The Effects of Mutation and Natural Selection on Codon Bias in the Genes of Drosophila

Codon bias varies widely among the loci of Drosophila melanogaster, and some of this diversity has been explained by variation in the strength of natural selection. A study of correlations between intron and coding region base composition shows that variation in mutation pattern also contributes to codon bias variation. This finding is corroborated by an analysis of variance (ANOVA), which shows a tendency for introns from the same gene to be similar in base composition. The strength of base composition correlations between introns and codon third positions is greater for genes with low codon bias than for genes with high codon bias. This pattern can be explained by an overwhelming effect of natural selection, relative to mutation, in highly biased loci. In particular, this correlation is absent when examining fourfold degenerate sites of highly biased genes. In general, it appears that selection acts more strongly in choosing among fourfold degenerate codons than among twofold degenerate codons. Although the results indicate regional variation in mutational bias, no evidence is found for large scale regions of compositional homogeneity.     

Are humans increasing bacterial evolvability?

Attempts to control bacterial pathogens have led to an increase in antibiotic-resistant cells and the genetic elements that confer resistance phenotypes. These cells and genes are disseminated simultaneously with the original selective agents via human waste streams. This might lead to a second, unintended consequence of antimicrobial therapy; an increase in the evolvability of all bacterial cells. The genetic variation upon which natural selection acts is a consequence of mutation, recombination and lateral gene transfer (LGT). These processes are under selection, balancing genomic integrity against the advantages accrued by genetic innovation. Saturation of the environment with selective agents might cause directional selection for higher rates of mutation, recombination and LGT, producing unpredictable consequences for humans and the biosphere.     

Preservation of ranking order in the expression of human Housekeeping genes

Housekeeping (HK) genes fulfill the basic needs for a cell to survive and function properly. Their ubiquitous expression, originally thought to be constant, can vary from tissue to tissue, but this variation remains largely uncharacterized and it could not be explained by previously identified properties of HK genes such as short gene length and high GC content. By analyzing microarray expression data for human genes, we uncovered a previously unnoted characteristic of HK gene expression, namely that the ranking order of their expression levels tends to be preserved from one tissue to another. Further analysis by tensor product decomposition and pathway stratification identified three main factors of the observed ranking preservation, namely that, compared to those of non-HK (NHK) genes, the expression levels of HK genes show a greater degree of dispersion (less overlap), stableness (a smaller variation in expression between tissues), and correlation of expression. Our results shed light on regulatory mechanisms of HK gene expression that are probably different for different HK genes or pathways, but are consistent and coordinated in different tissues.     

Phylogenetic analysis based on genome-scale metabolic pathway reaction content

Phylogenetic classifications based on single genes such as rRNA genes do not provide a complete and accurate picture of evolution because they do not account for evolutionary leaps caused by gene transfer, duplication, deletion and functional replacement. Here, we present a whole-genome-scale phylogeny based on metabolic pathway reaction content. From the genome sequences of 42 microorganisms, we deduced the metabolic pathway reactions and used the relatedness of these contents to construct a phylogenetic tree that represents the similarity of metabolic profiles (relatedness) as well as the extent of metabolic pathway similarity (evolutionary distance). This method accounts for horizontal gene transfer and specific gene loss by comparison of whole metabolic subpathways, and allows evaluation of evolutionary relatedness and changes in metabolic pathways. Thus, a tree based on metabolic pathway content represents both the evolutionary time scale (changes in genetic content) and the evolutionary process (changes in metabolism).     

Evolutionary origins of metabolic compartmentalization in eukaryotes

Many genes in eukaryotes are acquisitions from the free-living antecedents of chloroplasts and mitochondria. But there is no evolutionary ‘homing device’ that automatically directs the protein product of a transferred gene back to the organelle of its provenance. Instead, the products of genes acquired from endosymbionts can explore all targeting possibilities within the cell. They often replace pre-existing host genes, or even whole pathways. But the transfer of an enzymatic pathway from one compartment to another poses severe problems: over evolutionary time, the enzymes of the pathway acquire their targeting signals for the new compartment individually, not in unison. Until the whole pathway is established in the new compartment, newly routed individual enzymes are useless, and their genes will be lost through mutation. Here it is suggested that pathways attain novel compartmentation variants via a ‘minor mistargeting’ mechanism. If protein targeting in eukaryotic cells possesses enough imperfection such that small amounts of entire pathways continuously enter novel compartments, selectable units of biochemical function would exist in new compartments, and the genes could become selected. Dual-targeting of proteins is indeed very common within eukaryotic cells, suggesting that targeting variation required for this minor mistargeting mechanism to operate exists in nature.     

