GC-Content evolution in bacterial genomes: The biased gene conversion hypothesis expands

The characterization of functional elements in genomes relies on the identification of the footprints of natural selection. In this quest, taking into account neutral evolutionary processes such as mutation and genetic drift is crucial because these forces can generate patterns that may obscure or mimic signatures of selection. In mammals, and probably in many eukaryotes, another such confounding factor called GC-Biased Gene Conversion (gBGC) has been documented. This mechanism generates patterns identical to what is expected under selection for higher GC-content, specifically in highly recombining genomic regions. Recent results have suggested that a mysterious selective force favouring higher GC-content exists in Bacteria but the possibility that it could be gBGC has been excluded. Here, we show that gBGC is probably at work in most if not all bacterial species. First we find a consistent positive relationship between the GC-content of a gene and evidence of intra-genic recombination throughout a broad spectrum of bacterial clades. Second, we show that the evolutionary force responsible for this pattern is acting independently from selection on codon usage, and could potentially interfere with selection in favor of optimal AU-ending codons. A comparison with data from human populations shows that the intensity of gBGC in Bacteria is comparable to what has been reported in mammals. We propose that gBGC is not restricted to sexual Eukaryotes but also widespread among Bacteria and could therefore be an ancestral feature of cellular organisms. We argue that if gBGC occurs in bacteria, it can account for previously unexplained observations, such as the apparent non-equilibrium of base substitution patterns and the heterogeneity of gene composition within bacterial genomes. Because gBGC produces patterns similar to positive selection, it is essential to take this process into account when studying the evolutionary forces at work in bacterial genomes

Tests of achromatic phase shifters performed on the SYNAPSE test bench: a progress report

The achromatic phase shifter (APS) is a component of the Bracewell nulling interferometer studied in preparation for future space missions (viz. Darwin/TPF-I) focusing on spectroscopic study of Earth-like exo-planets. Several possible designs of such an optical subsystem exist. Four approaches were selected for further study. Thales Alenia Space developed a dielectric prism APS. A focus crossing APS prototype was developed by the OCA, Nice, France. A field reversal APS prototype was prepared by the MPIA in Heidelberg, Germany. Centre Spatial de Li\`ege develops a concept based on Fresnel's rhombs. This paper presents a progress report on the current work aiming at evaluating these prototypes on the SYNAPSE test bench at the Institut d'Astrophysique Spatiale in Orsay, France

Long-Range Bidirectional Strand Asymmetries Originate at CpG Islands in the Human Genome

In the human genome, CpG islands (CGIs), which are GC- and CpG-rich sequences, are associated with transcription starting sites (TSSs); in addition, there is evidence that CGIs harbor origins of bidirectional replication (OBRs) and are preferred sites for heteroduplex formation during recombination. Transcription, replication, and recombination processes are known to induce specific mutational patterns in various genomes, and therefore, these patterns are expected to be found around CGIs. We use triple alignments of human, chimp, and macaque to compute the rates of nucleotide substitutions in up to 1 Mbps long intergenic regions on both sides of CGIs. Our analysis revealed that around a CGI there is an asymmetry between complementary substitution rates that is similar to the one that found around the OBR in bacteria. We hypothesize that these asymmetries are induced by differences in the replication of the leading and lagging strand and that a significant number of CGIs overlap OBRs. Within CGIs, we observed a mutational signature of GC-biased gene conversion that is associated with recombination. We suggest that recombination has played a major role in the creation of CGIs

Rare Codons Cluster

Most amino acids are encoded by more than one codon. These synonymous codons are not used with equal frequency: in every organism, some codons are used more commonly, while others are more rare. Though the encoded protein sequence is identical, selective pressures favor more common codons for enhanced translation speed and fidelity. However, rare codons persist, presumably due to neutral drift. Here, we determine whether other, unknown factors, beyond neutral drift, affect the selection and/or distribution of rare codons. We have developed a novel algorithm that evaluates the relative rareness of a nucleotide sequence used to produce a given protein sequence. We show that rare codons, rather than being randomly scattered across genes, often occur in large clusters. These clusters occur in numerous eukaryotic and prokaryotic genomes, and are not confined to unusual or rarely expressed genes: many highly expressed genes, including genes for ribosomal proteins, contain rare codon clusters. A rare codon cluster can impede ribosome translation of the rare codon sequence. These results indicate additional selective pressures govern the use of synonymous codons, and specifically that local pauses in translation can be beneficial for protein biogenesis

A Dual Origin of the Xist Gene from a Protein-Coding Gene and a Set of Transposable Elements

X-chromosome inactivation, which occurs in female eutherian mammals is controlled by a complex X-linked locus termed the X-inactivation center (XIC). Previously it was proposed that genes of the XIC evolved, at least in part, as a result of pseudogenization of protein-coding genes. In this study we show that the key XIC gene Xist, which displays fragmentary homology to a protein-coding gene Lnx3, emerged de novo in early eutherians by integration of mobile elements which gave rise to simple tandem repeats. The Xist gene promoter region and four out of ten exons found in eutherians retain homology to exons of the Lnx3 gene. The remaining six Xist exons including those with simple tandem repeats detectable in their structure have similarity to different transposable elements. Integration of mobile elements into Xist accompanies the overall evolution of the gene and presumably continues in contemporary eutherian species. Additionally we showed that the combination of remnants of protein-coding sequences and mobile elements is not unique to the Xist gene and is found in other XIC genes producing non-coding nuclear RNA

