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Genome-wide allele-specific analysis: insights into regulatory variation

Abstract

Functional genomics is rapidly progressing towards the elucidation of elements that are crucial for the cis-regulatory control of gene expression, and population-based studies of disease and gene expression traits are yielding widespread evidence of the influence of non-coding variants on trait variance. Recently, genome-wide allele-specific approaches that harness high-throughput sequencing technology have started to allow direct evaluation of how these cis-regulatory polymorphisms control gene expression and affect chromatin states. The emerging data is providing exciting opportunities for comprehensive characterization of the allele-specific events that govern human gene regulation.

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Figure 1: The advantage of allelic expression measurements in the presence of trans-acting feedback.
Figure 2: Targeted and global approaches to study allele-specific function.
Figure 3: Cis-regulatory SNP mapping by allelic expression.

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Acknowledgements

I thank T. Kwan for critical reading of the manuscript. T.P. holds a Canada Research Chair and is supported by grants from Genome Canada, Genome Quebec and the Canadian Institutes of Health Research.

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Glossary

Clonal read

NGS produces, in principle, independent reads from each molecule in the input sample. However, in some cases, the amplification of molecules yields copies of the same short read, which can potentially bias allelic read counts.

DNase I hypersensitivity

The susceptibility of a genomic region to digestion by DNase I. Promoter, enhancer and other active regulatory DNA sequences are more easily digested than inactive non-coding sequences.

Expression quantitative trait locus

A locus at which gene expression variance in a population —typically measured by microarrays or by RNA-seq — correlates significantly with genotype. This locus can be near the measured gene (cis) or elsewhere in the genome (trans).

Histone modification

Regulatory elements in actively transcribed versus repressed loci have differences in post-translational modifications (for example, methylation or acetylation of lysines) of histones that can be identified by ChIP using modification-specific antibodies.

Padlock probe

An oligonucleotide with 5′ and 3′ sequences that are specific for target regions of the genome and are separated by generic sequence. After binding to its target, the probe can be circularized by ligase, and the generic sequence portion is used to amplify or capture the probes.

Standing genetic variation

Allelic variation that is currently segregating within a population; as opposed to alleles that appear by new mutation events.

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Pastinen, T. Genome-wide allele-specific analysis: insights into regulatory variation. Nat Rev Genet 11, 533–538 (2010). https://doi.org/10.1038/nrg2815

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