Mapping Determinants of Gene Expression Plasticity by Genetical Genomics in C. elegans

Li, Yang; Álvarez, O. Alda; Gutteling, E.W.; Tijsterman, Marcel; Fu, Jingyuan; Riksen, J.A.G.; Hazendonk, Esther; Prins, Pjotr; Plasterk, Ronald H.A.; Jansen, Ritsert C.; Breitling, Rainer; Kammenga, J.E.

doi:10.1371/journal.pgen.0020222

Cited by 265 publications

(298 citation statements)

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“…For these distal linkages, 105 out of 107 peaks were found on different chromosomes as the target genes. Results from our previous study (Smirnov et al 2009) and those from model organisms (Li et al 2006;Smith and Kruglyak 2008) have shown that the individual variation in the responses to cellular perturbations is mostly due to polymorphic trans-acting factors.…”

Section: Dna Variants That Affect Radiationinduced Gene Expression Anmentioning

confidence: 86%

Genetic variation in radiation-induced cell death

et al. 2011

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Radiation exposure through environmental, medical, and occupational settings is increasingly common. While radiation has harmful effects, it has utility in many applications such as radiotherapy for cancer. To increase the efficacy of radiation treatment and minimize its risks, a better understanding of the individual differences in radiosensitivity and the molecular basis of radiation response is needed. Here, we integrated human genetic and functional genomic approaches to study the response of human cells to radiation. We measured radiation-induced changes in gene expression and cell death in B cells from normal individuals. We found extensive individual variation in gene expression and cellular responses. To understand the genetic basis of this variation, we mapped the DNA sequence variants that influence expression response to radiation. We also identified radiation-responsive genes that regulate cell death; silencing of these genes by small interfering RNA led to an increase in radiation-induced cell death in human B cells, colorectal and prostate cancer cells. Together these results uncovered DNA variants that contribute to radiosensitivity and identified genes that can be targeted to increase the sensitivity of tumors to radiation. [Supplemental material is available for this article.]Radiation exposure is increasingly common. Medical diagnostic tools such as the X-ray and computed tomography imaging expose patients to ionizing radiation (IR), which can cause DNA damage and increase one's risk of malignancies. However, these radiation-based devices have greatly improved the diagnosis and treatment of many diseases. Thus, the solution is not to eliminate radiation exposure but to protect individuals who are the most sensitive to radiation and to minimize dose and exposure to all individuals (Barnett et al. 2009).Pharmacogenetics has made significant contributions in maximizing therapeutic gains while minimizing side effects; however, those studies have focused mainly on chemicals as therapeutics and have not included radiation. The exclusion of radiation in pharmacogenetics is not surprising since radiation presents a unique set of challenges. Most people are exposed to radiation in nonmedical settings in addition to medical exposures, thus complicating the monitoring of exposure. Safety trials of radiation are impossible given its known toxic effects. Third, most drugs are developed for one or a few diseases. In contrast, radiation is used in a wide range of treatment; over 50% of all cancer treatment protocols include the use of radiation. Target tissues range from skin to skeletal muscles and bone marrow; each tissue type has special cellular components that influence the absorbed radiation dose, and manifests side effects differently.In recent years, cell-based and genetic studies have improved our understanding of the molecular and genetic basis of radiosensitivity by identifying the genes and pathways that are involved in radiation response (Amundson et al. 2001(Amundson et al. , 2008Smirnov et al. ...

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Section: Dna Variants That Affect Radiationinduced Gene Expression Anmentioning

confidence: 86%

Genetic variation in radiation-induced cell death

et al. 2011

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“…Several such panels have been or are being developed for a variety of species, including yeast, Drosophila (Ayroles et al 2009), Arabidopsis (Kover et al 2009), maize (Buckler et al 2009), Caenorhabditis elegans ( Johnson and Wood 1982;Li et al 2006;Rockman and Kruglyak 2009), and mice (Chesler et al 2008;Iraqi et al 2008;Morahan et al 2008). Efforts are also being made to expand (Peirce et al 2004) and maximize the potential of existing populations (Bennett et al 2010).…”

