Reassessment of weak parent-of-origin expression bias shows it rarely exists outside of known imprinted regions
In mouse and human, genes subjected to genomic imprinting have been shown to function in development, behaviour, and post-natal adaptations. Failure to correctly imprint genes in human is associated with developmental syndromes, adaptive and metabolic disorders during life as well as numerous forms of cancer. In recent years researchers have turned to RNA-seq technologies applied to reciprocal hybrid strains of mice to identify novel imprinted genes, causing a 3-fold increase in genes reported as having a parental origin specific expression bias. The functional relevance of parental origin-specific expression bias is not fully appreciated especially since many are reported with only minimal parental bias (e.g. 51:49). Here we present an in-depth meta-analysis of previously generated RNA-seq data and show that the methods used to generate and analyse libraries greatly influence the calling of allele-specific expression. Validation experiments show that most novel genes called with parental-origin specific allelic bias are artefactual, with the mouse strain contributing a larger effect on expression biases than parental origin. Of the weak novel genes that do validate, most are located at the periphery of known imprinted domains, suggesting they may be affected by local allele- and tissue-specific conformation. Together these findings highlight the need for robust tools, definitions, and validation of putative imprinted genes to provide meaningful information within imprinting databases and to understand the functional and mechanistic implications of the process.
All data generated or analysed during this study are included in the manuscript and supporting files. Allele specific pyrosequencing data and clonal bisulfite sequencing data generated in this study is available at https://doi.org/10.17863/CAM.90155.
Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouseSequence Read Archive, SRP020526.
Noncanonical Genomic Imprinting Effects in OffspringNCBI Gene Expression Omnibus, GSE70484.
Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brainNCBI Gene Expression Omnibus, GSE67556.
Mapping the mouse Allelome reveals tissue-specific regulation of allelic expressionNCBI Gene Expression Omnibus, GSE75957.
Article and author information
Medical Research Council (MR/R009791/1)
- Lisa C Hulsmann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal procedures were subject to local institutional ethical approval and performed under a UK Government Home Office license (project license number: PC213320E).
- Deborah Bourc'his, Institut Curie, France
- Received: October 8, 2022
- Accepted: March 8, 2023
- Accepted Manuscript published: March 14, 2023 (version 1)
© 2023, Edwards et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Funding: RD is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915).