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The evolution of X chromosome inactivation in mammals: the demise of Ohno’s hypothesis?

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Abstract

Ohno’s hypothesis states that dosage compensation in mammals evolved in two steps: a twofold hyperactivation of the X chromosome in both sexes to compensate for gene losses on the Y chromosome, and silencing of one X (X-chromosome inactivation, XCI) in females to restore optimal dosage. Recent tests of this hypothesis have returned contradictory results. In this review, we explain this ongoing controversy and argue that a novel view on dosage compensation evolution in mammals is starting to emerge. Ohno’s hypothesis may be true for a few, dosage-sensitive genes only. If so few genes are compensated, then why has XCI evolved as a chromosome-wide mechanism? This and several other questions raised by the new data in mammals are discussed, and future research directions are proposed.

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Abbreviations

XCI:

X-chromosome inactivation

PAR:

Pseudoautosomal region

rXCI:

Random X-chromosome inactivation

pXCI:

Paternal X-chromosome inactivation

Xi:

Inactivated X chromosome

PolII:

RNA polymerase II

ZGA:

Zygote genome activation

NGS:

Next-generation sequencing

Ne:

Effective population size

PAM:

Parental antagonism model

XIC:

X-inactivation center

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Acknowledgments

We thank Fangqin Lin for providing us with the exact X:AA and X:XX median values from [34]. GABM is supported by Agence Nationale de la Recherche (Grant ref. ANR-12-BSV7-0002). GABM thanks Instituto Gulbenkian de Ciência for hosting him during several periods strongly overlapping with the writing of this article.

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Authors and Affiliations

  1. Laboratoire de Biométrie et Biologie Évolutive, Centre National de la Recherche Scientifique, Université Lyon 1, Bat. Gregor Mendel, 16 rue Raphaël Dubois, 69622, Villeurbanne Cedex, France

    Eugénie Pessia & Gabriel A. B. Marais

  2. School of Biological Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia

    Jan Engelstädter

  3. Instituto Gulbenkian de Ciência, 2780-156, Oeiras, Portugal

    Gabriel A. B. Marais

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  1. Eugénie Pessia
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  3. Gabriel A. B. Marais
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Correspondence to Gabriel A. B. Marais.

Appendices

Box 1: testing Ohno’s hypothesis with expression data

Ohno’s hypothesis has been tested by comparing the expression of the X chromosome to that of the autosomes taken together, the X:AA ratio.

Microarray versus RNAseq data

Initially, microarray data have been used for this test [22–26]. Microarray may give less precise estimates of expression levels [27]. Moreover, microarray data have to be filtered prior to analysis. The procedures for data filtering rely on arbitrary thresholds, which applied similarly to the X and autosomes remove many lowly expressed X-linked genes and generate an artifactual X:AA of 1 [68]. RNAseq data are supposed to give more precise estimates of expression levels. However, there is also some noise in RNAseq data due to unspecific mapping of RNAseq reads onto the genome, and how this noise is removed can also affect the results [69]. Removing this noise is at the heart of the controversy between the different studies using RNAseq [27–30, 35]. As the threshold for considering a given expression level different from 0 increases, the X:AA ratio increases and reaches a plateau at 1 [28]. It is clear, however, that when using conservative thresholds, the number of X-linked genes analyzed becomes small, and one cannot conclude from this about a “global” X hyperactivation [32].

X:AA, X:XX, and other expression ratios

Using X:AA expression relies on the assumption that expression were similar between the proto-sex chromosomes and the autosomes (XX:AA = 1). Using the present-day and ancestral expression of the X chromosome, the X:XX ratio, is thus a more direct way to test for Ohno’s hypothesis. Computing the X:XX ratio in mammals has implied finding an outgroup where the 1-to-1 orthologs of the X-linked genes are autosomal, namely birds [33]. This guarantees that only genes that were originally on the sex chromosomes before they diverged are analyzed, which is what should be done as dosage compensation is expected for these genes only. The new genes that evolved (e.g. through intra-X duplication or translocation to the X) after X and Y stopped recombining and diverged should not be included in studies on dosage compensation, are correctly excluded of the X:XX analysis but not in the X:AA ones. However, finding 1-to-1 orthologs between distantly related species may be difficult and result in a small number of genes being analyzed. Moreover, all these chromosome-wide comparisons may be problematic as different selective forces (dosage compensation, sexual selection) may affect expression levels [43, 70]. A more precise way of testing Ohno’s hypothesis is to study X-linked and autosomal genes that are expected to interact in some ways and for which equal dosage may be required. Considering genes from the same network is one possibility [33], and considering genes belonging to protein complexes is another [32].

Box 2: The parental antagonism model of X chromosome inactivation

The parental antagonism model (PAM) for the evolution of XCI was proposed by Haig [49, 50]. It is embedded within the general evolutionary theory of parental investment in offspring [71] and closely related to the kinship theory of genomic imprinting [49, 72]. The argument can be presented in a number of steps.

Step 0 A prerequisite for PAM to work is that offspring are provisioned with an adjustable amount of resources from their mother following fertilization. This is indeed the case in therians where resources are provided through the placenta during embryonic development.

Step 1 At the core of PAM is the expectation that there will be an evolutionary conflict between maternally and paternally derived genes within a developing organism with respect to the amount of resources provided by the mother of that individual. Both genes derived from the mother and from the father will be selected to induce the mother to provide resources. However, the optimal amount of resources provided may be greater for paternally than for maternally derived genes. This is because when females mate with multiple males during their lifetimes, paternal interests will be limited to the current offspring whereas maternal interests extend to all future offspring that a mother will have.

Step 2 The X chromosome is two-thirds of the time inherited from the mother but only one-third of the time from the father (simply because females have two Xs and males just one). As a consequence, genes on the X chromosome are expected to reflect maternal interests more than paternal ones. In particular, it is expected that genes coding for embryonic growth inhibitors will accumulate on the X chromosome, whereas growth enhancers will be scarce [51].

Step 3 As an evolutionary response to this accumulation of growth inhibitor genes on the X chromosome, there will be selection on paternally inherited genes on the X chromosome to inactivate these genes in embryos, thereby increasing embryo growth. This inactivation may then also spread to other genes on the paternally derived X, either for mechanistic reasons or for dosage compensation. The resulting state of inactivation of the paternally derived X (pXCI) is found in marsupials.

Step 4 pXCI entails that an organism becomes functionally haploid, so that recessive deleterious mutations on the maternally derived X chromosome will be expressed and reduce fitness. This may create selection pressure for random XCI (rXCI), alleviating this burden because half of the cells will then express the functional gene copy [50]. This transition from pXCI to rXCI does not involve parental conflict because the choice of which X chromosome is inactivated does not affect gene dosage.

Step 5 Nevertheless, parental conflict over which of the X chromosomes is inactivated may persist or re-emerge. This is because there may still be imprinted growth inhibitor genes on the X chromosome that are silenced when paternally inherited, so that the maternally derived X chromosome will be under selection to remain the active X. As a consequence, pXCI can re-evolve from rXCI, which may explain pXCI in mouse trophoblast tissues.

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Pessia, E., Engelstädter, J. & Marais, G.A.B. The evolution of X chromosome inactivation in mammals: the demise of Ohno’s hypothesis?. Cell. Mol. Life Sci. 71, 1383–1394 (2014). https://doi.org/10.1007/s00018-013-1499-6

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  • DOI: https://doi.org/10.1007/s00018-013-1499-6

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