Genetic Basis and Functional Consequences of Chromatin State Variability across Individuals. F. Grubert1, J. Zaugg1, M. Kasowski1, O. Ursu1, D. Spacek1, A. Martin1, L. Steinmetz1,2, A. Kundaje1, M. Snyder1 1) Dept Genetics, Stanford University, Stanford, CA; 2) European Molecular Biology Laboratory, Genome Biology, Heidelberg, Germany.
One of the continuing challenges in biomedical research is to understand the genetic contribution to hereditary traits and diseases. The number of associations between genetic variants (e.g. single nucleotide polymorphisms (SNPs)) and complex diseases is rising rapidly, however, our understanding of the underlying molecular mechanisms is lagging far behind. One reason for this lack of understanding is that most disease-associated loci lie in the non-coding part of the genome. Previously we have shown that disease-loci are enriched in regulatory elements that show great variability among individuals. Here we performed ChIP-Seq experiments for three different histone modifications (H3K4m3, H3K4me1 and H3K27ac) across 70 unrelated individuals to better understand the genetic contribution of the observed variability in chromatin-states. Using the histone marks as quantitative traits we identified a quantitative trait locus (QTL) for more than 10% of all regulatory elements, whereby enhancers are more likely to have a QTL than are promoters. More than 50% of the chromatin QTLs we identified for a single mark also significantly affect at least one other mark indicating a shared mechanism influencing the activity of different histone marks. A potential mechanism that could explain the genetic basis of variable chromatin activity is the disruption of transcription factor (TF) binding sites through single SNPs. These motif disruptions could prevent binding of sequence-specific TFs, which often recruit histone-modifying enzymes to their genomic targets. We also found that chromatin QTLs are significantly enriched in SNPs previously identified in genome-wide association studies (GWAS), providing further evidence of the functional implications of chromatin variability in humans. Overall our study will allow us to better understand the molecular mechanism that underlie known associations between genotype and complex genetic diseases.
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