Genetics of global gene expression

“In most cases, evidence for cis -regulatory mutations underlying adaptive divergence is obtained only by allele-specific gene expression analysis using heterozygous individuals [15, 16] or expression quantitative trait loci (eQTL) analysis using admixed populations/strains [17, 18].”

“Gene expression variation among individuals corresponds to an essential step linking genetic variation and phenotypic diversity observed in natural populations (Hill et al, 2021; Albertand Kruglyak, 2015, 15; Rockman and Kruglyak, 2006).”

“Gene expression variation among individuals corresponds to an essential step linking genetic variation and phenotypic diversity observed in natural populations (Hill et al , 2021; Albert & Kruglyak, 2015, 15; Rockman & Kruglyak, 2006).”

“, transcription factors) called expression 46 quantitative trait genes or eQTGs (Rockman and Kruglyak 2006; Brem et al. 2002).”

“By the combination of GWAS and global gene expression, the expression quantitative trait loci (eQTLs) study can identify QTLs that explain fractions of variation in the expression levels [61].”

“Quantitative variation of protein abundance is the result of a complex network of regulatory mechanisms that integrate genetic variation and interaction with the environment of individual plants [14,15].”

“05, (3) quantile normalization for all 1,656 arrays, (4) removal of samples for which 3 replicated samples were not clustered for the remaining 25,216 probes, (5) median value of 3 replicates selected for further analysis, and (6) use of ComBat20, an empirical Bayes method (R package: SVA), to remove remaining batch e…”

“Trans-eQTL, on the other hand, can be located anywhere in the genome in relation to the genes which they regulate [2].”

“Genetic and epigenetic mechanisms act together to organize the fine-tuned gene regulatory circuitries underlying cell-type identities and functions.(1,2) Misregulation of these pathways has been associated with diseases.”

“The use of microarray technology to simultaneously measure expression of many different genes has been a driving force for the systematic mapping of eQTLs [17,18], since gene expression in many individuals is the substrate for investigating the effects of genomic changes on the expression of individual genes.”

“Conversely, improper gene expression can lead to a variety of abnormal metabolic, developmental, and/or physiological states [1–7].”

“…of brook charr (Mavarez et al. 2009) and in hybrids between lake whitefish species pairs (Renaut et al. 2009), pointing to the common existence of complex interactions between parental species’ regulatory machineries when divergent genomes are admixed (Gibson & Weir 2005; Rockman & Kruglyak 2006).”

“Recent advances in the integration of quantitative genetics and expression genomics have provided a global view of gene expression traits and their implications in high-order phenotype variations [1,2,3,4,5,6,7,8].”

“health services at risk to malaria attack (Rockman and Kruglyak, 2006; Emiliana et al., 2008).”

“enotypic diversity is gene expression analysis. One hard-to-grasp issue is that the process of gene expression by itself is a complex one, both from the biochemical and thermodynamical points of view [1]. The transcription of messenger RNA (mRNA) for a given gene from a DNA template often is regulated by different gen…”

“…analyses such as microarrays have, however, started to extend our knowledge on the regulation of lignin biosynthesis (Kirst et al. 2004) and, more generally, on the potential connections between the DNA sequence and phenotypic variation (global molecular phenotyping) (Rockman & Kruglyak 2006).”

“…implies that a genetic difference between the parental karyotypes (INV/INV and STD/STD) affecting gene expression is in linkage disequilibrium (LD) with the gene whose expression is affected (see Wang et al. 2020; also cf. Rockman and Kruglyak 2006; Wittkopp et al. 2008; Signor and Nuzhdin 2018).”

“Gene expression acts as a pivotal bridge between genotype and phenotype, playing a crucial role in adaptive processes (Rockman 2005; Rockman and Kruglyak 2006).”

“Local and distal are often referred to as cis or trans, where cis implies variants affecting transcription factor binding sites or other regulatory sequences near a gene, and trans implies variants affecting changes in the structure or function of transcription factors or other regulatory proteins for a more ‘global’…”

“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 ​(Rockman and Kruglyak 2006)​.”

“In other words, increases or decreases in the expression amount of a gene may be results of changes in expressions of other genes or environmental factors (28).”

“This is likely to be especially critical in genomic studies like eQTL analyses of transcript abundances [37,38], where the cost of generating and sequencing additional genotypes far”

“[27,28] and natural polymorphism among Arabidopsis accessions has been already reported to be considerable at the genome [29] as well as transcriptome levels [30].”

“Rockman & Kruglyak (2006) define the two types of regulatory sequence variation as local and distant regulatory variation.”

“…or association analysis, to detect association within pedigrees or in the population, respectively, (Brem et al. , 2002; Cheung et al. , 2003a, 2003b, 2005; Jansen and Nap, 2001; Monks et al. , 2004; Morley et al. , 2004; Rockman and Kruglyak, 2006; Schadt et al. , 2003; Stranger et al. , 2005).”

“…DNA variation (quantitative trait loci; QTLs) associated with individual differences in gene expression (expression QTLs; eQTLs; Breitling et al., 2008; Dixon et al., 2007; Emilsson et al., 2008; Goring et al., 2007; Nica & Dermitzakis, 2008; Rockman & Kruglyak, 2006; Stranger et al., 2007).”

“12,13 Here, we systematically used the data for analysis, identification, analysis tools, and subsequent analysis for researchers.”

“[13,14] In this study, we confirmed the relationship between CRC survival and eQTLs by conducting a two-stage population study in Chinese population and further experimentally validated the function of CRC survival-associated SNP.”

