X chromosome reactivation perturbs intracellular self/not-self discrimination 

[by increasing aggregation pressure so predisposing females to autoimmune disease]

[This latter part of the title was too long for ICB and so had to be omitted from the final paper]

Donald R. Forsdyke                           

Immunology and Cell Biology (2009) 87, 525-528  (For ICB website click here)

New reports indicate a chromosomal rather than hormonal basis for the susceptibility of females to autoimmune disease. It is held that if females reactivate an inactivated X chromosome there will be overexpression of certain X-located genes affecting immune function. Hence, normal mechanisms of self/not-self discrimination might be impaired resulting in immune reaction to self antigens. 

    However, the data are also consistent with the long-held view that the demands of intracellular self/not-self discrimination have driven the evolution of X-chromosome dosage compensation. It was proposed that, whether cells are in male or female bodies, concentrations of proteins are fine-tuned up to their aggregation thresholds. A disruption of this equilibrium, by agents originating either externally (e.g. virus) or internally (e.g. reactivated X chromosome), generates homoaggregates that trigger responses against the respective not-self or self antigens. 

   Thus female susceptibility to autoimmune disease may not be because certain immune system genes happen to be X-located, but because self/not-self discrimination was the raison d’être for X chromosome dosage compensation in the first place.

Keywords: autoimmunity; dosage compensation; double-stranded RNA; protein aggregation; systemic lupus erythematosus; X chromosome









End Note (June 2009)





I have proposed that a need for intracellular self/not-self discrimination drove the evolution of X chromosome dosage compensation.1,2 New reports, implicating sex chromosomes rather than hormones in the female predisposition to autoimmune disease,3-6 suggest an update will be helpful.


 In human females one X chromosome is inactivated so that, like males, each cell has only one functional X chromosome. This phenomenon, seen in various forms across a wide range of species, equalizes the concentrations of X chromosome gene products (for present purposes proteins) between males and females, and is referred to as “dosage compensation.” The value-laden term “compensation” implies that intolerance to dosage differences has been beneficial, thus ensuring the differential survival of organisms that evolved mechanisms to bring it about. However, why compensation should be adaptively advantageous – a paradox noted by Muller7 – receives little attention.

    One possibility is that a concentration-dependent function to which many proteins contribute is likely to be favored by dosage compensation. Thus a given protein has both a specific function (e.g. enzymic) and a collective function (e.g. contributing to total protein concentration). The concentration of the protein should be sufficient to meet both specific and collective needs. An example of a collective function is the Gibbs-Donnan equilibrium by which intracellular proteins influence the distribution of ions across cell membranes.8,9 Failure precisely to regulate protein concentrations could perturb cell membrane potential which, in turn, could impair various processes that depended on that potential. Thus, over evolutionary time rates of protein synthesis and/or degradation within cells would have been fine-tuned to sustain constant protein concentrations from generation to generation, whether the cells are in male or female bodies. We are here concerned with another, largely unrecognized, collective protein function, which relates dosage compensation to self/not-self discrimination and hence to immune function.1,2



 Invading viruses and bacteria normally mobilize cells of the immune system (lymphocytes, phagocytes) and the resulting inflammatory response (often seen as reddening and swelling) acts to limit the spread of, and destroy, the foreign organisms. The term “autoimmune” is applied to diseases that are considered to result from a failure to distinguish immunologically “self” from “not-self” (foreign). In systemic lupus erythematosus (SLE) many tissues become inflamed without the obvious involvement of a foreign organism. Complement components promote the inflammation, but they may also be important in deleting the self-reactive lymphocytes that initiate the process.10 Thus, the incidence of SLE is higher when there is complement-deficiency.11,12

    The fact that the incidence of SLE in human males is nine-fold less than in females, where the onset is usually post-pubertal and prior to menopause, has suggested an influence of female hormones.13 However, Klinefelter syndrome males (chromosomally XXY) are also predisposed to SLE, implying a direct X chromosome gene dosage effect.3 Furthermore, studies in mice, where manipulation of the testis-determining Sry gene has permitted separation of chromosomal and hormonal backgrounds, have implicated the X chromosomes themselves in the female bias towards experimental autoimmune encephalitis and SLE.4 Consistent with this, SLE has a low incidence in Turner’s syndrome (XO).