环境中抗生素抗性基因的水平传播扩散

抗生素抗性基因作为一类新型环境污染物,其在不同环境介质中的传播扩散可能比抗生素本身的环境危害更大,其中,水平基因转移是抗生素抗性基因传播的重要方式,是造成抗性基因环境污染日益严重的原因之一.本文系统阐述了抗生素抗性基因在环境中发生水平转移的主要分子传播元件及其影响因素,这对于正确揭示抗性基因的分子传播机制具有重要意义.结合多重抗药性的传播扩散机制,探讨了行之有效的遏制抗生素抗性基因传播扩散的方法和途径,并针对目前的污染现状,对今后有关抗生素抗性基因水平转移的研究重点进行了展望.     

Patterns of variation during adaptation in functionally linked loci

An understanding of the distribution of natural patterns of genetic variation is relevant to such fundamental biological fields as evolution and development. One recent approach to understanding such patterns has been to focus on the constraints that may arise as a function of the network or pathway context in which genes are embedded. Despite theoretical expectations of higher evolutionary constraint for genes encoding upstream versus downstream enzymes in metabolic pathways, empirical results have varied. Here we combine two complementary models from population genetics and enzyme kinetics to explore genetic variation as a function of pathway position when selection acts on whole-pathway flux. We are able to qualitatively reproduce empirically observed patterns of polymorphism and divergence and suggest that expectations should vary depending on the evolutionary trajectory of a population. Upstream genes are initially more polymorphic and diverge faster after an environmental change, while we see the opposite trend as the population approaches its fitness optimum.     

The role of mobile genetic elements in bacterial adaptation to xenobiotic organic compounds

Retrospective studies clearly indicate that mobile genetic elements (MGEs) play a major role in the in situ spread and even de novo construction of catabolic pathways in bacteria, allowing bacterial communities to rapidly adapt to new xenobiotics. The construction of novel pathways seems to occur by an assembly process that involves horizontal gene transfer: different appropriate genes or gene modules that encode different parts of the novel pathway are recruited from phylogenetically related or distant hosts into one single host. Direct evidence for the importance of catabolic MGEs in bacterial adaptation to xenobiotics stems from observed correlations between catabolic gene transfer and accelerated biodegradation in several habitats and from studies that monitor catabolic MGEs in polluted sites.     

Rapid birth-death evolution specific to xenobiotic cytochrome P450 genes in vertebrates

Genes vary greatly in their long-term phylogenetic stability and there exists no general explanation for these differences. The cytochrome P450 (CYP450) gene superfamily is well suited to investigating this problem because it is large and well studied, and it includes both stable and unstable genes. CYP450 genes encode oxidase enzymes that function in metabolism of endogenous small molecules and in detoxification of xenobiotic compounds. Both types of enzymes have been intensively studied. My analysis of ten nearly complete vertebrate genomes indicates that each genome contains 50-80 CYP450 genes, which are about evenly divided between phylogenetically stable and unstable genes. The stable genes are characterized by few or no gene duplications or losses in species ranging from bony fish to mammals, whereas unstable genes are characterized by frequent gene duplications and losses (birth-death evolution) even among closely related species. All of the CYP450 genes that encode enzymes with known endogenous substrates are phylogenetically stable. In contrast, most of the unstable genes encode enzymes that function as xenobiotic detoxifiers. Nearly all unstable CYP450 genes in the mouse and human genomes reside in a few dense gene clusters, forming unstable gene islands that arose by recurrent local gene duplication. Evidence for positive selection in amino acid sequence is restricted to these unstable CYP450 genes, and sites of selection are associated with substrate-binding regions in the protein structure. These results can be explained by a general model in which phylogenetically stable genes have core functions in development and physiology, whereas unstable genes have accessory functions associated with unstable environmental interactions such as toxin and pathogen exposure. Unstable gene islands in vertebrates share some functional properties with bacterial genomic islands, though they arise by local gene duplication rather than horizontal gene transfer.     

CTnscr94, a conjugative transposon found in enterobacteria.

Conjugational transposons are important for horizontal gene transfer in gram-positive and gram-negative bacteria, but have not been reported yet for enteric bacteria. Salmonella senftenberg 5494-57 has previously been shown to transfer by conjugation genes for a sucrose fermentation pathway which were located on a DNA element called scr-94. We report here that the corresponding scr genes for a phosphoenolpyruvate-dependent sucrose:phosphotransferase system and a sucrose metabolic pathway are located on a large (ca. 100 kb) conjugative transposon renamed CTnscr94. The self-transmissible element integrates at two specific attachment sites in a RecA-independent way into the chromosome of Escherichia coli K-12 strains. One site was identified within pheV, the structural gene for a tRNA(Phe). Sequencing of both ends of CTnscr94 revealed the presence of the 3' part of pheV on one end such that after integration of the element, a complete pheV gene is retained. CTnscr94 represents, to our knowledge, the first conjugational transposon found in enteric bacteria.     

