Biomedical subjects

Josep M Comeron

Publications and source records attributed to Josep M Comeron.

11 recordsLinked to original sources

PubMed2006

Establishment of endolithic populations of extremophilic Cyanidiales (Rhodophyta).

BACKGROUND: Cyanidiales are unicellular extremophilic red algae that inhabit acidic and high temperature sites around hot springs and have also adapted to life in endolithic and interlithic habitats. Comparative genomic analysis of Cyanidioschyzon merolae and Galdieria sulphuraria predicts that the latter may be more broadly distributed in extreme environments because its genome contains membrane transporters involved in the uptake of reduced carbon compounds that are absent from C. merolae. Analysis of an endolithic site in the Phlegrean Fields near Naples, Italy is consistent with this prediction showing this population to be comprised solely of the newly described lineage Galdieria-B and C. merolae to be limited to humid habitats. Here, we conducted an environmental PCR survey of another extreme environment in Tuscany, Italy and contrasted Cyanidiales population structure at endolithic and interlithic habitats in Naples and Tuscany. RESULTS: We find a second Galdieria lineage (Galdieria-A) in endolithic and interlithic habitats in Tuscany but surprisingly Cyanidium was also present at these sites. The photoautotrophic Cyanidium apparently survives below the rock surface where sufficient light is available for photosynthesis. C. merolae is absent from all endolithic and interlithic sites in Tuscany. Population genetic analyses of a partial calmodulin gene fragment suggest a recent establishment or recurrent gene flow between populations in Tuscany, whereas the highly structured Galdieria-B population in Naples likely originated from 2-3 founder events. We find evidence of several recombination events across the calmodulin gene, potentially indicating the presence of sexual reproduction in the Tuscany populations. CONCLUSION: Our study provides important data regarding population structure in extreme endolithic environments and insights into how Cyanidiales may be established in and adapt to these hostile environments.

Ecosystem↗

PubMed2006

Weak selection and recent mutational changes influence polymorphic synonymous mutations in humans.

Recent large-scale genomic and evolutionary studies have revealed the small but detectable signature of weak selection on synonymous mutations during mammalian evolution, likely acting at the level of translational efficacy (i.e., translational selection). To investigate whether weak selection, and translational selection in particular, plays any role in shaping the fate of synonymous mutations that are present today in human populations, we studied genetic variation at the polymorphic level and patterns of evolution in the human lineage after human-chimpanzee separation. We find evidence that neutral mechanisms are influencing the frequency of polymorphic mutations in humans. Our results suggest a recent increase in mutational tendencies toward AT, observed in all isochores, that is responsible for AT mutations segregating at lower frequencies than GC mutations. In all, however, changes in mutational tendencies and other neutral scenarios are not sufficient to explain a difference between synonymous and noncoding mutations or a difference between synonymous mutations potentially advantageous or deleterious under a translational selection model. Furthermore, several estimates of selection intensity on synonymous mutations all suggest a detectable influence of weak selection acting at the level of translational selection. Thus, random genetic drift, recent changes in mutational tendencies, and weak selection influence the fate of synonymous mutations that are present today as polymorphisms. All of these features, neutral and selective, should be taken into account in evolutionary analyses that often assume constancy of mutational tendencies and complete neutrality of synonymous mutations.

Animals↗

PubMed2006

First exons and introns--a survey of GC content and gene structure in the human genome.

Most transcriptional regulatory elements are located in non-coding DNA. In particular, some first introns play a vital role in transcriptional control and splicing. The length and GC-content of first exons and introns in complex organisms suggests that these structural units are likely to be important functional elements in large genomes. Hence, in this paper we perform a systematic comparison of exon-intron structure and GC content on all known genes in the human genome. Our in-silico analysis found that the GC content of introns and exons varies significantly depending on their length. On average, the first intron of a gene is significantly longer than other introns in the same gene. Our results also show that first introns and exons are more GC rich than last and internal. This study provides insight into the structure of eukaryotic genes. These results confirm and expand the previously identified regulatory potential of first exons and introns.

Base Composition↗

PubMed2005

Intragenic Hill-Robertson interference influences selection intensity on synonymous mutations in Drosophila.

