Allele-specific expression reveals interactions between genetic variation and environment

Knowles, David A.; Davis, Joe R.; Raj, Anil; Zhu, Xiaowei; Potash, James B.; Weissman, Myrna M.; Shi, Jianxin; Levinson, Douglas F.; Mostafavi, Sara; Montgomery, Stephen B.; Battle, Alexis

doi:10.1101/025874

Cited by 14 publications

(15 citation statements)

References 49 publications

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“…Thus, while the gene expression signature of social stress may be somewhat conserved across different types of social adversity, and potentially across species, it does not appear to be highly conserved across pathogen environments. Our findings are consistent with previous reports that social status interacts with LPS and glucocorticoid exposure (18,31), and that genetic effects on gene expression can also be altered by local cellular conditions (i.e., gene-environment interactions, e.g., (51)(52)(53)(54)). However, while prior work has primarily shown environment or genotype-dependent differences in the presence or magnitude of effects, here we observed a more striking pattern: directional shifts in the effects of social status, specifically for genes involved in the antiviral response.…”

Section: Discussionsupporting

confidence: 93%

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

Sanz

Maurizio²,

Snyder‐Mackler

et al. 2019

Preprint

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Social experiences are an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here, we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κBdependent pro-inflammatory pathways and lower expression of genes involved in the antiviral response and type I interferon (IFN) signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are not only linked to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history -in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

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Section: Discussionsupporting

confidence: 93%

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

Sanz

Maurizio²,

Snyder‐Mackler

et al. 2019

Preprint

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“…Of these genes, 83 were heterozygous and could be tested for cASE in our data (Maranville et al 2011Idaghdour et al 2012;Franco et al 2013;Mangravite et al 2013;Çalisķan et al 2015;Knowles et al 2015). Sixty-three out of 83 genes were identified as cASE genes in our analysis (P < 0.05) (Supplemental Table S13).…”

Section: Features Of Gxe Interactionsmentioning

confidence: 68%

“…While association mapping compares genotypic effects across individuals that have different genetic backgrounds, allele-specific expression (ASE) approaches compare allelic effects within individuals, thereby controlling for genetic background and cellular environment. Currently, ASE approaches represent the most effective assay to quantify cis-regulatory variants within a defined cellular environment and to control for trans-acting modifiers of gene expression, such as genotype at other loci (Kasowski et al 2010;McDaniell et al 2010;Pastinen 2010;Skelly et al 2011;Cowper-Sal·lari et al 2012;Reddy et al 2012;McVicker et al 2013;Buil et al 2014;Hasin-Brumshtein et al 2014;Kukurba et al 2014;Knowles et al 2015;Kumasaka et al 2016). …”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

High-throughput allele-specific expression across 250 environmental conditions

et al. 2016

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Gene-by-environment (GxE) interactions determine common disease risk factors and biomedically relevant complex traits. However, quantifying how the environment modulates genetic effects on human quantitative phenotypes presents unique challenges. Environmental covariates are complex and difficult to measure and control at the organismal level, as found in GWAS and epidemiological studies. An alternative approach focuses on the cellular environment using in vitro treatments as a proxy for the organismal environment. These cellular environments simplify the organism-level environmental exposures to provide a tractable influence on subcellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE interactions in response to drug treatment and pathogen exposure. However, eQTL mapping approaches are infeasible for large-scale analysis of multiple cellular environments. Recently, allele-specific expression (ASE) analysis emerged as a powerful tool to identify GxE interactions in gene expression patterns by exploiting naturally occurring environmental exposures. Here we characterized genetic effects on the transcriptional response to 50 treatments in five cell types. We discovered 1455 genes with ASE (FDR < 10%) and 215 genes with GxE interactions. We demonstrated a major role for GxE interactions in complex traits. Genes with a transcriptional response to environmental perturbations showed sevenfold higher odds of being found in GWAS. Additionally, 105 genes that indicated GxE interactions (49%) were identified by GWAS as associated with complex traits. Examples include GIPR-caffeine interaction and obesity and include LAMP3-selenium interaction and Parkinson disease. Our results demonstrate that comprehensive catalogs of GxE interactions are indispensable to thoroughly annotate genes and bridge epidemiological and genomewide association studies.

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“…While an allelic signature is expected on the X-chromosome, we wished to extend this to a genome-wide assessment. Typically, allelic imbalance is attributed to the impact of a variant: either the variant within the gene has an effect on the stability of the mRNA, or an upstream SNV has cis-regulatory effects (9). As armadillos are genetically identical, any variant that has the same impact on gene expression will not distinguish individuals.…”

Section: Main Textmentioning

confidence: 99%

The transcriptional legacy of developmental stochasticity

Ballouz

Peña

Knight

et al. 2019

Preprint

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Genetic variation, epigenetic regulation and major environmental stimuli are key contributors to phenotypic variation, but the influence of minor perturbations or "noise" has been difficult to assess in mammals. In this work, we uncover one major axis of random variation with a large and permanent influence: developmental stochasticity. By assaying the transcriptome of wild monozygotic quadruplets of the nine-banded armadillo, we find that persistent changes occur early in development, and these give rise to clear transcriptional signatures which uniquely characterize individuals relative to siblings. Comparing these results to human twins, we find the transcriptional signatures which define individuals exhibit conserved co-expression, suggesting a substantial fraction of phenotypic and disease discordance within mammals arises from developmental stochasticity. One sentence summaryLongitudinal gene expression in identical armadillo quadruplets reveals a major role for developmental stochasticity.

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Allele-specific expression reveals interactions between genetic variation and environment

Abstract: IntroductionThe impact of environment on human health is dramatic, with major risk factors including

Cited by 14 publications

References 49 publications

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

High-throughput allele-specific expression across 250 environmental conditions

The transcriptional legacy of developmental stochasticity

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