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Genetics of human gene expression: mapping DNA variants that influence gene expression

Nature Reviews Genetics volume 10, pages 595–604 (2009)Cite this article

Key Points

  • Expression levels of genes are heritable traits. Genetic determinants of individual variation in human gene expression can be mapped by linkage and association analyses.

  • Cis- and trans-acting DNA variants influence expression levels of genes. Genetics of gene expression (GOGE) studies have identified cis-acting regulatory variants of many genes; however, few trans-acting variants have yet been identified.

  • In humans, ∼30–50% of cis-acting variants identified in immortalized B cells have the same effects in other cell types, such as adipose tissue and blood.

  • Differences in genotype frequencies of regulatory alleles contribute to population differences in gene expression.

  • By combining results from GOGE studies with correlation analysis, one can construct directed gene co-expression networks that provide information on causal rather than just correlative relationships. The results also extend regulatory relationships from pairs to groups of genes.

  • GOGE studies in cells exposed to cellular, medical or environmental perturbations will uncover additional regulators of human gene expression.

Abstract

There is extensive natural variation in human gene expression. As quantitative phenotypes, expression levels of genes are heritable. Genetic linkage and association mapping have identified cis- and trans-acting DNA variants that influence expression levels of human genes. New insights into human gene regulation are emerging from genetic analyses of gene expression in cells at rest and following exposure to stimuli. The integration of these genetic mapping results with data from co-expression networks is leading to a better understanding of how expression levels of individual genes are regulated and how genes interact with each other. These findings are important for basic understanding of gene regulation and of diseases that result from disruption of normal gene regulation.

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Figure 1: Inter-individual variation in gene expression levels.
Figure 2: Effect of cis- and trans-acting DNA variants on expression levels of genes.
Figure 3: The expression level of copine I (CPNE1) is cis regulated.
Figure 4: The expression level of programmed cell death 10 (PDCD10) is trans regulated.

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Acknowledgements

We thank the members of our laboratories for comments and discussions. I (V.G.C.) thank C. Gunter for support and encouragement in finishing this Review. This work is supported by the National Institutes of Health and the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Vivian G. Cheung

  2. Department of Pediatrics, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Vivian G. Cheung

  3. Department of Genetics, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Vivian G. Cheung & Richard S. Spielman

  4. This Review is dedicated to the memory of Richard Spielman, who passed away in April 2009 during the preparation of this article.,

    Richard S. Spielman

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Correspondence to Vivian G. Cheung.

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FURTHER INFORMATION

The Cheung laboratory

CEPH

International HapMap Project

Glossary

Gene expression phenotype

The expression level of a gene in an individual as determined by his or her genotype and the cellular environments in which the gene is expressed.

Co-expression network

Groups of interconnected genes that are linked by the correlations in their expression levels.

Heritability

The proportion of total phenotypic variation that is due to genetic variation.

Regulatory polymorphism

DNA sequence variants that regulate cellular processes such as gene expression.

Differential allelic expression

Polymorphic forms (different sequences) of a gene have different expression levels.

Admixed

An admixed population contains offspring of individuals originating from genetically divergent parental populations.

RNA-Seq

Sequence analysis of RNA (for example, after conversion into cDNA); the results can be used for various analyses, including study of gene expression, identification of coding SNPs and determination of allele-specific gene expression.

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Cheung, V., Spielman, R. Genetics of human gene expression: mapping DNA variants that influence gene expression. Nat Rev Genet 10, 595–604 (2009). https://doi.org/10.1038/nrg2630

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