Such considerations have given rise to the hypothesis of interference with normal dosage compensation by reactivation of the inactive X chromosome in certain females and certain Klinefelter males.5,6 This is in keeping with reports that the DNA methylation necessary for the inactivation is defective in SLE.14 Thus, doubling the activities of certain X-linked genes whose products are involved in immune processes might explain the susceptibility to SLE.15 However, the defect in DNA methylation should have a genome-wide impact. Accordingly, without a correlated increase in cell volume, the cytosolic concentrations of many proteins, especially those encoded by the X chromosomes, should increase. While the specific activities of certain proteins would be increased, there should also be an influence on collective protein functions – perhaps on one concerned with intracellular self/not-self discrimination.


 A possible mechanism for intracellular self/not-self discrimination implicating a collective protein function was developed from four premises:

(i) Single celled organisms arose before multi-cellular organisms.

(ii) There existed pathogens capable of gaining entry into single celled organisms.

(iii) The cells developed internal systems for distinguishing pathogen molecules from their own.

(iv) Multi-cellular organisms adapted these pre-existing systems when evolving their own immune defences.

The case, elaborated elsewhere,16-22 will be briefly summarized.

    As it approaches the limits of its solubility (i.e. if its concentration is progressively increased) a given macromolecular species (protein) will form, with high specificity, relatively insoluble like-with-like homoaggregates.23,24 In the crowded cytosol, with a total protein concentration around 300mg/ml,25 the concentration of a protein affects not only its own solubility but also the solubilities of other proteins. Thus, a group of proteins exerts a collective "pressure" tending to make individual protein species self-aggregate. A protein species with the greatest propensity to self-aggregate (a function of factors such as structure, molecular size, and initial concentration) will aggregate first. As the pressure (i.e. total protein concentration) increases, other protein species follow suite. Each individual protein species both contributes to, and is influenced by, this pressure. Each protein has this collective function as well as its own specific function. Both functions affect phenotype and hence influence selection by evolutionary forces.26

    So, over evolutionary time, the concentration of each protein has been fine-tuned to the concentrations of the other proteins with which, from generation to generation (be it male or female) it has shared a common cytosol. Sex chromosome dosage compensation is part of this process. Each protein, through its personal degree of solubilization, pleiotropically influences the solubilization, and hence activities, of numerous other proteins with which it may not otherwise be functionally related.27 The homeostatic fine-tuning of the concentration of a protein to that of its companion proteins implies high conservation of the degree of macromolecular crowding.28

    When a foreign pathogen (e.g. virus) enters a cell this equilibrium is perturbed. Whereas self protein-encoding genes are at peace with the concentrations at which their products have arrived, the raison d'être of most viruses is, at some time within the lifespan of their host, to increase in number. This implies the synthesis of virus-specific proteins at rates that may result in unacceptably high cytosolic concentrations. This would cause aggregation of virus proteins (supplemented by coaggregation of some host proteins), to a degree that could constitute a not-self signal. This, in turn, would trigger various adaptive options, one of which would be apoptosis.

    However, given that most viruses have higher mutation rates than their hosts, viruses would soon adjust their synthesis rates to avoid triggering host defence mechanisms. Thus, the aggregation-triggered defence mechanism should mainly serve to limit the rate of virus growth, so slowing its multiplication and spread to other host cells. Supporting roles of molecular chaperones, heat-shock proteins and nucleic acids in this process have been proposed.16-22 Recently, the emergence of a “hidden transcriptome” from what was formerly regarded as “junk DNA”,29-31 has lent credence to the hypothesis of an independent role for nucleic acids in self/not-self discrimination.19,32,33


Double-stranded RNA has long been known as an alarm signal that activates immune defenses.32-35 Indeed, viruses often first express themselves in foreign cytosols in the form of RNA transcripts that can fold into stem-loop structures. If double-stranded stem segments of a particular length, which originated entirely from a virus, were sufficient to alert a host, then it is likely that viruses which had mutated to prevent duplexes of that length from appearing or being detected,32,33,36 would have preferentially survived. Hence, on a priori grounds, duplex formation between host RNA and virus RNA seems more plausible. It was proposed that the spectrum of host cytosolic RNAs should be regarded, not in terms of their individual specific functions (e.g. as mRNAs specifying proteins), but as an RNA collective that is best equated with the antibodies which mediate extracellular immune responses in higher organisms.19,22 However, whereas antibodies (immunoglobulins) are dedicated, each to a range of related antigenic determinants with varying affinity, many intracellular RNA “antibodies” have additional roles, such as encoding protein. When there is a crisis – invasion by a virus – the latter roles would become of relatively minor importance (see later).

