結(jié)核分枝桿菌北京家族菌株的起源、進(jìn)化及其與現(xiàn)代人類(lèi)遷移的聯(lián)系
發(fā)布時(shí)間：2019-06-25 11:47
【摘要】：我國(guó)是全球22個(gè)結(jié)核高負(fù)擔(dān)國(guó)家之一,結(jié)核病人數(shù)位居世界第二。我國(guó)的結(jié)核疫情主要由結(jié)核分枝桿菌北京家族菌株(簡(jiǎn)稱(chēng)北京菌株)所致。該菌株在東亞各國(guó)高度流行,并在全球廣泛傳播。在表型上,北京菌株通常被認(rèn)為具有更強(qiáng)的致病性和耐藥性,但不同實(shí)驗(yàn)或地區(qū)的結(jié)果并不一致；在基因型上,北京菌株被認(rèn)為是一個(gè)遺傳相似度極高的群體,但近期大量分型或測(cè)序數(shù)據(jù)提示該群體內(nèi)部存在一定的遺傳差異性。目前為止,北京菌株的遺傳結(jié)構(gòu)仍缺乏系統(tǒng)的研究；北京菌株的起源問(wèn)題也存在爭(zhēng)議。了解北京菌株的起源、進(jìn)化和傳播歷史對(duì)進(jìn)一步認(rèn)識(shí)其在全球的廣泛分布及其致病性和耐藥性有重要意義。 通過(guò)對(duì)從全球范圍內(nèi)收集的58株北京菌株的22個(gè)3R基因進(jìn)行測(cè)序分析,我們首先建立了北京菌株高分辨率的系統(tǒng)發(fā)生樹(shù)；根據(jù)該系統(tǒng)樹(shù),北京菌株可被進(jìn)一步分為多個(gè)相互間具有一定遺傳距離的亞型。隨后通過(guò)對(duì)305株北京菌株進(jìn)行單核苷酸多態(tài)性(SNP)分型,我們進(jìn)一步研究了全球北京菌株的群體結(jié)構(gòu)。分型結(jié)果提示,全球范圍流行的北京菌株主要由一個(gè)近期進(jìn)化出的Bmyc10亞型所致。 為了進(jìn)一步探索北京菌株的起源、進(jìn)化及其與人類(lèi)遷移的聯(lián)系,我們對(duì)全國(guó)范圍內(nèi)11個(gè)省市收集的北京菌株進(jìn)行了SNP分型。同時(shí)我們從上海市收集的北京菌株中挑選了各亞型的代表菌株(共計(jì)39株)進(jìn)行全基因組測(cè)序。聯(lián)合已發(fā)表的22個(gè)結(jié)核全基因組測(cè)序數(shù)據(jù),我們構(gòu)建了全基因組系統(tǒng)發(fā)生樹(shù)；同時(shí),通過(guò)貝葉斯進(jìn)化分析我們推算了北京及其亞型菌株的起源年代。根據(jù)該系統(tǒng)發(fā)生樹(shù),我們發(fā)現(xiàn)前期在東南亞地區(qū)分離的“前北京”菌株代表了北京菌株祖先最早分化的一個(gè)分枝；而對(duì)全國(guó)范圍內(nèi)的菌株分型結(jié)果表明“前北京”菌株非常稀少且僅存在于我國(guó)南方地區(qū)(廣西、福建、浙江和四川)。時(shí)間推算結(jié)果顯示北京菌株的起源年代為距今2-3萬(wàn)年左右,該時(shí)間和東亞人口在東南亞起源的年代完全相符。綜上我們推斷北京菌株很可能起源于東南亞和我國(guó)南方交界的地區(qū)。 北京家族各亞型菌株在11個(gè)省市的分布表明,早期分化的“古老”型菌株在全國(guó)廣泛存在,且在西藏和日韓等地為主要流行菌株。聯(lián)合東亞早期人口遷移路線(xiàn),我們推測(cè)北京菌株在東南亞一帶起源后,隨著人群從南向北的遷移傳播到我國(guó)大部分地區(qū)并到達(dá)日韓等地�！艾F(xiàn)代”型菌株是我國(guó)除西藏外其他地區(qū)的主要流行菌株,其在漢族人群中的比例顯著高于在少數(shù)名族人群中的比例。而漢族人群中,北方人群中的比例顯著高于南方。因此我們推測(cè)“現(xiàn)代”型菌株可能起源于北方漢族的祖先人群中。全基因組系統(tǒng)發(fā)生樹(shù)顯示“現(xiàn)代”型菌株在距今約6000年前發(fā)牛了次大規(guī)模的擴(kuò)張,這與“新石器”時(shí)期農(nóng)業(yè)產(chǎn)生后仰韶社會(huì)人群(北方漢族祖先)擴(kuò)張的年代完全相符,從而進(jìn)一步證明了“現(xiàn)代”菌株很可能起源于我國(guó)北方。北方漢族人群在近2000多年的時(shí)間在東亞發(fā)生了大規(guī)模擴(kuò)張和遷移,我們推測(cè)“現(xiàn)代”型菌株在我國(guó)及東亞各地區(qū)廣泛的分布很可能與漢族人群的遷移相關(guān)。在漢族人口較少的西藏和日韓等地,“現(xiàn)代”型菌株比例甚至低于“古老”型,從而進(jìn)一步證明了這一假設(shè)。 “現(xiàn)代”型北京菌株在早期北方人群中的擴(kuò)張及后來(lái)在東亞及世界各地廣泛流行都提示該亞型菌株很可能具有較強(qiáng)的致病性。我們相信通過(guò)更深入的比較基因組學(xué)研究很可能找出該亞型菌株菌株成為優(yōu)勢(shì)菌株的遺傳學(xué)機(jī)制。另外,“現(xiàn)代”菌株在我國(guó)的高度流行提示結(jié)防部門(mén)需加大病例發(fā)現(xiàn)和早期診斷的力度,從而降低該菌株在人群中的傳播和進(jìn)一步擴(kuò)張。 “現(xiàn)代”型北京菌株在我國(guó)龐大群體數(shù)量及菌株間高度的遺傳相似性使得研究該菌株的近期傳播比較困難。目前歐美推行的15和24位點(diǎn)可變串聯(lián)重復(fù)序列(VNTR)分型方法在運(yùn)用于我國(guó)流行的北京菌株群體時(shí)往往存在簇病例間無(wú)流行病學(xué)聯(lián)系的情況。通過(guò)對(duì)上海市崇明地區(qū)以人群為基礎(chǔ)收集的191株北京菌株進(jìn)行15位點(diǎn)VNTR和8位點(diǎn)SNP分型,我們發(fā)現(xiàn)5個(gè)15位點(diǎn)定義的簇菌株包含了兩個(gè)或多個(gè)北京亞型的菌株。通過(guò)聯(lián)合VNTR和SNP構(gòu)建系統(tǒng)樹(shù),我們證明以上現(xiàn)象一方面是由于15位點(diǎn)VNTR對(duì)“現(xiàn)代”型菌株分辨力偏低所致；另一方面,“現(xiàn)代”型菌株間通過(guò)趨同或平行進(jìn)化形成的VNTR基因型非同源相似性也會(huì)導(dǎo)致錯(cuò)誤的定義簇菌株。所以,我們推薦聯(lián)合SNP和VNTR分型在“現(xiàn)代”型北京菌株高度流行的地區(qū)進(jìn)行分子流行病學(xué)研究。但目前為止,仍缺乏統(tǒng)一的VNTR分型方案用于我國(guó)結(jié)核分子流行病學(xué)研究。標(biāo)準(zhǔn)的15和24位點(diǎn)VNTR因其位點(diǎn)數(shù)較多且很多位點(diǎn)分辨力較低而不太適用于我國(guó)結(jié)核分型。通過(guò)對(duì)篩選的24個(gè)位點(diǎn)在全國(guó)范圍6個(gè)地區(qū)以人群為基礎(chǔ)收集的1375株菌株中進(jìn)行分辨力及各種VNTR組合的HGI值進(jìn)行研究,我們挑選了廣泛適用的10個(gè)VNTR位點(diǎn)(MIRU10,26,31,40; QUB11b,18,26; Mtub04,21及ETR-A)作為研究我國(guó)結(jié)核分子流行病學(xué)的一線(xiàn)分型方案。這10個(gè)位點(diǎn)聯(lián)合3個(gè)高變位點(diǎn)及QUB11a作為二線(xiàn)分型方案,可準(zhǔn)確的定義不同地區(qū)菌株的近期傳播。 全基因組比對(duì)的結(jié)果表明,北京各亞型菌株間存在一定的遺傳學(xué)差異。我們推測(cè)這些差異會(huì)導(dǎo)致不同亞型菌株間對(duì)抗生素適應(yīng)性的異同。通過(guò)對(duì)上海市疾控中心2004-2008年收集的242個(gè)耐多藥菌株進(jìn)行SNP分型及一線(xiàn)藥物耐藥突變分析,我們發(fā)現(xiàn)高度流行的“現(xiàn)代”型北京菌株在rpoB531位點(diǎn)的突變頻率較其在其它亞型菌株高(OR=1.8,P=0.04)；而在幾個(gè)低度流行的“古老”亞型菌株中,利福平耐藥突變主要分布在rpoB531和rpoB526位點(diǎn)以外(OR=3.16,P0.01)。rpoB531和ropB526位點(diǎn)的突變由于對(duì)細(xì)菌適應(yīng)力的損傷較低,被認(rèn)為是導(dǎo)致利福平耐藥的優(yōu)勢(shì)突變�！艾F(xiàn)代”型菌株可能具有更強(qiáng)的致病性使其在病人體內(nèi)具有更高的菌載量,從而更易篩選出攜帶優(yōu)勢(shì)突變的耐藥菌株。根據(jù)這242個(gè)耐多藥菌株的突變特征,我們篩選出了11個(gè)位點(diǎn)用于預(yù)測(cè)一線(xiàn)藥物耐藥表型。該11位點(diǎn)可預(yù)測(cè)93.8%利福平耐藥,89.3%異煙肼耐藥及86.8%耐多藥表型�；谶@些突變位點(diǎn),我們進(jìn)一步研發(fā)了一種基于實(shí)時(shí)熒光PCR探針溶解曲線(xiàn)分析的新技術(shù)用于耐藥結(jié)核的快速診斷。由于該方法只用了一種熒光標(biāo)記的探針,所以成本較低且可廣泛適用于各種熒光PCR檢測(cè)平臺(tái)。 綜上,本論文通過(guò)研究結(jié)核北京菌株的起源和進(jìn)化進(jìn)一步揭示了結(jié)核的傳播與現(xiàn)代人類(lèi)遷移、擴(kuò)張之間密切的聯(lián)系。我們的結(jié)論為進(jìn)一步研究結(jié)核菌致病機(jī)制提供了重要線(xiàn)索。同時(shí)我們?yōu)槲覈?guó)結(jié)核分子流行病學(xué)研究提供了可靠的、廣泛適用的分型方案；為耐藥結(jié)核的快速診斷提供了可靠的分子生物學(xué)方法。
