title: Characterisation of the global transcriptional response to heat shock and the impact of individual genetic variation.
abstract: The heat shock transcriptional response is essential to effective cellular function under stress. This is a highly heritable trait but the nature and extent of inter-individual variation in heat shock response remains unresolved.
  
  
  
  We determined global transcription profiles of the heat shock response for a panel of lymphoblastoid cell lines established from 60 founder individuals in the Yoruba HapMap population. We explore the observed differentially expressed gene sets following heat shock, establishing functional annotations, underlying networks and nodal genes involving heat shock factor 1 recruitment. We define a multivariate phenotype for the global transcriptional response to heat shock using partial least squares regression and map this quantitative trait to associated genetic variation in search of the major genomic modulators.
  
  
  
  A comprehensive dataset of differentially expressed genes following heat shock in humans is presented. We identify nodal genes downstream of heat shock factor 1 in this gene set, notably involving ubiquitin C and small ubiquitin-like modifiers together with transcription factors. We dissect a multivariate phenotype for the global heat shock response which reveals distinct clustering of individuals in terms of variance of the heat shock response and involves differential expression of genes involved in DNA replication and cell division in some individuals. We find evidence of genetic associations for this multivariate response phenotype that involves trans effects modulating expression of genes following heat shock, including HSF1 and UBQLN1.
  
  
  
  This study defines gene expression following heat shock for a cohort of individuals, establishing insights into the biology of the heat shock response and hypotheses for how variation in this may be modulated by underlying genetic diversity.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Humburg
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Queensland Institute of Medical Research, Brisbane, 4029, Queensland, Australia.
authors.forename: Narelle
authors.initials: N
authors.lastname: Maugeri
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Wanseon
authors.initials: W
authors.lastname: Lee
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Bert
authors.initials: B
authors.lastname: Mohr
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. julian@well.ox.ac.uk.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018703:Founder Effect; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D005838:Genotype; D060148:HapMap Project; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics*; D006801:Humans; D058977:Molecular Sequence Annotation; D009549:Nigeria; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; C107792:UBQLN1 protein, human