Jianying Gu

Evolutionary analysis for functional divergence of the toll-like receptor gene family and altered functional constraints.

The Toll-like receptor (TLR) gene family consists of type 1 transmembrane receptors, which play essential roles in both innate immunity and adaptive immune response by ligand recognition and signal transduction. Using all available vertebrate TLR protein sequences, we inferred the phylogenetic tree and then characterized critical amino acid residues for functional divergence by detecting altered functional constraints after gene duplications. We found that the extracellular domain of TLR genes showed higher functional divergence than that of the cytoplasmic domain, particularly in the region between leucine-rich repeat (LRR) 10 and LRR 15 of TLR 4. Our finding supports the concept that sequence evolution in the extracellular domain may be responsible for the broad diversity of TLR ligand-binding affinity, providing a testable hypothesis for potential targets that could be verified by further experimentation.

Evolutionary analysis for functional divergence of Jak protein kinase domains and tissue-specific genes.

Abstract. Jak (Janus kinase) is a nonreceptor tyrosine kinase, which plays important roles in signal transduction pathways. The unique feature of Jak is that, in addition to a fully functional tyrosine kinase domain (JH1), Jak possesses a pseudokinase domain (JH2). Although JH2 lost its catalytic function, experimental evidence has shown that this domain may have acquired some new but unknown functions. This apparent functional divergence after the (internal) domain duplication may result in dramatic changes of selective constraints at some sites. We conducted a data analysis to test this hypothesis. Our result shows that shifted selective constraints (or shifted evolutionary rates) between the JH1 and the JH2 domains are statistically significant. Predicted amino acid sites by posterior analysis can be classified into two groups: very conserved in JH1 but highly variable in JH2, and vice versa. Moreover, we have studied the evolutionary pattern of four tissue-specific genes, Jak1, Jak2, Jak3, and Tyk2, which were generated in the early stages of vertebrates. We found that after the (first) gene duplication, site-specific rate shifts between Jak2/Jak3 and Jak1/Tyk are significant, presumably as a consequence of functional divergence among these genes. The implication of our study for functional genomics is discussed.

Genome plasticity and systems evolution in Streptomyces

BackgroundStreptomycetes are filamentous soil-dwelling bacteria. They are best known as the producers of a great variety of natural products such as antibiotics, antifungals, antiparasitics, and anticancer agents and the decomposers of organic substances for carbon recycling. They are also model organisms for the studies of gene regulatory networks, morphological differentiation, and stress response. The availability of sets of genomes from closely related Streptomyces strains makes it possible to assess the mechanisms underlying genome plasticity and systems adaptation.ResultsWe present the results of a comprehensive analysis of the genomes of five Streptomyces species with distinct phenotypes. These streptomycetes have a pan-genome comprised of 17,362 orthologous families which includes 3,096 components in the core genome, 5,066 components in the dispensable genome, and 9,200 components that are uniquely present in only one species. The core genome makes up about 33%-45% of each genome repertoire. It contains important genes for Streptomyces biology including those involved in gene regulation, secretion, secondary metabolism and morphological differentiation. Abundant duplicate genes have been identified, with 4%-11% of the whole genomes composed of lineage-specific expansions (LSEs), suggesting that frequent gene duplication or lateral gene transfer events play a role in shaping the genome diversification within this genus. Two patterns of expansion, single gene expansion and chromosome block expansion are observed, representing different scales of duplication.ConclusionsOur results provide a catalog of genome components and their potential functional roles in gene regulatory networks and metabolic networks. The core genome components reveal the minimum requirement for streptomycetes to sustain a successful lifecycle in the soil environment, reflecting the effects of both genome evolution and environmental stress acting upon the expressed phenotypes. A better understanding of the LSE gene families will, on the other hand, bring a wealth of new insights into the mechanisms underlying strain-specific phenotypes, such as the production of novel antibiotics, pathogenesis, and adaptive response to environmental challenges.

