生物谷报道：一项新研究显示，自闭症障碍症候群患者比正常人更可能有某些DNA序列的额外拷贝。这项研究结果被发表在3月15日的《科学》杂志在线版上。
这些被称为“拷贝数变异”的突变在不同的患者身上影响不同的基因，意味着自闭症行为能来自许多不同的遗传缺陷。拷贝数变异主要影响偶发病例，也就是兄弟姐妹中只有一人患自闭症的情况，而在家庭病例（多个兄弟姐妹患病）中不太重要。虽然双胞胎研究曾揭示自闭症具有高度遗传性，但是大多数病例没有家族自闭症史。研究遗传模式的连锁和关联分析未能找到强的候选基因，意味着自闭症的遗传风险是一个相当复杂的问题。Jonathan Sebat和同事分析了264个家庭中的拷贝数变异，包括118个有一个自闭症患者的“单纯性”家庭、47个有多个患者的“多发性”家庭、以及99个没有自闭症诊断的对照家庭。他们在10%的单纯性家庭、2%的多发性家庭、以及1%的对照家庭中发现拷贝数变异。文章作者指出，这些变异看来在自闭症中起主要作用，但是不知道变异是如何起作用的。
原文出处：
Strong Association of De Novo Copy Number Mutations with Autism
Jonathan Sebat, B. Lakshmi, Dheeraj Malhotra, Jennifer Troge, Christa Lese-Martin, Tom Walsh, Boris Yamrom, Boris Yamrom, Seungtai Yoon, Alex Krasnitz, Jude Kendall, Anthony Leotta, Deepa Pai, Ray Zhang, Yoon-Ha Lee, James Hicks, Sarah J. Spence, Annette T. Lee, Kaija Puura, Terho Lehtimäki, David Ledbetter, Peter K. Gregersen, Joel Bregman, James S. Sutcliffe, Vaidehi Jobanputra, Wendy Chung, Dorothy Warburton, Mary-Claire King, David Skuse, Daniel H. Geschwind, T. Conrad Gilliam, Kenny Ye, and Michael Wigler
Published online 15 March 2007 [DOI: 10.1126/science.1138659] (in Science Express Reports)
Abstract » PDF » Supporting Online Material »
作者简介：
Jonathan Sebat
Assistant Professor
Ph.D. University of Idaho, 2002
Copy number variation; segmental duplication; genetics; neurogenetics; ROMA; microarray
Large-scale differences in gene copy number, known as copy number polymorphisms (CNPs), are a significant source of human genetic variation. In contrast to DNA sequence variants such as SNPs and microsatellite repeats, CNPs have not been well characterized. Much remains to be learned about the genomic locations, frequency, and stability of these structural variants and their importance in human genetic disease.
Our laboratory is interested in the role of gene copy number variation in neurological disease. Almost invariably, visible alterations of the genome result in cognitive defects. In addition, some neurological disorders are the result of heritable chromosomal variants invisible at the cytogenetic level. We hypothesize that submicroscopic alterations in gene dosage are underlying causes of diseases such as autism, schizophrenia, and Parkinson’s disease. We are currently investigating chromosomal variation in disease using a method for high-resolution analysis of DNA copy number called Representational Oligonucleotide Microarray Analysis (ROMA).
We have previously applied ROMA to the analysis of cytogenetic aberrations. This analysis has served to validate the method and to illustrate the resolution with which we can define chromosomal imbalances. In addition, through our studies of “normal” genetic variation, we have shown that CNPs are abundant and widely distributed in the human genome. We have now adapted ROMA for use in population studies of genomic variation. Our flagship project is an exploration of copy number variation in familial and sporadic autism.
Selected Publications
Jobanputra,V., J. Sebat, W. Chung, K. Anyane-Yeboa, M. Wigler, and D. Warburton. 2005. Application of ROMA (representational oligonucleotide microarray analysis) to patients with cytogenetic rearrangements. Genet. Med. 7: 111-118.
Sebat, J., L. Muthuswamy, J.,Troge, J. Alexander, J. Young, P. Lundin, S. Maner, H. Massa, M. Walker, M. Chi, N. Navin, R. Lucito, J. Healy, A. Reiner, J. Hicks, K. Ye, A. Reiner, T.C. Gilliam, B. Trask, N. Patterson, A. Zetterberg, and M. Wigler. 2004. Large-Scale Copy Number Polymorphism in the Human Genome. Science 305: 525-528.
Lucito, R., J. Healy, J. Alexander, A. Reiner, D. Esposito, M. Chi, L. Rodgers, A. Brady, J. Sebat, J. Troge, J.A. West, S. Rostan, K.C. Nguyen, S. Powers K.Q. Ye, A. Olshen, E. Venkatraman, L. Norton, and M. Wigler. 2003. Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. Genome Res. 13: 2291-2305.
