Indirect and suboptimal control of gene expression is widespread in bacteria

Gene regulation in bacteria is usually described as an adaptive response to an environmental change so that genes are expressed when they are required. We instead propose that most genes are under indirect control: their expression responds to signal(s) that are not directly related to the genes’ function. Indirect control should perform poorly in artificial conditions, and we show that gene regulation is often maladaptive in the laboratory. In Shewanella oneidensis MR‐1, 24% of genes are detrimental to fitness in some conditions, and detrimental genes tend to be highly expressed instead of being repressed when not needed. In diverse bacteria, there is little correlation between when genes are important for optimal growth or fitness and when those genes are upregulated. Two common types of indirect control are constitutive expression and regulation by growth rate; these occur for genes with diverse functions and often seem to be suboptimal. Because genes that have closely related functions can have dissimilar expression patterns, regulation may be suboptimal in the wild as well as in the laboratory.     

Gene-chromosome locations of neuropsychiatric diseases

A number of genes are involved in various neuropsychiatric disorders. A comprehensive compilation of these genes is important for a better understanding of these diseases. We report an online file that lists genes by chromosome number and location. This is useful for the rapid examination of chromosome bands for genes involved in these diseases. This is not an exhaustive list and does not include single nucleotide polymorphism (SNP) results for genes that are currently being examined by genome wide association studies (GWAS) and other molecular methodologies. AVAILABILITY: The database is available for free at http://www.bioinformation.net/007/paul.xls.     

GOOD GENES AND DIRECT SELECTION IN THE EVOLUTION OF MATING PREFERENCES

A model is used to study quantitatively the impact of a good genes process and direct natural selection on the evolution of a mating preference. The expression of a male display trait is proportional to genetic quality, which is determined by the number of deleterious mutations a male carries throughout his genome. Genetic variances and covariances, including the covariance between the preference and male trait that drives the good genes process, are allowed to evolve under an infinitesimal model. Results suggest that the good genes process generates only weak indirect selection on preferences, with an effective selection intensity of a few percent or less. If preferences are subject to direct natural selection of the intensity observed for other characters, the good genes process alone is not expected to exaggerate the male trait by more than a few phenotypic standard deviations, contrary to what is observed in highly sexually selected species. Good genes can, however, cause substantial exaggeration if preference genes are nearly selectively neutral. Alternatively, direct selection on preference genes, acting on mating behavior itself or on the genes' pleiotropic effects, can cause mating preferences and male display traits to be exaggerated by any degree. Direct selection of preference genes may therefore play an important role in species that show extreme sexual selection.     

Embryogenomics: developmental biology meets genomics

Fundamental questions in developmental biology are: what genes are expressed, where and when they are expressed, what is the level of expression and how are these programs changed by the functional and structural alteration of genes? These questions have been addressed by studying one gene at a time, but a new research field that handles many genes in parallel is emerging. The methodology is at the interface of large-scale genomics approaches and developmental biology. Genomics needs developmental biology because one of the goals of genomics – collection and analysis of all genes in an organism – cannot be completed without working on embryonic tissues in which many genes are uniquely expressed. However, developmental biology needs genomics – the high-throughput approaches of genomics generate information about genes and pathways that can give an integrated view of complex processes. This article discusses these new approaches and their applications to mammalian developmental biology.     

A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney

Polycystic kidney disease (PKD) is a common human genetic illness. It is characterized by the formation of multiple kidney cysts that are thought to result from over-proliferation of epithelial cells. Zebrafish larvae can also develop kidney cysts. In an insertional mutagenesis screen in zebrafish, we identified 12 genes that can cause cysts in the glomerular-tubular region when mutated and we cloned 10 of these genes. Two of these genes, vhnf1 (tcf2) and pkd2, are already associated with human cystic kidney diseases. Recently, defects in primary cilia have been linked to PKD. Strikingly, three out of the 10 genes cloned in this screen are homologues of Chlamydomonas genes that encode components of intraflagellar transport (IFT) particles involved in cilia formation. Mutation in a fourth blocks ciliary assembly by an unknown mechanism. These results provide compelling support for the connection between cilia and cystogenesis. Our results also suggest that lesions in genes involved in cilia formation and function are the predominant cause of cystic kidney disease, and that the genes identified here are excellent candidates for novel human PKD genes.     

Histone genes inPhysarum polycephalum: Transcription and analysis of the flanking regions of the two H4 genes

The histone H4 multigene family of Physarum polycephalum consists of two genes, H41 and H42. Both genes have an unusual structure in that they are interrupted by a small intron. The structure of the P. polycephalum H4 genes is discussed and compared to the structure of histone genes of other organisms. S1 nuclease analysis was used to map the 5' and 3' ends of the histone H4 messengers. We show that the histone H4 genes have a hybrid structure; they are interrupted by an intervening sequence, as in replacement variant histone genes of higher eukaryotes, but their 5' and 3' noncoding regions have the properties of replication-dependent histone genes: the 5' and 3' leader and trailer sequences are short, possess a 3'-hyphenated dyad symmetry element, and a CAGA sequence is found 3' to the hyphenated hairpin structure. This report also provides evidence that both genes are expressed in late G2 phase as well as in S phase and that their expression is temporally coordinated and quantitatively similar during the cell cycle.     