   Thus, host transcripts can be regarded as presenting a wide range of specificities for RNA targets. Some host transcripts have the potential to recognize, and pair to form lengths of double-stranded RNA with, sequences in the genomes or transcripts of viruses. The recognition process involves initial “kissing” interactions between RNA secondary structures, which is followed by duplex formation in the regions of complementarity.19,22 Furthermore, just as self/not-self discrimination at the protein level might be subverted by inadvertent expression of autologous proteins due to failed X inactivation (see above), so self/not-self discrimination at the RNA level might also be subverted by inadvertent formation of self duplexes, with pathologically “toxic” results.37,38

   While the evidence for the RNA “antibody” role in eukaryotes is at present fragmentary,19,22,33 there is now compelling evidence in prokaryotes. To deal with bacteriophages, bacteria have long been known to distinguish self from not-self at the DNA level (i.e. restriction enzymes). A distinction is also made at the RNA level by an RNA antibody-like mechanism.39,40 By mutating its target sequences a phage can evade this bacterial defense system. Since secondary structure is required for the initial recognition event, mutations near the target sequence that interfere with phage secondary structure should also be evasive. Host defenses can indeed be evaded by mutating the non-targeted flanking sequences.41

   In a multicellular organism it can be supposed that, following a primary self/not-self discrimination event at the RNA level, host “alarms would ring” (e.g. interferon induction and upregulation of MHC protein synthesis). Certain heat-shock proteins would shift from chaperone-mode (i.e. disaggregation mode), to aggregation-mode.17,42 The above aggregates of foreign or self proteins would then be directed to proteosomes,43 leading to their preferential degradation to peptides that would associate with MHC proteins and be displayed at the cell surface for recognition by cytotoxic T cells.22




The magnitude of the aggregation in SLE is such that there is often systemic involvement of many tissues. However, in certain diseases aggregation is restricted to a limited number of gene products.44 Here there might be an opportunity for multiplication of neighboring cells so that a cell targeted for T-cell destruction would be quickly replaced. Overt inflammation might not be apparent and cells with visible aggregates (inclusion bodies) might not be detected. However, T cells have limited access to the central nervous system, which is less able to replace cells that are destroyed. Thus, although these diseases may be systemic, they could appear to target the nervous system specifically.32


A self/not-self alarm (“stress”) invokes collective RNA and protein functions that should normally operate independently of any specific roles of individual RNA and protein species (see above). Thus, collective functions trump specific functions. However, as part of collective responses specific proteins could either increase (following increased general transcription) or decrease (following coaggregation) to extents sufficient to influence phenotypes. For example, malexpression at the wrong time or place of a key regulatory protein (e.g. during embryonic development) could produce unwelcome “phenocopies” of forms normally encountered as inheritable mutants.20,45


The proposal that the aggregation mechanism for self/not-self discrimination initially evolved at the unicellular level and was subsequently adapted by multicellular organisms, implies a fundamental process that should apply universally whenever an aneuploid threat to dosage balance arises.2,46 Yet, sex chromosome dosage compensation in birds has long been in doubt.47,48 However, recent studies suggest that birds dosage-compensate on a gene-by-gene basis – locally rather than globally.49 Indeed, even in organisms where compensation mechanisms appears global, certain genes are compensated more than others.50 The present hypothesis predicts that genes whose products most powerfully exert aggregation pressure (e.g. large size and high abundance) are most likely to be compensated than those less powerful in this respect (e.g. small size and low abundance).51 Since aggregation propensity increases with temperature,23 pyrexia in the early stages of an infection should be beneficial. By the same token, the severity of autoimmune disease should be decreased by vigilant employment of antipyretic medication.