[Abstract]:China is one of the 22 high-burden countries in the world, and the number of tuberculosis is the second in the world. The tuberculosis epidemic in China is mainly caused by the Beijing family strain of Mycobacterium tuberculosis (the Beijing strain). The strain is highly popular in the East Asian countries and is widely disseminated in the world. In the phenotype, the Beijing strain is generally considered to have stronger pathogenicity and drug resistance, but the results of different experiments or regions are not consistent; in the genotype, the Beijing strain is considered to be a highly genetic population, However, in recent years, a lot of typing or sequencing data suggest that there is a certain genetic difference within the population. So far, the genetic structure of the Beijing strain still lacks a systematic study, and the origin of the Beijing strain is also controversial. To understand the origin, evolution and propagation history of the Beijing strain, it is of great significance to further know its wide distribution and its pathogenicity and drug resistance in the world. By sequencing and analyzing the 22 3R genes of 58 Beijing strains collected worldwide, we first set up a high-resolution system-generating tree of Beijing strain. According to the system tree, the Beijing strain can be further divided into a plurality of sub-regions with a certain genetic distance from each other. Then, by using the single nucleotide polymorphism (SNP) of 305 Beijing strains, we further studied the group knot of the global Beijing strain. The results suggest that the global-wide Beijing strain is mainly composed of a recently-developed Bmyc10 subtype. To further explore the origin and evolution of the Beijing strain and its relation to human migration, we have carried out the SN of the Beijing strain collected in 11 provinces and cities throughout the country. P. At the same time, we selected the representative strains of each subtype (total of 39 strains) from the Beijing strain collected in Shanghai to carry out the whole gene. Group sequencing. The whole genome sequencing data of 22 nodules that have been published, we constructed the whole genome phylogenetic tree; at the same time, through the Bayesian evolution analysis, we calculated the origin of the Beijing and its subtype strains In the source age, according to the phylogenetic tree, we found that the "Former Beijing" strains isolated in the early stage represent the first branch of the earliest differentiation of the ancestors of the Beijing strain; and the typing of the strains in the whole country shows that the "Former Beijing" strains are very rare and only exist in the southern region of China (Guangxi, Fujian, Zhejiang and The time-reckoning result shows that the origin of the Beijing strain is about 2-30,000 years, and the time and the East Asian population are over the period of the origin of South-East Asia. Overall, we conclude that the Beijing strain is likely to originate from South-East Asia and the southern border of our country The distribution of each subtype of the Beijing family in 11 provinces shows that the early-differentiated "ancient"-type strain is widely present in the whole country, and it is mainly in Tibet and Japan in combination with that early population migration route in east Asia, we have speculated that the Beijing strain, after the origin of the south-east Asia region, has spread to most of our region with the migration of the population from south to