Survey of variation in human transcription factors reveals prevalent DNA binding changes.
Survey of variation in human transcription factors reveals prevalent DNA binding changes.
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DOI：
10.1126/science.aad2257
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发表时间：
2016-03-25
期刊：
影响因子：
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通讯作者：
Bulyk ML
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文献类型：
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作者：
Barrera LA;Vedenko A;Kurland JV;Rogers JM;Gisselbrecht SS;Rossin EJ;Woodard J;Mariani L;Kock KH;Inukai S;Siggers T;Shokri L;Gordân R;Sahni N;Cotsapas C;Hao T;Yi S;Kellis M;Daly MJ;Vidal M;Hill DE;Bulyk ML
外显子组和基因组的测序已经揭示了影响人类转录因子（TF）编码序列的丰富的遗传变异，但是这种变异的后果在很大程度上仍然未被探索。我们开发了一种基于结构的计算方法来评估TF变体对DNA结合活性的影响，并使用通用蛋白结合微阵列来测定在不同祖先和孟德尔疾病家族的个体中发现的41个参考和117个变体等位基因的序列特异性DNA结合活性。我们在28个基因中发现了77个影响DNA结合亲和力或特异性的变异，并鉴定了数千个可能改变人类序列特异性TF的DNA结合活性的罕见等位基因。我们的研究结果表明，大多数人都有独特的TF DNA结合活性，这可能有助于表型变异。
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.