Hypotheses on the hormonal basis, and on the mono- or oligo-genic specific immune basis, of the female predisposition to autoimmune disease, now appear less persuasive than the polygenic hypothesis. Under the latter, independently of their specific functions, proteins collectively exert an aggregation pressure the homeostatic regulation of which is perturbed, either by foreign agents (normal immune response), or by failure to dosage compensate an X chromosome (autoimmune response). This intracellular system for self/not-self discrimination works in concert with a double-stranded RNA-based discrimination system. A possible role for other collective macromolecular functions (e.g. Gibbs-Donnan equilibrium) has not been excluded.


Queen’s University hosts my web-pages where some of the cited articles may be found.  


1. Forsdyke DR. Intracellular discrimination between self and not-self: X chromosome inactivation compensates for protein concentration, not function. Proc Int Cong Immunol (Budapest) 1992; 8: 331.

2. Forsdyke DR. Relationship of X-chromosome dosage compensation to intracellular self/not-self discrimination: A resolution of Muller’s paradox? J Theor Biol 1994; 167: 7-12.

3. Scofield RH. Bruner GR. Namjou B. Kimberly RP. Ramsey-Goldman R. Petri M. et al. Klinefelter’s syndrome (47, XXY) in male systemic lupus erythematosus patients. Support for the notion of a gene-dose effect from the X chromosome. Arth Rheum 2008; 58: 2511-2517.

4. Smith-Bouvier DL. Divekar AA. Sasidhar M. Du S. Tiwari-Woodruff SK. King JK. et al. A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 2008; 205: 1099-1108.

5. Pan HF. Ye DQ. Li XP. Reactivation of inactive X chromosome: a potential culprit and therapeutic target for systemic lupus erythematosus. Med Hypoth 2008; 70: 1231-1232.

6. Pan H-F. Li W-X. Yuan H. Li L-H. Feng J-B. Li J. et al. Susceptibility to systemic lupus erythematosus may be related to gene dosage effect on the X chromosome. Med Hypoth 2009; 72: 104-105.

7. Muller HJ. Evidence on the precision of genetic adaptation. Harvey Lect 1948; 43: 165-229.

8. Hitchcock DI. Proteins and the Donnan equilibrium. Physiol Rev 1924; 4: 505-531.

9. Kurbel S. Are extracellular osmolality and sodium concentration determined by Donnan effects of intracellular protein charges and of pumped sodium? J Theor Biol 2008; 252: 769-772.  

10. Forsdyke DR. Serum factors affecting the incorporation of [3H]thymidine by lymphocytes stimulated by antigen. II. Evidence for a role of complement from studies with heated serum. Immunol 1973; 25: 597-612.

11. Manderson AP. Botto M. Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immun 2004; 22: 431-456.

12. Agyemang AF. Tsiftsoglou SA. Alimzhanov MB . Imanishi-Kari T. Carroll MC. A role for complement in the regulation of autoimmunity. Mol Immunol 2008; 45: 4141-4142.

13. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol 2001; 2: 777-780.

14. Richardson B. DNA methylation and autoimmune disease. Clin Immunol 2003; 109: 72-79.

15. Lu Q. Wu A. Tesmer L. Ray D. Yousif N. Richardson B. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 2007; 179: 6352-6358.  

16. Forsdyke DR. Entropy-driven protein self-aggregation as the basis for self/not-self discrimination in the crowded cytosol: what the Greeks did not know. J Biol Sys 1995; 3: 273-287.

17. Forsdyke DR. 2000. Double-stranded RNA and/or heat-shock as initiators of chaperone mode switches in diseases associated with protein aggregation? Cell Stress Chaper 5: 375-376.

18. Forsdyke DR. Adaptive value of polymorphism in intracellular self/not-self discrimination. J Theor Biol 2001; 210: 425-434.

19. Forsdyke DR. Madill CA. Smith SD. Immunity as a function of the unicellular state: implications of emerging genomic data. Trends Immunol 2002; 23: 575-579.

20. Forsdyke DR. The heat-shock response and intracellular self/not-self discrimination. Immunol 2005; 114: 142-143.

21. Forsdyke DR. “Altered-self" or "near-self" in the positive selection of lymphocyte repertoires? Immun Lett 2005; 100: 103-106.

22. Forsdyke DR. Evolutionary Bioinformatics. Springer: New York, 2006, pp. 251-290.

23. Lauffer MA. Entropy-Driven Processes in Biology. Springer-Verlag: New York, 1975.

24. Rajan RS. Illing ME. Bence NF. Kopito RR. Specificity in intracellular protein aggregation and inclusion body formation. Proc Natl Acad Sci USA 2001; 98: 13060-13065.