A study of the distribution of phylogenetically conserved blocks within clusters of mammalian homeobox genes

Genome sequencing efforts of the last decade have produced a large amount of data, which has enabled whole-genome comparative analyses in order to locate potentially functional elements and study the overall patterns of phylogenetic conservation. In this paper we present a statistically based method for the characterization of these patterns in mammalian DNA sequences. We have applied this approach to the study of exceptionally well conserved homeobox gene clusters (Hox), based on an alignment of six species, and we have constructed a map of Hox cataloguing the conserved fragments, along with their locations in relation to the genes and other landmarks, sometimes showing unexpected layouts

Large scale variation in the rate of germ-line de novo mutation, base composition, divergence and diversity in humans

It has long been suspected that the rate of mutation varies across the human genome at a large scale based on the divergence between humans and other species. However, it is now possible to directly investigate this question using the large number of de novo mutations (DNMs) that have been discovered in humans through the sequencing of trios. We investi- gate a number of questions pertaining to the distribution of mutations using more than 130,000 DNMs from three large datasets. We demonstrate that the amount and pattern of variation differs between datasets at the 1MB and 100KB scales probably as a consequence of differences in sequencing technology and processing. In particular, datasets show differ- ent patterns of correlation to genomic variables such as replication time. Never-the-less there are many commonalities between datasets, which likely represent true patterns. We show that there is variation in the mutation rate at the 100KB, 1MB and 10MB scale that can- not be explained by variation at smaller scales, however the level of this variation is modest at large scales–at the 1MB scale we infer that ~90% of regions have a mutation rate within 50% of the mean. Different types of mutation show similar levels of variation and appear to vary in concert which suggests the pattern of mutation is relatively constant across the genome. We demonstrate that variation in the mutation rate does not generate large-scale variation in GC-content, and hence that mutation bias does not maintain the isochore struc- ture of the human genome. We find that genomic features explain less than 40% of the explainable variance in the rate of DNM. As expected the rate of divergence between spe- cies is correlated to the rate of DNM. However, the correlations are weaker than expected if all the variation in divergence was due to variation in the mutation rate. We provide evidence that this is due the effect of biased gene conversion on the probability that a mutation will become fixed. In contrast to divergence, we find that most of the variation in diversity can be explained by variation in the mutation rate. Finally, we show that the correlation between divergence and DNM density declines as increasingly divergent species are considered

Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation

Transitions at CpG dinucleotides, referred to as “CpG substitutions”, are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates

Widespread Recurrent Evolution of Genomic Features

The recent explosion of genome sequences from all major phylogenetic groups has unveiled an unexpected wealth of cases of recurrent evolution of strikingly similar genomic features in different lineages. Here, we review the diverse known types of recurrent evolution in eukaryotic genomes, with a special focus on metazoans, ranging from reductive genome evolution to origins of splice-leader trans-splicing, from tandem exon duplications to gene family expansions. We first propose a general classification scheme for evolutionary recurrence at the genomic level, based on the type of driving force—mutation or selection—and the environmental and genomic circumstances underlying these forces. We then discuss various cases of recurrent genomic evolution under this scheme. Finally, we provide a broader context for repeated genomic evolution, including the unique relationship of genomic recurrence with the genotype–phenotype map, and the ways in which the study of recurrent genomic evolution can be used to understand fundamental evolutionary processes

Expression of Human nPTB Is Limited by Extreme Suboptimal Codon Content

Background: The frequency of synonymous codon usage varies widely between organisms. Suboptimal codon content limits expression of viral, experimental or therapeutic heterologous proteins due to limiting cognate tRNAs. Codon content is therefore often adjusted to match codon bias of the host organism. Codon content also varies between genes within individual mammalian species. However, little attention has been paid to the consequences of codon content upon translation of host proteins. Methodology/Principal Findings: In comparing the splicing repressor activities of transfected human PTB and its two tissue-restricted paralogs–nPTB and ROD1–we found that the three proteins were expressed at widely varying levels. nPTB was expressed at 1–3 % the level of PTB despite similar levels of mRNA expression and 74 % amino acid identity. The low nPTB expression was due to the high proportion of codons with A or U at the third codon position, which are suboptimal in human mRNAs. Optimization of the nPTB codon content, akin to the ‘‘humanization’ ’ of foreign ORFs, allowed efficient translation in vivo and in vitro to levels comparable with PTB. We were then able to demonstrate that all three proteins act as splicing repressors. Conclusions/Significance: Our results provide a striking illustration of the importance of mRNA codon content in determining levels of protein expression, even within cells of the natural host species