全新非侵入性产前诊断方法推动胎儿先天性疾病筛查发展

全新非侵入性产前诊断方法推动胎儿先天性疾病筛查发展

本帖最后由 woodsy 于 2010-12-14 17:43 编辑

转自:http://www.bioask.cn/html/1375.html

Sci Transl Med:全新非侵入性产前诊断方法推动胎儿先天性疾病筛查发展

Time:2010-12-10 PM 19:46  Author:web  Hits: 16 times  


     只需获得母亲的血液就可对发育中的胎儿进行全基因组筛查,这种全新的非侵入性的产前诊断方法有可能在不久的将来提供给准父母们,为他们的胎儿进行先天性的疾病筛查。

     近期香港和美国的科学家们利用这种方法对一个胎儿进行了全基因组筛查以确定它是否遗传了来自父母的一种罕见的血液疾病。研究人员称这种方法还可适用于对出生前胎儿进行遗传性囊肿纤维病、镰状细胞贫血和其他先天性疾病筛查。研究论文发表在《科学转化医学》(Science Translational Medicine)杂志的网络版上。

     “目前离进入商业应用仅一步之遥,我相信这种情况很快就会获得改变,”论文的共同作者、美国加州圣地亚哥Sequenom 公司的首席科学顾问Charles Cantor说。

     在证实母亲的血浆中存在胎儿的DNA片段后,科学家们就致力于开发新的产前DNA筛查方法以取代羊膜穿刺术及其他的产前诊断技术。由于常规的产前诊断方法都是以侵入性的方式获取发育胎儿的DNA从而提高了孕妇流产的风险。

     “尽管我们通过检测母亲血液中的胎儿DNA已经可以鉴别出胎儿的性别和遗传自父亲的其他性状。但是从母亲那里找到胎儿的完全基因组仍然是非常困难的事情,”研究的负责人、中国香港大学的化学病理学家卢煜明说道:“如果母亲有两个不同的等位基因,由于其血液中也会同时存在这两种等位基因,因而用常规的遗传检测方法则无法确定她会将哪个等位基因传递给她的孩子。”

     卢煜明的研究小组在对一对夫妇进行研究时遭遇了这一难题。这对父母每人都携带了一个与血红蛋白生成有关的不同类型的突变等位基因。由于胎儿是分别从他的父母那里遗传获得一个等位基因,这意味着他们的孩子有25%的几率获得两个正常的等位基因,50%的几率获得一个错误和一个正确的等位基因:还有25%的几率获得两个突变的等位基因,从而导致胎儿患上β地中海贫血。

     医生在妊娠12周的时候采用一种侵入性的方法获得了胎儿的DNA。同时,卢煜明的研究小组也采集了父母双方的血液想看看他们是否能够获得相同的检测结果。

     研究人员进而对母亲血液中的几百亿个DNA碱基对进行了测序,并将它们与父母基因组中的90万个位点进行了比对。研究人员非常容易地就检测到母亲的血液中有父亲的突变出现这表明胎儿已经遗传了来自父亲的错误等位基因。为了确定是否母亲的突变也进入了胎儿的DNA,卢煜明课题组找到了一种新方法计算母亲的健康和突变的等位基因出现在血液样本中的频率。

     “如果它们以相同的比例存在,那么就意味着这个孩子确实遗传了来自母亲的基因突变。获得来自父母两个错误的基因将导致胎儿患上β地中海贫血,”卢煜明说。然而检测结果表明血液样本中存在更多的健康等位基因,这表明胎儿从母亲那里获得的是正确的基因拷贝,因而不会患上β地中海贫血。直接从胎儿那采集的DNA结果验证了卢煜明的结论。

     卢煜明课题组称目前他们已经对94%的胎儿DNA进行了测序。“但是由于胎儿的测序结果是从父母的基因筛查结果中推导出来的,要获得完整的胎儿基因组就必须比对父母的全基因序列(而非仅仅比对90万个位点),”卢煜明说。

     “我相信通过母亲的血液可以实现大部分胎儿基因组的测序,”斯坦福大学的生物工程师Steve Quake说。目前Steve Quake实验室的研究生Christina Fan也想出了类似的方法通过母亲对胎儿DNA进行筛查。他们已经在《Nature Precedings》网站发布了他们的研究成果。

     瑞士巴塞尔大学的分子生物学家Sinuhe Hahn称赞说这项研究预示着“新一代产前诊断技术时代的到来”。

推荐原文出处:

Sci Transl Med   DOI: 10.1126/scitranslmed.3001720

Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Fetus

Y. M. Dennis Lo1,2,*, K. C. Allen Chan1,2, Hao Sun1,2, Eric Z. Chen1,2, Peiyong Jiang1,2, Fiona M. F. Lun1,2, Yama W. Zheng1,2, Tak Y. Leung3, Tze K. Lau3, Charles R. Cantor4 and Rossa W. K. Chiu1,2