Natural selection influences synonymous mutations and synonymous codon usage in many eukaryotes to improve the efficiency of translation in highly expressed genes. Recent studies of gene composition in eukaryotes have shown that codon usage also varies independently of expression levels, both among genes and at the intragenic level. Here, we investigate rates of evolution (Ks) and intensity of selection (gamma(s)) on synonymous mutations in two groups of genes that differ greatly in the length of their exons, but with equivalent levels of gene expression and rates of crossing-over in Drosophila melanogaster. We estimate gamma(s) using patterns of divergence and polymorphism in 50 Drosophila genes (100 kb of coding sequence) to take into account possible variation in mutation trends across the genome, among genes or among codons. We show that genes with long exons exhibit higher Ks and reduced gamma(s) compared to genes with short exons. We also show that Ks and gamma(s) vary significantly across long exons, with higher Ks and reduced gamma(s) in the central region compared to flanking regions of the same exons, hence indicating that the difference between genes with short and long exons can be mostly attributed to the central region of these long exons. Although amino acid composition can also play a significant role when estimating Ks and gamma(s), our analyses show that the differences in Ks and gamma(s) between genes with short and long exons and across long exons cannot be explained by differences in protein composition. All these results are consistent with the Interference Selection (IS) model that proposes that the Hill-Robertson (HR) effect caused by many weakly selected mutations has detectable evolutionary consequences at the intragenic level in genomes with recombination. Under the IS model, exon size and exon-intron structure influence the effectiveness of selection, with long exons showing reduced effectiveness of selection when compared to small exons and the central region of long exons showing reduced intensity of selection compared to flanking coding regions. Finally, our results further stress the need to consider selection on synonymous mutations and its variation--among and across genes and exons--in studies of protein evolution.

Animals↗

PubMed2004

A test of the CoHR motif associated with meiotic double-strand breaks in Saccharomyces cerevisiae.

Meiotic recombination is not random along chromosomes; rather, there are preferred regions for initiation called hotspots. Although the general properties of meiotic hotspots are known, the requirements at the DNA sequence level for the determination of hotspot activity are still unclear. The sequence of six known hotspots in Saccharomyces cerevisiae was compared to identify a common homology region (CoHR). They reported that the locations of CoHR sequences correspond to mapped double-strand break (DSB) sites along three chromosomes (I, III, VI). We report here that a deletion of CoHR at HIS2, a hotspot used to identify the motif, has no significant effect on recombination. In the absence of CoHR, DSB formation occurs at a high frequency and at the same sequences as in wild-type strains. In cases where the deletion of sequences containing the CoHR motif has been shown to reduce recombination, we propose that it may be a reflection of the location of the deletion, rather than the loss of CoHR, per se.

Amino Acid Motifs↗

PubMed2004

Selective and mutational patterns associated with gene expression in humans: influences on synonymous composition and intron presence.

We report the results of a comprehensive study of the influence of gene expression on synonymous codons, amino acid composition, and intron presence and size in human protein-coding genes. First, in addition to a strong effect of isochores, we have detected the influence of transcription-associated mutational biases (TAMB) on gene composition. Genes expressed in different tissues show diverse degrees of TAMB, with genes expressed in testis showing the greatest influence. Second, the study of tissues with no evidence of TAMB reveals a consistent set of optimal synonymous codons favored in highly expressed genes. This result exposes the consequences of natural selection on synonymous composition to increase efficiency of translation in the human lineage. Third, overall amino acid composition of proteins closely resembles tRNA abundance but there is no difference in amino acid composition in differentially expressed genes. Fourth, there is a negative relationship between expression and CDS length. Significantly, this is observed only among genes with introns, suggesting that the cause for this relationship in humans cannot be associated only with costs of amino acid biosynthesis. Fifth, we show that broadly and highly expressed genes have more, although shorter, introns. The selective advantage for having more introns in highly expressed genes is likely counterbalanced by containment of transcriptional costs and a minimum exon size for proper splicing.

Amino Acids↗

PubMed2004

Intragenic spatial patterns of codon usage bias in prokaryotic and eukaryotic genomes.

To study the roles of translational accuracy, translational efficiency, and the Hill-Robertson effect in codon usage bias, we studied the intragenic spatial distribution of synonymous codon usage bias in four prokaryotic (Escherichia coli, Bacillus subtilis, Sulfolobus tokodaii, and Thermotoga maritima) and two eukaryotic (Saccharomyces cerevisiae and Drosophila melanogaster) genomes. We generated supersequences at each codon position across genes in a genome and computed the overall bias at each codon position. By quantitatively evaluating the trend of spatial patterns using isotonic regression, we show that in yeast and prokaryotic genomes, codon usage bias increases along translational direction, which is consistent with purifying selection against nonsense errors. Fruit fly genes show a nearly symmetric M-shaped spatial pattern of codon usage bias, with less bias in the middle and both ends. The low codon usage bias in the middle region is best explained by interference (the Hill-Robertson effect) between selections at different codon positions. In both yeast and fruit fly, spatial patterns of codon usage bias are characteristically different from patterns of GC-content variations. Effect of expression level on the strength of codon usage bias is more conspicuous than its effect on the shape of the spatial distribution.

Animals↗

PubMed2003

Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor.

