Genetics of global gene expression

“Comparison Analysis of Federated GEIDI and Matrix eQTL Expression quantitative trait loci (eQTL) analysis (54, 55) is designed to identify the significant associations between SNPs and gene expression, which can help understand the biochemical processes occurring in living systems, discover the genetic factors that in…”

“Loci with such pleiotropic effects known as genetic hubs or buffers are a common feature of the genetics of gene expression [26] and their existence emerges from the concept of CGV [36].”

“variation in complex phenotypes has been a central goal of systems genetics [1].”

“Gene expression is a crucial aspect of the genotype to phenotype map and expression studies provide a large set of traits that can be easily measured without prior information about how these traits might relate to fitness [6] .”

“Segregating allelic variation provides many small-effect mutations in regulatory and coding regions of almost every gene reviewed in [23].”

“…of the TF c-Fos and the local chromatin structure, the KM allele C might be the causative allele associated with affecting B cell differentiation and the autoimmune system. eQTLs are genomic regions that are correlated with a change in the level of gene expression (Rockman and Kruglyak 2006).”

“In addition, there has been some discussion that trans-eQTL are more likely to be eQTL ‘‘hot spots’’ than cis-eQTL as their effects may be more pleiotropic [45].”

“G ENOME-WIDE studies of expression quantitative trait loci (eQTL) have been widely used to dissect the genetic basis of gene expression and molecular mechanisms underlying complex traits (Bochner 2003; Rockman and Kruglyak 2006; Michaelson et al. 2009).”

“Therefore, in the absence of allele-specific expression data (see elsewhere in this review), it is better to use the terms ‘local’ and ‘distant’ eQTL (Rockman and Kruglyak, 2006) (Fig.”

“These have led to some general principles of genetic mapping of genome-wide gene expression as reviewed by Rockman and Kruglyak (2006).”

“The eQTLs can be classified into cis (local) or trans (distant) acting eQTLs according to the location of the transcription site and that of the eQTL or eSNP significantly correlated with the transcriptional activity (Rockman and Kruglyak 2006).”

“Rockman, M.V. & Kruglyak, L. (2006) Genetics of global gene expression.”

“Another approach, which appears to be more productive, utilises the results of genome-wide searches for quantitative trait loci (QTL) that are associated with changes in gene expression (eQTL) or the ratio of RNA isoforms (isoQTL) in the neuronal tissues of healthy people [74,75].”

“Because these eQTL have yet to be demonstrated to act in cis or trans, they may be more appropriately termed local or distant regulators (Rockman and Kruglyak, 2006), respectively, but the more familiar terms cis-acting and trans-acting are used for clarity.”

“…genetic variation contributes to polygenic disease susceptibility via protein-coding variants (that modify protein function or stability) or more often intra-or intergenic variants in regulatory regions that modify mRNA expression (expression or protein quantitative loci in polygenic diseases) [1].”

“In addition to clinical phenotypes, QTL mapping can be applied to molecular traits such as gene expression [17-22], chromatin accessibility [23], and protein abundance [24, 25].”

“The different alleles of a SNP may cause variation in expression levels of messenger RNAs (mRNAs), if they are located in a gene regulatory noncoding chromatin element (Rockman and Kruglyak 2006).”

“Variation in transcript abundance has been studied as an inherited quantitative trait [5] and association mapping of loci for expression traits has been performed in several species for a wide range of tissues [6].”

“In general, the presence of eQTL hotspots suggests either the presence of a master regulator gene which controls the expression of groups of genes together or the presence of several tightly linked genes within the hotspot, each of which regulates the expression of a subset of genes mapping to this locus [31,33,34].”

“The mapping of the QTLs responsible of gene expression variability (eQTLs, [10, 11]) permits to identify genome regions acting as master regulators of the expression of many genes, and to establish networks of co-regulated genes [9, 12, 13].”

“Although frequently considered to be the phenotype level closest to DNA sequence variation [11], transcript abundance does actually reflect the balance between production and decay rates.”

“Coupling with DNA polymorphism information, these models are capable of mapping quantitative trait loci (QTLs) that control transcriptional (eQTL), proteomic (pQTL), and metabolomic (mQTL) expressions 20 and their interaction networks among these different types of QTLs.”

