Rapid and asymmetric divergence of duplicate genes in the human gene coexpression network

BACKGROUND: While gene duplication is known to be one of the most common mechanisms of genome evolution, the fates of genes after duplication are still being debated. In particular, it is presently unknown whether most duplicate genes preserve (or subdivide) the functions of the parental gene or acquire new functions. One aspect of gene function, that is the expression profile in gene coexpression network, has been largely unexplored for duplicate genes. RESULTS: Here we build a human gene coexpression network using human tissue-specific microarray data and investigate the divergence of duplicate genes in it. The topology of this network is scale-free. Interestingly, our analysis indicates that duplicate genes rapidly lose shared coexpressed partners: after approximately 50 million years since duplication, the two duplicate genes in a pair have only slightly higher number of shared partners as compared with two random singletons. We also show that duplicate gene pairs quickly acquire new coexpressed partners: the average number of partners for a duplicate gene pair is significantly greater than that for a singleton (the latter number can be used as a proxy of the number of partners for a parental singleton gene before duplication). The divergence in gene expression between two duplicates in a pair occurs asymmetrically: one gene usually has more partners than the other one. The network is resilient to both random and degree-based in silico removal of either singletons or duplicate genes. In contrast, the network is especially vulnerable to the removal of highly connected genes when duplicate genes and singletons are considered together. CONCLUSION: Duplicate genes rapidly diverge in their expression profiles in the network and play similar role in maintaining the network robustness as compared with singletons. Contact: [email protected] Supplementary information: Please see additional files

Distinct expression and methylation patterns for genes with different fates following a single whole-genome duplication in flowering plants

For most sequenced flowering plants, multiple whole-genome duplications (WGDs) are found. Duplicated genes following WGD often have different fates that can quickly disappear again, be retained for long(er) periods, or subsequently undergo small-scale duplications. However, how different expression, epigenetic regulation, and functional constraints are associated with these different gene fates following a WGD still requires further investigation due to successive WGDs in angiosperms complicating the gene trajectories. In this study, we investigate lotus (Nelumbo nucifera), an angiosperm with a single WGD during the K–pg boundary. Based on improved intraspecific-synteny identification by a chromosome-level assembly, transcriptome, and bisulfite sequencing, we explore not only the fundamental distinctions in genomic features, expression, and methylation patterns of genes with different fates after a WGD but also the factors that shape post-WGD expression divergence and expression bias between duplicates. We found that after a WGD genes that returned to single copies show the highest levels and breadth of expression, gene body methylation, and intron numbers, whereas the long-retained duplicates exhibit the highest degrees of protein–protein interactions and protein lengths and the lowest methylation in gene flanking regions. For those long-retained duplicate pairs, the degree of expression divergence correlates with their sequence divergence, degree in protein–protein interactions, and expression level, whereas their biases in expression level reflecting subgenome dominance are associated with the bias of subgenome fractionation. Overall, our study on the paleopolyploid nature of lotus highlights the impact of different functional constraints on gene fate and duplicate divergence following a single WGD in plant

Evolution of Stress-Regulated Gene Expression in Duplicate Genes of Arabidopsis thaliana

Due to the selection pressure imposed by highly variable environmental conditions, stress sensing and regulatory response mechanisms in plants are expected to evolve rapidly. One potential source of innovation in plant stress response mechanisms is gene duplication. In this study, we examined the evolution of stress-regulated gene expression among duplicated genes in the model plant Arabidopsis thaliana. Key to this analysis was reconstructing the putative ancestral stress regulation pattern. By comparing the expression patterns of duplicated genes with the patterns of their ancestors, duplicated genes likely lost and gained stress responses at a rapid rate initially, but the rate is close to zero when the synonymous substitution rate (a proxy for time) is >∼0.8. When considering duplicated gene pairs, we found that partitioning of putative ancestral stress responses occurred more frequently compared to cases of parallel retention and loss. Furthermore, the pattern of stress response partitioning was extremely asymmetric. An analysis of putative cis-acting DNA regulatory elements in the promoters of the duplicated stress-regulated genes indicated that the asymmetric partitioning of ancestral stress responses are likely due, at least in part, to differential loss of DNA regulatory elements; the duplicated genes losing most of their stress responses were those that had lost more of the putative cis-acting elements. Finally, duplicate genes that lost most or all of the ancestral responses are more likely to have gained responses to other stresses. Therefore, the retention of duplicates that inherit few or no functions seems to be coupled to neofunctionalization. Taken together, our findings provide new insight into the patterns of evolutionary changes in gene stress responses after duplication and lay the foundation for testing the adaptive significance of stress regulatory changes under highly variable biotic and abiotic environments