Improved prediction of malaria degradomes by supervised learning with SVM and profile kernel

The spread of drug resistance through malaria parasite populations calls for the development of new therapeutic strategies. However, the seemingly promising genomics-driven target identification paradigm is hampered by the weak annotation coverage. To identify potentially important yet uncharacterized proteins, we apply support vector machines using profile kernels, a supervised discriminative machine learning technique for remote homology detection, as a complement to the traditional alignment based algorithms. In this study, we focus on the prediction of proteases, which have long been considered attractive drug targets because of their indispensable roles in parasite development and infection. Our analysis demonstrates that an abundant and complex repertoire is conserved in five Plasmodium parasite species. Several putative proteases may be important components in networks that mediate cellular processes, including hemoglobin digestion, invasion, trafficking, cell cycle fate, and signal transduction. This catalog of proteases provides a short list of targets for functional characterization and rational inhibitor design.

Module-based subnetwork alignments reveal novel transcriptional regulators in malaria parasite Plasmodium falciparum

BackgroundMalaria causes over one million deaths annually, posing an enormous health and economic burden in endemic regions. The completion of genome sequencing of the causative agents, a group of parasites in the genus Plasmodium, revealed potential drug and vaccine candidates. However, genomics-driven target discovery has been significantly hampered by our limited knowledge of the cellular networks associated with parasite development and pathogenesis. In this paper, we propose an approach based on aligning neighborhood PPI subnetworks across species to identify network components in the malaria parasite P. falciparum.ResultsInstead of only relying on sequence similarities to detect functional orthologs, our approach measures the conservation between the neighborhood subnetworks in protein-protein interaction (PPI) networks in two species, P. falciparum and E. coli. 1,082 P. falciparum proteins were predicted as functional orthologs of known transcriptional regulators in the E. coli network, including general transcriptional regulators, parasite-specific transcriptional regulators in the ApiAP2 protein family, and other potential regulatory proteins. They are implicated in a variety of cellular processes involving chromatin remodeling, genome integrity, secretion, invasion, protein processing, and metabolism.ConclusionsIn this proof-of-concept study, we demonstrate that a subnetwork alignment approach can reveal previously uncharacterized members of the subnetworks, which opens new opportunities to identify potential therapeutic targets and provide new insights into parasite biology, pathogenesis and virulence. This approach can be extended to other systems, especially those with poor genome annotation and a paucity of knowledge about cellular networks.

The -omics Era- Toward a Systems-Level Understanding of Streptomyces.

Streptomyces is a group of soil bacteria of medicinal, economic, ecological, and industrial importance. It is renowned for its complex biology in gene regulation, antibiotic production, morphological differentiation, and stress response. In this review, we provide an overview of the recent advances in Streptomyces biology inspired by -omics based high throughput technologies. In this post-genomic era, vast amounts of data have been integrated to provide significant new insights into the fundamental mechanisms of system control and regulation dynamics of Streptomyces.

Genomic and systems evolution in Vibrionaceae species.

BackgroundThe steadily increasing number of prokaryotic genomes has accelerated the study of genome evolution; in particular, the availability of sets of genomes from closely related bacteria has facilitated the exploration of the mechanisms underlying genome plasticity. The family Vibrionaceae is found in the Gammaproteobacteria and is abundant in aquatic environments. Taxa from the family Vibrionaceae are diversified in their life styles; some species are free living, others are symbiotic, and others are human pathogens. This diversity makes this family a useful set of model organisms for studying bacterial evolution. This evolution is driven by several forces, among them gene duplication and lateral gene transfer, which are believed to provide raw material for functional redundancy and novelty. The resultant gene copy increase in one genome is then detected as lineage-specific expansion (LSE).ResultsHere we present the results of a detailed comparison of the genomes of eleven Vibrionaceae strains that have distinct life styles and distinct phenotypes. The core genome shared by all eleven strains is composed of 1,882 genes, which make up about 31%–50% of the genome repertoire. We further investigated the distribution and features of genes that have been specifically expanded in one unique lineage of the eleven strains. Abundant duplicate genes have been identified in the eleven Vibrionaceae strains, with 1–11% of the whole genomes composed lineage specific radiations. These LSEs occurred in two distinct patterns: the first type yields one or more copies of a single gene; we call this a single gene expansion. The second pattern has a high evolutionary impact, as the expansion involves two or more gene copies in a block, with the duplicated block located next to the original block (a contiguous block expansion) or at some distance from the original block (a discontiguous block expansion). We showed that LSEs involve genes that are tied to defense and pathogenesis mechanisms as well as in the fundamental life cycle of Vibrionaceae species.ConclusionOur results provide evidence of genome plasticity and rapid evolution within the family Vibrionaceae. The comparisons point to sources of genomic variation and candidates for lineage-specific adaptations of each Vibrionaceae pathogen or nonpathogen strain. Such lineage specific expansions could reveal components in bacterial systems that, by their enhanced genetic variability, can be tied to responses to environmental challenges, interesting phenotypes, or adaptive pathogenic responses to host challenges.