Phycoerythrin evolution and diversification of spectral phenotype in marine Synechococcus and related picocyanobacteria

In marine Synechococcus there is evidence for the adaptive evolution of spectrally distinct forms of the major light harvesting pigment phycoerythrin (PE). Recent research has suggested that these spectral forms of PE have a different evolutionary history than the core genome. However, a lack of explicit statistical testing of alternative hypotheses or for selection on these genes has made it difficult to evaluate the evolutionary relationships between spectral forms of PE or the role horizontal gene transfer (HGT) may have had in the adaptive phenotypic evolution of the pigment system in marine Synechococcus. In this work, PE phylogenies of picocyanobacteria with known spectral phenotypes, including newly co-isolated strains of marine Synechococcus from the Gulf of Mexico, were constructed to explore the diversification of spectral phenotype and PE evolution in this group more completely. For the first time, statistical evaluation of competing evolutionary hypotheses and tests for positive selection on the PE locus in picocyanobacteria were performed. Genes for PEs associated with specific PE spectral phenotypes formed strongly supported monophyletic clades within the PE tree with positive directional selection driving evolution towards higher phycourobilin (PUB) content. The presence of the PUB-lacking phenotype in PE-containing marine picocyanobacteria from cyanobacterial lineages identified as Cyanobium is best explained by HGT into this group from marine Synechococcus. Taken together, these data provide strong examples of adaptive evolution of a single phenotypic trait in bacteria via mutation, positive directional selection and horizontal gene transfer.     

The Genome of Pseudomonas fluorescens Strain R124 Demonstrates Phenotypic Adaptation to the Mineral Environment

Microbial adaptation to environmental conditions is a complex process, including acquisition of positive traits through horizontal gene transfer or the modification of existing genes through duplication and/or mutation. In this study, we examined the adaptation of a Pseudomonas fluorescens isolate (R124) from the nutrient-limited mineral environment of a silica cave in comparison with P. fluorescens isolates from surface soil and the rhizosphere. Examination of metal homeostasis gene pathways demonstrated a high degree of conservation, suggesting that such systems remain functionally similar across chemical environments. The examination of genomic islands unique to our strain revealed the presence of genes involved in carbohydrate metabolism, aromatic carbon metabolism, and carbon turnover, confirmed through phenotypic assays, suggesting the acquisition of potentially novel mechanisms for energy metabolism in this strain. We also identified a twitching motility phenotype active at low-nutrient concentrations that may allow alternative exploratory mechanisms for this organism in a geochemical environment. Two sets of candidate twitching motility genes are present within the genome, one on the chromosome and one on a plasmid; however, a plasmid knockout identified the functional gene as being present on the chromosome. This work highlights the plasticity of the Pseudomonas genome, allowing the acquisition of novel nutrient-scavenging pathways across diverse geochemical environments while maintaining a core of functional stress response genes.     

The Complete Genome Sequence of Natrinema sp. J7-2, a Haloarchaeon Capable of Growth on Synthetic Media without Amino Acid Supplements

Natrinema sp. J7-2 is an extreme haloarchaeon capable of growing on synthetic media without amino acid supplements. Here we report the complete genome sequence of Natrinema sp. J7-2 which is composed of a 3,697,626-bp chromosome and a 95,989-bp plasmid pJ7-I. This is the first complete genome sequence of a member of the genus Natrinema. We demonstrate that Natrinema sp. J7-2 can use gluconate, glycerol, or acetate as the sole carbon source and that its genome encodes complete metabolic pathways for assimilating these substrates. The biosynthetic pathways for all 20 amino acids have been reconstructed, and we discuss a possible evolutionary relationship between the haloarchaeal arginine synthetic pathway and the bacterial lysine synthetic pathway. The genome harbors the genes for assimilation of ammonium and nitrite, but not nitrate, and has a denitrification pathway to reduce nitrite to N(2)O. Comparative genomic analysis suggests that most sequenced haloarchaea employ the TrkAH system, rather than the Kdp system, to actively uptake potassium. The genomic analysis also reveals that one of the three CRISPR loci in the Natrinema sp. J7-2 chromosome is located in an integrative genetic element and is probably propagated via horizontal gene transfer (HGT). Finally, our phylogenetic analysis of haloarchaeal genomes provides clues about evolutionary relationships of haloarchaea.     

