Systematic Evaluation of DNA Sequence Variations on Transcription Factor Binding Affinity

Overview

Journal Front Genet

Date 2021 Sep 27

PMID 34567058

Citations 4

Authors

Yutong Jin

Jiahui Jiang

Ruixuan Wang

Zhaohui S Qin

Affiliations

Soon will be listed here.

Abstract

The majority of the single nucleotide variants (SNVs) identified by genome-wide association studies (GWAS) fall outside of the protein-coding regions. Elucidating the functional implications of these variants has been a major challenge. A possible mechanism for functional non-coding variants is that they disrupted the canonical transcription factor (TF) binding sites that affect the binding of the TF. However, their impact varies since many positions within a TF binding motif are not well conserved. Therefore, simply annotating all variants located in putative TF binding sites may overestimate the functional impact of these SNVs. We conducted a comprehensive survey to study the effect of SNVs on the TF binding affinity. A sequence-based machine learning method was used to estimate the change in binding affinity for each SNV located inside a putative motif site. From the results obtained on 18 TF binding motifs, we found that there is a substantial variation in terms of a SNV's impact on TF binding affinity. We found that only about 20% of SNVs located inside putative TF binding sites would likely to have significant impact on the TF-DNA binding.

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References

Ionita-Laza I, McCallum K, Xu B, Buxbaum J . A spectral approach integrating functional genomic annotations for coding and noncoding variants. Nat Genet. 2016; 48(2):214-20. PMC: 4731313. DOI: 10.1038/ng.3477. View

Xu T, Li B, Zhao M, Szulwach K, Street R, Lin L . Base-resolution methylation patterns accurately predict transcription factor bindings in vivo. Nucleic Acids Res. 2015; 43(5):2757-66. PMC: 4357735. DOI: 10.1093/nar/gkv151. View

Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M . Mapping complex disease traits with global gene expression. Nat Rev Genet. 2009; 10(3):184-94. PMC: 4550035. DOI: 10.1038/nrg2537. View

Pasquali L, Gaulton K, Rodriguez-Segui S, Mularoni L, Miguel-Escalada I, Akerman I . Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat Genet. 2014; 46(2):136-143. PMC: 3935450. DOI: 10.1038/ng.2870. View

Vinga S . Information theory applications for biological sequence analysis. Brief Bioinform. 2013; 15(3):376-89. PMC: 7109941. DOI: 10.1093/bib/bbt068. View

Weirauch M, Yang A, Albu M, Cote A, Montenegro-Montero A, Drewe P . Determination and inference of eukaryotic transcription factor sequence specificity. Cell. 2014; 158(6):1431-1443. PMC: 4163041. DOI: 10.1016/j.cell.2014.08.009. View

Kulakovskiy I, Vorontsov I, Yevshin I, Sharipov R, Fedorova A, Rumynskiy E . HOCOMOCO: towards a complete collection of transcription factor binding models for human and mouse via large-scale ChIP-Seq analysis. Nucleic Acids Res. 2017; 46(D1):D252-D259. PMC: 5753240. DOI: 10.1093/nar/gkx1106. View

Zhou L, Zhao F . Prioritization and functional assessment of noncoding variants associated with complex diseases. Genome Med. 2018; 10(1):53. PMC: 6042373. DOI: 10.1186/s13073-018-0565-y. View

Lee D, Gorkin D, Baker M, Strober B, Asoni A, McCallion A . A method to predict the impact of regulatory variants from DNA sequence. Nat Genet. 2015; 47(8):955-61. PMC: 4520745. DOI: 10.1038/ng.3331. View

10.

Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H . The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2013; 42(Database issue):D1001-6. PMC: 3965119. DOI: 10.1093/nar/gkt1229. View

11.

Hu M, Yu J, Taylor J, Chinnaiyan A, Qin Z . On the detection and refinement of transcription factor binding sites using ChIP-Seq data. Nucleic Acids Res. 2010; 38(7):2154-67. PMC: 2853110. DOI: 10.1093/nar/gkp1180. View

12.

Siebert M, Soding J . Bayesian Markov models consistently outperform PWMs at predicting motifs in nucleotide sequences. Nucleic Acids Res. 2016; 44(13):6055-69. PMC: 5291271. DOI: 10.1093/nar/gkw521. View

13.

Chen L, Wang Y, Yao B, Mitra A, Wang X, Qin X . TIVAN: tissue-specific cis-eQTL single nucleotide variant annotation and prediction. Bioinformatics. 2018; 35(9):1573-1575. DOI: 10.1093/bioinformatics/bty872. View

14.

Gao L, Uzun Y, Gao P, He B, Ma X, Wang J . Identifying noncoding risk variants using disease-relevant gene regulatory networks. Nat Commun. 2018; 9(1):702. PMC: 5816022. DOI: 10.1038/s41467-018-03133-y. View

15.

Sandelin A, Alkema W, Engstrom P, Wasserman W, Lenhard B . JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res. 2003; 32(Database issue):D91-4. PMC: 308747. DOI: 10.1093/nar/gkh012. View

16.

Stormo G, Schneider T, Gold L, Ehrenfeucht A . Use of the 'Perceptron' algorithm to distinguish translational initiation sites in E. coli. Nucleic Acids Res. 1982; 10(9):2997-3011. PMC: 320670. DOI: 10.1093/nar/10.9.2997. View

17.

Hertz G, Stormo G . Identifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics. 1999; 15(7-8):563-77. DOI: 10.1093/bioinformatics/15.7.563. View

18.

Ritchie G, Dunham I, Zeggini E, Flicek P . Functional annotation of noncoding sequence variants. Nat Methods. 2014; 11(3):294-6. PMC: 5015703. DOI: 10.1038/nmeth.2832. View

19.

Keilwagen J, Grau J . Varying levels of complexity in transcription factor binding motifs. Nucleic Acids Res. 2015; 43(18):e119. PMC: 4605289. DOI: 10.1093/nar/gkv577. View

20.

Wingender E, Chen X, Hehl R, Karas H, Liebich I, Matys V . TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res. 1999; 28(1):316-9. PMC: 102445. DOI: 10.1093/nar/28.1.316. View