Cryptic genetic variation of expression quantitative trait locus architecture revealed by genetic perturbation in <i>Caenorhabditis elegans</i>

Wijk, Marijke H. van; Riksen, J.A.G.; Elvin, Mark; Poulin, Gino; Maulana, Muhammad I; Kammenga, J.E.; Snoek, L. Basten; Sterken, Mark G.

doi:10.1093/g3journal/jkad050

Cited by 4 publications

(3 citation statements)

References 57 publications

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“…Our eQTL mapping experiment identified a large number of trans-bands, many noticeably located on chromosome V. We found 1,827 genes with a cis-eQTL, 2,406 genes with a trans-eQTL, and 18 trans-bands. This is on the higher end compared with previous eQTL studies in C. elegans on similar microarray platforms, that report between 819 -1,722 cis-eQTL and 816 -1533 trans-eQTL (as deposited in WormQTL2.0) (15,41,45,47,62). This could indicate that the number of trans-eQTL increased due to genetic perturbations.…”

Section: Ample Quantitative Genetic Variation In Gene Expression In T...mentioning

confidence: 54%

eQTL mapping in transgenic alpha-synuclein carryingCaenorhabditis elegansrecombinant inbred line

Huang,

Wang,

van Sluijs

et al. 2023

Preprint

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Protein aggregation of alpha-synuclein (alphaS) is a genetic and neuropathological hallmark of Parkinson disease (PD). Studies in the model nematode Caenorhabditis elegans suggested that variation of alphaS aggregation depends on the genetic background. However, which genes and genetic modifiers underlie individual differences in alphaS pathology remains unknown. To study the genotypic-phenotypic relationship of alphaS aggregation, we constructed a Recombinant Inbred Line (RIL) panel derived from a cross between genetically divergent strains C. elegans NL5901 and SCH4856, both harboring the human alphaS gene. As a first step to discover genetic modifiers 70 alphaS-RILs were measured for whole-genome gene expression and expression quantitative locus analysis (eQTL) were mapped. We detected multiple eQTL hot-spots, many of which were located on Chromosome V. To confirm a causal locus, we developed Introgression Lines (ILs) that contain SCH4856 introgressions on Chromosome V in an NL5901 background. We detected 74 genes with an interactive effect between alphaS and the genetic background, including the human p38 MAPK homologue pmk-1 that has previously been associated with PD. Together, we present a unique alphaS-RIL panel for defining effects of natural genetic variation on alphaS pathology, which contributes to finding genetic modifiers of PD.

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Section: Ample Quantitative Genetic Variation In Gene Expression In T...mentioning

confidence: 54%

eQTL mapping in transgenic alpha-synuclein carryingCaenorhabditis elegansrecombinant inbred line

Huang,

Wang,

van Sluijs

et al. 2023

Preprint

Self Cite

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“…)linear processes affecting gene expression on a genome-wide scale and can be applied to other published eQTL studies in C. elegans [35][36][37][38][39][40] and beyond 27 . Furthermore, our method, despite being simpler, provided an ordering of the expression of developmental indicator genes that was more consistent with a monotonic linear increase.…”

Section: Discussionmentioning

confidence: 99%

The effect of developmental variation on expression QTLs in a multi parentalC. eleganspopulation

Eijnatten

Sterken

Kammenga

et al. 2023

Preprint

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Regulation of gene expression plays a crucial role in the development and adaptation of organisms to changing environments. A population-based procedure used to investigate the genetic regulation of gene expression is eQTL mapping. Typically, the age of the population used for eQTL mapping at the time of sampling is strictly controlled. This is necessary because the developmental process causes changes in gene expression, complicating the interpretation of eQTL mapping experiments. However, organisms can differ in their "developmental age", even if they are of the same chronological age. As a result, eQTL patterns are affected by uncontrolled developmental variation in gene expression. The model organism C. elegans is particularly suited for studying the effect of developmental variation on eQTL mapping patterns. In a span of days C. elegans transitions from embryo through four larval stages to adult while undergoing massive changes to its transcriptome. Here we use C. elegans to investigate the effect of developmental age variation on eQTL patterns and an available normalization procedure. We used dynamical eQTL mapping, which includes developmental age as a cofactor, to separate the variation in development from genotypic variation and explain variation in gene expression levels. We compare classical single marker eQTL mapping and dynamical eQTL mapping using RNA-seq data of ~200 multi-parental recombinant inbred lines of C. elegans. The results show that many eQTLs are actually caused by developmental variation, that most trans-bands are associated with developmental age and that dynamical eQTL mapping detects additional eQTLs not found with classical eQTL mapping.

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“…Because we wanted a method that was generally applicable, we did not want to be completely dependent on a reference (time) series. Our approach enables the detection of other (semi-)linear processes affecting gene expression on a genome-wide scale and can be applied to other published eQTL studies in C. elegans ( Li et al 2006 , 2010 ; Snoek et al 2017 ; Sterken et al 2017 , 2020 ; van Wijk et al 2023 ) and beyond ( Ben-David et al 2021 ). Furthermore, our method, despite being simpler, provided an ordering of the expression of developmental indicator genes that was more consistent with the monotonic linear increase described in previous literature.…”

Section: Discussionmentioning

confidence: 99%

The effect of developmental variation on expression QTLs in a multi parental Caenorhabditis elegans population

van Eijnatten,

Sterken,

Kammenga

et al. 2023

G3: Genes, Genomes, Genetics

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Regulation of gene expression plays a crucial role in developmental processes and adaptation to changing environments. expression quantitative trait locus (eQTL) mapping is a technique used to study the genetic regulation of gene expression using the transcriptomes of recombinant inbred lines (RILs). Typically, the age of the inbred lines at the time of RNA sampling is carefully controlled. This is necessary because the developmental process causes changes in gene expression, complicating the interpretation of eQTL mapping experiments. However, due to genetics and variation in ambient micro-environments, organisms can differ in their “developmental age,” even if they are of the same chronological age. As a result, eQTL patterns are affected by developmental variation in gene expression. The model organism Caenorhabditis elegans is particularly suited for studying the effect of developmental variation on eQTL mapping patterns. In a span of days, C. elegans transitions from embryo through 4 larval stages to adult while undergoing massive changes to its transcriptome. Here, we use C. elegans to investigate the effect of developmental age variation on eQTL patterns and present a normalization procedure. We used dynamical eQTL mapping, which includes the developmental age as a cofactor, to separate the variation in development from genotypic variation and explain variation in gene expression levels. We compare classical single marker eQTL mapping and dynamical eQTL mapping using RNA-seq data of ∼200 multi-parental RILs of C. elegans. The results show that (1) many eQTLs are caused by developmental variation, (2) most trans-bands are developmental QTLs, and (3) dynamical eQTL mapping detects additional eQTLs not found with classical eQTL mapping. We recommend that correction for variation in developmental age should be strongly considered in eQTL mapping studies given the large impact of processes like development on the transcriptome.

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Cryptic genetic variation of expression quantitative trait locus architecture revealed by genetic perturbation in Caenorhabditis elegans

Cited by 4 publications

References 57 publications

eQTL mapping in transgenic alpha-synuclein carryingCaenorhabditis elegansrecombinant inbred line

eQTL mapping in transgenic alpha-synuclein carryingCaenorhabditis elegansrecombinant inbred line

The effect of developmental variation on expression QTLs in a multi parentalC. eleganspopulation

The effect of developmental variation on expression QTLs in a multi parental Caenorhabditis elegans population

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