Survey of variation in human transcription factors reveals prevalent DNA binding changes

被引：96

作者：

Barrera, Luis A. ^{[1
,2
,3
,4
,5
]}

Vedenko, Anastasia ^{[1
,2
]}

Kurland, Jesse V. ^{[1
,2
]}

Rogers, Julia M. ^{[1
,2
,3
]}

Gisselbrecht, Stephen S. ^{[1
,2
]}

Rossin, Elizabeth J. ^{[4
,6
,7
,8
]}

Woodard, Jaie ^{[1
,2
,3
]}

Mariani, Luca ^{[1
,2
]}

Kock, Kian Hong ^{[1
,2
,9
]}

Inukai, Sachi ^{[1
,2
]}

Siggers, Trevor ^{[1
,2
]}

Shokri, Leila ^{[1
,2
]}

Gordan, Raluca ^{[1
,2
]}

Sahni, Nidhi ^{[10
,11
,12
]}

Cotsapas, Chris ^{[6
,7
,8
]}

Hao, Tong ^{[10
,11
,12
]}

Yi, Song ^{[10
,11
,12
]}

Kellis, Manolis ^{[5
,8
]}

Daly, Mark J. ^{[6
,7
,13
,14
]}

Vidal, Marc ^{[10
,11
,12
]}

Hill, David E. ^{[10
,11
,12
]}

Bulyk, Martha L. ^{[1
,2
,3
,4
,8
,9
,10
,15
]}

机构：

[1] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Boston, MA 02115 USA

[3] Harvard Univ, Comm Higher Degrees Biophys, Cambridge, MA 02138 USA

[4] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA 02115 USA

[5] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA

[6] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[7] Harvard Univ, Sch Med, Boston, MA 02114 USA

[8] Broad Inst Harvard & MIT, Cambridge, MA 02139 USA

[9] Harvard Univ, Program Biol & Biomed Sci, Cambridge, MA 02138 USA

[10] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA

[11] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[12] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[13] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[14] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA

[15] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

来源：

SCIENCE | 2016年 / 351卷 / 6280期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

CONE-ROD DYSTROPHY; HOMEOBOX GENE; IDENTIFICATION; EXPRESSION; MUTATIONS; MODEL; LIMB; CRX;

D O I：

10.1126/science.aad2257

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.

引用

页码：1450 / 1454

页数：5

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