人类基因组解读的最新进展

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Nature：人类基因组解读的最新进展
生物谷报道：DNA元素百科全书协会（ENCODE）14日发表的一系列文章，让人们重新理解了人类基因组是如何发挥作用的。ENCODE的研究指出，人类基因组是一个由基因、调控元素以及某些非蛋白质编码DNA序列组成的复杂网络，并以部分重叠的方式相互作用。这与基因组是一个个不连续基因规整组合的传统观点大相径庭。
2003年4月，人类基因组计划的完成是一项非常重要的成就，但只是人类利用基因信息来诊断、治疗和预防疾病的第一步。有了人类基因组序列，就好比有了一本如何制造人体的指导手册，研究者还必须学会如何读懂手册，这样才能将每个部件搞清楚，理解这些部件是如何协同工作来影响人的健康。
　　ENCODE协议是由美国基因组研究所和美国健康研究所组织的国际合作项目，目标是为人类基因组中所有具有关键生物功能的元素绘制一份全范围的详细目录。第一阶段是为期4年的试验性研究，主要是测试该项目的可行性，这也是迄今为止第一次对基因组中所有类型的功能元素进行的系统测定。这些元素包括蛋白质编码基因、非蛋白质编码基因、控制基因转录的调节元素、维持染色体结构以及调控染色体复制的元素。该研究聚焦于44个靶位，总共占人类基因组序列的1％，也就是3000万个DNA碱基对。这些靶位是经过精心选择的有代表性的部分，横跨整个人类基因组序列。全世界35个研究小组参与了此项研究，一共测得了200多个数据集，分析了6亿多个数据点。
　　长期以来，人们一直认为人类基因组是由一系列相对较小的不连续的基因组成，还有大量没有生物活性的无用DNA。但EN鄄CODE的研究发现，人类基因组中的大多数DNA转录成功能性的分子RNA，而且这些转录是广泛重叠的，无用的DNA序列很少。实际上，人类基因组是一个交织复杂的网络，基因只不过是众多DNA序列中具有特定生物功能的一种。\"我们对基因及其转录的看法有必要进化，\"研究人员称，\"基因组的网络模型提出了一些很有趣的机械问题，需要进一步研究才能回答。\"
　　ENCODE的另一发现有助于对基因组（特别是哺乳动物的基因组）进化的理解。直到最近，科学界还认为绝大多数具有重要生物功能的DNA序列处于基因组中进化受约束的区域，也就是说它们极有可能是作为一个种群进化的。但新的研究发现，基因组中大约一半的功能元素在进化过程中并未受到明显的约束，这表明许多基因包含有一个功能元素池，这个元素池在进化过程中可能会变成一个\"自然选择仓库\"，为每个种群提供其独有的功能元素。
　　ENCODE的研究成果发表在14日的英国《自然》以及6月份的《基因组研究》杂志上。



FIGURE 1. Hidden message.
Ishihara's test for red–green colour deficiencies uses several coloured plates, similar to this one, in which a number is disguised in a different colour within the dot pattern. Similarly, we are so fascinated by genes (green dots) that we have become blinded to non-gene components (magenta dots) of the genome. However, in studying 1% of the genome, the researchers of the ENCODE consortium2 found that non-gene sequences have essential regulatory functions, and thus cannot be ignored.
原文出处：
Nature  Volume 447 Number 7146
Genomics: Encyclopaedia of humble DNA p782
Researchers of the ENCODE consortium have analysed 1% of the human genome. Their findings bring us a step closer to understanding the role of the vast amount of obscure DNA that does not function as genes.
John M. Greally
doi:10.1038/447782a
Full Text | PDF (340K)
See also: Editor's summary

Genome Research  Volume 17, Issue 6: June 2007
George M. Weinstock
ENCODE: More genomic empowerment
Genome Res. 2007 17: 667-668. [Full Text] [PDF] OPEN ACCESS ARTICLE  


作者简介：
John M. Greally, M.B.,B.Ch., Ph.D.
Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
Assistant Professor, Department of Medicine (Hematology)
Assistant Professor, Department of Molecular Genetics
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George Weinstock, Ph.D.
Professor, Departments of Molecular and Human Genetics and Molecular Virology & Microbiology
Co-Director, Human Genome Sequencing Center
Adjunct Professor, Department of Microbiology and Molecular Genetics, UTHHSC
Adjunct Professor, Department of Health Informatics, UTHHSC
B.S., University of Michigan, 1970
Ph.D., Massachusetts Institute of Technology, 1977
Postdoc, Stanford University Medical School, 1980
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Last modified: October 2005
Research Interests  Selected Publications  Contact Information
RESEARCH INTERESTS:
George Weinstock received a B.S. from the Univ. Michigan (Biophysics, 1970) and a Ph.D. from MIT (Microbiology, 1977), studying transposition and gene control in phage P22, and constructing one of the first genomic physical maps. His postdoctoral research (Biochemistry Department, Stanford Univ. Medical School ) studied mechanisms of genetic recombination and enzymology of RecA protein. In 1980, he joined the NCI-Frederick Cancer Research Facility and established the DNA Metabolism Section, Laboratory of Recombinant DNA. In 1984, he moved to The Univ. Texas-Houston Health Science Center (Dept. Biochemistry and Molecular Biology, 1984-95; Dept. Microbiology and Molecular Genetics, 1995-2001). He applied molecular genetics and genomics to study infectious disease pathogens Escherichia coli, Treponema pallidum, and the enterococci. In 1998, he joined the BCM Human Genome Sequencing Center as Co-Director and became a tenured Professor in the Molecular and Human Genetics Department in 2001.
As Co-Director of the HGSC, he helped lead one of three NIH-funded large-scale Genome Centers involved in the Human Genome Project, completed in 2003. The HGSC was responsible for chromosomes 3, 12, and part of X in the HGP. Since then he has helped oversee a number of other HGSC genome projects: the rat, mouse, cow, macaque, sea urchin, honey bee, Drosophila melanogaster and pseudoobscura, Dictyostelium discoideum, which are complete or nearly so, and new projects the orangutan, wasp, acorn worm, Ascosphaera apis, and Acanthamoeba.
In addition he has continued to sequence bacterial genomes of interest in infectious diseases and evolutionary studies including Treponema pallidum (syphilis), periodontal pathogens Fusobacterium nucleatum and Treponema denticola, bioterroism agents Rickettsia typhi and Francisella tularensis, superbugs Enteroccus faecium and faecalis and Staphylococcus aureus, plant pathogen Pantoea stewartii, bovine pathogens Mannheimia haemolytica and Moraxella bovis, honey bee pathogen Paenibacillus larvae, and Bacillus pumilis (highly radiation resistant).
Sequenced genomes are analyzed and annotated. For eukaryotic genomes, this involves coordination of experts in gene prediction, evolutionary analysis, genome structure, and functional themes of interest for each organism. Genome assembly, annotation, and analysis involve sophisticated bioinformatics.
For bacterial genomes, this information is used for post-sequencing functional genomics. This includes cloning and expressing all genes into E. coli from a bacterium to identify functions, antigens, and vaccine candidates, making microarrays, or constructing null mutants in all members of gene families such as regulators or pumps. These are analyzed for virulence, antibiotic sensitivity, or other phenotypes.
Future projects focus on sequencing individuals with altered phenotypes, for disease gene discovery, or closely related bacteria to correlate phenotype with genotype. In both cases a deep survey of genetic variation is realized.
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SELECTED PUBLICATIONS:
1. Smajs D, McKevitt M, Howell JK, Norris SJ, Cai WW, Palzkill T, Weinstock GM (2005). Transcriptome of Treponema pallidum: gene expression profile during experimental rabbit infection. J. Bacteriol. 187: 1866-1874.