north, The "modern"-type strain is the main epidemic strain of China except Tibet, the proportion of which is significantly higher in the Han population than in the minority. The proportion of the population in the population, and the proportion of the northern population in the Han population It's higher than the South. So we're speculating that the "modern"-type strain may have originated in the northern Han population The phylogenetic tree of the whole genome shows that the "modern"-type strain has been expanded on a large scale from about 6000 years ago, which is the same as that of the back-up social group (the ancestors of the northern Han people) after the agricultural production in the "Neolithic" period. The generation of the "modern" strain is further proved to be of the origin In the northern part of China, the large-scale expansion and migration of the Chinese Han population in East Asia over the last 2000 years, we have speculated that the modern "-type strain is widely distributed in the regions of China and East Asia and is likely to be the same as that of the Han population The proportion of the "modern"-type strain is even lower than that of the "ancient" type in the Tibetan and Japanese-Korean and other places in the Han population. This assumption is that the expansion of the "modern"-type Beijing strain in the early population of the North and later in East Asia and the wide spread of the world suggest that the subtype strain is likely to be It is highly pathogenic. We believe that by a more in-depth comparative genomics study, it is possible to identify the strain of this subtype as an advantage. In addition, the high prevalence of the "modern" strain in China suggests that the prevention and control department need to increase the number of case discovery and early diagnosis, so as to reduce the transmission of the strain in the population The genetic similarity of "modern"-type Beijing strain on the number of large population and the height of the strain in China, so as to study the strain The recent communication between the 15 and 24-site variable tandem repeats (VNTR) in Europe and the United States has been applied to the popular Beijing strain population in China, and there is often no cluster case among the cluster cases. According to the epidemiological connection, we found that five 15-site-defined cluster strains contained two or more of the 191 Beijing strains collected on the basis of the population-based population in Chongming, Shanghai. A number of strains of the Beijing Subtype. The system tree was constructed by the combination of VNTR and SNP, and we prove that the above phenomenon is due to the 15-site VNTR's resolution of the "modern"-type strain On the other hand, the non-homologous similarity of the VNTR genotypes formed by the convergent or parallel evolution between the "modern"-type strains can also guide The wrong definition of cluster strains. Therefore, we recommend the combination of SNP and VNTR typing in the highly popular region of the "modern"-type Beijing strain To date, there is still a lack of a unified VNTR classification scheme for the junction of our country. Nuclear molecular epidemiological studies. The standard 15 and 24 sites, VNTR, are not too numerous and have a low resolution of many sites We selected a wide range of 10 VNTR sites (MIRU10,26,31,40; QUB) by conducting a study on the resolution of the screened 24 sites in a population-based 1375 strain and a variety of VNTR-combined HGI values in a population-based collection of 1375 strains in six regions of the country (11b,18,26; Mtb04,21 and ETR-A) as a study of the prevalence of tuberculosis in China The first line of the disease is a first-line classification scheme. The 10 sites are combined with 3 high-displacement points and QUB11a as the two-line classification scheme, and the exact definition is different. Short-term spread of the regional strains. The results of the full-genome comparison show that all the strains of Beijing There is a certain genetic difference between them. We are speculating that these differences can lead to different subtype strains We found that the mutation frequency of the high-prevalence "modern"-type Beijing strain at the rpoB531 site is higher than that of other subtype strains (OR =) by using the SNP typing and the first-line drug-resistance mutation analysis of 242 drug-resistant strains collected in the disease control center in Shanghai in 2004-2008. 