“Local gene expression level is formally considered as a quantitative trait that is directly modified by allelic variation in regulatory elements (3,4).”

“This gave rise to the concept of local eQTL, namely expression quantitative trait loci that map to the location of the target gene (Rockman & Kruglyak, 2006).”

“Gene expression varies between individuals and has been successfully mapped as a quantitative trait in model organisms and more recently in humans.(82,83) Genome-wide mapping of disease association and of global gene expression offers a complimentary and synergistic approach, which was elegantly demonstrated by a rece…”

“lation, when mapped near the genomic location of the gene encoding the transcript, or ‘‘distant’’ regulation, when mapped elsewhere in the genome (Rockman and Kruglyak 2006).”

“, polymorphism of protein amounts) is the result of a complex network of regulatory mechanisms subject themselves to genetic variation and interaction with the environment (Thiellement et al. 2002; Rockman and Kruglyak 2006).”

“Variants in the coding sequence could also influence expression if a gene has auto-regulatory functionality or by triggering changes in feedback loops controlling that gene’s expression (Rockman and Kruglyak 2006).”

“Thus, as we have expected, all of this miRNA, except one, was not found in the eQTL database (Rockman and Kruglyak, 2006; West et al., 2007; Majewski and Pastinen, 2011).”

“Noncoding genetic variation makes a significant contribution to phenotypic diversity and disease susceptibility by modulating gene expression (Rockman and Kruglyak 2006; Skelly et al. 2009).”

“INTRODUCTION Thanks to the advanced high-throughput technologies for profiling gene expressions and assaying genetic variations, genome-wide study of expression quantitative trait loci (eQTL) has been widely applied to dissect genetic basis of gene expression and molecular mechanisms underlying complex traits [5, 40,…”

“2005), and to detect gene expression quantitative trait loci (eQTL) (Rockman and Kruglyak 2006).”

“However, distant cis and local trans effects have also been reported [28].”

“These kinds of analyses are performed by regressing gene expression levels for individual samples against locus-specific genotypes for matched samples [42, 43], and they are usually referred to as expression Quantitative Trait Loci (eQTL).”

“This variant seems to be an expression quantitative trait locus (eQTL), defined as genomic loci that explain all or a fraction of variation in expression levels of mRNAs.(118) Specifically, rs613355 is listed as located in a ciseQTL locus for OPRM1,(44) a locus that maps to the approximate location of their gene-of-or…”

“This trans-sQTL hotspot is similar to what has been observed in many eQTL studies, where genomic loci that are linked with abnormally high numbers of eQTLs are called trans-eQTL hotspots (Joo et al., 2014; King et al., 2014) or trans-eQTL bands (Rockman and Kruglyak, 2006).”

“The trans-acting mechanism is manifested because of effects of other genes that influence its expression, which involves a complex gene regulatory network (Rockman and Kruglyak, 2006).”

“Most of the available studies have discussed eQTL mapping in a simple scenario in which they only modeled the relationship between single gene expression and a single SNP at a time [20,24,26,28,31,39-45].”

“Regarding the relationship between SNP and GE markers, the regulation of GE may be unrelated to DNA sequences, as with epigenetic mechanisms [25], or it may be associated with SNPs, as with expression quantitative trait locus (eQTL) [22,26-28]; nevertheless, even in the case of an eQTL, only a limited proportion of GE…”

“Diversified factors underlying the complexity of gene regulation could contribute to this phenomenon, such as polygenic regulation, environmental input and possibly interactions among loci [13,25].”

“Classic correlation methods or multivariate statistics have been used to correlate gene expression data with proteomic and metabolomic data [47, 48], but they fail to capture the true quantitative variation and relationship between activity of thousands of gene–protein couples or protein–metabolite couples in a cellul…”

“In eQTL studies, the alleles or genotypes of genetic variants are correlated with the quantitative expression level of transcripts [10], thereby identifying genetic variants that influence the expression level of a gene.”

“We concentrate specifically on expression Quantitative Trait Loci association (eQTL) [28] networks and investigate whether mRNAs related to complex disease SNPs are more central than the remaining mRNAs in the network of eQTL associations.”

