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Independent specialization of the human and mouse X chromosomes for the male germ line

Abstract

We compared the human and mouse X chromosomes to systematically test Ohno's law, which states that the gene content of X chromosomes is conserved across placental mammals1. First, we improved the accuracy of the human X-chromosome reference sequence through single-haplotype sequencing of ampliconic regions. The new sequence closed gaps in the reference sequence, corrected previously misassembled regions and identified new palindromic amplicons. Our subsequent analysis led us to conclude that the evolution of human and mouse X chromosomes was bimodal. In accord with Ohno's law, 94–95% of X-linked single-copy genes are shared by humans and mice; most are expressed in both sexes. Notably, most X-ampliconic genes are exceptions to Ohno's law: only 31% of human and 22% of mouse X-ampliconic genes had orthologs in the other species. X-ampliconic genes are expressed predominantly in testicular germ cells, and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.

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Figure 1: A dot-plot comparison of the nucleotide sequences of the human and mouse X chromosomes shows large, divergent ampliconic regions on the mouse X chromosome.
Figure 2: Comparison of mosaic and SHIMS-based sequence assemblies across one region of the human X chromosome.
Figure 3: Comparison of X-linked gene classes between humans and mice.

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Primary accessions

NCBI Reference Sequence

Sequence Read Archive

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Acknowledgements

We thank D. Albracht, J. Collins, M. Gill, N. Koutseva, C. Kremitzki, A. van der Veen and J. Wood for technical assistance and D. Bellott, R. Desgraz, G. Dokshin, T. Endo, A. Godfrey, Y. Hu, J. Hughes, M. Kojima, B. Lesch, L. Okumura, K. Romer and Y. Soh for comments on the manuscript. This work was supported by the US National Institutes of Health and the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Contributions

J.L.M., H.S., W.C.W., R.K.W. and D.C.P. planned the project. J.L.M. and L.G.B. performed BAC mapping. J.L.M. performed RNA deep sequencing. T.G., S.R., K.A. and S.Z. were responsible for finished BAC sequencing. J.L.M. and H.S. performed sequence analyses. J.L.M. and D.C.P. wrote the manuscript.

Corresponding author

Correspondence to David C Page.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1, 5 and 9 (PDF 5830 kb)

Supplementary Table 2

Genes shared between human and mouse X chromosomes (XLS 155 kb)

Supplementary Table 3

Human X-linked genes with no detectable ortholog on the mouse X chromosome (XLS 53 kb)

Supplementary Table 4

Mouse X-linked genes with no detectable ortholog on the human X chromosome (XLS 62 kb)

Supplementary Table 6

Tissue expression of X-linked genes shared between human and mouse (XLS 239 kb)

Supplementary Table 7

Expression patterns of independently acquired human X-linked genes (XLS 52 kb)

Supplementary Table 8

Expression patterns of independently acquired mouse X-linked genes (XLS 57 kb)

Supplementary Table 10

Expression patterns of all human autosomal genes (XLS 3622 kb)

Supplementary Table 11

Expression patterns of all mouse autosomal genes (XLS 2626 kb)

Supplementary Table 12

All OMIM X-linked phenotypes where the molecular basis is known (XLS 62 kb)

Supplementary Table 13

Expression patterns between the sexes, in the heart and kidney, of human genes that follow Ohno's law (XLSX 60 kb)

Supplementary Table 14

Expression patterns between the sexes, in the heart and kidney, of mouse genes that follow Ohno's law (XLSX 65 kb)

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Mueller, J., Skaletsky, H., Brown, L. et al. Independent specialization of the human and mouse X chromosomes for the male germ line. Nat Genet 45, 1083–1087 (2013). https://doi.org/10.1038/ng.2705

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