Key Points
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DNA sequence variation that influences gene expression is an important source of variation in higher-order organismal traits.
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Variants that influence transcription factor binding often affect multiple levels of chromatin organization and gene expression.
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Genetic variation in protein levels is studied much less frequently than that in mRNA levels. Based on current knowledge, most loci that influence a given mRNA also seem to affect the abundance of the corresponding protein.
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Model organisms show that the interplay between regulatory variation and higher-order traits can be highly complex.
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Rapidly growing data sets and detailed functional follow-up studies show that regulatory variation contributes to disease risk in humans, sometimes in surprisingly complex ways.
Abstract
We are in a phase of unprecedented progress in identifying genetic loci that cause variation in traits ranging from growth and fitness in simple organisms to disease in humans. However, a mechanistic understanding of how these loci influence traits is lacking for the majority of loci. Studies of the genetics of gene expression have emerged as a key tool for linking DNA sequence variation to phenotypes. Here, we review recent insights into the molecular nature of regulatory variants and describe their influence on the transcriptome and the proteome. We discuss conceptual advances from studies in model organisms and present examples of complete chains of causality that link individual polymorphisms to changes in gene expression, which in turn result in physiological changes and, ultimately, disease risk.
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Acknowledgements
The authors thank members of L.K.'s laboratory and many colleagues for discussions. L.K. is supported by funds from the Howard Hughes Medical Institute, the US National Institutes of Health and the James S. McDonnell Foundation. F.W.A. was supported by the German Science Foundation (DFG).
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Glossary
- Expression quantitative trait loci
-
(eQTLs). Genomic regions that carry one or more DNA sequence variants that influence the expression level (typically mRNA abundance) of a given gene.
- Recombinant offspring
-
Offspring of sexually reproducing organisms that carry a random combination of the alleles that they have inherited from their parents.
- Protein QTLs
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(pQTLs). Genomic regions that carry one or more DNA sequence variants that influence the protein abundance of a given gene.
- eQTL hot spots
-
Regions of the genome that contain more expression quantitative trait loci (eQTLs) than expected by chance.
- Organismal phenotypes
-
Traits that are detectable at the level of the whole organism, such as shape, size, colour, growth rate or the risk of developing a certain disease.
- Linkage disequilibrium
-
The phenomenon whereby specific allele combinations occur more frequently than expected by chance, typically because they are physically close to each other on the same chromosome.
- QTLs
-
Genomic regions that carry one or several DNA sequence variants which influence a continuously variable trait of interest.
- Homologous
-
Pertaining to the two copies of the same chromosome that were inherited from the mother and the father in diploid organisms (such as humans).
- RNA sequencing
-
A method to determine the sequence of RNA molecules in a biological sample. By counting the RNA molecules that were transcribed from each gene, RNA sequencing can be used to quantify mRNA expression levels.
- Genetic distance
-
A measure of how often two sites in a genome are separated during meiosis. Genetic distance is correlated with physical distance but can differ quantitatively because of variation in recombination rate along a chromosome.
- Linkage blocks
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Continuous haplotypes that are not broken up in the population under study such that sequence variants within them all show the same patterns of association with a certain trait of interest.
- Haplotypes
-
Stretches of DNA that carry certain combinations of alleles at two or more DNA variants.
- Variance
-
A statistical measure of the variability of a trait in a population.
- Heritability
-
The fraction of variance in a trait that is due to genetic differences among the individuals in a population.
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Albert, F., Kruglyak, L. The role of regulatory variation in complex traits and disease. Nat Rev Genet 16, 197–212 (2015). https://doi.org/10.1038/nrg3891
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DOI: https://doi.org/10.1038/nrg3891
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