Abstract

Cell-free fetal DNA is present in the plasma of pregnant women. It consists of short DNA fragments among primarily maternally derived DNA fragments. We sequenced a maternal plasma DNA sample at up to 65-fold genomic coverage. We showed that the entire fetal and maternal genomes were represented in maternal plasma at a constant relative proportion. Plasma DNA molecules showed a predictable fragmentation pattern reminiscent of nuclease-cleaved nucleosomes, with the fetal DNA showing a reduction in a 166–base pair (bp) peak relative to a 143-bp peak, when compared with maternal DNA. We constructed a genome-wide genetic map and determined the mutational status of the fetus from the maternal plasma DNA sequences and from information about the paternal genotype and maternal haplotype. Our study suggests the feasibility of using genome-wide scanning to diagnose fetal genetic disorders prenatally in a noninvasive way.
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求全文啊
本帖最后由 woodsy 于 2010-12-14 22:25 编辑

原文全文

Sci Transl Med 8 December 2010:Vol. 2, Issue 61, p. 61ra91

Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Fetus
abbr_c69dcdfed888dfe4f9bcf50ce5ec4ba9.pdf (1.61 MB)
坛子出问题了,我这暂时上传不了附件,就林博调下
wow,这确实方便了很多
回复 5# 大巧不工


    是的,如果准确性和可行性提高,那将是很好的方法。
OK了,已上传全文,需要的战友慢用
再传这个文章的补充材料
Supplementary Materials of Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Fetus

abbr_ff8d6d3f3b1500fadeb7ce56d0a705c6.pdf (629.37 KB)
感觉会比穿一下羊水费很多的劲,不过,谁知道以后会不会就变得很容易了呢?支持这种有创意的思路,即使以后不能真正临床应用。
回复 9# doctorlzm


    个人感觉就是方便了‘取材’,但检测的难度和不准确性就相应增加了,呵呵,不过还是值得关注的。
总是这个罗先生在发相关文章。。。
回复 11# azure

你说的极是!为什么没有别人跟进?是重复不出来还是别的原因?
回复  azure

你说的极是!为什么没有别人跟进?是重复不出来还是别的原因? ...
杨勇 发表于 2010-12-16 09:18



    咱们的RNA的最基本的那步,就是性别那步,重复好几次都重复不出来...
   也是Lo先生发明的
偶没认真看原文,只是觉得从一些零碎的片段去拼去推,准确性有限,所以他们自己也说了,要知道父母双方的基因背景,呵呵,所以说,这个···
我总算基本看完这篇文章了,累死我了。
总体来说,目前是个费钱、费事又不是特别准确的方法。
最烦的是要一堆堆数据才能准确判断,母亲的致病基因是否被遗传到,其实从哪个角度来说,这都是非常难判定的,他们提出的RHDO方法理论上确实是对的,实际上,要是胎儿的DNA不到10%呢?我估计就够呛了吧。而这个数据,应该跟胎儿不同发育时期关系很大吧?
回复 15# doctorlzm


    分析的很对。还不如冒个风险做羊穿。
下周组会志淼给大家讲一讲吧,省得大家再看了。这个老罗RP如何?诺大岁数还又作一作又作责任作者?woodsy 有空打探打探?有点上纲上线了,呵呵
回复 17# 杨勇


    呵呵,中大的,离深圳不远,呵呵。一般来说,作假的机会少,因为后果很严重,但不是没有,呵呵。
回复 17# 杨勇


    在中大主页上查了下,得到如下信息,呵呵
http://www.cpy.cuhk.edu.hk/academic%20staff/Dennis.htm      

  
Professor Dennis Lo
Email: loym@cuhk.edu.hk

Professor Dennis Lo is the Professor of Chemical Pathology and Li Ka Shing Professor of Medicine of The Chinese University of Hong Kong. He is also the Associate Dean (Research) of the Faculty of Medicine, the Director of the Li Ka Shing Institute of Health Sciences and an Associate Director of the State Key Laboratory in Oncology in South China. He obtained his B.A. degree from the University of Cambridge and his B.M.B.Ch. degree from the University of Oxford. Following his clinical studies, he pursued a period of postgraduate research, resulting in the award of a D.Phil. degree from Oxford. He received his clinical training in internal medicine and chemical pathology from John Radcliffe Hospital, the teaching hospital of the University of Oxford Clinical School, where he was appointed University Lecturer in Clinical Biochemistry and Honorary Consultant Chemical Pathologist. Prof. Lo is a Fellow of the Royal College of Physicians ( London and Edinburgh) and a Fellow of the Royal College of Pathologists of the U.K.

