Genome-wide characteristics of de novo mutations in autism

被引：150

作者：

Yuen, Ryan K. C. ^{[1
]}

Merico, Daniele ^{[1
,2
]}

Cao, Hongzhi ^{[3
]}

Pellecchia, Giovanna ^{[1
]}

Alipanahi, Babak ^{[2
,4
]}

Thiruvahindrapuram, Bhooma ^{[1
]}

Tong, Xin ^{[3
]}

Sun, Yuhui ^{[3
]}

Cao, Dandan ^{[3
]}

Zhang, Tao ^{[3
]}

Wu, Xueli ^{[3
]}

Jin, Xin ^{[3
]}

Zhou, Ze ^{[3
]}

Liu, Xiaomin ^{[3
]}

Nalpathamkalam, Thomas ^{[1
]}

Walker, Susan ^{[1
]}

Howe, Jennifer L. ^{[1
]}

Wang, Zhuozhi ^{[1
]}

MacDonald, Jeffrey R. ^{[1
]}

Chan, Ada J. S. ^{[1
]}

D'Abate, Lia ^{[1
,5
]}

Deneault, Eric ^{[1
,5
]}

Siu, Michelle T. ^{[6
]}

Tammimies, Kristiina ^{[7
]}

Uddin, Mohammed ^{[1
]}

Zarrei, Mehdi ^{[1
]}

Wang, Mingbang ^{[3
]}

Li, Yingrui ^{[3
]}

Wang, Jun ^{[3
]}

Wang, Jian ^{[3
]}

Yang, Huanming ^{[3
]}

Bookman, Matt ^{[8
,9
]}

Bingham, Jonathan ^{[8
,9
]}

Gross, Samuel S. ^{[8
,9
]}

Loy, Dion ^{[8
]}

Pletcher, Mathew ^{[10
]}

Marshall, Christian R. ^{[1
,11
]}

Anagnostou, Evdokia ^{[12
]}

Zwaigenbaum, Lonnie ^{[13
]}

Weksberg, Rosanna ^{[5
,6
,14
]}

Fernandez, Bridget A. ^{[15
,16
]}

Roberts, Wendy ^{[17
]}

Szatmari, Peter ^{[17
,18
,19
]}

Glazer, David ^{[8
,9
]}

Frey, Brendan J. ^{[2
,4
,20
]}

Ring, Robert H. ^{[10
]}

Xu, Xun ^{[3
]}

Scherer, Stephen W. ^{[1
,5
,21
]}

机构：

[1] Hosp Sick Children, Ctr Appl Gen Genet & Genome Biol, Toronto, ON, Canada

[2] Deep Genom Inc, Toronto, ON, Canada

[3] BGI Shenzhen, Shenzhen, Peoples R China

[4] Univ Toronto, Dept Elect & Comp Engn, Toronto, ON, Canada

[5] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[6] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON, Canada

[7] Karolinska Inst, Pediat Neuropsychiat Unit, Ctr Neurodev Disorders KIND, Stockholm, Sweden

[8] Google Inc, Google Gen, Google Cloud Platform, Mountain View, CA USA

[9] Verily Life Sci, San Francisco, CA USA

[10] Autism Speaks, Princeton, NJ USA

[11] Hosp Sick Children, Dept Mol Genet, Paediat Lab Med, Toronto, ON, Canada

[12] Univ Toronto, Bloorview Res Inst, Toronto, ON, Canada

[13] Univ Alberta, Dept Pediat, Edmonton, AB, Canada

[14] Univ Toronto, Dept Pediat, Toronto, ON, Canada

[15] Mem Univ Newfoundland, Disciplines Genet & Med, St John, NF, Canada

[16] Eastern Hlth, Prov Med Genet Program, St John, NF, Canada

[17] Hosp Sick Children, Autism Res Unit, Toronto, ON, Canada

[18] Ctr Addict & Mental Hlth, Child Youth & Family Serv, Toronto, ON, Canada

[19] Univ Toronto, Dept Psychiat, Toronto, ON, Canada

[20] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON, Canada

[21] Univ Toronto, McLaughlin Ctr, Toronto, ON, Canada

来源：

NPJ GENOMIC MEDICINE | 2016年 / 1卷

基金：

加拿大健康研究院; 瑞典研究理事会;

关键词：

SPECTRUM DISORDER; GENETIC-VARIANTS; STRUCTURAL VARIATION; RECURRENCE RISK; CANCER GENOMES; DNA; MECHANISMS; METHYLATION; ARCHITECTURE; DISRUPTION;

D O I：

10.1038/npjgenmed.2016.27

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

De novo mutations (DNMs) are important in autism spectrum disorder (ASD), but so far analyses have mainly been on the similar to 1.5% of the genome encoding genes. Here, we performed whole-genome sequencing (WGS) of 200 ASD parent-child trios and characterised germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (P = 4.2 x 10(-10)). However, when clustered DNMs (those within 20 kb) were found in ASD, not only did they mostly originate from the mother (P = 7.7 x 10(-13)), but they could also be found adjacent to de novo copy number variations where the mutation rate was significantly elevated (P = 2.4 x 10(-24)). By comparing with DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (P = 8.0 x 10(-9); odds ratio = 1.84), of which 15.6% (P = 4.3 x 10(-3)) and 22.5% (P = 7.0 x 10(-5)) were non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, regulatory sequences involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/ 185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD-risk and epigenetic genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the aetiology of ASD.

引用

页数：10

共 50 条

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