Coding region structural heterogeneity and turnover of transcription start sites contribute to divergence in expression between duplicate genes

Gene expression data for duplicated gene pairs in humans provides insights into the regulatory factors affecting the expression divergence of these genes and implications for their evolution

Protein interactions across and between eukaryotic kingdoms: networks, inference strategies, integration of functional data and evolutionary dynamics

Thesis (Ph.D.)--Boston UniversityHow cellular elements coordinate their function is a fundamental question in biology. A crucial step towards understanding cellular systems is the mapping of physical interactions between protein, DNA, RNA and other macromolecules or metabolites. Genome-scale technologies have yielded protein-protein interaction networks for several eukaryotic species and have provided insight into biological processes and evolution, but many of the currently available networks are biased. Towards a true human protein-protein interaction network, we examined literature-based aggregations of lowthroughput experiments, high-throughput experimental networks validated using different strategies, and predicted interaction networks to infer how the underlying interactome may differ from current maps. Using systematically mapped interactome networks, which appear to be the least biased, we explored the functional organization of Arabidopsis thaliana and characterize the asymmetric divergence of duplicated paralogous proteins through their interaction profiles. To further dissect the relationship between interactions and function enforced by evolution, we investigated a first-of-its-kind systematic crossspecies human-yeast hybrid interactome network. Although the cross-species network is topologically similar to conventional intra-species networks, we found signatures of dynamic changes in interaction propensities due to countervailing evolutionary forces. Collectively, these analyses of human, plant and yeast interactome networks bridge separate experiments to characterize bias, function and evolution across eukaryotic kingdoms

Always read the introduction : integrating regulatory and coding sequence evolution in yeast

We analyze duplicate genes in a yeast, Saccharomyces cerevisiae with the aim of determining a genes history and to observe that gene in its genomic context. In Chapter 2 we show that the fate of a duplicate gene pair is in part determined by its genome location. Moreover, we show that for two classes of duplicate genes, resulting from either small-scale duplication or whole-genome duplication, this fate can often be assessed by measuring the patterns of asymmetry in the sequence divergence of the genes in question. In Chapter 3 we study duplicate genes in the context of their local environments by comparing the patterns of evolution in the coding sequences of duplicate genes for ribosomal proteins with their upstream non-coding sequences. We found that while the coding sequences show strong evidence of recent gene conversion events, similar patterns are not seen in the non-coding regulatory elements. These duplicated ribosomal proteins are not functionally redundant despite their very high degree of protein sequence identity. This analysis confirms that the duplicated proteins have diverged considerably in expression despite their similar protein sequences. In Chapter 4 we analyze the structure of the transcriptional regulation network and characterize the molecular evolution of both its transcriptional regulators and their regulated genes. We found that both subfunctionalization and neofunctionalization of transcription factor binding play a role in divergence

Tissue-Specificity of Gene Expression Diverges Slowly between Orthologs, and Rapidly between Paralogs.

The ortholog conjecture implies that functional similarity between orthologous genes is higher than between paralogs. It has been supported using levels of expression and Gene Ontology term analysis, although the evidence was rather weak and there were also conflicting reports. In this study on 12 species we provide strong evidence of high conservation in tissue-specificity between orthologs, in contrast to low conservation between within-species paralogs. This allows us to shed a new light on the evolution of gene expression patterns. While there have been several studies of the correlation of expression between species, little is known about the evolution of tissue-specificity itself. Ortholog tissue-specificity is strongly conserved between all tetrapod species, with the lowest Pearson correlation between mouse and frog at r = 0.66. Tissue-specificity correlation decreases strongly with divergence time. Paralogs in human show much lower conservation, even for recent Primate-specific paralogs. When both paralogs from ancient whole genome duplication tissue-specific paralogs are tissue-specific, it is often to different tissues, while other tissue-specific paralogs are mostly specific to the same tissue. The same patterns are observed using human or mouse as focal species, and are robust to choices of datasets and of thresholds. Our results support the following model of evolution: in the absence of duplication, tissue-specificity evolves slowly, and tissue-specific genes do not change their main tissue of expression; after small-scale duplication the less expressed paralog loses the ancestral specificity, leading to an immediate difference between paralogs; over time, both paralogs become more broadly expressed, but remain poorly correlated. Finally, there is a small number of paralog pairs which stay tissue-specific with the same main tissue of expression, for at least 300 million years

Preferential regulation of duplicated genes by microRNAs in mammals

Analysis of duplicate genes and predicted microRNA targets in human and mouse shows that microRNAs are important in how the regulatory patterns of mammalian paralogs have evolved