scholarly journals Decision letter: Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross

2020 ◽  
2020 ◽  
Author(s):  
Kaushik Renganaath ◽  
Rocky Cheung ◽  
Laura Day ◽  
Sriram Kosuri ◽  
Leonid Kruglyak ◽  
...  

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kaushik Renganaath ◽  
Rocky Cheung ◽  
Laura Day ◽  
Sriram Kosuri ◽  
Leonid Kruglyak ◽  
...  

Sequence variation in regulatory DNA alters gene expression and shapes genetically complex traits. However, the identification of individual, causal regulatory variants is challenging. Here, we used a massively parallel reporter assay to measure the cis-regulatory consequences of 5832 natural DNA variants in the promoters of 2503 genes in the yeast Saccharomyces cerevisiae. We identified 451 causal variants, which underlie genetic loci known to affect gene expression. Several promoters harbored multiple causal variants. In five promoters, pairs of variants showed non-additive, epistatic interactions. Causal variants were enriched at conserved nucleotides, tended to have low derived allele frequency, and were depleted from promoters of essential genes, which is consistent with the action of negative selection. Causal variants were also enriched for alterations in transcription factor binding sites. Models integrating these features provided modest, but statistically significant, ability to predict causal variants. This work revealed a complex molecular basis for cis-acting regulatory variation.


Science ◽  
2014 ◽  
Vol 343 (6175) ◽  
pp. 1246949-1246949 ◽  
Author(s):  
B. P. Fairfax ◽  
P. Humburg ◽  
S. Makino ◽  
V. Naranbhai ◽  
D. Wong ◽  
...  

2017 ◽  
Vol 16 (3) ◽  
pp. 2397-2410 ◽  
Author(s):  
Maria Caracausi ◽  
Allison Piovesan ◽  
Francesca Antonaros ◽  
Pierluigi Strippoli ◽  
Lorenza Vitale ◽  
...  

2017 ◽  
Author(s):  
Rajesh K. Gazara ◽  
Kanhu C. Moharana ◽  
Daniel Bellieny-Rabelo ◽  
Thiago M. Venancio

ABSTRACTGibberellic acid (gibberellins, GA) controls key developmental processes in the life-cycle of land plants. By interacting with the GIBBERELLIN INSENSITIVE DWARF1 (GID1) receptor, GA regulates the expression of a wide range of genes through different pathways. Here we report the systematic identification and classification of GID1s in 52 plants genomes, encompassing from bryophytes and lycophytes, to several monocots and eudicots. We investigated the evolutionary relationship of GID1s using a comparative genomics framework and found strong support a previously proposed phylogenetic classification of this family in land plants. We identified lineage-specific expansions of particular subfamilies (i.e. GID1ac and GID1b) in different eudicot lineages (e.g. GID1b in legumes). Further, we found both, shared and divergent structural features between GID1ac and GID1b subgroups in eudicots, which provide mechanistic insights on their functions. Gene expression data from several species show that at least one GID1 gene is expressed in every sampled tissue, with a strong bias of GID1b expression towards underground tissues and dry legume seeds (typically with low GA levels). Taken together, our results support that GID1ac retained canonical GA signaling roles, whereas GID1b specialized in conditions of low GA concentrations. We propose that this functional specialization occurred initially at the gene expression level and was later fine-tuned by specific mutations that conferred greater GA affinity to GID1b, including a Phe residue in the GA-binding pocket. Finally, we discuss the importance of our findings to understand the diversification of GA perception mechanisms in land plants.


2021 ◽  
Author(s):  
Hao Lu ◽  
Luyu Ma ◽  
Lei Li ◽  
Cheng Quan ◽  
Yiming Lu ◽  
...  

Noncoding genomic variants constitute the majority of trait-associated genome variations; however, identification of functional noncoding variants is still a challenge in human genetics, and a method systematically assessing the impact of regulatory variants on gene expression and linking them to potential target genes is still lacking. Here we introduce a deep neural network (DNN)-based computational framework, RegVar, that can accurately predict the tissue-specific impact of noncoding regulatory variants on target genes. We show that, by robustly learning the genomic characteristics of massive variant-gene expression associations in a variety of human tissues, RegVar vastly surpasses all current noncoding variants prioritization methods in predicting regulatory variants under different circumstances. The unique features of RegVar make it an excellent framework for assessing the regulatory impact of any variant on its putative target genes in a variety of tissues. RegVar is available as a webserver at http://regvar.cbportal.org/.


2015 ◽  
Author(s):  
Melissa Gymrek ◽  
Thomas Willems ◽  
Haoyang Zeng ◽  
Barak Markus ◽  
Mark J Daly ◽  
...  

Expression quantitative trait loci (eQTLs) are a key tool to dissect cellular processes mediating complex diseases. However, little is known about the role of repetitive elements as eQTLs. We report a genome-wide survey of the contribution of Short Tandem Repeats (STRs), one of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from linked SNPs and indels and found that eSTRs contribute 10%-15% of the cis-heritability mediated by all common variants. Functional genomic analyses showed that eSTRs are enriched in conserved regions, co-localize with regulatory elements, and are predicted to modulate histone modifications. Our results show that eSTRs provide a novel set of regulatory variants and highlight the contribution of repeats to the genetic architecture of quantitative human traits.


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