Impact of selection on genes involved in regulatory network: a modelling study

Complex phenotypes are often controlled by many interacting genes. One question emerging from such organization is how selection, acting at the phenotypic level, shapes the evolution of genes involved in regulatory networks controlling the phenotypes. We studied this issue through a matrix model of such networks. In a population submitted to selection, we simulated the evolution of a quantitative trait controlled by a set of loci that regulate each other through positive or negative interactions. Investigating several levels of selection intensity on the trait, we studied the evolution of regulation intensity between the genes and the evolution of the genetic diversity of those genes as an indirect measure of the strength of selection acting on them. We show that an increasing intensity of selection on the phenotype leads to an increased level of regulation between the loci. Moreover, we found that the genes responding more strongly to selection within the network were those evolving towards stronger regulatory action on the other genes and/or those that are the less regulated by the other genes. This observation is strongest for an intermediate level of selection. This may explain why several experimental studies have shown evidence of selection on regulatory genes inside gene networks.     

Organization of spliceosomal U6 snRNA genes in the mouse genome

U6 RNA is an abundant small nuclear RNA (snRNA) required for splicing of pre-mRNAs. In mammalian cells, the genes for U1 to U4 snRNAs consist of multigene families ranging from 10 to 100 copies of real genes per haploid genome, and are transcribed by RNA polymerase II. In contrast, results obtained in this study indicate that U6 RNA, which is transcribed by RNA polymerase II and III, may be coded for in mouse cells by only two genes. These two U6 genes are at least 9 kb apart from each other, and the flanking sequences are highly conserved, indicating that the organization of U6 genes is similar to that observed for other mammalian U-snRNA genes.This investigation was supported by Grant GM 38320, awarded by the Department of Health and Human Services, United States Public Health Service.     

Comparative genomic analysis of soybean flowering genes

Flowering is an important agronomic trait that determines crop yield. Soybean is a major oilseed legume crop used for human and animal feed. Legumes have unique vegetative and floral complexities. Our understanding of the molecular basis of flower initiation and development in legumes is limited. Here, we address this by using a computational approach to examine flowering regulatory genes in the soybean genome in comparison to the most studied model plant, Arabidopsis. For this comparison, a genome-wide analysis of orthologue groups was performed, followed by an in silico gene expression analysis of the identified soybean flowering genes. Phylogenetic analyses of the gene families highlighted the evolutionary relationships among these candidates. Our study identified key flowering genes in soybean and indicates that the vernalisation and the ambient-temperature pathways seem to be the most variant in soybean. A comparison of the orthologue groups containing flowering genes indicated that, on average, each Arabidopsis flowering gene has 2-3 orthologous copies in soybean. Our analysis highlighted that the CDF3, VRN1, SVP, AP3 and PIF3 genes are paralogue-rich genes in soybean. Furthermore, the genome mapping of the soybean flowering genes showed that these genes are scattered randomly across the genome. A paralogue comparison indicated that the soybean genes comprising the largest orthologue group are clustered in a 1.4 Mb region on chromosome 16 of soybean. Furthermore, a comparison with the undomesticated soybean (Glycine soja) revealed that there are hundreds of SNPs that are associated with putative soybean flowering genes and that there are structural variants that may affect the genes of the light-signalling and ambient-temperature pathways in soybean. Our study provides a framework for the soybean flowering pathway and insights into the relationship and evolution of flowering genes between a short-day soybean and the long-day plant, Arabidopsis.     

Adaptive evolution of the Populus tremula photoperiod pathway

Perennial plants monitor seasonal changes through changes in environmental conditions such as the quantity and quality of light and genes in the photoperiodic pathway are known to be involved in controlling these processes. Here, we examine 25 of genes from the photoperiod pathway in Populus tremula (Salicaceae) for signatures of adaptive evolution. Overall, levels of synonymous polymorphism in the 25 genes are lower than at control loci selected randomly from the genome. This appears primarily to be caused by lower levels of synonymous polymorphism in genes associated with the circadian clock. Natural selection appears to play an important role in shaping protein evolution at several of the genes in the photoperiod pathways, which is highlighted by the fact that approximately 40% of the genes from the photoperiod pathway have estimates of selection on nonsynonymous polymorphisms that are significantly different from zero. A surprising observation we make is that circadian clock-associated genes appear to be over-represented among the genes showing elevated rates of protein evolution; seven genes are evolving under positive selection and all but one of these genes are involved in the circadian clock of Populus.     

