X‐Chromosome Dosage Compensation


The X and Y chromosomes of placental and marsupial mammals originated from a pair of autosomes. Ohno hypothesised nearly 50 years ago that the expression levels of X‐linked genes should be doubled to compensate for the degeneration of their Y‐linked homologues during sex chromosome evolution. The advent of microarray and RNA (ribonucleic acid) sequencing technologies in the past decade prompted a series of empirical tests of Ohno's hypothesis. Surprisingly, X‐chromosome dosage compensation is found to be largely absent in mammals. Studies of multiple independently evolved sex chromosome systems from a variety of species revealed a large variation in sex‐chromosome dosage compensation, ranging from absence of compensation to complete compensation, although further scrutiny is required because of the high heterogeneities in expression data acquisition and analysis methods among studies. The lack of sex chromosome dosage compensation in at least some lineages has important implications for understanding gene expression evolution and sex chromosome evolution.

Key Concepts

  • Ohno proposed that the expression levels of mammalian X‐linked genes should be doubled to compensate for the degeneration of their Y‐linked homologues during sex chromosome evolution.
  • Initial microarray studies of genome‐wide gene expression levels found an X : AA ratio of ∼1, consistent with Ohno's hypothesis.
  • Subsequent analysis of transcriptomic data generated by the more sensitive RNA sequencing method found an X : AA ratio of ∼0.5, inconsistent with Ohno's hypothesis.
  • Some argued that Ohno's hypothesis is supported because X : AA is about 1 for actively expressed genes, but this assertion is caused by a common misunderstanding of Ohno's hypothesis.
  • A direct comparison between human X‐linked genes and their one‐to‐one orthologues located in chicken autosomes that are homologous to the mammalian proto‐X found no upregulation in mammalian X‐linked gene expression, refuting Ohno's hypothesis.
  • A human proteomic analysis found no evidence for a twofold upregulation of protein concentrations of X‐linked genes.
  • Transcriptome analyses of multiple species with independently evolved sex chromosomes revealed a large variation in the presence/absence and degree of sex chromosome dosage compensation, but further scrutiny is required due to the high heterogeneities in the data and methods used in the published studies.
  • The lack of sex chromosome dosage compensation in at least some lineages suggests that halving the expression level of a gene usually has no appreciable fitness consequences.

Keywords: dosage compensation; sex chromosome; autosome; evolution; gene expression; mammals; birds

Figure 1. The prevailing evolutionary model of mammalian X‐chromosome dosage compensation that has recently been tested and challenged. Each arrowhead represents the expression of one allele, with the height of the arrowhead indicating the expression level of the allele.
Figure 2. Comparison of expression levels of orthologous genes from human and chicken. (A) Human X : chicken XX expression ratios for one‐to‐one orthologues in six male (M) or four female (F) tissues, when the medians of human AA : chicken AA expression ratios are normalised to 1. The null hypothesis of X : XX = AA : AA is rejected in each tissue (P < 10−9, Mann–Whitney U‐test). There are 325 gene pairs for calculating X : XX and 10 171 gene pairs for calculating AA : AA. The central bold line shows the median, the box encompasses 50% of genes, and the error bars include 90% of genes. Reproduced with permission from Lin et al. () © Proceedings of the National Academy of Sciences of the United States of America.


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Further Reading

Graves JA (2016) Evolution of vertebrate sex chromosomes and dosage compensation. Nature Reviews Genetics 17: 33–46.

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He, Xionglei, and Zhang, Jianzhi(May 2016) X‐Chromosome Dosage Compensation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026517]