【作者】 刘国庆；

【导师】 李宏；

【作者基本信息】 内蒙古大学 ， 理论物理， 2009， 博士

【摘要】 进化论是整个生物学的指导思想。生命进化的物质基础是变异,而变异的主要来源是突变和重组。如果没有重组,只有突变发生时才能改变基因组,这无疑将大大降低生命进化的效率。减数分裂重组是真核细胞减数分裂过程中同源染色体之间遗传物质的交换。重组过程通过形成交叉对减数分裂期同源染色体的正确分离起到至关重要的作用。除此之外,重组可通过选择或突变的方式在基因组进化过程中扮演着很多重要角色。尽管随着许多真核基因组测序工作的完成和遗传图谱的不断完善,重组与序列之间的相互作用机理一直在被人们探索并发现,但由于重组与各种序列特征之间的相互影响在基因组这个大环境中显得尤为复杂,还有很多未知问题有待探索和解决。二核苷相对丰度谱是反映基因组整体水平上的选择压力或突变偏好性的“基因组指纹”,它在基因组进化研究、系统发生分析中发挥着独特而重要的作用。因此,揭示基因组指纹的形成与进化压力是基因组进化研究的重要内容之一。假基因是丧失蛋白质编码能力的基因拷贝,它从分子水平上记录了基因组序列数百万年的进化路线,为基因组动力学和进化研究提供了理想的材料。尤其,加工假基因由于其反转座起源而在基因组进化研究中备受青睐。揭示加工假基因分布中所蕴含的进化压力对基因组进化研究有重要意义。基于这一思路,本文主要研究了减数分裂重组对基因组序列二核苷偏好性及加工假基因分布和进化的影响,并对其机理性的问题进行了探讨。主要研究内容如下:1.在得到果蝇重组率数据的基础上,研究果蝇基因组中二核苷偏好性和重组率的相关性。结果发现,在整个基因组范围内编码和非编码序列的总体二核苷偏好性均与重组率显著正相关。我们给出了不同二核苷偏好性与重组率的关联模式,并讨论了重组与二核苷偏好性的相互作用机理。就重组如何影响二核苷偏好性这一问题,我们提出了一种新的解释模型,即重组可能通过一种在整个基因组范围内普遍存在的机制——依赖紧邻碱基的基因转换影响二核苷偏好性。2.利用高密度人类遗传图谱得到重组率数据的基础上,研究人类基因组中二核苷偏好性和重组率的关系。结果发现在整个基因组范围内编码序列的总体二核苷偏好性与重组率显著负相关,而对非编码序列来说却显著正相关。另外,给出了具体二核苷偏好性与重组率的关联模式,讨论了重组与二核苷偏好性的相互作用机理,并与果蝇基因组进行了比较。研究结果表明,重组对基因组指纹的形成与进化有着重要作用。3.传统的观点认为,加工假基因在染色体上的插入是随机的。然而,通过分析发现人类加工假基因密度与重组率负相关,这有以下几种可能的解释:重组抑制模型认为,加工假基因可能会通过降低同源染色体同源性的方式起到降低重组率的作用;有害插入模型认为,若加工假基因在染色体上的插入突变是有害的,则在低重组区由于Hill-Robertson干涉较多,选择效率降低,导致加工假基因偏好插入到低重组区;异位重组模型认为,加工假基因在低重组区的偏好分布是对高重组区同源加工假基因之间异位重组事件负选择的结果;弱选择模型认为,由于低重组区Hill-Robertson干涉较多,选择压力会使加工假基因偏好插入到低重组区来减少干涉,促进相邻基因或外显子之间的独立进化。我们还发现,加工假基因密度与基因密度正相关,有两种可能的解释:一、加工假基因在基因密区的插入可能具有选择优势,因为这种插入突变可能有助于提高弱选择位点间的重组频率,从而减少Hill-Robertson干涉并促进相邻基因或外显子的独立进化;二、相比基因分布稀少的区域,异位重组在基因密区较少发生,这可以导致加工假基因较多地保留在基因密区。4.重组抑制模型、有害插入模型、异位重组模型和弱选择模型均有可能解释人类加工假基因密度与重组率之间的负相关性。区分验证这些不同的模型具有重要意义。通过分析发现,相比其它加工假基因,具有异位重组潜能的加工假基因,即同源相邻加工假基因更加偏好分布于低重组区(0.0-0.4 cM/Mb),差异检验也显示同源相邻加工假基因位点的重组率显著低于其它加工假基因重组率(P＜0.0001),这表明同源相邻加工假基因的分布中存在异位重组效应。不具有异位重组潜能的加工假基因也具有偏好分布于低重组区的趋势,这表明加工假基因的分布中还存在与异位重组无关的效应。另外还发现较长的加工假基因更加偏好分布于低重组区的长度效应。更多还原

