The Molecular Features, Genomic Chara Cteristics And Evolutionary Processes Of Developmental Stage-Related Genes

The identification of the correlations between the molecular features of mammalian genes and their patterns of expression, as well as the exploration of the evolutionary processes of these molecular features are fundamental biological issues and remain subjects of controversy. Developmental processes are believed to be of critical importance to the investigation of evolutionary mechanisms. Moreover, stem cells, progenitor cells and their derivates, defined by their distinct differentiation potential, provide ideal models of the mammalian developmental hierarchy. Therefore, in this thesis, we tried to establish the correlations between the molecular features of mammalian genes and their patterns of expression, based on the developmental stage-related patterns of gene expression in models of mouse stem cell differentiation.We established the correlations between the levels of gene expression and codon usage in different cell types. Our results showed that the optimal codons exhibited variation within the developmental hierarchy. Specifically, in certain mouse stem cells and progenitor cells in early developmental stages of ontogeny, the optimal codons were the AT-ending ones, while the mouse major codons are the GC-ending ones. We also found that genes that were enriched (developmental-pivotal genes, DPGs) or specifically expressed (developmental-specific genes, DSGs) at different developmental stages had different patterns of codon usage. Moreover, at the same developmental stage, DSGs generally used more GC-ending codons compared with DPGs. Further analyses suggest that the model of translational selection might be consistent with the developmental stage-related patterns of codon usage, especially for the AT-ending optimal codons.It has been indicated that codon usage (GC3) and local genomic GC content (GCg) are closely correlated in mammalian genome. Our results also showed that the variations of GCg were correlated with the developmental-stage related patterns of gene expression. We further investigated the distribution and organization of developmental stage-related genes in mouse chromosomes. We found that the distributions of genes corresponding to each developmental stage were not homogeneous among different chromosomes, suggesting the contributions of different chromosomes could be distinct at each developmental stage. We also observed that many developmental stage- related genes were organized as clusters in chromosomes. Moreover, genes within clusters generally used more GC-ending codons than genes out of the clusters. By a comparative genomics approach, we further investigated the origin and the evolutionary processes of developmental stage-related genes. First, our data showed that the evolutionary rates of highly expressed genes were lower than that of mid-lowly expressed genes, indicating the influence of selective constraints on highly expressed genes was still detectable after the human-mouse and mouse-rat divergence. In contrast with these observations, DPGs and DSGs generally had higher evolutionary rates than non-developmental-pivotal genes (NDPGs). The higher rates might infer different functional constraints of these genes after the human-mouse and mouse–rat divergence. Second, we indicated that there were similar patterns of codon usage among orthologous genes of warm-blood vertebrates. These results suggested that the codon usage biases of mouse genes were formed in the common ancestor of warm-blood vertebrates. Third, we found highly expressed genes and NDPGs, compared with mid-lowly expressed genes and developmental-selectively expressed genes (DPGs and DSGs) respectively, could find more orthologous genes in genome of fruit fly. We also showed that both expression patterns and molecular features were correlated with the age of mouse genes.The investigations above are dependent on the published high-throughput studies of stem cells and their derivates from ectoderm and mesoderm. We in turn to explore whether the codon usage, genomic GC content, gene distribution, and gene age are also correlated with the developmental stage- related patterns of gene expression in differentiation processes of endoderm. We defined a precursor cell population from adult mouse pancreas by selective culture. We found these precursor cells were located in the islets and around the pancreatic ducts. Based on the analyses of the expression profiling of both this pancreatic precursor cell population and mouse islets, our data showed that the molecular features, genomic characteristics and evolutionary processes are also correlated with developmental-stage related patterns of gene expression in endoderm, generally consistent with the observations in ectoderm and mesoderm.Using the models of stem cell differentiation, the current study provides certain useful clues of evolutionary issues at the molecular level. For example, we showed new patterns of mammalian codon usage and new evidence of the presence of natural selection at mammalian synonymous sites. Moreover, our data also assist our understanding of the biological meaning of genomic GC content and the evolutionary processes of mammalian genes.The current study has applied theoretical analyses of molecular evolution into stem cell research to gain a better understanding of stem cell differentiation at the genomic level. For example, we found that mammalian genes that specifically expressed at different developmental stages bear different molecular features. In addition, we also suggested that the genome segments that are involved in chromatin remodeling might correlate with their GC content. Further investigation will be needed to better understand the significance and implications of the findings presented here.