1.8, P = 0.04); whereas in several low-prevalence "ancient" subtype strains, rifampin-resistant mutations were mainly distributed outside the rpoB531 and rpoB526 sites (OR = 3.16, P0.01). The mutation at the rpoB531 and pB526 sites is considered to be a guide due to the low damage to the bacterial strain The "modern"-type strain may have stronger pathogenicity so that it has higher bacterial load in the patient and is more easily screened out. The resistance strain carrying the dominant mutation is screened out for 11 sites according to the mutation characteristics of the 242 multi-drug resistant strains. The first-line drug-resistant phenotype was predicted. The 11-site could be predicted to be 93.8% rifampin resistance and 89.3% of the drug-resistant drug resistance. and 86.8% of the multi-drug resistant phenotype. Based on these mutation sites, we further developed a new technology based on real-time fluorescence PCR probe dissolution profile analysis The method has the advantages of low cost and wide application to the rapid diagnosis of drug-resistant tuberculosis, In this paper, we study the origin and evolution of the Beijing strain of the tuberculosis, and further reveal the transmission of the tuberculosis and the modern people. A close link between the migration and expansion of the class. Our conclusion is to further study the knot. At the same time, we provide a reliable and widely applicable classification scheme for the epidemiological study of tuberculosis in our country, and provide a rapid diagnosis for drug-resistant tuberculosis.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R378.911
本文編號(hào)：2505659
[Abstract]:China is one of the 22 high-burden countries in the world, and the number of tuberculosis is the second in the world. The tuberculosis epidemic in China is mainly caused by the Beijing family strain of Mycobacterium tuberculosis (the Beijing strain). The strain is highly popular in the East Asian countries and is widely disseminated in the world. In the phenotype, the Beijing strain is generally considered to have stronger pathogenicity and drug resistance, but the results of different experiments or regions are not consistent; in the genotype, the Beijing strain is considered to be a highly genetic population, However, in recent years, a lot of typing or sequencing data suggest that there is a certain genetic difference within the population. So far, the genetic structure of the Beijing strain still lacks a systematic study, and the origin of the Beijing strain is also controversial. To understand the origin, evolution and propagation history of the Beijing strain, it is of great significance to further know its wide distribution and its pathogenicity and drug resistance in the world. By sequencing and analyzing the 22 3R genes of 58 Beijing strains collected worldwide, we first set up a high-resolution system-generating tree of Beijing strain. According to the system tree, the Beijing strain can be further divided into a plurality of sub-regions with a certain genetic distance from each other. Then, by using the single nucleotide polymorphism (SNP) of 305 Beijing strains, we further studied the group knot of the global Beijing strain. The results suggest that the global-wide Beijing strain is mainly composed of a recently-developed Bmyc10 subtype. To further explore the origin and evolution of the Beijing strain and its relation to human