The influence of genetic variation on gene expression.

The view that changes to the control of gene expression rather than alterations to protein sequence are central to the evolution of organisms has become something of a truism in molecular biology. In reality, the direct evidence for this is limited, and only recently have we had the ability to look more globally at how genetic variation influences gene expression, focusing upon inter-individual variation in gene expression and using microarrays to test for differences in mRNA levels. Here, we review the scope of these experimental analyses, what they are designed to tell us about genetic variation, and what are their limitations from both a technical and a conceptual viewpoint. We conclude that while we are starting to understand the impact of this class of genetic variation upon steady-state mRNA levels, we are still far from identifying the potential phenotypic and evolutionary outcomes.

[1]  M. King,et al.  Evolution at two levels in humans and chimpanzees. , 1975, Science.

[2]  A. Riggs,et al.  A sensitive, quantitative assay for measurement of allele-specific transcripts differing by a single nucleotide. , 1992, PCR methods and applications.

[3]  J. Todd,et al.  Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus , 1995, Nature Genetics.

[4]  B. Birren,et al.  Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region. , 1999, American journal of human genetics.

[5]  C. Duijn,et al.  Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression. , 2000, Human molecular genetics.

[6]  J. Nap,et al.  Genetical genomics: the added value from segregation. , 2001, Trends in genetics : TIG.

[7]  E. Lander,et al.  Detection of regulatory variation in mouse genes , 2002, Nature Genetics.

[8]  Bert Vogelstein,et al.  Allelic Variation in Human Gene Expression , 2002, Science.

[9]  L. Kruglyak,et al.  Genetic Dissection of Transcriptional Regulation in Budding Yeast , 2002, Science.

[10]  E. Vellenga,et al.  A genetic and genomic analysis identifies a cluster of genes associated with hematopoietic cell turnover. , 2002, Blood.

[11]  Vivian G. Cheung,et al.  The genetics of variation in gene expression , 2002, Nature Genetics.

[12]  T. Maniatis,et al.  An extensive network of coupling among gene expression machines , 2002, Nature.

[13]  E. O’Shea,et al.  Global analysis of protein expression in yeast , 2003, Nature.

[14]  Rachel B. Brem,et al.  Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors , 2003, Nature Genetics.

[15]  R. Stoughton,et al.  Genetics of gene expression surveyed in maize, mouse and man , 2003, Nature.

[16]  N. Anderson,et al.  The Human Plasma Proteome: History, Character, and Diagnostic Prospects , 2003, Molecular & Cellular Proteomics.

[17]  Andrew G Clark,et al.  Mapping determinants of variation in energy metabolism, respiration and flight in Drosophila. , 2003, Genetics.

[18]  C. Molony,et al.  Genetic analysis of genome-wide variation in human gene expression , 2004, Nature.

[19]  E. Schadt,et al.  Genomic analysis of metabolic pathway gene expression in mice , 2005, Genome Biology.

[20]  Robert W. Williams,et al.  Weighting by heritability for detection of quantitative trait loci with microarray estimates of gene expression , 2005, Genome Biology.

[21]  E. Schadt,et al.  Genetic inheritance of gene expression in human cell lines. , 2004, American journal of human genetics.

[22]  J. Zhu,et al.  An integrative genomics approach to the reconstruction of gene networks in segregating populations , 2004, Cytogenetic and Genome Research.

[23]  Andrew I Su,et al.  Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics' , 2005, Nature Genetics.

[24]  B. Weir,et al.  The quantitative genetics of transcription. , 2005, Trends in genetics : TIG.

[25]  E. Petretto,et al.  Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease , 2005, Nature Genetics.

[26]  Rudi Alberts,et al.  A Statistical Multiprobe Model for Analyzing cis and trans Genes in Genetical Genomics Experiments With Short-Oligonucleotide Arrays , 2005, Genetics.

[27]  Robert W. Williams,et al.  Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function , 2005, Nature Genetics.

