frequent in GC-poor than in GC-rich isochores; (2) intervening sequences (= sum of introns) are on average three times longer in GC-poor than in GC-rich isochores. These patterns are observed among human, mouse, rat, cow, and even chicken genes and are therefore likely to be common to all warm-blooded vertebrates. Analysis of Xenopus sequences suggests that the same patterns exist in cold-blooded vertebrates. It could be argued that such results do not reflect the reality because sequence databases are not representative of entire genomes. However, analysis of biases in GenBank revealed that the observed discrepancies between GC-rich and GC-poor isochores are not artifactual, and are probably largely underestimated. We investigated the distribution of microsatellites and interspersed repeats in introns of human and mouse genes from different isochores. This analysis confirmed previous studies showing that L1 repeats are almost absent from GC-rich isochores. Microsatellites and SINES (Alu, B1, B2) are found at roughly equal frequencies in introns from all isochore classes. Globally, the presence of repeated sequences does not account for the increased intron length in GC-poor isochores. The relationships between gene structure and global genome organization and evolution are discussed.

Animals↗
PubMed2006

A computational prediction of isochores based on hidden Markov models.

Mammalian genomes are organised into a mosaic of regions (in general more than 300 kb in length), with differing, relatively homogeneous G+C contents. The G+C content is the basic characteristic of isochores, but they have also been associated with many other biological properties. For instance, the genes are more compact and their density is highest in G+C rich isochores. Various ways of locating isochores in the human genome have been developed, but such methods use only the base composition of the DNA sequences. The present paper proposes a new method, based on a hidden Markov model, which takes into account several of the biological properties associated with the isochore structure of a genome. This method leads to good segmentation of the human genome into isochores, and also permits a new analysis of the known heterogeneity of G+C rich isochores: most (60%) of the G+C poor genes embedded in G+C rich isochores have UTR sequences characteristic of G+C rich genes. This genomic feature is discussed in the context of both evolution and genome function.

5' Untranslated Regions↗
PubMed2004

Isochore structures in the mouse genome.

The distribution of the G+C content in the mouse genome has been studied using a windowless technique. We have found that: (i). Abrupt variations of the G+C content from a GC-rich region to a GC-poor region, and vice versa, occur frequently at some sites along the sequence of the mouse genome. (ii). Long domains with relatively homogeneous G+C content (isochores) exist, which usually have sharp boundaries. Consequently, 28 isochores longer than 1 Mb have been identified in the mouse genome. A homogeneity index was used to quantify the variations of the G+C content within isochores. The precise boundaries, sizes, and G+C contents of these isochores have been determined. The windowless technique for the G+C content computation was also used to analyze the DNA sequence containing the mouse MHC region, which has a GC-poor isochore. This isochore is located at the central part of the sequence with boundaries at 468459 and 812716 bp, where the sequence is extended from the centromeric end to the telomeric end. In addition, the analysis of a segment of the rat genome shows that the rat genome also has clear isochore structures.

Algorithms↗
PubMed1999

Isochore specificity of AUG initiator context of human genes.

The efficiency of AUG start codon recognition in translation initiation is modulated by its sequence context. Here we investigated a non-redundant set of 5914 human genes and show that this context is different in genes located in different isochores. In particular, of the two main consensus start sequences, RCCaugR is five-fold more represented than AARaugR in genes from the GC-rich H3 isochores compared to genes from the GC-poor L isochores. Furthermore, genes located in GC-rich isochores have shorter 5' UTRs and stronger avoidance of upstream AUG than genes located in GC-poor isochores. This suggests that genes requiring highly efficient translation are located in GC-rich isochores and genes requiring fine modulation of expression are located in GC-poor isochores. This is in agreement with independent data from the literature concerning the location of housekeeping and tissue-specific genes, respectively.

5' Untranslated Regions↗
PubMed1998

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

A computer analysis of 946 human DNA sequences larger than 50kb and representing about 118Mb of DNA has led to the following observations. (i) Positive correlations hold between CpG levels and the GC levels of isochores and coding sequences, as expected from previous results. (ii) The correlation between CpG levels and the GC levels of pseudogenes is characterized by lower CpG values (at comparable GC levels) and by a lower slope compared with the correlation with coding sequences; this finding suggests that an extensive methylation followed by deamination has taken place on CpG doublets from inactive genes leading to a further CpG shortage. (iii) The frequency of CpG islands in long human sequences increases with increasing GC and almost parallels gene frequency. (iv) The frequency of Alu sequences also increases with increasing GC, but attains a maximum in H2 isochores, in agreement with previous experimental data. (v) The ratio 5mC/CpG (namely, the methylation level over available sites) decreases with increasing GC levels of isochores. This decrease is due only to a small extent to the increase of (unmethylated) CpG islands in GC-rich isochores, and takes place in spite of the increase of strongly methylated Alu sequences in GC-rich isochores; this stresses the much lower relative methylation (5mC/CpG) of single-copy sequences located in GC-rich isochores relative to those located in GC-poor isochores. (vi) CpG levels of Alus and CpG islands are positively correlated with the GC levels of the long sequences in which they are located. (vii) The CpG levels of both Alus and CpG islands increase with their GC levels.

5-Methylcytosine↗
PubMed2002

Vanishing GC-rich isochores in mammalian genomes.

To understand the origin and evolution of isochores-the peculiar spatial distribution of GC content within mammalian genomes-we analyzed the synonymous substitution pattern in coding sequences from closely related species in different mammalian orders. In primate and cetartiodactyls, GC-rich genes are undergoing a large excess of GC --> AT substitutions over AT --> GC substitutions: GC-rich isochores are slowly disappearing from the genome of these two mammalian orders. In rodents, our analyses suggest both a decrease in GC content of GC-rich isochores and an increase in GC-poor isochores, but more data will be necessary to assess the significance of this pattern. These observations question the conclusions of previous works that assumed that base composition was at equilibrium. Analysis of allele frequency in human polymorphism data, however, confirmed that in the GC-rich parts of the genome, GC alleles have a higher probability of fixation than AT alleles. This fixation bias appears not strong enough to overcome the large excess of GC --> AT mutations. Thus, whatever the evolutionary force (neutral or selective) at the origin of GC-rich isochores, this force is no longer effective in mammals. We propose a model based on the biased gene conversion hypothesis that accounts for the origin of GC-rich isochores in the ancestral amniote genome and for their decline in present-day mammals.

Alleles↗
PubMed2005

How not to search for isochores: a reply to Cohen et Al.

In a recent paper in these pages, Cohen et al. search for isochores in the human genome, based on a system of attributes that they assign to isochores. The putative isochores that they find and choose for presentation are almost all below 45% GC and cover only about 41% of the genome. Closer inspection reveals that the authors' methodology systematically loses GC-rich isochores because it does not anticipate the considerable fluctuations and corresponding long-range correlations that characterize mammalian DNA and that are highest in GC-rich DNA. Thus, they over-fragment GC-rich isochores (and also many GC-poor isochores) beyond recognition.

Base Composition↗