Biology subjects

Reilly, S. K.

Publications and source records attributed to Reilly, S. K..

2 recordsLinked to original sources

bioRxiv2020

Functional characterization of thousands of type 2 diabetes-associated and chromatin-modulating variants under steady state and endoplasmic reticulum stress

A major goal in functional genomics and complex disease genetics is to identify functional cis-regulatory elements (CREs) and single nucleotide polymorphisms (SNPs) altering CRE activity in disease-relevant cell types and environmental conditions. We tested >13,000 sequences containing each allele of 6,628 SNPs associated with altered in vivo chromatin accessibility in human islets and/or type 2 diabetes risk (T2D GWAS SNPs) for transcriptional activity in {beta} cell under steady state and endoplasmic reticulum (ER) stress conditions using the massively parallel reporter assay (MPRA). Approximately 30% (n=1,983) of putative CREs were active in at least one condition. SNP allelic effects on in vitro MPRA activity strongly correlated with their effects on in vivo islet chromatin accessibility (Pearson r=0.52), i.e., alleles associated with increased chromatin accessibility exhibited higher MPRA activity. Importantly, MPRA identified 220/2500 T2D GWAS SNPs, representing 104 distinct association signals, that significantly altered transcriptional activity in {beta} cells. This study has thus identified functional {beta} cell transcription-activating sequences with in vivo relevance, uncovered regulatory features that modulate transcriptional activity in {beta} cells under steady state and ER stress conditions, and substantially expanded the set of putative functional variants that modulate transcriptional activity in {beta} cells from thousands of genetically-linked T2D GWAS SNPs.

genomics↗

bioRxiv2019

Massively parallel discovery of human-specific substitutions that alter neurodevelopmental enhancer activity

Genetic changes that altered the function of gene regulatory elements have been implicated in the evolution of the human brain. However, identifying the particular changes that modified regulatory activity during neurodevelopment remains challenging. Here we used massively parallel enhancer assays in human neural stem cells to measure the impact of 32,776 human-specific substitutions on enhancer activity in 1,363 Human Accelerated Regions (HARs) and 3,027 Human Gain Enhancers (HGEs), which include enhancers with novel activities in humans. We found that 31.9% of active HARs and 36.4% of active HGEs exhibited differential activity between human and chimpanzee. This enabled us to isolate the effects of 401 human-specific substitutions from other types of genetic variation in HARs and HGEs. Substitutions acted in both an additive and non-additive manner to alter enhancer activity. Human-specific substitutions altered predicted binding sites for a specific set of human transcription factors (TFs) that were a subset of TF binding sites associated with enhancer activity in our assay. Substitutions within HARs, which are overall highly constrained compared to HGEs, showed smaller effects on enhancer activity, suggesting that the impact of human-specific substitutions may be buffered in enhancers with constrained ancestral functions. Our findings yield insight into the mechanisms by which human-specific genetic changes impact enhancer function and provide a rich set of candidates for experimental studies of regulatory evolution in humans.

genomics↗