Rapid Pathway Evolution Facilitated by Horizontal Gene Transfers across Prokaryotic Lineages

The evolutionary history of biological pathways is of general interest, especially in this post-genomic era, because it may provide clues for understanding how complex systems encoded on genomes have been organized. To explain how pathways can evolve de novo, some noteworthy models have been proposed. However, direct reconstruction of pathway evolutionary history both on a genomic scale and at the depth of the tree of life has suffered from artificial effects in estimating the gene content of ancestral species. Recently, we developed an algorithm that effectively reconstructs gene-content evolution without these artificial effects, and we applied it to this problem. The carefully reconstructed history, which was based on the metabolic pathways of 160 prokaryotic species, confirmed that pathways have grown beyond the random acquisition of individual genes. Pathway acquisition took place quickly, probably eliminating the difficulty in holding genes during the course of the pathway evolution. This rapid evolution was due to massive horizontal gene transfers as gene groups, some of which were possibly operon transfers, which would convey existing pathways but not be able to generate novel pathways. To this end, we analyzed how these pathways originally appeared and found that the original acquisition of pathways occurred more contemporaneously than expected across different phylogenetic clades. As a possible model to explain this observation, we propose that novel pathway evolution may be facilitated by bidirectional horizontal gene transfers in prokaryotic communities. Such a model would complement existing pathway evolution models.     

细菌固有耐药的研究进展

人们以往大多只关注由敏感细菌通过基因水平转移和自发突变方式获得的耐药性,而忽略了细菌对某类抗生素天然耐药的重要特性,细菌的这种特性又被称为固有耐药。固有耐药由固有耐药基因决定,这类基因是指存在于某类细菌染色体上位置保守的与耐药相关的一类基因。近年来,对固有耐药基因的研究已经越来越受到重视。固有耐药基因的发现不仅可以为新药研制提供药物作用靶标,而且通过阻断病原菌固有耐药基因还可使以往对该类菌不起作用的抗生素药物重新焕发抗菌活性。此外,已有研究表明固有耐药基因能够被移动元件捕获进而可水平转移至其他细菌,因此通过监测固有耐药基因可以预测耐药菌的出现。本文对传统的细菌固有耐药机制包括细胞膜的低渗透性和多药外排泵系统,以及已知重要病原菌的转移酶和代谢相关酶的固有耐药机制进行了介绍。同时,进一步对隐性固有耐药基因的特性进行了阐释,最后探讨了固有耐药与获得性耐药的进化关系,指出固有耐药基因很可能是一些获得性耐药基因的来源。     

Personalized pathway enrichment map of putative cancer genes from next generation sequencing data

BACKGROUND: Pathway analysis of a set of genes represents an important area in large-scale omic data analysis. However, the application of traditional pathway enrichment methods to next-generation sequencing (NGS) data is prone to several potential biases, including genomic/genetic factors (e.g., the particular disease and gene length) and environmental factors (e.g., personal life-style and frequency and dosage of exposure to mutagens). Therefore, novel methods are urgently needed for these new data types, especially for individual-specific genome data. METHODOLOGY: In this study, we proposed a novel method for the pathway analysis of NGS mutation data by explicitly taking into account the gene-wise mutation rate. We estimated the gene-wise mutation rate based on the individual-specific background mutation rate along with the gene length. Taking the mutation rate as a weight for each gene, our weighted resampling strategy builds the null distribution for each pathway while matching the gene length patterns. The empirical P value obtained then provides an adjusted statistical evaluation. PRINCIPAL FINDINGS/CONCLUSIONS: We demonstrated our weighted resampling method to a lung adenocarcinomas dataset and a glioblastoma dataset, and compared it to other widely applied methods. By explicitly adjusting gene-length, the weighted resampling method performs as well as the standard methods for significant pathways with strong evidence. Importantly, our method could effectively reject many marginally significant pathways detected by standard methods, including several long-gene-based, cancer-unrelated pathways. We further demonstrated that by reducing such biases, pathway crosstalk for each individual and pathway co-mutation map across multiple individuals can be objectively explored and evaluated. This method performs pathway analysis in a sample-centered fashion, and provides an alternative way for accurate analysis of cancer-personalized genomes. It can be extended to other types of genomic data (genotyping and methylation) that have similar bias problems.     

Functional replacement of a primary metabolic pathway via multiple independent eukaryote‐to‐eukaryote gene transfers and selective retention

Although lateral gene transfer (LGT) is now recognized as a major force in the evolution of prokaryotes, the contribution of LGT to the evolution and diversification of eukaryotes is less understood. Notably, transfers of complete pathways are believed to be less likely between eukaryotes, because the successful transfer of a pathway requires the physical clustering of functionally related genes. Here, we report that in one of the closest unicellular relatives of animals, the choanoflagellate, Monosiga, three genes whose products work together in the glutamate synthase cycle are of algal origin. The concerted retention of these three independently acquired genes is best explained as the consequence of a series of adaptive replacement events. More generally, this study argues that (i) eukaryote‐to‐eukaryote transfers of entire metabolic pathways are possible, (ii) adaptive functional replacements of primary pathways can occur, and (iii) functional replacements involving eukaryotic genes are likely to have also contributed to the evolution of eukaryotes. Lastly, these data underscore the potential contribution of algal genes to the evolution of nonphotosynthetic lineages.