【Abstract】 Genetic variation is the material basis of evolution that underlies the whole biology. There are two sources of genetic variation, mutation and recombination. Without recombination, genomes would undergo very little change merely by mutations, and the evolution of organisms would be severely restricted. Meiotic recombination occurs as a consequence of the exchange of genetic information between homologous chromosomes during meiosis. Recombination plays a crucial role in disjunction of the homologous chromosomes through generating chiasma. Besides, it plays various important roles in genome evolution either selectively or neutrally. With the increasing success in genome sequencing and construction of genetic maps, much progress has been made in the science of the mechanisms via which the recombination and genome interacts. Due to the complicity of the interaction between the recombination and genomic sequences in the whole genome background, however, many open questions still requires further investigation.The profile of the dinucleotide relative abundances is a "genomic signature" that reflects the overall selective pressures or mutational biases in the genome, and plays a unique and important role in the study of genome evolution and phylogeny. Therefore, revealing the pressures or factors that contribute to the formation and evolution of the genomic signature has been an important issue in the study of genome evolution. Pseudogene is a disabled copy of gene that lost the ability to encode protein. It records the evolution footprints at the molecular level and thus provides an ideal material for the study of the genome dynamics and evolution. Processed pseudogene has been a subject applied more in the study of genome evolution due to its reverse transcribed origin. It is very important to explore the evolutionary pressures that impose on the distribution of the processed pseudogenes. The present paper focus on the effect of the meiotic recombination on dinucletide bias and processed pseudogene distribution, and the underlying mechanisms are discussed. The main contributions are summarized as follows: 1. The recombination data of the Drosophila melanogaster is obtained first and then the correlation between dinucleotide bias and recombination is investigated. The results show that the overall dinucleotide bias is positively correlated with recombination rate for both non-coding and coding sequences. The correlation patterns of individual dinucleotide biases with recombination rate are presented and possible mechanisms of interaction between recombination and dinucleotide bias are discussed. We propose that recombination might influence the dinucleotide bias through a genome-wide universal mechanism, which is likely to be neighbor-dependent biased gene conversion.2. Based on the recombination data obtained from high resolution genetic map of human genome, the correlation between meiotic recombination rate and dinucleotide bias is analyzed. Our results show that the overall dinucleotide bias is positively correlated with recombination rate for coding sequences while negatively correlated for introns and intergenic sequences that both are non-coding sequences. The correlation patterns of individual dinucleotide biases with recombination rate are presented and possible mechanisms of interaction between recombination and dinucleotide bias are discussed comparing human with Drosophila melanogaster. Our results indicate that recombination has been playing an important role in the formation and evolution of the genomic signature.3. It is conventionally thought that the integration of the processed pseudogenes into genome is random. Our analysis, however, shows that the density of the processed pseudogene is correlated negatively with recombination rate and positively with gene density in human genome. Several possible models that could be invoked to explain the phenomena are proposed. The suppressor model describes an effect that processed pseudogene may act as a sppressor of recombination by reducing homology of the homologous chromosmomes. The deleterious insertion model refers to selection against deleterious insertion of processed pseudogene into the genome, which expects an accumulation of processed pseudogenes in regions of reduced recombination where selection efficiency decreased due to Hill-Robertson interference. The ectopic recombination model states processed pseudogenes will accumulate in regions of reduced recombination as a passive consequence of their elimination from high recombination rate regions, where ectopic recombination, supposed to be intense, would have more deleterious effects. The weak selection model, however, assumes that the insertion of processed pseudogenes into regions of low recombination rates might be favored by selection due to its effect of decreasing the Hill-Robertson interference between weakly selected mutations, which allows adjacent genes or exons evolve more efficiently. The positive correlation between processed pseudogene density and gene density has two possible interpretations. First, the processed pseudogene insertion into gene-dense regions might be selectively beneficial, because such insertion, as the effect descrbed in the weak selection model, could increase recombination between weakly selected mutations and facilitate adjacent genes or exons evolve more efficiently. Second, processed pseudogenes tend to be retained more in gene-dense regions than gene-rare regions probably because ectopic recombination less occurs in gene-dense regions.4. Several models including the suppressor model, deleterious insertion model, ectopic recombination model, and weak selection model might explain the negative correlation between the processed pseudogene density and recombination rate. It is of great importance to distinguish the various models. Our analysis shows that the homologous adjacent processed pseudogenes which have the potential of ectopic recombination more preferentially accumulate in the regions of low recombination rate (0.0-0.4 cM/Mb) than other processed pseudogenes, and the recombination rates of the regions where the homologous adjacent processed pseudogenes distribute are significantly lower (P<0.0001) than that corresponds to other processed pseudogenes. The results definitely indicate that there exists selective effect associated with ectopic recombination in the distribution of the homologous adjacent processed pseudogenes. Although not strong as the homologous adjacent processed pseudogenes, the processed pseudogenes that do not have the potential of ectopic recombination also exhibit a biased distribution in regions of low recombination, suggesting the existence of the effects that are not associated with ectopic recombination. Additionally, we found a length effect that long processed pseudogenes more preferentially accumulate in regions of low recombination rates.更多还原