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Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse

Abstract

Genomic imprinting is an epigenetic process that restricts gene expression to either the maternally or paternally inherited allele1,2. Many theories have been proposed to explain its evolutionary origin3,4, but understanding has been limited by a paucity of data mapping the breadth and dynamics of imprinting within any organism. We generated an atlas of imprinting spanning 33 mouse and 45 human developmental stages and tissues. Nearly all imprinted genes were imprinted in early development and either retained their parent-of-origin expression in adults or lost it completely. Consistent with an evolutionary signature of parental conflict, imprinted genes were enriched for coexpressed pairs of maternally and paternally expressed genes, showed accelerated expression divergence between human and mouse, and were more highly expressed than their non-imprinted orthologs in other species. Our approach demonstrates a general framework for the discovery of imprinting in any species and sheds light on the causes and consequences of genomic imprinting in mammals.

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Figure 1: Atlas of genomic imprinting in mouse.
Figure 2: Atlas of genomic imprinting in human.
Figure 3: Species comparisons of imprinting.

Accession codes

Primary accessions

Sequence Read Archive

Referenced accessions

Gene Expression Omnibus

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Acknowledgements

We thank members of the Fraser laboratory for critical evaluation of the manuscript. This work was supported by US National Institutes of Health (NIH) grant 1R01GM097171-01A1. H.B.F. is an Alfred P. Sloan Fellow and a Pew Scholar in the Biomedical Sciences. The work of S.B.M. and J.B.L. was supported by US NIH grant U01HG007593. E.K.T. was supported by a Hewlett-Packard Stanford Graduate Fellowship. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by US National Science Foundation grant OCI-1053575. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the US NIH. Additional GTEx funds were provided by the National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health and National Institute Neurological Disorders and Stroke. Donors were enrolled at Biospecimen Source Sites funded by National Cancer Institute/SAIC-Frederick, Inc. subcontracts to the National Disease Research Interchange (10XS170), the Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the Broad Institute. Biorepository operations were funded through an SAIC-Frederick subcontract to the Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-Frederick (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941), the University of Chicago (MH090951 and MH090937), the University of North Carolina, Chapel Hill (MH090936) and Harvard University (MH090948).

Author information

Authors and Affiliations

Authors

Contributions

B.D. and D.v.d.K. generated the mouse crosses and performed the dissections. T.B., Y.Z. and B.D. performed the mouse RNA-seq experiments. E.K.T., K.S.S., K.R.K., R.Z., J.B.L. and S.B.M. performed the human ASE validation by mmPCR-seq. X.L. and S.B.M. contributed the pedigree data. T.B. performed the analysis. T.B. and H.B.F. wrote the manuscript. All authors contributed to reading and editing the manuscript.

Corresponding author

Correspondence to Hunter B Fraser.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–24 and Supplementary Note. (PDF 34475 kb)

Supplementary Table 1

Detailed annotation of the biological samples and input data used to generate the imprinting atlas in mouse. (XLSX 21 kb)

Supplementary Table 2

Detailed annotation of the pyrosequencing validation effort in mouse. Included are assay design (heterozygous SNPs, biological samples targeted, primer sequences), a summary of raw outputs and validation calls. (XLS 113 kb)

Supplementary Table 3

Novel mouse and human imprinted genes discovered in this study. (XLSX 29 kb)

Supplementary Table 4

Detailed ASE expression and literature evidence for 23 genes for which we did not observe imprinting that were previously reported to be imprinted. (XLSX 11 kb)

Supplementary Table 5

Summary of the functional enrichments among similarly imprinted sets of genes in mouse. Databases used included Gene Ontology, KEGG pathways, Genego pathways and the JAX Phenome Database. KEGG and Genego pathways were based on human annotation and were mapped to mouse via Ensembl orthologs. Similarly imprinted genes were selected manually as obvious clusters from Figure 1. (XLSX 26 kb)

Supplementary Table 6

Detailed annotation of the samples and input GTEx.v3 data used to generate the imprinting atlas in human. A summary of the number of individuals sequenced for each tissue is also included. The majority of this table was downloaded directly from the Sequence Read Archive. (XLSX 467 kb)

Supplementary Table 7

mmPCR-seq primer design details. (XLSX 16 kb)

Supplementary Table 8

Summary of functional enrichments among similarly imprinted sets of genes in human. The databases used included Gene Ontology, KEGG pathways and Genego pathways. Similarly imprinted genes were selected manually as obvious clusters from Figure 1. (XLSX 26 kb)

Supplementary Table 9

The most significant mouse co-expression pairwise gene interactions. MMPP, maternal-maternal or paternal-paternal interaction; MPPM, maternal-paternal or paternal-maternal interaction. Human Euclidean distances of imprinted orthologs are shown in the second tab. (XLSX 11 kb)

Supplementary Data Set

Supplementary Data Set (XLSX 10251 kb)

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Babak, T., DeVeale, B., Tsang, E. et al. Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse. Nat Genet 47, 544–549 (2015). https://doi.org/10.1038/ng.3274

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