Higher duplicability of less important genes in yeast genomes

Gene duplication plays an important role in evolution because it is the primary source of new genes. Many recent studies showed that gene duplicability varies considerably among genes. Several considerations led us to hypothesize that less important genes have higher rates of successful duplications, where gene importance is measured by the fitness reduction caused by the deletion of the gene. Here, we test this hypothesis by comparing the importance of two groups of singleton genes in the yeast Saccharomyces cerevisiae (Sce). Group S genes did not duplicate in four other yeast species examined, whereas group D experienced duplication in these species. Consistent with our hypothesis, we found group D genes to be less important than group S genes. Specifically, 17% of group D genes are essential in Sce, compared to 28% for group S. Furthermore, deleting a group D gene in Sce reduces the fitness by 24% on average, compared to 38% for group S. Our subsequent analysis showed that less important genes have more cis-regulatory motifs, which could lead to a higher chance of subfunctionalization of duplicate genes and result in an enhanced rate of gene retention. Less important genes may also have weaker dosage imbalance effects and cause fewer genetic perturbations when duplicated. Regardless of the cause, our observation indicates that the previous finding of a less severe fitness consequence of deleting a duplicate gene than deleting a singleton gene is at least in part due to the fact that duplicate genes are intrinsically less important than singleton genes and suggests that the contribution of duplicate genes to genetic robustness has been overestimated.     

Trypanosome variant surface glycoprotein genes expressed early in infection

We have studied further the genes for trypanosomal variant surface glycoproteins expressed during a chronic infection of rabbits with Trypanosoma brucei, strain 427. We show that there are three closely related chromosomal-internal isogenes for VSG 121; expression of one of these genes is accompanied by the duplicate transposition of the gene to a telomeric expression site, also used by other chromosome-internal VSG genes. The 3' end of the 121 gene is replaced during transposition with another sequence, also found in the VSG mRNAs of two other variants. We infer that an incoming VSG gene duplicate recombines with the resident gene in the expression site and may exchange ends in this process. The extra expression-linked copy of the 121 gene is lost when another gene enters the expression site. However, when the telomeric VSG gene 221 is activated without duplication the extra 121 gene copy is inactivated without detectable alterations in or around the gene. We have also analysed the VSG genes expressed very early when trypanosomes are introduced into rats or tissue culture. The five genes identified in 24 independent switching events were all found to be telomeric genes and we calculate that the telomeric 1.8 gene has a 50% chance of being activated in this trypanosome strain when the trypanosome switches the VSG that is synthesized. We argue that the preferential expression of telomeric VSG genes is due to two factors: first, some telomeric genes reside in an inactive expression site, that can be reactivated; second, telomeric genes can enter an active expression site by a duplicative telomere conversion and this process occurs more frequently than the duplicative transposition of chromosome-internal genes to an expression site.     

Synonymous Codon Choices in the Extremely GC-Poor Genome of Plasmodium falciparum: Compositional Constraints and Translational Selection

We have analyzed the patterns of synonymous codon preferences of the nuclear genes of Plasmodium falciparum, a unicellular parasite characterized by an extremely GC-poor genome. When all genes are considered, codon usage is strongly biased toward A and T in third codon positions, as expected, but multivariate statistical analysis detects a major trend among genes. At one end genes display codon choices determined mainly by the extreme genome composition of this parasite, and very probably their expression level is low. At the other end a few genes exhibit an increased relative usage of a particular subset of codons, many of which are C-ending. Since the majority of these few genes is putatively highly expressed, we postulate that the increased C-ending codons are translationally optimal. In conclusion, while codon usage of the majority of P. falciparum genes is determined mainly by compositional constraints, a small number of genes exhibit translational selection. Received: 10 November 1998 / Accepted: 28 January 1999     

A secreted factor and cyclic AMP jointly regulate cell-type-specific gene expression in Dictyostelium discoideum.

We are studying cell differentiation in Dictyostelium discoideum by examining the regulation of genes that are preferentially expressed in different cell types. A system has been established in which prestalk- and prespore-cell-specific genes are expressed in single cells in response to culture conditions. We confirm our previous results showing that cyclic AMP induces prestalk genes and now show that it is also required for prespore gene induction. The expression of both classes of genes is additionally dependent on the presence of a factor(s) secreted by developing cells which we call conditioned medium factor(s). An assay for conditioned medium factor(s) shows that it is detectable within 2.5 h after the onset of development. Conditioned medium factor(s) also promotes the expression of genes induced early in development, but has no detectable effect on the expression of actin genes and a gene expressed maximally in vegetative cells. In the presence of conditioned medium factor(s), exogenous cyclic AMP at the onset of starvation fails to induce the prespore and prestalk genes. The addition of cyclic AMP between 2 and 12 h of starvation results in rapid prestalk gene expression, whereas prespore genes are induced at an invarient time (approximately 18 h after the onset of starvation). These data suggest that cyclic AMP and conditioned medium factor(s) are sufficient for prestalk gene induction, whereas an additional parameter(s) is involved in the control of prespore gene induction. In contrast to several previous studies, we show that multicellularity is not essential for the expression of either prespore or prestalk genes. These data indicate that prespore and prestalk genes have cell-type-specific as well as shared regulatory factors.