| Summary: | 博士 === 國立臺灣大學 === 動物學研究研究所 === 95 === The mechanisms of how duplicate genes are retained in genomes remain an important question. Retrogenes are those intronless duplicate genes originated from reverse transcriptions of mRNA and integrated into genomic locations which are different from parental genes. More and more retrogenes are identified as being responsible for novel functions in mammals, particularly those involving in male fertilities. In my dissertation, I used insulin genes in rodent as a model for studying evolution of mammalian retrogenes and also identified several X chromosome related novel retrogenes in the mouse genome.
In Chapter 2, we show the first case of the retention of a retrogene by co-adaptive evolution with its parental copy in the mouse genome. Unlike human, preproinsulins previously were identified as a two-gene system with a duplicate retrogene in mouse and rat. Preproinsulin 1 (Ins1) was found to be retroposed from the partial processed mRNA of preproinsulin 2 (Ins2). Here we further demonstrate that Ins1 only exists within the subfamily Murinae, indicating its specificity to the rodent species, and both Ins2 and Ins1 are under strong functional constraints in these species. Interestingly, by examining spectra of nucleotide polymorphisms, we detect positive selection acting on both Ins2 and Ins1 gene regions in the mouse natural population. The analyses of gene flanking regions and substitutions further indicate that the positive Darwinian selection is unique to the gene surrounding regions. The existence of Ins1 was posited to accelerate diabetes in non obese diabetic mice in the previous literatures. Our studies demonstrate the first case of the fixation and adaptation of a retrogene in association with a harmful phenotype, Type 1 Diabetes. Moreover, several amino acid sites were also identified as evolving under positive Darwinian selection in both insulin coding regions. In conclusion, our data suggests a rapid adaptive divergence in the mouse insulin two-gene system and cast the new insight into the mechanisms that retain new gene duplicates in the genomes.
In Chapter 3, we integrated genome-wide investigations and expression analyses to elucidate the evolution of X-related retrogene pairs in rodents. Directional movements of male-related retrogenes have been identified in mammals and flies. Several selection-based mechanisms have been proposed. Testing these selection-based hypotheses requires examinations of evolutionary genetics and expression-related biological properties of these new retrogenes. We demonstrate that all the X-derived autosomal retrogenes evolved a more restricted male function: they are expressed exclusively or predominantly in the testis, particularly, during the late stages of spermatogenesis. In contrast, parental genes are expressed in various tissues and all the spermatogenetic stages. We further observed that positive selection is only targeting on X-derived autosomal retrogenes with new male functions, suggesting that retrogenes may have evolved new testis functions complementary to the parental genes without male specific functions. In the two cases we observed in this study, not only retrogenes but also parental counterparts evolve adaptively, indicating a tendency of increasing in diversity selectively by gene duplication. Furthermore, most retrogenes we identified to have recruited novel sequences as the untranslated regions (UTRs), suggesting evolution of new regulatory elements in these UTRs.
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