Research On The Mechanism Of Functional Divergence Between Yeast Duplicate Genes

Gene duplication with subsequent functional divergence is generally thought to be a major driving force for genome evolution, and is one of reasons for the origin of organismal complexity, the introduction of genes with new functions and generating a new species. The study of functional divergence between duplicate genes is the primary aim in functional genomics, and is very important for us to understand the origin of new genes and organism evolution. In this study, using genome-wide functional genomic data (mainly yeast), we conducted an extensive phylogenetic analysis and related statistical processing to investigate how the function of these duplicate genes diverged, and finally were fixed and retained in the genome. Our research focusing is on the evolution of three transcriptional regulatory factors cis-regulatory element (TATA box), trans-regulatory element (trans-acting eQTL) and epigenetic modification (histone modification), after gene duplication, as well as the mechanism uncovering of functional compensation between duplicate genes. The main findings are as follows:1) We observed that TATA box (stress response related cis-regulatory element) is significantly overrepresented in duplicate genes compared with singletons in human, worm, Arabidopsis and yeast genomes. To further study the evolution of the TATA box after gene duplications, we reconstructed ancestral TATA box status of over 700 yeast gene family phylogenies, and found ancestors of most yeast gene families were TATA box absent, and significantly higher number of TATA box gain events than loss events had occurred since the gene duplication---the overall gain-loss ratio is about 3-4 to 1. Interestingly, these TATA-gain duplicate genes are evidently enriched in stress-associated functional categories (other TATA-containing duplicate genes usually involved in metabolic related processes), and on average have experienced greater expression divergence under environmental stress conditions (the asymmetric evolution). Together, we thus conclude that after the gene duplication, gain of the TATA box in duplicate promoters may have played an important role in yeast duplicate preservation by accelerating expression divergence that may facilitate the adaptive evolution of organism in response to environmental changes.2) After yeast genomic eQTL data analysis, we found duplicate genes have higher heritability for gene expression than single copy genes, but little difference in their epistasis and directional effect; The divergence of trans-acting eQTLs between duplicate pairs increases with the evolutionary time since the gene duplication; Trans-acting eQTL divergence can explain about 21% of the variation in expression divergence between duplicate genes, which increases to 27% when the TF-target interaction divergence was combined; Trans-acting eQTL divergence between duplicate pairs is correlated with gene ontology (GO) categories'Biological processes'and Cellular components', but not with'Molecular functions'. We consider that eQTL analysis provides a novel sight or approach to explore the effect of gene duplications on the genetic regulatory network.3) Analyzing yeast genome-wide histone modification profile data, we noticed that duplicate genes share more common hisotone modification pattern both associated with promoter and coding regions (ORF) than singletons. Moreover, both promoter and ORF histone modification divergence between duplicate genes are coupled with the evolution of coding sequence,trans-regulators and cis-regulators of duplicates. Further analysis revealed that trans-regulator-targeted duplicate genes experienced more rapid histone modification divergence. We speculate that during gene duplication, histone modification profile of genes was also duplicated; after that, histone modification profile between duplicate genes diverges with the evolution of other genetic characters like sequence or regulatory factor of duplicate genes.4) We proposed two hypotheses on functional compensation of duplicate genes. One is environment-specific loss of functional compensation models:because of the selection from natural environment, the extant duplicate genes were required and uncompensable for the survival and reproduction of organism in certain period or specific environments of evolutionary history?Functional compensation of duplicates was lost in these environments. The other one is gene network-protein function hypothesis:to avoid being pseudogenizated, duplicate genes should undergo functional divergence (except for genes under positive selection). If regulatory network of duplicates firstly evolves, protein function has the chance not to be diverged, leading to high functional compensation effect for these duplicate genes; otherwise, if protein function of duplicates diverges first, the regulatory network can evolve slowly, but effect of functional compensation for duplicates are also largely weakened. We gave the evidence to support these two hypotheses. Our research provides the new insight into genetic robustness against null mutation.