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Megabase deletions of gene deserts result in viable mice

Nature volume 431, pages 988–993 (2004)Cite this article

Abstract

The functional importance of the roughly 98% of mammalian genomes not corresponding to protein coding sequences remains largely undetermined1. Here we show that some large-scale deletions of the non-coding DNA referred to as gene deserts2,3,4 can be well tolerated by an organism. We deleted two large non-coding intervals, 1,511 kilobases and 845 kilobases in length, from the mouse genome. Viable mice homozygous for the deletions were generated and were indistinguishable from wild-type littermates with regard to morphology, reproductive fitness, growth, longevity and a variety of parameters assaying general homeostasis. Further detailed analysis of the expression of multiple genes bracketing the deletions revealed only minor expression differences in homozygous deletion and wild-type mice. Together, the two deleted segments harbour 1,243 non-coding sequences conserved between humans and rodents (more than 100 base pairs, 70% identity). Some of the deleted sequences might encode for functions unidentified in our screen; nonetheless, these studies further support the existence of potentially ‘disposable DNA’ in the genomes of mammals.

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Figure 1: Design of genomic deletions in gene deserts MMU3 and MMU19, displaying a wild-type (WT) and a deletion (DEL) allele for each desert.
Figure 2: Survival and growth curves of mice carrying the MMU3 and MMU19 deletions.
Figure 3: Expression of genes bracketing the chromosomal deletions in a panel of 12 tissues.
Figure 4: Conservation profile between human, mouse, rat and chicken.

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Acknowledgements

We thank I. Ovcharenko, G. Loots and J. Schwartz for help with the identification and annotation of the gene deserts; D. Boffelli, L. Pennacchio, N. Ahituv, J. Bristow and other Rubin laboratory members for suggestions and criticisms on the manuscript; and H. Jacob for providing the clinical chemistry assays. Research was conducted at the E. O. Lawrence Berkeley National Laboratory and at the Joint Genome Institute, with support by grants from the Programs for Genomic Application, the NHLBI and the DOE.

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Author notes

  1. Correspondence and requests for materials should be addressed to E.M.R.

  2. Marcelo A. Nóbrega and Yiwen Zhu: These authors contributed equally to this work

Authors and Affiliations

  1. DOE Joint Genome Institute Walnut Creek, California, 94598, USA

    Marcelo A. Nóbrega, Yiwen Zhu, Ingrid Plajzer-Frick, Veena Afzal & Edward M. Rubin

  2. Genomics Division Lawrence Berkeley National Laboratory Berkeley, 94720, California, USA

    Marcelo A. Nóbrega, Yiwen Zhu, Ingrid Plajzer-Frick, Veena Afzal & Edward M. Rubin

Authors
  1. Marcelo A. Nóbrega
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  2. Yiwen Zhu
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  3. Ingrid Plajzer-Frick
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  4. Veena Afzal
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  5. Edward M. Rubin
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Corresponding author

Correspondence to Edward M. Rubin.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Methods

Methods used to generate and screen the animals generated in this study, as well as details of the annotation of the genomic intervals targeted for deletion. (DOC 36 kb)

Supplementary Tables

A total of seven tables listing all relevant primer sequences used in the protocols, and results from functional analysis of the ice concerning general fitness, survival and reproduction. (DOC 91 kb)

Supplementary Figure 1

Results from the clinical chemistry assays tested in the various strains of mice. (JPG 53 kb)

Supplementary Figure 2

Results from macroscopic pathology in 12 organs analysed. (JPG 38 kb)

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Nóbrega, M., Zhu, Y., Plajzer-Frick, I. et al. Megabase deletions of gene deserts result in viable mice. Nature 431, 988–993 (2004). https://doi.org/10.1038/nature03022

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