migration, we have carried out the SN of the Beijing strain collected in 11 provinces and cities throughout the country. P. At the same time, we selected the representative strains of each subtype (total of 39 strains) from the Beijing strain collected in Shanghai to carry out the whole gene. Group sequencing. The whole genome sequencing data of 22 nodules that have been published, we constructed the whole genome phylogenetic tree; at the same time, through the Bayesian evolution analysis, we calculated the origin of the Beijing and its subtype strains In the source age, according to the phylogenetic tree, we found that the "Former Beijing" strains isolated in the early stage represent the first branch of the earliest differentiation of the ancestors of the Beijing strain; and the typing of the strains in the whole country shows that the "Former Beijing" strains are very rare and only exist in the southern region of China (Guangxi, Fujian, Zhejiang and The time-reckoning result shows that the origin of the Beijing strain is about 2-30,000 years, and the time and the East Asian population are over the period of the origin of South-East Asia. Overall, we conclude that the Beijing strain is likely to originate from South-East Asia and the southern border of our country The distribution of each subtype of the Beijing family in 11 provinces shows that the early-differentiated "ancient"-type strain is widely present in the whole country, and it is mainly in Tibet and Japan in combination with that early population migration route in east Asia, we have speculated that the Beijing strain, after the origin of the south-east Asia region, has spread to most of our region with the migration of the population from south to north, The "modern"-type strain is the main epidemic strain of China except Tibet, the proportion of which is significantly higher in the Han population than in the minority. The proportion of the population in the population, and the proportion of the northern population in the Han population It's higher than the South. So we're speculating that the "modern"-type strain may have originated in the northern Han population The phylogenetic tree of the whole genome shows that the "modern"-type strain has been expanded on a large scale from about 6000 years ago, which is the same as that of the back-up social group (the ancestors of the northern Han people) after the agricultural production in the "Neolithic" period. The generation of the "modern" strain is further proved to be of the origin In the northern part of China, the large-scale expansion and migration of the Chinese Han population in East Asia over the last 2000 years, we have speculated that the modern "-type strain is widely distributed in the regions of China and East Asia and is likely to be the same as that of the Han population The proportion of the "modern"-type strain is even lower than that of the "ancient" type in the Tibetan and Japanese-Korean and other places in the Han population. This assumption is that the expansion of the "modern"-type Beijing strain in the early population of the North and later in East Asia and the wide spread of the world suggest that the subtype strain is likely to be It is highly pathogenic. We believe that by a more in-depth comparative genomics study, it is possible to identify the strain of this subtype as an advantage. In addition, the high prevalence of the "modern" strain in China suggests that the prevention and control department need to increase the number of case discovery and early diagnosis, so as to reduce the transmission of the strain in the population The genetic similarity of "modern"-type Beijing strain on the number of large population and the height of the strain in China, so as to study the strain The recent communication between the 15 and 24-site variable tandem repeats (VNTR) in Europe and the United States has been applied to the popular Beijing strain population