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An X-to-autosome retrogene is required for spermatogenesis in mice

Nature Genetics volume 36, pages 872–876 (2004)Cite this article

Abstract

We identified the gene carrying the juvenile spermatogonial depletion mutation (jsd), a recessive spermatogenic defect mapped to mouse chromosome 1 (refs. 1,2). We localized jsd to a 272-kb region and resequenced this area to identify the underlying mutation: a frameshift that severely truncates the predicted protein product of a 2.3-kb genomic open reading frame. This gene, Utp14b, evidently arose through reverse transcription of an mRNA from an X-linked gene and integration of the resulting cDNA into an intron of an autosomal gene, whose promoter and 5′ untranslated exons are shared with Utp14b. To our knowledge, Utp14b is the first protein-coding retrogene to be linked to a recessive mammalian phenotype. The X-linked progenitor of Utp14b is the mammalian ortholog of yeast Utp14, which encodes a protein required for processing of pre-rRNA3 and hence for ribosome assembly. Our findings substantiate the hypothesis4 that mammalian spermatogenesis is supported by autosomal retrogenes that evolved from X-linked housekeeping genes to compensate for silencing of the X chromosome during male meiosis5,6,7. We find that Utp14b-like retrogenes arose independently and were conserved during evolution in at least four mammalian lineages. This recurrence implies a strong selective pressure, perhaps to enable ribosome assembly in male meiotic cells.

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Figure 1: Insertion-deletion mutation in a transcribed ORF (ORF2.3) in the jsd critical region.
Figure 2: Transcription of Utp14b (ORF2.3) and Acsl3.
Figure 3: Schematic alignment of transcripts from mouse Utp14b, its X-linked homologs Utp14a and UTP14A in mouse and human, respectively, and its human autosomal homolog UTP14C.
Figure 4: Phylogenetic comparison of Utp14b homologs in diverse eutherian mammals indicates that a minimum of four retroposition events (indicated by blue, red, yellow and green branches) occurred.

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Acknowledgements

We thank W. Beamer for providing C57BL/6J jsd/+ mice; the Genome Sequencing group at the Whitehead/MIT Center for Genome Research for BAC sequencing; B. Birren and E.S. Lander for support; and A. Bortvin, J. Alfoldi, J. Koubova, J. Lange, J. Potash, J. Saionz, J. Wang, K. Kleene and S. Rozen for comments on the manuscript. This work was supported by the Howard Hughes Medical Institute.

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Author notes

  1. Ken Dewar

    Present address: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, H3A 1A4, Canada

  2. Julie Bradley and Andrew Baltus: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute, Whitehead Institute,

    Julie Bradley, Andrew Baltus, Helen Skaletsky, Morgan Royce-Tolland & David C Page

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Julie Bradley, Andrew Baltus, Helen Skaletsky, Morgan Royce-Tolland & David C Page

  3. Whitehead Institute/MIT Center for Genome Research, Cambridge, 02142, Massachusetts, USA

    Ken Dewar

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Supplementary information

Supplementary Fig. 1

Genetic linkage mapping of jsd. (PDF 74 kb)

Supplementary Fig. 2

Gene maps of the regions of the mouse and human X chromosomes that contain the Utp14a/UTP14A gene. (PDF 42 kb)

Supplementary Fig. 3

Amino acid alignments of human and mouse proteins homologous to yeast Utp14. (PDF 225 kb)

Supplementary Fig. 4

Gene maps of the UTP14C insertion region on human chromosome 13 and the syntenic region of the mouse genome. (PDF 39 kb)

Supplementary Fig. 5

Phylogenetic tree of jsd sequences. (PDF 19 kb)

Supplementary Table 1

Novel genetic markers generated in the course of genetic and physical mapping of the jsd critical region. (XLS 17 kb)

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Bradley, J., Baltus, A., Skaletsky, H. et al. An X-to-autosome retrogene is required for spermatogenesis in mice. Nat Genet 36, 872–876 (2004). https://doi.org/10.1038/ng1390

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