COMPLEX GENOMIC REARRANGEMENTS IN NEUROLOGICAL DISEASE

神经系统疾病中的复杂基因组重排

• 批准号: 9317539
• 负责人: JAMES R. LUPSKI
• 金额: $ 55.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317539
• 关键词: Address; Adult; Alzheimer' s Disease; Autistic Disorder; Behavior Disorders; Biological Assay; Characteristics; Charcot-Marie-Tooth Disease; Chromosomal Rearrangement; Chromosomes; Clinical; Complex; Consensus; Copy Number Polymorphism; DNA Sequence Rearrangement; Data; Development; Diagnostic; Disease; Evaluation; Event; Family; Family Study; Frequencies; Gene Dosage; Genes; Genome; Genome Stability; Genomic approach; Genomics; Germ Cells; Grant; Haploidy; Heterozygote; Homologous Gene; Human; Human Genome; Individual; Intellectual functioning disability; Laboratory Study; Length; Malignant Neoplasms; Mediating; Mental Retardation; Modeling; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neuropathy; PMP22 gene; Parents; Parkinson Disease; Patients; Pattern; Pelizaeus-Merzbacher Disease; Phenotype; Population; Process; Public Health; Recurrence; Resolution; SNP array; Schizophrenia; Sequence Analysis; Sister Chromatid; Somatic Cell; Stretching; Structure; Syndrome; Testing; Variant; chromothripsis; comparative genomic hybridization; disease phenotype; dosage; exome sequencing; gene correction; genome sequencing; genome-wide; infancy; insight; malformation; nervous system disorder; novel; public health relevance; trait; whole genome

DESCRIPTION (provided by applicant): During the previous two decades it has become apparent that genomic rearrangements are often the type of mutation that underlies neurological disease. This is so not only for neurodevelopmental disorders such as intellectual disability (ID) and different recognizable patterns of human malformation (e.g. Potocki- Lupski syndrome), but also for late-onset adult neurological disorders such as Charcot-Marie-Tooth disease. Moreover, genomic rearrangement can often underlie complex traits and sporadic diseases such as Parkinson, Alzheimer disease and other neurodegenerative processes. Contrary to prior interpretations, experimental evaluation of disease associated genomic rearrangements has often documented that they can be much more complex than anticipated. Complexities can occur at individual loci and give specific patterns for complex genomic rearrangements (CGR) such as duplication - normal - duplication (DUP-NML-DUP), or a triplication embedded within duplications (DUP-TRP-DUP). Furthermore, complexities can occur on a genomic level leading to complex chromosomal rearrangements and the phenomena of chromothripsis observed both in cancer and neurodevelopmental disorders, as well as an unusual pattern of multiple de novo copy number variants (CNVs) spread apparently randomly throughout the genome. The elucidation of mechanisms that can generate such complexities is a field that is truly in its infancy. We propose to further characterize complex genomic rearrangements (CGR) that have been found in association with neurological disease. Specifically, we will investigate and attempt to elucidate mechanisms for: 1) A CGR that consists of a triplicated segment in inverse orientation embedded within a duplicated segment of the genome (DUP-TRP/INV-DUP); a newly observed type of CGR with a proposed mechanism elucidated in our previous application; 2) The mechanism for recurrent triplications; 3) Elucidate the underlying molecular characteristics and breakpoint junctions of CGR that are accompanied by long genomic stretches of absence of heterozygosity (AOH), and resulting in both genomic (CGR) and genetic (AOH) alterations, and 4) We will attempt to isolate a gene important to the phenomena of multiple de novo CNV seemingly randomly distributed throughout the genome. The experimental approaches to be utilized to accomplish each one of these specific aims are now within our reach. It predominately requires genomic approaches that enable genomewide assays of variation such as array comparative genomic hybridization, genomewide SNP chips, exome sequencing, whole genome sequencing, and other mapping and molecular approaches for the delineation of specific breakpoint junctions. It is anticipated that completion of these ais will characterize these novel types of rearrangements and lend further insight into basic molecular mutational mechanisms that can cause myriad of neurological diseases.