[28]  D. Nott,et al.  Genetic dissection of gene regulation in multiple mouse tissues , 2006, Mammalian Genome.

[29]  Eric E Schadt,et al.  Cis-acting expression quantitative trait loci in mice. , 2005, Genome research.

[30]  E E Schadt,et al.  Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits , 2005, Nature Genetics.

[31]  Margit Burmeister,et al.  Genetical genomics: combining genetics with gene expression analysis. , 2005, Human molecular genetics.

[32]  Joshua T. Burdick,et al.  Mapping determinants of human gene expression by regional and genome-wide association , 2005, Nature.

[33]  J. Castle,et al.  An integrative genomics approach to infer causal associations between gene expression and disease , 2005, Nature Genetics.

[34]  Rachel B. Brem,et al.  The landscape of genetic complexity across 5,700 gene expression traits in yeast. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Hunt,et al.  Genome-Wide Associations of Gene Expression Variation in Humans , 2005, PLoS genetics.

[37]  Leonid Kruglyak,et al.  Local Regulatory Variation in Saccharomyces cerevisiae , 2005, PLoS genetics.

[38]  John D. Storey,et al.  Multiple Locus Linkage Analysis of Genomewide Expression in Yeast , 2005, PLoS biology.

[39]  John D. Storey,et al.  Genetic interactions between polymorphisms that affect gene expression in yeast , 2005, Nature.

[40]  L. Kruglyak,et al.  Genetics of global gene expression , 2006, Nature Reviews Genetics.

[41]  S. Horvath,et al.  Evidence for anti-Burkitt tumour globulins in Burkitt tumour patients and healthy individuals. , 1967, British Journal of Cancer.

[42]  Hanlee P. Ji,et al.  The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements. , 2006, Nature biotechnology.

[43]  Jingyuan Fu,et al.  Mapping Determinants of Gene Expression Plasticity by Genetical Genomics in C. elegans , 2006, PLoS genetics.

[44]  Eric E Schadt,et al.  DNA variation and brain region-specific expression profiles exhibit different relationships between inbred mouse strains: implications for eQTL mapping studies , 2007, Genome Biology.

[45]  Christina Kendziorski,et al.  Combined Expression Trait Correlations and Expression Quantitative Trait Locus Mapping , 2006, PLoS genetics.

[46]  Enrico Petretto,et al.  Heritability and Tissue Specificity of Expression Quantitative Trait Loci , 2006, PLoS genetics.

[47]  Maqc Consortium The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements , 2006, Nature Biotechnology.

[48]  A. Arnold,et al.  Tissue-specific expression and regulation of sexually dimorphic genes in mice. , 2006, Genome research.

[49]  D. Pe’er,et al.  Identifying regulatory mechanisms using individual variation reveals key role for chromatin modification , 2006, Proceedings of the National Academy of Sciences.

[50]  David J Nott,et al.  Normalization procedures and detection of linkage signal in genetical-genomics experiments , 2006, Nature Genetics.

[51]  Nevan J Krogan,et al.  Systems-level analyses identify extensive coupling among gene expression machines , 2006, Molecular systems biology.

[52]  Yan Cui,et al.  Integrative genetic analysis of transcription modules: towards filling the gap between genetic loci and inherited traits. , 2006, Human molecular genetics.

[53]  P. Silver,et al.  Communication between levels of transcriptional control improves robustness and adaptivity , 2006, Molecular systems biology.

[54]  F. Wright,et al.  Large-Scale Gene Expression Differences Across Brain Regions and Inbred Strains Correlate With a Behavioral Phenotype , 2006, Genetics.

[55]  David R Goodlett,et al.  Genetic basis of proteome variation in yeast , 2007, Nature Genetics.

[56]  G. Gibson,et al.  Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster , 2007, Nature Genetics.

[57]  Martin S. Taylor,et al.  Identification of Common Genetic Variation That Modulates Alternative Splicing , 2007, PLoS genetics.

[58]  E. Marcotte,et al.  Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation , 2007, Nature Biotechnology.

[59]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.