Reassessment of weak parent-of-origin expression bias shows it rarely exists outside of known imprinted regions

Abstract

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.

Data availability

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Carol A Edwards

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    cae28@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. William MD Watkisnon

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Stephanie B Telerman

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Lisa C Hulsmann

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Russell S Hamilton

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0598-3793
  6. Anne C Ferguson-Smith

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    afsmith@gen.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7608-5894

Funding

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.

Ethics

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).

Reviewing Editor

  1. Deborah Bourc'his, Institut Curie, France

Publication history

  1. Received: October 8, 2022
  2. Accepted: March 8, 2023
  3. Accepted Manuscript published: March 14, 2023 (version 1)

Copyright

© 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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  1. Carol A Edwards
  2. William MD Watkisnon
  3. Stephanie B Telerman
  4. Lisa C Hulsmann
  5. Russell S Hamilton
  6. Anne C Ferguson-Smith
(2023)
Reassessment of weak parent-of-origin expression bias shows it rarely exists outside of known imprinted regions
eLife 12:e83364.
https://doi.org/10.7554/eLife.83364

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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).