重要病原微生物比较基因组研究的生物信息学方法和应用

发布时间：2018-05-16 07:24

本文选题：病原微生物 + 比较基因组学　；参考：《中国科学院研究生院（上海生命科学研究院）》2007年博士论文

【摘要】： 由病原微生物引起的感染,特别是爆发性的疾病,一直是人类健康的主要威胁之一。随着基因组学的发展,越来越多的全基因组序列被测序研究。对基因组序列进行比较分析,并探索基因组序列结构与病原微生物的致病能力的关系的比较基因组学也应运而生,对病原微生物学的研究注入了新的活力。基于我们自己发展的比较基因组生物信息学分析方法和策略,我们对多种病原微生物的基因组序列进行了比较分析。包括能够导致人畜感染的猪链球菌,能引起伴随外源植入的医疗设备感染的表皮葡萄球菌,还有从感染肺炎的艾滋病病人分离得到的酿酒酵母YJM789菌株。在对猪链球菌的研究中,我们首次对已测序的猪链球菌(Streptococcus suis)的两个菌株(P1/7, 89-1591)进行了全面的功能注释和分析比较。比较结果显示两个基因组有1306个同源基因,两菌株中可能的毒性因子大多数具同源性,4个荚膜多糖基因cps2A,2B,2I,2J只在P1/7菌株中发现。另外还第一次在P1/7菌株中鉴定到了8个可能与其致病性相关的基因岛。在表皮葡萄球菌基因组序列分析研究中,通过对ATCC1228菌株和RP62A菌株之间的SNP序列通过dN/dS的值差异的统计学分析找到了的40个可能与致病性相关的基因。生物学功能分析发现,这些基因可分为两类,一类是可能会在逃避免疫系统中起作用的表面蛋白;另一类是对在新的环境中生存非常重要的基因。研究发现其中的甲硫氨酸亚砜还原酶可能会在净化活性氧过程中起作用,随后,我们对两株细菌进行了在有氧化剂存在的条件下的生存能力的试验,试验结果也证实了两株菌在抗氧化生存能力上的差异。在对表皮葡萄球菌和酿酒酵母YJM789菌株的基因组序列分析研究中,我们进行了YJM789的全基因组序列与试验菌株S288c的比较分析,表明两者的基因组之间有59000个SNPs(单核苷酸多态性),和约45Kb的插入缺失。两者在1号染色体的右臂有一段区域的多态性的差异显著的大于其他区域,其中包括5个膜蛋白,分析显示其可能来自于进化上与酵母Saccharomyces paradoxus相近的真菌的基因渗入。而编码多药抗性的基因PDR5,也表现出了与周围区域差异显著的高多态性。另外还发现包括GCN5相关的N-乙酰基转移酶和糖蜜抗性蛋白在内的几个蛋白是从其它的微生物平行转移而来。我们对以上病原微生物物种内的单核苷酸多态序列,插入缺失等这些序列多态,与致病能力的相关性进行了仔细深入的研究。我们的研究为病原微生物的毒性因子的鉴定提供了新的方法,为病原微生物的致病机制的理解提供了新的思路。同时也为以上重要病原微生物的致病机理的分子机制的研究以及防治、疫苗的开发、治疗药物的设计等提供了广泛的基因组学信息。
[Abstract]:Infection caused by pathogenic microorganisms, especially the explosive disease, has been one of the major threats to human health. With the development of genomics, more and more genome sequences have been sequenced. The comparative analysis of genome sequences and the comparison of the relationship between the genome sequence and the pathogenicity of the pathogenic microorganism Comparative genomics has also emerged, which has injected new vitality into the research of pathogenic microbiology.
Based on our own developed comparative genomic bioinformatics analysis methods and strategies, we compare the genome sequences of various pathogenic microorganisms, including Streptococcus suis, which can lead to human and animal infections, which can cause Staphylococcus epidermidis infected with medical equipment with exogenous implantation, and AIDS infected with pneumonia. The isolated strain of Saccharomyces cerevisiae YJM789 was isolated from the patient.
In the study of Streptococcus suis, we made a comprehensive functional annotation and analysis of two strains of Streptococcus suis (Streptococcus suis) (P1/7, 89-1591), which had been sequenced for the first time. The results showed that two genomes had 1306 homologous genes, and the most likely toxicity factors of the two strains were homologous, 4 capsular polysaccharide genes were found. Cps2A, 2B, 2I and 2J were found only in P1/7 strain. In addition, the 8 gene islands related to pathogenicity were identified in P1/7 strain for the first time.
In the genome sequence analysis of Staphylococcus epidermidis, 40 genes related to pathogenicity were found by statistical analysis of the difference between the SNP sequence of the ATCC1228 strain and the RP62A strain through the difference in the value of dN/dS. The biological functional analysis found that these genes could be divided into two categories, one of which might be in the escape of the immune system. The effect of surface proteins; the other is a very important gene for the survival of the new environment. The study found that the methionine sulfoxide reductase may play a role in the purification of reactive oxygen species. Then, we have tested the viability of two strains of bacteria under the presence of oxidants, and the results have also been confirmed. The difference in antioxidant viability between two strains of bacteria.
In the genomic sequence analysis of Staphylococcus epidermidis and Saccharomyces cerevisiae strain YJM789, we compared the whole genome sequence of YJM789 with the test strain S288c, which showed that there were 59000 SNPs (single nucleotide polymorphisms) between the two genomes and the insertion deletion of about 45Kb. Both of them had a section on the right arm of chromosome 1. The polymorphism of the region was significantly greater than that in other regions, including 5 membrane proteins. Analysis showed that it might come from the genetic infiltration of the fungi that were similar to the yeast Saccharomyces paradoxus. The gene PDR5 encoding the multidrug resistance also showed high polymorphism in the surrounding region. In addition, it was found to include GC N5 related N- acetyltransferases and molasses resistant proteins are parallel transferred from other microorganisms.
We studied the polymorphism of single nucleotide polymorphisms in the pathogenic microorganism species, insertion deletion and so on, and studied the correlation with the pathogenicity. Our study provides a new method for the identification of the toxic factors of pathogenic microbes and provides a new idea for the understanding of pathogenic mechanism of pathogenic microbes. It also provides a wide range of genomics information for the molecular mechanism of the pathogenic mechanism of the important pathogenic microbes, the prevention and control of the vaccine, the development of the vaccine, and the design of the therapeutic drugs.

【学位授予单位】：中国科学院研究生院（上海生命科学研究院）
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R37

【引证文献】