描述（由申请人提供）：在过去的二十年中，很明显基因组重排通常是神经系统疾病的突变类型。这不仅适用于智力障碍 (ID) 等神经发育障碍和不同可识别的人类畸形模式（例如 Potocki-Lupski 综合征），也适用于迟发性成人神经系统障碍（例如腓骨肌萎缩症）。此外，基因组重排通常可能是复杂性状和散发性疾病的基础，例如帕金森病、阿尔茨海默病和其他神经退行性疾病。与之前的解释相反，疾病相关基因组重排的实验评估经常证明它们可能比预期复杂得多。单个位点可能存在复杂性，并给出复杂基因组重排 (CGR) 的特定模式，例如重复 - 正常 - 重复 (DUP-NML-DUP) 或嵌入重复中的三倍体 (DUP-TRP-DUP)。此外，基因组水平上可能发生复杂性，导致复杂的染色体重排和在癌症和神经发育障碍中观察到的染色体碎裂现象，以及在整个基因组中明显随机传播的多个从头拷贝数变异（CNV）的不寻常模式。阐明产生如此复杂性的机制确实是一个处于起步阶段的领域。 我们建议进一步表征与神经系统疾病相关的复杂基因组重排（CGR）。具体来说，我们将研究并尝试阐明以下机制：1）由嵌入基因组重复片段（DUP-TRP/INV-DUP）中的反向三重片段组成的 CGR；一种新观察到的 CGR 类型，其机制在我们之前的申请中得到阐明； 2）循环三倍的机制； 3) 阐明 CGR 的潜在分子特征和断点连接，这些特征和断点连接伴随着杂合性缺失 (AOH) 的长基因组延伸，并导致基因组 (CGR) 和遗传 (AOH) 改变，4) 我们将尝试分离对看似随机分布在整个基因组中的多个从头 CNV 现象重要的基因。用于实现这些具体目标中每一项的实验方法现在已经触手可及。它主要需要能够进行全基因组变异分析的基因组方法，例如阵列比较基因组杂交、全基因组SNP芯片、外显子组测序、全基因组测序以及用于描绘特定断点连接的其他作图和分子方法。预计这些ais的完成将表征这些新型重排的特征，并有助于进一步了解可导致多种神经系统疾病的基本分子突变机制。

项目成果

Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

• DOI: 10.1056/nejmoa1408028
• 发表时间: 2014-12-18
• 期刊: The New England journal of medicine
• 作者: Trivellin G;Daly AF;Faucz FR;Yuan B;Rostomyan L;Larco DO;Schernthaner-Reiter MH;Szarek E;Leal LF;Caberg JH;Castermans E;Villa C;Dimopoulos A;Chittiboina P;Xekouki P;Shah N;Metzger D;Lysy PA;Ferrante E;Strebkova N;Mazerkina N;Zatelli MC;Lodish M;Horvath A;de Alexandre RB;Manning AD;Levy I;Keil MF;Sierra Mde L;Palmeira L;Coppieters W;Georges M;Naves LA;Jamar M;Bours V;Wu TJ;Choong CS;Bertherat J;Chanson P;Kamenický P;Farrell WE;Barlier A;Quezado M;Bjelobaba I;Stojilkovic SS;Wess J;Costanzi S;Liu P;Lupski JR;Beckers A;Stratakis CA
• 通讯作者: Stratakis CA

Structural variation mutagenesis of the human genome: Impact on disease and evolution.

• DOI: 10.1002/em.21943
• 发表时间: 2015-06
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Lupski JR

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

• DOI: 10.1007/s00439-016-1655-9
• 发表时间: 2016-05
• 期刊: Human genetics
• 影响因子: 5.3
• 作者: Szafranski P;Gambin T;Dharmadhikari AV;Akdemir KC;Jhangiani SN;Schuette J;Godiwala N;Yatsenko SA;Sebastian J;Madan-Khetarpal S;Surti U;Abellar RG;Bateman DA;Wilson AL;Markham MH;Slamon J;Santos-Simarro F;Palomares M;Nevado J;Lapunzina P;Chung BH;Wong WL;Chu YWY;Mok GTK;Kerem E;Reiter J;Ambalavanan N;Anderson SA;Kelly DR;Shieh J;Rosenthal TC;Scheible K;Steiner L;Iqbal MA;McKinnon ML;Hamilton SJ;Schlade-Bartusiak K;English D;Hendson G;Roeder ER;DeNapoli TS;Littlejohn RO;Wolff DJ;Wagner CL;Yeung A;Francis D;Fiorino EK;Edelman M;Fox J;Hayes DA;Janssens S;De Baere E;Menten B;Loccufier A;Vanwalleghem L;Moerman P;Sznajer Y;Lay AS;Kussmann JL;Chawla J;Payton DJ;Phillips GE;Brosens E;Tibboel D;de Klein A;Maystadt I;Fisher R;Sebire N;Male A;Chopra M;Pinner J;Malcolm G;Peters G;Arbuckle S;Lees M;Mead Z;Quarrell O;Sayers R;Owens M;Shaw-Smith C;Lioy J;McKay E;de Leeuw N;Feenstra I;Spruijt L;Elmslie F;Thiruchelvam T;Bacino CA;Langston C;Lupski JR;Sen P;Popek E;Stankiewicz P
• 通讯作者: Stankiewicz P

Complex human chromosomal and genomic rearrangements.

• DOI: 10.1016/j.tig.2009.05.005
• 发表时间: 2009-07
• 期刊: TRENDS IN GENETICS
• 影响因子: 11.4
• 作者: Zhang, Feng;Carvalho, Claudia M. B.;Lupski, James R.
• 通讯作者: Lupski, James R.

Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms.

• DOI: 10.1093/hmg/ddt113
• 发表时间: 2013-07
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Weichen Zhou;Feng Zhang;Xiaoli Chen;Yiping Shen;J. Lupski;Li Jin