“Traditional QTL methods need to measure the genotype and gene expression level of each individual studied, and then use association analysis (outbred population) or linkage analysis (family or experimental hybrid population) to assess the association between genotype and gene expression level (Rockman and Kruglyak, 20…”

“The most well investigated QTLs are eQTLs, which are associated with the expression level of gene transcripts [2].”

“polymorphism on trans-regulatory factors located far away from the target genes (Rockman and Kruglyak 2006).”

“…9–35% (R2 values for allelic correlations) of the phenotypic variation between large and small animals, which is consistent with other results obtained by similar studies in both abalone and other species (Rockman and Kruglyak 2006; Liu et al. 2007; Baranski et al. 2008; Slabbert 2010).”

“the same species [10,11] and by analysis of hybrid species [12,13].”

“Such a QTL is called an “expression QTL” or eQTL (specifically reviewed in (58;59)).”

“In doing so, there are far fewer markers to analyze; however, this type of study may suffer by missing common variants not present in the studied cohort and may lack the ability to resolve the location of the eQTL to a high degree [1].”

“Systems Genetics approaches provide a new paradigm of large-scale genome and network analysis (Jansen and Nap 2001; Jansen 2003; Rockman and Kruglyak 2006; Rockman 2008).”

“Thousands of transcripts can be assayed simultaneously, therefore providing data on a large and unbiased set of traits (17).”

“The genetic architecture of gene regulatory variation in hybrids includes whether genes are cis-or trans-regulated and can provide insight into the mechanistic basis of hybrid phenotypes (Rockman and Kruglyak, 2006).”

“…the nearest TSS.), the causal transcriptome-wide association study (cTWAS) [21], the maximally correlated gene within the cis-window (cis-eQTL) [22], colocalization with approximate Bayes factors (ABF) [23], and colocalization with Sum of Single Effects model (SuSiE) [24] without performing…”

“It is emphasized that Scenarios 2-4 and 6-8 also represent settings where there are individual-specific variations in gene expression (Cheung et al., 2003; Rockman and Kruglyak, 2006; Stranger et al., 2007).”

“First, more than half of the genes are influenced by one “local” eQTL per gene, which are typically caused by DNA variants in cis-regulatory elements in the gene’s immediate vicinity 27,28 .”

“RNA sequencing (RNA-seq) is the state-of-the-art assay for measuring gene expression in bulk tissue and is therefore the assay of choice for eQTL mapping.(7,8) However, the high cost of RNA-seq often limits the sample size and therefore reduces the discovery power of eQTL studies based on RNA-seq.”

“Expression quantitative trait loci (eQTLs) are genomic loci that explain all or a fraction of variations in expression levels of mRNAs [9] and eQTL mapping offers a simple but powerful tool for identifying genetic variants which can affect gene expression [10].”

“Consequently, expression quantitative trait loci (eQTLs), the genetic association analysis of these variants and quantitative gene expression, has flourished as one of the research directions in the last decade (Nica & Dermitzakis, 2013; Rockman & Kruglyak, 2006).”

“Some studies found evidence for ubiquitous transgressive expression inherited in F1 hybrids (i.e. over- or under-dominance) (Ranz et al. 2004; Rockman and Kruglyak 2006; Roberge et al. 2008), while others found predominately additive patterns (Hughes et al. 2006; Rottscheidt and Harr 2007; Davidson…”

“Trans-eQTLs, or genetic variants that affect gene expression levels of distant target genes, have received much less attention in comparison to cis-eQTLs, in part due to the considerable multiple hypotheses testing burden 9 .”

“However, the correspondences between genes, alleles and environments on the one hand, and phenotypes on the other have been found to be increasingly complex (Rockman and Kruglyak, 2006).”

“There is already strong evidence to suggest that mRNA expression is a quantitative trait which can be inherited [7, 8].”

“Background One common feature observed in studies of transcript expression is the presence of hot spots, that is, individual loci that affect large number of transcripts [1].”

“In addition, cis-regulated genes might encode regulators affecting the expression of downstream target genes in trans (Rockman and Kruglyak 2006).”

“After endocytosis, the modifed mRNA is present in the cytosol to be expressed, which can be highly variable depending on host genetics [42, 43].”

“See Supplementary Methods for additional details on preparation steps. eQTL mapping (Rockman and Kruglyak 2006) was performed on quantile normalized residual gene expression for each of the six datasets using R/qtl2 (Broman et al. 2019). eQTL mapping treats each gene expression measure as a trait,…”

“QTLs have provided valuable information about gene function and regulation (GTEx Consortium et al., 2017, 2020; Rockman and Kruglyak, 2006), in particular in the analysis and interpretation of the”

“Advances in genomics have allowed the analysis of genetic contributions to variation in gene expression, in terms of so-called expression quantitative trait loci (eQTL) [1, 2].”

“With the advent of microarrays, it is possible to view the transcriptome of an organism as a suite of quantitative traits (Rockman and Kruglyak 2006).”

“Whilst this subject has been covered extensively elsewhere [14], we wish to highlight that many studies have now found that gene-expression levels are both heritable and influenced by common genetic variation in humans [13,15], rodents [16,17], yeast [18] and plants [19].”

“Phenotypic diversity between organisms is therefore partially explained by DNA sequence variation [126].”

“Cis -regulatory variants affect nearby genes through changes in local CREs, whereas trans -regulatory effects are mediated by diffusible factors, often transcription factors or chromatin regulators, that can act on many CREs throughout the genome [11].”