PT  - JOURNAL ARTICLE
AU  - Zeyang Shen
AU  - Jenhan Tao
AU  - Gregory J. Fonseca
AU  - Christopher K. Glass
TI  - Natural genetic variation affecting transcription factor spacing at regulatory regions is generally well tolerated
AID  - 10.1101/2020.04.02.021535
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.02.021535
4099  - http://biorxiv.org/content/early/2020/04/03/2020.04.02.021535.short
4100  - http://biorxiv.org/content/early/2020/04/03/2020.04.02.021535.full
AB  - Regulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Single nucleotide polymorphisms (SNPs) and short insertions and deletions (InDels) can influence gene expression by altering the sequences of TF binding sites. Prior studies also showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of altered TF spacing has not been systematically analyzed in the context of natural genetic variation. Here, we exploit millions of InDels provided by five diverse strains of mice to globally investigate the effects of altered spacing on TF binding and local histone acetylation in macrophages. We find that spacing alterations resulting from InDels are generally well tolerated in comparison to genetic variants that directly alter TF binding sites. These findings have implications for interpretation of non-coding genetic variation and comparative analysis of regulatory elements across species.