in China, and there is often no cluster case among the cluster cases. According to the epidemiological connection, we found that five 15-site-defined cluster strains contained two or more of the 191 Beijing strains collected on the basis of the population-based population in Chongming, Shanghai. A number of strains of the Beijing Subtype. The system tree was constructed by the combination of VNTR and SNP, and we prove that the above phenomenon is due to the 15-site VNTR's resolution of the "modern"-type strain On the other hand, the non-homologous similarity of the VNTR genotypes formed by the convergent or parallel evolution between the "modern"-type strains can also guide The wrong definition of cluster strains. Therefore, we recommend the combination of SNP and VNTR typing in the highly popular region of the "modern"-type Beijing strain To date, there is still a lack of a unified VNTR classification scheme for the junction of our country. Nuclear molecular epidemiological studies. The standard 15 and 24 sites, VNTR, are not too numerous and have a low resolution of many sites We selected a wide range of 10 VNTR sites (MIRU10,26,31,40; QUB) by conducting a study on the resolution of the screened 24 sites in a population-based 1375 strain and a variety of VNTR-combined HGI values in a population-based collection of 1375 strains in six regions of the country (11b,18,26; Mtb04,21 and ETR-A) as a study of the prevalence of tuberculosis in China The first line of the disease is a first-line classification scheme. The 10 sites are combined with 3 high-displacement points and QUB11a as the two-line classification scheme, and the exact definition is different. Short-term spread of the regional strains. The results of the full-genome comparison show that all the strains of Beijing There is a certain genetic difference between them. We are speculating that these differences can lead to different subtype strains We found that the mutation frequency of the high-prevalence "modern"-type Beijing strain at the rpoB531 site is higher than that of other subtype strains (OR =) by using the SNP typing and the first-line drug-resistance mutation analysis of 242 drug-resistant strains collected in the disease control center in Shanghai in 2004-2008. 1.8, P = 0.04); whereas in several low-prevalence "ancient" subtype strains, rifampin-resistant mutations were mainly distributed outside the rpoB531 and rpoB526 sites (OR = 3.16, P0.01). The mutation at the rpoB531 and pB526 sites is considered to be a guide due to the low damage to the bacterial strain The "modern"-type strain may have stronger pathogenicity so that it has higher bacterial load in the patient and is more easily screened out. The resistance strain carrying the dominant mutation is screened out for 11 sites according to the mutation characteristics of the 242 multi-drug resistant strains. The first-line drug-resistant phenotype was predicted. The 11-site could be predicted to be 93.8% rifampin resistance and 89.3% of the drug-resistant drug resistance. and 86.8% of the multi-drug resistant phenotype. Based on these mutation sites, we further developed a new technology based on real-time fluorescence PCR probe dissolution profile analysis The method has the advantages of low cost and wide application to the rapid diagnosis of drug-resistant tuberculosis, In this paper, we study the origin and evolution of the Beijing strain of the tuberculosis, and further reveal the transmission of the tuberculosis and the modern people. A close link between the migration and expansion of the class. Our conclusion is to further study the knot. At the same time, we provide a reliable and widely applicable classification scheme for the epidemiological study of tuberculosis in our country, and provide a rapid diagnosis for drug-resistant tuberculosis.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R378.911
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