Core genome components and lineage specific expansions in malaria parasites Plasmodium

BackgroundThe increasing resistance of Plasmodium, the malaria parasites, to multiple commonly used drugs has underscored the urgent need to develop effective antimalarial drugs and vaccines. The new direction of genomics-driven target discovery has become possible with the completion of parasite genome sequencing, which can lead us to a better understanding of how the parasites develop the genetic variability that is associated with their response to environmental challenges and other adaptive phenotypes.ResultsWe present the results of a comprehensive analysis of the genomes of six Plasmodium species, including two species that infect humans, one that infects monkeys, and three that infect rodents. The core genome shared by all six species is composed of 3,351 genes, which make up about 22%-65% of the genome repertoire. These components play important roles in fundamental functions as well as in parasite-specific activities. We further investigated the distribution and features of genes that have been expanded in specific Plasmodium lineage(s). Abundant duplicate genes are present in the six species, with 5%-9% of the whole genomes composed lineage specific radiations. The majority of these gene families are hypothetical proteins with unknown functions; a few may have predicted roles such as antigenic variation.ConclusionsThe core genome components in the malaria parasites have functions ranging from fundamental biological processes to roles in the complex networks that sustain the parasite-specific lifestyles appropriate to different hosts. They represent the minimum requirement to maintain a successful life cycle that spans vertebrate hosts and mosquito vectors. Lineage specific expansions (LSEs) have given rise to abundant gene families in Plasmodium. Although the functions of most families remain unknown, these LSEs could reveal components in parasite networks that, by their enhanced genetic variability, can contribute to pathogenesis, virulence, responses to environmental challenges, or interesting phenotypes.

Comparative genomics of the family Vibrionaceae reveals the wide distribution of genes encoding virulence-associated proteins.

BackgroundSpecies of the family Vibrionaceae are ubiquitous in marine environments. Several of these species are important pathogens of humans and marine species. Evidence indicates that genetic exchange plays an important role in the emergence of new pathogenic strains within this family. Data from the sequenced genomes of strains in this family could show how the genes encoded by all these strains, known as the pangenome, are distributed. Information about the core, accessory and panproteome of this family can show how, for example, genes encoding virulence-associated proteins are distributed and help us understand how virulence emerges.ResultsWe deduced the complete set of orthologs for eleven strains from this family. The core proteome consists of 1,882 orthologous groups, which is 28% of the 6,629 orthologous groups in this family. There were 4,411 accessory orthologous groups (i.e., proteins that occurred in from 2 to 10 proteomes) and 5,584 unique proteins (encoded once on only one of the eleven genomes). Proteins that have been associated with virulence in V. cholerae were widely distributed across the eleven genomes, but the majority was found only on the genomes of the two V. cholerae strains examined.ConclusionsThe proteomes are reflective of the differing evolutionary trajectories followed by different strains to similar phenotypes. The composition of the proteomes supports the notion that genetic exchange among species of the Vibrionaceae is widespread and that this exchange aids these species in adapting to their environments.

Proteases in malaria parasites - A phylogenomic perspective

Malaria continues to be one of the most devastating global health problems due to the high morbidity and mortality it causes in endemic regions. The search for new antimalarial targets is of high priority because of the increasing prevalence of drug resistance in malaria parasites. Malarial proteases constitute a class of promising therapeutic targets as they play important roles in the parasite life cycle and it is possible to design and screen for specific protease inhibitors. In this mini-review, we provide a phylogenomic overview of malarial proteases. An evolutionary perspective on the origin and divergence of these proteases will provide insights into the adaptive mechanisms of parasite growth, development, infection, and pathogenesis.B