Professor Lo's main research interests lie in the clinical applications of molecular biology. He is a pioneer in noninvasive prenatal diagnosis using cell-free fetal DNA and RNA in maternal plasma/serum. Professor Lo is also actively pursuing the application of plasma-based molecular technology to the diagnosis and monitoring of nasopharyngeal carcinoma and hepatocellular carcinoma. Professor Lo has produced over 243 publications in international journals. His research is currently supported by the Hong Kong Research Grants Council, the Innovation and Technology Fund, the Research Fund for the Control of Infectious Diseases (from the Health, Welfare and Food Bureau), the Kadoorie Charitable Foundation and the Li Ka Shing Foundation.

Professor Lo is a past President of the Hong Kong Society of Clinical Chemistry. Professor Lo is an Associate Editor of Clinical Chemistry, and serves on the Editorial Boards of American Journal of Hematology, Disease Markers, Prenatal Diagnosis, Chimerism and Fetal Diagnosis and Therapy.

Selected publications from Prof. Lo's group include:

Lo YMD , Chiu RWK. Prenatal diagnosis: progress through plasma nucleic acids. Nature Reviews Genetics 2007; 8: 71-77.


Lo YMD , Tsui NB, Chiu RW, Lau TK, Leung TN, Heung MM, Gerovassili A, Jin Y, Nicolaides KH, Cantor CR, Ding C. Plasma placental RNA allelic ratio permits noninvasive prenatal chromosomal aneuploidy detection. Nature Medicine 2007; 13: 218-223.


Lo YMD , Lun FM, Chan KC, Tsui NB, Chong KC, Lau TK, Leung TY, Zee BC, Cantor CR, Chiu RWK. Digital PCR for the molecular detection of fetal chromosomal aneuploidy. Proceedings of the National Academy of Sciences ( USA) 2007; 104: 13116-13121.


Chim SS, Tong YK, Chiu RWK, Lau TK, Leung TN, Chan LY, Oudejans CB, Ding C, Lo YMD. Detection of the placental epigenetic signature of the maspin gene in maternal plasma. Proceedings of the National Academy of Sciences ( USA) 2005; 102: 14753-14758.


Ding C, Chiu RW, Lau TK, Leung TN, Chan LC, Chan AY, Charoenkwan P, Ng IS, Law HY, Ma ES, Xu X, Wanapirak C, Sanguansermsri T, Liao C, Ai MA, Chui DH, Cantor CR, Lo YMD. MS analysis of single-nucleotide differences in circulating nucleic acids: Application to noninvasive prenatal diagnosis. Proceedings of the National Academy of Sciences ( USA) 2004; 101: 10762-10767.


Ng EKO, Tsui NB , Lau TK, Leung TN , Chiu RWK, Panesar NS , Lit LC, Chan KW, Lo YMD. mRNA of placental origin is readily detectable in maternal plasma. Proceedings of the National Academy of Sciences ( USA) 2003; 100: 4748-4753.


Chiu RWK, Lau TK, Leung TN, Chow KCK, Chui DHK, Lo YMD. Prenatal exclusion of beta-thalassaemia major by examination of maternal plasma. Lancet 2002; 360: 998-1000.


Chan KCA, Zhang J, Hui AB, Wong N, Lau TK, Leung TN, Lo KW, Huang DW, Lo YMD. Size distributions of maternal and fetal DNA in maternal plasma. Clinical Chemistry 2004; 50: 88-92.


Chan KCA, Zhang J, Chan ATC, Lei KIK, Leung SF, Chan LYS , Chow KCK, Lo YMD. Molecular characterization of circulating Epstein-Barr virus DNA in the plasma of nasopharyngeal carcinoma and lymphoma patients. Cancer Research 2003; 63: 2028-2032.


The Chinese SARS molecular epidemiology consortium: He JF, Peng GW, Min J, Yu DW, Liang WJ, Zhang SY, Xu RH, Zheng HY, Wu XW, Xu J, Wang ZH, Fang L, Zhang X, Li H, Yan XG, Lu HJ, Hu ZH, Huang JC, Wan ZY, Hou JL, Lin JY, Song HD, Wang SY, Zhou XJ, Zhang GW, Gu BW, Zheng HJ, Zhang XL, He M, Zheng K, Wang BF, Fu G, Wang XN, Chen SJ, Zhu Chen Z, Hao P, Tang H, Ren SX, Zhong Y, Guo ZM, Liu Q, Miao YG, Kong XY, He WZ, Li YX, Wu CI, Zhao GP, Chiu RWK, Chim SSC, Tong YK, Chan PKS, Tam JS, Lo YMD. Molecular evolution of the SARS-coronavirus during the course of the SARS epidemic in China. Science 2004; 303: 1666-1669.
下面资料也是在中大主页上搜到的
無創性唐氏綜合症產前檢查研究屢獲國際傳媒稱許
Noninvasive Prenatal Testing for Down’s Syndrome Repeatedly Recognized by World Media

12.pdf (938.44 KB)
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