Bussemaker, H. | bioRxiv Science

bioRxiv2018

Systematic identification of human SNPs affecting regulatory element activity

Most of the millions of single-nucleotide polymorphisms (SNPs) in the human genome are non-coding, and many overlap with putative regulatory elements. Genome-wide association studies have linked many of these SNPs to human traits or to gene expression levels, but rarely with sufficient resolution to identify the causal SNPs. Functional screens based on reporter assays have previously been of insufficient throughput to test the vast space of SNPs for possible effects on enhancer and promoter activity. Here, we have leveraged the throughput of the SuRE reporter technology to survey a total of 5.9 million SNPs, including 57% of the known common SNPs. We identified more than 30 thousand SNPs that alter the activity of putative regulatory elements, often in a cell-type specific manner. These data indicate that a large proportion of human non-coding SNPs may affect gene regulation. Integration of these SuRE data with genome-wide association studies may help pinpoint SNPs that underlie human traits.

genomics↗

bioRxiv2016

K-mer Motif Multinomial Mixtures

1MotivationThe advent of inexpensive high-throughput sequencing (HTS) places new demands on motif discovery algorithms. To confront the challenges and embrace the opportunities presented by the growing wealth of information tied up in HTS datasets, we developed K-mer motif multinomial mixtures (KMMMs), a flexible class of Bayesian models for identifying multiple motifs in sequence sets using K-mer tables. Advantages of this framework are inference with time and space complexities that only scale with K, and the ability to be incorporated into larger Bayesian models.\n\nResultsWe derived a class of probabilistic models of K-mer tables generated from sequence containing multiple motifs. KMMMs model the K-mer table as a multinomial mixture, with motif and background components, which are distributions over K-mers overlapping with each of the latent motifs and over K-mers that do not overlap with any motif, respectively. The framework casts motif discovery as a posterior inference problem, and we present several approximate inference methods that provide accurate reconstructions of motifs in synthetic data. Finally we apply the method to discover motifs in DNAse hypersensitive sites and ChIP-seq peaks obtained from the ENCODE project.

bioinformatics↗