Systematic Evaluation of The Impact of DNA Sequence Variants on The in vivo Binding Affinity at Transcription Factor Binding Sites Open Access

Abstract

 

The majority of the single nucleotide variants (SNVs) identified by genome-wide association studies (GWASs) fall outside of the protein-coding regions. Elucidating the functional implications of these variants has been a major challenge due to the lack of functional annotation in the non-coding part of the genome. A possible mechanism for some of the functional non-coding variants is that they disrupted the canonical transcription factor (TF) binding sites which affect the in vivo binding affinity of the TF. However, not all variants located within TF binding sites will impact TF binding since a substantial proportion of most TF binding motifs is not well conserved. Therefore, simply annotate all variants located in putative TF binding sites is not ideal. In this project, we conducted a comprehensive survey to study the effect of SNVs on the TF binding affinity. Using CTCF as an example, we found that mutations occur at about 30% of positions inside a putative CTCF binding motif sites will likely to have significant effect on the TF-DNA binding. Our results provide key guidance on annotating variants in terms of the impact of TF binding. 

Table of Contents

 

1. Introduction ................................................................................................................................1

2. Materials and Methods ................................................................................................................2

2.1 Overview ...........................................................................................................................2

2.2 Statistical Analysis Methods .............................................................................................3

2.2.1 Comparing correlation between difference in PWM score and weights.................3

2.2.2 Using delta-SVM score to determine the impact of variations on each particular position ........................................................................................................................................4

2.2.3 Determine the threshold value to identify significant SNPs ..................................5

3. Result ............................................................................................................................................5

4. Discussion .....................................................................................................................................7

5. Reference ......................................................................................................................................8

6. Tables and Figures ......................................................................................................................11

7. Supplementary Materials ............................................................................................................15

About this Master's Thesis

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School	Rollins School of Public Health
Department	Biostatistics
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Biology, Biostatistics
Keyword	Annotation CTCF transcription factor binding sites SNV
Committee Chair / Thesis Advisor	Qin, Zhaohui, Emory University
Committee Members	Yu, Tianwei, Emory University
Partnering Agencies	Does not apply (no collaborating organization)

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