孤獨(dú)癥對(duì)于遺傳學(xué)家而言一直是個(gè)未解之謎?？茖W(xué)家們一直在尋找與這種疾病有關(guān)的基因,，他們發(fā)現(xiàn)，大約有10%的孤獨(dú)癥可能與遺傳有關(guān),。如今,，一個(gè)研究小組向著搞清另外90%孤獨(dú)癥患者——即所謂的散發(fā)病例——的致病原因邁出了新的一步。
由美國(guó)紐約州冷泉港實(shí)驗(yàn)室的Jonathan Sebat領(lǐng)導(dǎo)的研究小組,，對(duì)來(lái)自264個(gè)家庭的脫氧核糖核酸（DNA）進(jìn)行了研究,。利用一系列相關(guān)技術(shù)，研究人員分析了導(dǎo)致復(fù)制數(shù)字變異的遺傳物質(zhì)——復(fù)制數(shù)字變異是指復(fù)制過(guò)程中丟失或得到相對(duì)較長(zhǎng)的DNA片段,。Sebat和同事發(fā)現(xiàn)，在參與這項(xiàng)研究的196名非孤獨(dú)癥患者中,，只有約1%的人具有這一遺傳缺陷,，而在112名孤獨(dú)癥患者當(dāng)中，這一比例卻是前者的10倍（這些人都是家庭中唯一的孤獨(dú)癥患者）,。與此相反的是,，在47個(gè)顯然通過(guò)遺傳患上孤獨(dú)癥且有多名患者的家庭中，出現(xiàn)復(fù)制數(shù)字變異的比例卻高達(dá)2%。研究小組在3月16日出版的美國(guó)《科學(xué)》雜志上報(bào)告了這一研究成果,。研究人員在對(duì)那些只有一個(gè)孤獨(dú)癥患者的家庭進(jìn)行了更為深入的研究后發(fā)現(xiàn),，這些患者的父母并沒(méi)有攜帶遺傳變異，這意味著這種疾病并非來(lái)自于遺傳,，但有可能源于母親的卵子或父親的精子,。
Sebat推斷，至少15%的孤獨(dú)癥病例以及相關(guān)的疾病與這種基因變異有關(guān),。他希望隨著研究小組利用更靈敏的DNA探針對(duì)更多的家庭進(jìn)行研究,，能夠搞清更多的相關(guān)細(xì)節(jié)，同時(shí)確定導(dǎo)致這種疾病的基因,。Sebat表示：“隨著采樣范圍和分析工作的不斷增加,，我們將對(duì)這種疾病的致病原理有一個(gè)更好的認(rèn)識(shí)。”
與此同時(shí),，這一發(fā)現(xiàn)將為那些孤獨(dú)癥患者的父母提供幫助——這些父母通常擔(dān)心這種疾病會(huì)在家族中遺傳,，并且導(dǎo)致今后生育的孩子也患上孤獨(dú)癥。美國(guó)新澤西州Rutgers大學(xué)的Linda Brzustowicz指出：“如果能夠確定這種疾病是由于自發(fā)的染色體缺失所導(dǎo)致,，那么家族中重復(fù)發(fā)病的可能性將大為降低,。”
部分英文原文：
Published Online March 15, 2007
Science DOI: 10.1126/science.1138659
Science Express Index
Submitted on December 11, 2006
Accepted on March 6, 2007
Strong Association of De Novo Copy Number Mutations with Autism
Jonathan Sebat 1*, B. Lakshmi 1, Dheeraj Malhotra 1, Jennifer Troge 1, Christa Lese-Martin 2, Tom Walsh 3, Boris Yamrom 1, Boris Yamrom 1, Seungtai Yoon 1, Alex Krasnitz 1, Jude Kendall 1, Anthony Leotta 1, Deepa Pai 1, Ray Zhang 1, Yoon-Ha Lee 1, James Hicks 1, Sarah J. Spence 4, Annette T. Lee 5, Kaija Puura 6, Terho Lehtimäki 7, David Ledbetter 7, Peter K. Gregersen 5, Joel Bregman 8, James S. Sutcliffe 9, Vaidehi Jobanputra 10, Wendy Chung 10, Dorothy Warburton 10, Mary-Claire King 3, David Skuse 11, Daniel H. Geschwind 12, T. Conrad Gilliam 13, Kenny Ye 14, Michael Wigler 1*
1 Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
2 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
3 Department of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195-7720, USA.
4 Pediatrics and Neurodevelopmental Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1255, USA.
5 Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA.
6 Department of Child Psychiatry, University of Tampere, Medical School, Tampere, Finland.
7 Department of Clinical Chemistry, University Hospital of Tampere and University of Tampere, Medical School, Tampere, Finland.
8 Fay J. Lindner Center for Autism and Developmental Disorders, North Shore-Long Island Jewish Health System, 4300 Hempstead Turnpike, Bethpage, NY 11714, USA.
9 Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232-8548, USA.
10 Departments of Genetics and Development, and Pediatrics, Columbia University, New York, NY 10027, USA.
11 Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WCIN 1EH, UK.
12 Interdepartmental Program in the Neurosciences, Program in Neurogenetics, Neurology Department, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1769, USA.
13 Department of Human Genetics, The University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
14 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
* To whom correspondence should be addressed.
Jonathan Sebat , E-mail: [email protected]
Michael Wigler , E-mail: [email protected]
We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (2%) of patients with an affected first-degree relative, and in 2 out of 196 (1.0%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