Although changes in nucleotide sequence affecting the composition and the structure of proteins are well known, functional changes resulting from nucleotide substitutions cannot always be inferred from simple analysis of DNA sequence. Because a strong synonymous codon usage bias in the human DRD2 gene, suggesting selection on synonymous positions, was revealed by the relative independence of the G+C content of the third codon positions from the isochoric G+C frequencies, we chose to investigate functional effects of the six known naturally occurring synonymous changes (C132T, G423A, T765C, C939T, C957T, and G1101A) in the human DRD2. We report here that some synonymous mutations in the human DRD2 have functional effects and suggest a novel genetic mechanism. 957T, rather than being 'silent', altered the predicted mRNA folding, led to a decrease in mRNA stability and translation, and dramatically changed dopamine-induced up-regulation of DRD2 expression. 1101A did not show an effect by itself but annulled the above effects of 957T in the compound clone 957T/1101A, demonstrating that combinations of synonymous mutations can have functional consequences drastically different from those of each isolated mutation. C957T was found to be in linkage disequilibrium in a European-American population with the -141C Ins/Del and TaqI 'A' variants, which have been reported to be associated with schizophrenia and alcoholism, respectively. These results call into question some assumptions made about synonymous variation in molecular population genetics and gene-mapping studies of diseases with complex inheritance, and indicate that synonymous variation can have effects of potential pathophysiological and pharmacogenetic importance.

Dopamine↗

PubMed2003

On the power to detect SNP/phenotype association in candidate quantitative trait loci genomic regions: a simulation study.

We use coalescent methods to investigate the ability of linked neutral "markers" to reveal in simulated population samples the presence of one or more single nucleotide polymorphisms that is contributing to a trait having a complex genetic basis (QTN: quantitative trait nucleotide). Realistic mutation and recombination rates in our simulations allow us to generate SNP data appropriate for analyzing human variation across short chromosomal intervals corresponding to approximately 100 kilobases. We investigate the performance of both single marker and multiple-marker (haplotype) data for several ad hoc procedures. Our results with single SNP markers indicate that (1) the density of SNP markers need not be much higher than 10% in order to achieve near-maximal detection of a QTN; (2) a higher density of markers does not improve much on the ability to localize a QTN within an interval unless the recombination rate is high. Haplotype-based tests were investigated for the case in which more than one QTN is present in the studied interval. Larger sample sizes improve both the probability of detecting the haplotype with the largest number of QTNs, as well as the ability to infer correct haplotypes from genotypic data. Testing a series of short haplotypes across a longer interval can also be beneficial. The rate of false positives (i.e., when the most significant haplotype does not contain the greatest number of QTNs in the sample) can be very high when the contribution of individual QTNs to a trait is small. The elimination of low-frequency haplotypes does not substantially reduce the probability of detecting the haplotype with the largest number of QTNs but it can reduce the rate of false positives.

Computational Biology↗

PubMed2002

Intron presence-absence polymorphism in Drosophila driven by positive Darwinian selection.

Comparisons of intron-exon structures between homologous genes in different eukaryotic species have revealed substantial variation in the number of introns. These observations imply that, in each case, an intron presence-absence polymorphism must have existed in the past. Such a polymorphism, created by a recent intron-loss mutation, is reported here in a eukaryotic organism. This gene structure, detected in the jingwei (jgw) gene, segregates at high frequency (77%) in natural populations of Drosophila teissieri and is associated with a marked change in mRNA levels. Furthermore, the intron loss does not result from a mRNA-mediated mechanism as is usually proposed, but from a partial deletion at the DNA level that also results in the addition of four new amino acids to the JGW protein. Population genetic analyses of the pattern of nucleotide variation surrounding the intron polymorphism indicate the action of positive Darwinian selection on the intron-absent variant. Forward simulations suggest that the intensity of this selection is weak to moderate, roughly equal to the selection intensity on most replacement mutations in Drosophila.

Animals↗

PubMed2002

Population, evolutionary and genomic consequences of interference selection.

Weakly selected mutations are most likely to be physically clustered across genomes and, when sufficiently linked, they alter each others' fixation probability, a process we call interference selection (IS). Here we study population genetics and evolutionary consequences of IS on the selected mutations themselves and on adjacent selectively neutral variation. We show that IS reduces levels of polymorphism and increases low-frequency variants and linkage disequilibrium, in both selected and adjacent neutral mutations. IS can account for several well-documented patterns of variation and composition in genomic regions with low rates of crossing over in Drosophila. IS cannot be described simply as a reduction in the efficacy of selection and effective population size in standard models of selection and drift. Rather, IS can be better understood with models that incorporate a constant "traffic" of competing alleles. Our simulations also allow us to make genome-wide predictions that are specific to IS. We show that IS will be more severe at sites in the center of a region containing weakly selected mutations than at sites located close to the edge of the region. Drosophila melanogaster genomic data strongly support this prediction, with genes without introns showing significantly reduced codon bias in the center of coding regions. As expected, if introns relieve IS, genes with centrally located introns do not show reduced codon bias in the center of the coding region. We also show that reasonably small differences in the length of intermediate "neutral" sequences embedded in a region under selection increase the effectiveness of selection on the adjacent selected sequences. Hence, the presence and length of sequences such as introns or intergenic regions can be a trait subject to selection in recombining genomes. In support of this prediction, intron presence is positively correlated with a gene's codon bias in D. melanogaster. Finally, the study of temporal dynamics of IS after a change of recombination rate shows that nonequilibrium codon usage may be the norm rather than the exception.

Animals↗