25. Fulton AB. How crowded is the cytoplasm? Cell 1982; 30: 345-347.

26. Chen Y. Dokholyan NV. Natural selection against protein aggregation on self-interacting and essential proteins in yeast, fly and worm. Mol Biol Evol 2008; 25: 1530-1533.

27. Gidalevitz T. Ben-Zvi A. Ho KH. Brignull HR. Morimoto RI. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 2006; 311: 1471-1474.

28. Guigas G. Kalla C. Weiss M. The degree of macromolecular crowding in the cytoplasm and nucleoplasm of mammalian cells is conserved. FEBS Lett 2007; 581: 5094-5098.

29. Kapranov P. Cawley SE. Drenkow J. Bekiranov S. Strausberg RL. Fodor SPA. et al. Large-scale transcriptional activity in Chromosomes 21 and 22. Science 2002; 296: 916–919.

30. Ota T. Suzuki Y. Nishikawa T. Otsuki T. Sugiyama, T. Irie R. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet 2004; 36: 40-45.

31. Dinger ME. Pang KC. Mercer TR. Mattick JS. Differentiating protein-coding and noncoding RNA: challenges and ambiguities. PLOS Comput Biol 2008: 4: e1000176.

32. Cristillo AD. Mortimer JR. Barrette IH. Lillicrap TP. Forsdyke DR. Double-stranded RNA as a not-self alarm signal: to evade, most viruses purine-load their RNAs, but some (HTLV-1, Epstein-Barr) pyrimidine-load. J Theor Biol 2001; 208: 475-491.  

33. Fire A. Nucleic acid structure and intracellular immunity: some recent ideas from the world of RNAi. Quart Rev Biophys 2006; 38: 303-309.  

34. Marcus P. Interferon induction by viruses: one molecule of dsRNA as the threshold for induction. Interferon 1983; 5: 115-180.  

35. Saito T. Gale M. Differential recognition of double-stranded RNA by RIG-1-like receptors. J Exp Med 2008; 205: 1523-1527.

36. Bull JJ. Jacobson A. Badgett MR. Molineux IJ. Viral escape from antisense RNA. Mol Microbiol 1998; 28: 835-846.

37. Li L-B. Yu Z. Teng X. Bonini NM. RNA toxicity is a component of ataxin-D degeneration in Drosophila. Nature 2008; 453: 1107-1110.  

38. O’Rourke JR. Swanson MS. Mechanisms of RNA-mediated disease. J Biol Chem 2009; 284: 7419-7423.

39. Makarova KS. Grishin NV . Shabalina SA. Wolf YI. Koonin EV. A putative RNA-interference-based immune system in prokaryotes: computational analysis of the predicted enzymatic machinery, functional analogies with eukaryotic RNAi, and hypothetical mechanisms of action. Biol Direct 2006; 1: 7.  

40. Sorek R. Kunin V. Hugenholtz P. CRISPR – a widespread system that provides acquired resistance against phages in bacteria and archaea. Nat Revs Mic 2008; 6: 181-186.

41. Deveau H. Barrangou R. Garneau JE. Labonté J. Fremaux C. Boyaval P. et al. Phage response to CRISPR-encoded resistance in Streptococcus thermophilus. J Bact 2008; 190: 1390-1400.

42. Douglas PM. Treusch S. Ren H-Y. Halfmann R. Duennwald ML. Lindquist S. et al. Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc Natl Acad Sci USA 2008; 105: 7206-7211.  

43. Yamano T. Mizukami S. Murata S. Chiba T. Tanaka K. Udono H. Hsp90-mediated assembly of the 26S proteosome is involved in major histocompatibility complex class I antigen processing. J Biol Chem 2008; 283: 28060-28065.

44. Orr HT. Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci 2007; 30: 575-621.

45. Goldschmidt RB. The Material Basis of Evolution. New Haven: Yale University Press, 1940, pp. 267-268.

46. Birchler JA. Avian dosage compensation. Dosage compensation for the birds. Heredity 2009; 102: 423-424.

47. Cock AG. Dosage compensation and sex-chromatin in non-mammals. Genet Res 1964; 5: 354-365.

48. Arnold AP. Itoh Y. Melamed E. A bird’s eye view of sex chromosome dosage compensation. Annu Rev Genomics Hum Genet 2008; 9: 109-127.  

