生物谷报道：一个国际研究小组于最近宣布已经完成了与人类疟疾寄生虫恶性疟原虫遗传变异性有关的基因图谱的绘制。12月10日提前出版的网上版《自然遗传学》杂志已经发表了这一研究成果：该研究揭示了病原体基因组的惊人变异，包括一个由全球各地收集病原体样本建立含大约47，000特定的遗传变异的初步目录。这些差异的发现为剖析主要病原体基因的功能，跟踪全球范围内疟疾的发生奠定了基础。由哈佛公共卫生学院和美国麻省哈佛总医院科学家领导，塞内加尔的研究人员共同参与的这项研究已经发现了对目前治疗疟疾药物产生抗性的基因。
哈佛大学公共卫生学院免疫和传染系主任、麻省哈佛总医院传染科共同主任、此项研究主要负责人Dyann Wirth教授说：“疟疾之所以仍然能对全球公共卫生产生威胁，主要是因为疟疾寄生虫致病基因的遗传变异性造成的。这项研究使我们第一次从疟原虫基因组上看到其遗传变异，为使用基因工具研究疟疾迈出了关键的一步”。恶性疟原虫是使人类患疟疾的四种疟原虫中毒性最强的一种，平均每30秒钟就有一个人死于这种疟原虫导致的疟疾，其中大多数是非洲的儿童。尽管已经研究了几十年，人们对恶性疟原虫是如何通过遗传转变逃脱人体自身免疫系统的，以及如何抵抗疟疾药物的等问题依然知之甚少。
为了得到全球范围内广泛的恶性疟原虫基因变化图谱，科学家分析了采集自不同地理区域的50份样本，包括两个深入研究的样本的基因组全长序列和另外16份隔离种群的DNA序列分析。这部分工作由波士顿地区的研究者和由the Cheikh Anta Diop 大学教授Souleymane Mboup领导的塞内加尔的研究人员合作完成，是同时发表在《自然遗传学》上三项大规模的寄生虫DNA序列研究之一。通过这些样本基因序列的比对，并且同时与2002年发表的P. falciparum基因组做比对，科学家发现差异及其显著：有大约47，000个单核苷酸变异即单核苷酸多态性（SNPs）。这些进化上差异的信息可以帮助发现与疟疾抗药性有关基因，抗药性基因的存在是控制疟疾的主要障碍物。用多种抗疟疾药物作用于各种疟原虫，比较疟原虫遗传图谱的差异，科学家发现在息疟定作用下疟原虫一段序列高度螺旋，同时确认了与氯奎抗药性有关的序列。麻省哈佛总医院博士后，文章第一作者Pardis Sabeti说：“研究人类进化时使用的遗传原理，可以为疟疾研究提供重要线索。从遗传图谱中已经可以洞察与不同药物处理相关的遗传转变，这将为我们发现抗药性基因提供可能。”
遗传图谱同时可以解释不同种群的遗传景观。通过遗传图谱比较不同大洲上的疟原虫，科学家发现从非洲采集的样本与从亚洲和美洲采集的样本在DNA水平上有巨大差异。这些知识可以指导示踪疟原虫传播的遗传标志的选择，特别是针对那些有毒或者耐药的疟原虫。同时，也将为把不同地域疟原虫基因与其特征联系起来，支持世界各地疟疾的研究奠定基础。
Figure 1. Geographic distribution of parasites and SNPs.
(a) Sequence data derived from 18 parasites were used for SNP identification, including HB3 (red) and Dd2 (green), for which we obtained the full genome sequence; 12 additional parasites (blue) for which we obtained low-coverage sequence and four additional parasites (gray) that were used with the 12 low-coverage parasites for PCR product sequencing of 20 core regions across the genome (Supplementary Table 2). (b) SNPs identified from the parasites shown in a provide four data sources, including full-genome sequencing of HB3 (red) and Dd2 (green), low-coverage sequencing of 12 additional parasites (blue) and sequencing of 18 kb across 20 core regions (PCR) in 16 parasites (gray). The total number of SNPs identified for each of the four sources (HB3, Dd2, low coverage and PCR) is indicated by source, totaling 46,937 overall. The inner pie chart (light shading) indicates the number of SNPs by source that were found in more than one source ('shared'), identifying a total of 12,188 individual SNP positions that were identified in at least two sources. The outer pie chart (dark shading) indicates the number of SNPs identified only in a single source ('private').
原文出处：
Nature Genetics December 2006 - Vol 38 No 12
A genome-wide map of diversity in Plasmodium falciparum
Sarah K Volkman, Pardis C Sabeti, David DeCaprio, Daniel E Neafsey, Stephen F Schaffner, Danny A Milner Jr, Johanna P Daily, Ousmane Sarr, Daouda Ndiaye, Omar Ndir, Soulyemane Mboup, Manoj T Duraisingh, Amanda Lukens, Alan Derr, Nicole Stange-Thomann, Skye Waggoner, Robert Onofrio, Liuda Ziaugra, Evan Mauceli, Sante Gnerre, David B Jaffe, Joanne Zainoun, Roger C Wiegand, Bruce W Birren, Daniel L Hartl, James E Galagan, Eric S Lander & Dyann F Wirth
Published online: 10 December 2006 | doi:10.1038/ng1930
Abstract | Full text | PDF (362K) | Supplementary Information
相关文献：
Genome variation and evolution of the malaria parasite Plasmodium falciparum
Daniel C Jeffares, Arnab Pain, Andrew Berry, Anthony V Cox, James Stalker, Catherine E Ingle, Alan Thomas, Michael A Quail, Kyle
Siebenthall, Anne-Catrin Uhlemann, Sue Kyes, Sanjeev Krishna, Chris Newbold, Emmanouil T Dermitzakis & Matthew Berriman
Published online: 10 December 2006 | doi:10.1038/ng1931
Abstract | Full text | PDF (385K) | Supplementary Information
Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome
Jianbing Mu, Philip Awadalla, Junhui Duan, Kate M McGee, Jon Keebler, Karl Seydel, Gilean A T McVean & Xin-zhuan Su
Published online: 10 December 2006 | doi:10.1038/ng1924
Abstract | Full text | PDF (218K) | Supplementary Information
作者简介：
Pardis Sabeti
Presenters
Broad Institute
http://www.broad.mit.edu/index.html
Pardis Sabeti is an M.D. Ph.D and graduate from MIT, Oxford and Harvard where she studied human evolution. She is also the lead singer and guitarist for the rock band Thousand Days. She is a Rhodes Scholar and was only the third woman ever to graduate Harvard Medical School with highest honors, summa cum laude. Her groundbreaking research on human evolution with advisor Eric Lander has been in the world's top journals, including Nature and Science. With already over 20 publications to her name, she is an expert in the study of recent human evolution and infectious disease. She is a co-investigator on project studying the malaria genome, and her team has just received a $2 million Gates Foundation Grant for their work. She has also received a Soros Fellowship, a L'Oreal For Women in Science Fellowship, a Burroughs Wellcome Career Award in Biomedical Sciences, a Damon Runyan Cancer Research Fellowship, and was named a Science Spectrum Magazine Trailblazer. She has also served on the MIT Board of Trustees and is a member of the Senior Common Room of Harvard University Winthrop House.