“The potential of genomewide eQTL identification has been shown originally in the yeast Saccharomyces cerevisiae [9] and then in humans, animals, and plants [10, 11].”

“Formally, tr nscription level is considered as a quantitative trait that is altered by allelic v ariation with thousands of SNPs reported as associated with changes in gene expression [10-13].”

“27,28 Second, the majority of the eQTLs (92%; 33,529) were located far from the genes they influence, typically on a different chromosome.”

“Still, trans-regulation may occur via downstream effects of cis-regulatory elements, like in the case of transcription factors (Rockman and Kru- glyak, 2006).”

“5B) are called transcriptional “hotspots”, and finding the causal genes underlying a hotspot is an important problem in quantitative genetics [26].”

“studied over the years and are known to be widespread over human populations [35, 36].”

“…known to influence economically important traits in cattle is no evidence that the adrenocortical transcript abundance is causal, but similar effects might be present in other organs and tissues [29] providing insight into molecular mechanisms that contribute to the phenotypic variation in cattle.”

“Furthermore, transcription regulation is highly polygenic [6] and demonstrates complex patterns of inheritance that contribute to gene expression variation in hybrids [5].”

“Allele-specific association studies advance these analyses and increase scientific knowledge of the regulatory process (Rockman and Kruglyak 2006; Serre et al. 2008; Stamatoyannopoulos 2004).”

“…two sub-problems of particular interest are (a) understanding how various genetic loci regulate gene expression, a problem known as eQTL mapping (Rockman and Kruglyak, 2006), and (b) determining which genes have a direct influence on the expression of other genes, a problem known as gene…”

“6 ((rs9268831 = T) or (rs9269190 = T)) or (rs9270652 = C) rs9268831 32427748 intergenic HLA-DRA (dist = 14922), HLA-DRB5 (dist = 57406) 5 (1) 31 (19) 71 (16) GM18951 (POL2) 1 Whole Blood (HLA-DQA1, HLADQA2, HLA-DQB1, HLA-DQB1-AS1, HLA-DQB2, HLADRB1, HLA-DRB6, HLA-DRB9); Lymphoblastoid (HLA-DQA2, HLA-DQB2, HLADRB6, HLA…”

“Name Molecular trait Other techniques Ref. eQTL Gene expression RNA-seq or microarray Rockman [108] dsQTL Open chromatin DNaseI-seq Degner [109] sQTL RNA splicing RNA-seq Monlong [110] rtQTL DNA replication timing FACS-sorting Amnon [111] haQTL Histone acetylation ChIP-seq Rosario [112] metQTL DNA methylation Bisulfit…”

“To make the first step towards this goal, we applied eQTL (Expression Quantitative Trait Loci) analysis to expression data from tumor-adjacent stroma, to define associations between gene activity and risk variants [33–36].”

“Expression quantitative trait locus (eQTL) analysis studies the association of genomic variations with gene expression variations, and is a key to decode the molecular network that regulates the expression of genes [1–6].”

“In these studies, the goal is to identify regions of the genome harboring genetic variation that affect gene expression levels or expression quantitative trait loci (eQTL) (Bochner, 2003; Rockman and Kruglyak, 2006; Cookson et al., 2009).”

“To identify genes with evidence for interacting loci [15] we focused on those ProbeSets with statistically significant (padjusted,0.”

“…past decades, studies have analyzed and unveiled the genetic variants in the human genome, such as single-nucleotide polymorphisms (SNPs) (Stranger et al., 2007) which contribute to gene expression variation, and eventually to phenotypic variation in human populations (Rockman and Kruglyak 2006).”

“In the past decade, studies have focused on demonstrating the potential of these variants to influence specific traits or diseases through transcriptomic regulation [2-4].”

“One hard-to-grasp issue is that the process of gene expression in itself is a complex one, both from the biochemical and thermodynamical points of view [1].”

“Transcript abundance of each single gene is treated as a quantitative trait and its regulation is genetically interrogated using QTL mapping approaches (Chen and Kendziorski 2007; Rockman and Kruglyak 2006).”

“…of tissue yields a less biased sampling of phenotypic traits compared with an observer’s opinions on what might be an important trait (Rockman and Kruglyak 2006; Josephs 2021), although investigators must still decide on growth or rearing environments, as well as the tissues and…”