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Genetics of global gene expression

Nature Reviews Genetics volume 7, pages 862–872 (2006)Cite this article

Key Points

  • A new field, the genetic analysis of global gene expression, has emerged in recent years, driven by the realization that traditional techniques of linkage and association analysis can be applied to thousands of transcript levels measured by microarrays.

  • Studies in a number of species have documented abundant heritable variation in gene expression among individuals and strains.

  • Linkage analysis has been used to map thousands of loci that affect gene expression.

  • Expression traits consistently show complex inheritance, explicable only by multiple underlying loci and possibly interactions among the loci.

  • Many types of genetic complexity are observed across the thousands of expression traits.

  • A locus that affects gene expression can be classified according to its location as 'local' (near the genomic location of the gene) or 'distant' (elsewhere in the genome).

  • Many gene expression traits are affected by local regulatory variation. It appears that most but not all local regulatory variation functions in cis, with perhaps a quarter to a third acting in trans.

  • Most transcripts link to loci that are distant from the genomic locations of the genes that encode the corresponding transcripts. One common feature of these loci is 'hot spots': individual loci that affect large numbers of transcripts.

  • Future research will focus on high-throughput identification and characterization of polymorphisms that affect expression, extending studies to population samples, and applying the approach to other global molecular phenotypes.

Abstract

A new field of genetic analysis of global gene expression has emerged in recent years, driven by the realization that traditional techniques of linkage and association analysis can be applied to thousands of transcript levels measured by microarrays. Genetic dissection of transcript abundance has shed light on the architecture of quantitative traits, provided a new approach for connecting DNA sequence variation with phenotypic variation, and improved our understanding of transcriptional regulation and regulatory variation.

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Figure 1: Most gene expression traits are affected by multiple loci.
Figure 2: Types of complex inheritance of transcript levels.
Figure 3: Local and distant regulatory variation.
Figure 4: Hot spots of distant regulatory variation.

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Acknowledgements

We regret that space constraints prevented us from citing additional work in the field. We thank past and current members of the Kruglyak laboratory and our collaborators for discussions. Work was supported in part by a grant from the National Institute of Mental Health and a James S. McDonnell Foundation Centennial Fellowship to L.K. M.V.R. is supported by The Jane Coffin Childs Memorial Fund for Medical Research.

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  1. Lewis-Sigler Institute for Integrative Genomics and Department of Ecology and Evolutionary Biology, Princeton University, Princeton, 08544, New Jersey, USA

    Matthew V. Rockman & Leonid Kruglyak

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Correspondence to Leonid Kruglyak.

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Glossary

Complex and quantitative traits

Phenotypes that are shaped by multiple and possibly interacting genetic and environmental factors. Quantitative traits (as distinguished from discrete traits) are measured on continuous scales.

Effect size

The magnitude of contribution of a locus to variation in a phenotype.

Recombinant inbred lines

Panels of genetically mosaic but homozygous strains generated by crossing parental strains and inbreeding the progeny.

False-discovery rate

The fraction of results declared significant at a given threshold that are expected to be false positives.

Dimensional reduction

A class of mathematical techniques for summarizing the main characteristics of multivariate data with fewer variables.

QTL

Quantitative trait locus; a region of the genome that contributes to variation in a quantitative trait.

Beavis effect

A statistical artefact that is due to the deviation of estimates from true values by random error. In a mapping experiment, the loci that are deemed significant are enriched for those in which the estimated effects benefit from random error that happens to fall in the right direction. Therefore, significant QTLs are disproportionately those in which the effect sizes are inflated by chance.

Heritability

The fraction of total phenotypic variance that is attributable to additive genetic effects. Estimators with different technical definitions and biological meanings abound. This is not an inherent property of a trait; heritability depends on the nature of the genetic sample (for example, intercross, inbred lines, twins and random populations) and the space of environments surveyed.

Transgressive segregation

A distribution of trait values for a segregating population that extends significantly beyond the range defined by the progenitor strains.

Directional genetics

A distribution of trait values for a segregating population that is significantly concentrated within the range defined by the progenitor strains.

Non-additivity

A property of alleles at a locus, such that the trait value of heterozygous individuals is not the average of the trait values of homozygotes for each allele.

Genetic interaction

A property of alleles at different loci, such that their combined effect on a phenotype deviates from the sum of their individual effects (this is often called epistasis).

Allelic heterogeneity

The phenomenon in which a genetically diverse population harbours many different alleles at a QTL.

Gene-by-environment interaction

The effect of a locus on a trait depends on the environment, and the effect of the environment on the trait depends on the locus.

Pleiotropy

The capacity of a single mutation to affect multiple traits.

Multiple testing problem

The number of false-positive results increases when multiple statistical tests are carried out, requiring more stringent thresholds to reach the same level of significance.

Linkage disequilibrium

The nonrandom association of alleles at different loci in a population.

QTN

Quantitative trait nucleotide; the actual sequence polymorphism responsible for variation in a quantitative trait.

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Rockman, M., Kruglyak, L. Genetics of global gene expression. Nat Rev Genet 7, 862–872 (2006). https://doi.org/10.1038/nrg1964

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