2. Ross MT et al. (2005). The DNA sequence of the human X chromosome. Nature 434: 325-337.
3. Eichinger L, Pachebat JA, Glockner G, Rajandream MA, Sucgang R, Berriman M, Song J, Olsen R, Szafranski K, Xu Q, Tunggal B, Kummerfeld S, Madera M, Konfortov BA, Rivero F, Bankier AT, Lehmann R, Hamlin N, Davies R, Gaudet P, Fey P, Pilcher K, Chen G, Saunders D, Sodergren E, Davis P, Kerhornou A, Nie X, Hall N, Anjard C, Hemphill L, Bason N, Farbrother P, Desany B, Just E, Morio T, Rost R, Churcher C, Cooper J, Haydock S, van Driessche N, Cronin A, Goodhead I, Muzny D, Mourier T, Pain A, Lu M, Harper D, Lindsay R, Hauser H, James K, Quiles M, Madan Babu M, Saito T, Buchrieser C, Wardroper A, Felder M, Thangavelu M, Johnson D, Knights A, Loulseged H, Mungall K, Oliver K, Price C, Quail MA, Urushihara H, Hernandez J, Rabbinowitsch E, Steffen D, Sanders M, Ma J, Kohara Y, Sharp S, Simmonds M, Spiegler S, Tivey A, Sugano S, White B, Walker D, Woodward J, Winckler T, Tanaka Y, Shaulsky G, Schleicher M, Weinstock G, Rosenthal A, Cox EC, Chisholm RL, Gibbs R, Loomis WF, Platzer M, Kay RR, Williams J, Dear PH, Noegel AA, Barrell B, Kuspa A (2005). The genome of the social amoeba Dictyostelium discoideum. Nature 435: 43-57.
4. Richards S, Liu Y, Bettencourt BR, Hradecky P, Letovsky S, Nielsen R, Thornton K, Hubisz MJ, Chen R, Meisel RP, Couronne O, Hua S, Smith MA, Zhang P, Liu J, Bussemaker HJ, van Batenburg MF, Howells SL, Scherer SE, Sodergren E, Matthews BB, Crosby MA, Schroeder AJ, Ortiz-Barrientos D, Rives CM, Metzker ML, Muzny DM, Scott G, Steffen D, Wheeler DA, Worley KC, Havlak P, Durbin KJ, Egan A, Gill R, Hume J, Morgan MB, Miner G, Hamilton C, Huang Y, Waldron L, Verduzco D, Clerc-Blankenburg KP, Dubchak I, Noor MA, Anderson W, White KP, Clark AG, Schaeffer SW, Gelbart W, Weinstock GM, Gibbs RA (2005). Comparative genome sequencing of Drosophila pseudoobscura: chromosomal, gene, and cis-element evolution. Genome Res. 15: 1-18.
5. Seshadri R et al. (2004). Comparison of the genome of the oral pathogen Treponema denticola with other spiRochete genomes. Proc. Natl. Acad. Sci. USA 101: 5646-5651.
6. Rat Genome Sequencing Project Consortium (2004). Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428: 493-521.
7. International Human Genome Sequencing Consortium (2004). Finishing the euchromatic sequence of the human genome.Nature 431: 931-945.
8. McLeod MP, Qin X, Karpathy SE, Gioia J, Highlander SK, Fox GE, McNeill TZ, Jiang H, Muzny D, Jacob LS, Hawes AC, Sodergren E, Gill R, Hume J, Morgan M, Fan G, Amin AG, Gibbs RA, Hong C, Yu XJ, Walker DH, Weinstock GM (2004). Complete Genome Sequence of Rickettsia typhi and Comparison with Sequences of Other Rickettsiae. J. Bacteriol. 186: 5842-5855.
9. Gibbs RA, Weinstock GM (2003). Evolving methods for the assembly of large genomes. In Cold Spring Harbor Symp. Quant. Biol. Cold Spring Harbor Press, Cold Spring Harbor, NY, Vol. LXVIII, pp. 189-194.
For more publications, see listing on Pub Med.
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