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confidence: 99%

Genetic analysis in the Collaborative Cross breeding population

Philip¹,

Sokoloff²,

et al. 2011

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Genetic reference populations in model organisms are critical resources for systems genetic analysis of disease related phenotypes. The breeding history of these inbred panels may influence detectable allelic and phenotypic diversity. The existing panel of common inbred strains reflects historical selection biases, and existing recombinant inbred panels have low allelic diversity. All such populations may be subject to consequences of inbreeding depression. The Collaborative Cross (CC) is a mouse reference population with high allelic diversity that is being constructed using a randomized breeding design that systematically outcrosses eight founder strains, followed by inbreeding to obtain new recombinant inbred strains. Five of the eight founders are common laboratory strains, and three are wild-derived. Since its inception, the partially inbred CC has been characterized for physiological, morphological, and behavioral traits. The construction of this population provided a unique opportunity to observe phenotypic variation as new allelic combinations arose through intercrossing and inbreeding to create new stable genetic combinations. Processes including inbreeding depression and its impact on allelic and phenotypic diversity were assessed. Phenotypic variation in the CC breeding population exceeds that of existing mouse genetic reference populations due to both high founder genetic diversity and novel epistatic combinations. However, some focal evidence of allele purging was detected including a suggestive QTL for litter size in a location of changing allele frequency. Despite these inescapable pressures, high diversity and precision for genetic mapping remain. These results demonstrate the potential of the CC population once completed and highlight implications for development of related populations.

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“…eQTL can be cis-or trans-acting, reflecting local and distant regulation of gene expression, respectively. They have been thoroughly studied in humans, yeast, plants, rats, mice, and worms (Brem et al 2002;Schadt et al 2003;Li et al 2006;Petretto et al 2006;Keurentjes et al 2007;Farber et al 2009). But, as far as we are aware of, all eQTL studies only focused on one time point or age group, whereas most complex traits and diseases such as cancer are age-related.…”

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confidence: 99%

“…Here we present the first genome-wide study of heritable gene expression regulation as a function of age using a set of 36 single nucleotide polymorphism (SNP)-genotyped recombinant inbred lines (RILs) (Supplemental Table 1) derived from C. elegans wild types N2 and CB4856 (Li et al 2006). The CB4856 3 N2 RIL population displays large genetic and phenotypic differences for a wide range of traits such as reproduction, growth (Gutteling et al 2007;Kammenga et al 2007), gene expression (Li et al 2006), and copulatory plug formation (Palopoli et al 2008), to name a few.…”

mentioning

confidence: 99%

“…The CB4856 3 N2 RIL population displays large genetic and phenotypic differences for a wide range of traits such as reproduction, growth (Gutteling et al 2007;Kammenga et al 2007), gene expression (Li et al 2006), and copulatory plug formation (Palopoli et al 2008), to name a few. We used microarrays to measure genome-wide gene expression using microarrays from the RILs reared at 24°C at three different ages: For young worms, t1, age was 40 h; for reproductive worms, t2, age was 96 h; and for old worms, t3, age was 214 h. In this way we obtained 108 observations perturbed by age and genotype per gene.…”

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confidence: 99%

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Genome-wide gene expression regulation as a function of genotype and age in C. elegans

Viñuela¹,

Snoek²,

Riksen³

et al. 2010

Genome Res.

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Gene expression becomes more variable with age, and it is widely assumed that this is due to a decrease in expression regulation. But currently there is no understanding how gene expression regulatory patterns progress with age. Here we explored genome-wide gene expression variation and regulatory loci (eQTL) in a population of developing and aging C. elegans recombinant inbred worms. We found almost 900 genes with an eQTL, of which almost half were found to have a genotype-by-age effect ( gxa eQTL). The total number of eQTL decreased with age, whereas the variation in expression increased. In developing worms, the number of genes with increased expression variation (1282) was similar to the ones with decreased expression variation (1328). In aging worms, the number of genes with increased variation (1772) was nearly five times higher than the number of genes with a decreased expression variation (373). The number of cis-acting eQTL in juveniles decreased by almost 50% in old worms, whereas the number of trans-acting loci decreased by~27%, indicating that cis-regulation becomes relatively less frequent than trans-regulation in aging worms. Of the 373 genes with decreased expression level variation in aging worms,~39% had an eQTL compared with~14% in developing worms. gxa eQTL were found for~21% of these genes in aging worms compared with only~6% in developing worms. We highlight three examples of linkages: in young worms (pgp-6), in old worms (daf-16), and throughout life (lips-16). Our findings demonstrate that eQTL patterns are strongly affected by age, and suggest that gene network integrity declines with age.

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Mapping Determinants of Gene Expression Plasticity by Genetical Genomics in C. elegans

Cited by 265 publications

References 31 publications

Genetic variation in radiation-induced cell death

Genetic variation in radiation-induced cell death

Genetic analysis in the Collaborative Cross breeding population

Genome-wide gene expression regulation as a function of genotype and age in C. elegans

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