49. Mank JE. Ellegren H. All dosage compensation is local: gene-by-gene regulation of sex-biased expression on the chicken Z chromosome. Heredity 2009; 102: 312-320.

50. Carrel L. Cottle AA. Goglin KC. Willard HF. A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci USA 1999; 96: 14440-14444.

51. Monsellier E. Ramazzotti M. Taddei N. Chiti F. Aggregation propensity of the human proteome. PLOS Comput Biol 2008; 4: e1000199.



End Note (June 2009)

Being based on a 1994 paper in the Journal of Theoretical Biology, it was to this journal that the present paper was first submitted on March 20th 2009. Those submitting to this journal are requested to suggest an appropriate handling Editor from amongst the members of the Editorial Board, and I chose one who was listed as having an interest in autoimmune diseases. He/she anonymously decided that the paper should be promptly rejected (March 30th) without being sent out for review. The communicated reasons were as follows:

"This paper is very badly flawed by selective referencing of the literature and failure to think about how its hypothesis applies beyond SLE. Thousands of papers are available on the genetics of SLE and on the genetics of other autoimmune diseases that link them to chromosomes other than the X chromosome. Thousands of papers have been written on animal models of SLE and other autoimmune diseases that initiate autoimmune diseases without the viral or retroviral invasion that the author's hypothesis requires to initiate protein aggregation. Thousands of papers have looked at susceptibility to autoimmune diseases in humans that do not show the huge sex difference in susceptibility to autoimmunity that SLE does. So at a minimum, the author MUST address the vast amount of data that do NOT fit his hypothesis: why do millions of xy males develop autoimmunity? why are viral infections unnecessary for initiating most animal models of autoimmunity? why are there so many non-x-chromosome genes associated with autoimmunity risk? etc. Theories don't just gather supporting evidence: they must also address apparently contrary evidence -- and in this case almost all the evidence fails to fit!"

Thus, the paper ended up in ICB (impact factor 3.0; citation half-life 5.5) instead of the JTB (impact factor 2.3; citation half-life >10).


End Note (Jan 2011)

Maintaining the concentrations of intracellular macromolecules between defined limits would seem to be important, but especially so in the case of proteins. Thus, it is of interest to note that "protein abundances are more conserved than mRNA abundances across diverse taxa" (Laurent et al. 2010; Proteomics, 10, 4209-4212).

End Note (May 2012)

What about the 1 out of 10 SLE patients who is male? Following up on his earlier studies (ref. 3) Scofield and colleagues (2012) report again that a significant proportion of these "males" have two X chromosomes (47, XXY or 46,XX). Citing the above paper, they conclude that "the number of X chromosomes, not phenotypic sex, is responsible for the sex-bias of SLE."  (Dillon et al. 2012; Journal of Autoimmunity 38, J129-J134).

End Note (July 2012)

These pages have been concerned more with Muller's "why" question (what evolutionary forces drove sex chromosome dosage compensation) than with the "how" question (by what biochemical  mechanism(s) is dosage compensation achieved).  The increasing availability of genomic sequence information from a wide range of organisms has given the mechanism-seekers fuller rein, and a new paper by Lin, Xing, Zhang & He (2012) on mammalian dosage compensation represents a substantial advance. In his famous treatise on sex chromosomes, Ohno (1967) noted:

In fishes, amphibians, and most reptiles, the X and the Y ... of each species are still largely homologous to one other. Thus, even the heterogametic sex maintains two doses of each sex-linked gene. In the case of placental mammals, however, the Y has shed all the Mendelian genes which were allelic to the genes on the X. As a result, most, if not all, of the X-linked genes exist in the hemizygous state in the male. Each X-linked gene must have accommodated itself to this hemizygous state by doubling the rate of product output. Once this doubling in efficiency was accomplished, the genetic disparity between the male with one X and the female with two Xs became very great. A need arose to adjust the dosage effect of X-linked genes between the two sexes. In mammals, the dosage compensation is accomplished by random inactivation of one or the other X in individual female somatic cells. Consequently, phenotypic expression of X-linked genes in individual somatic cells of both sexes is hemizygous, and the mammalian female is a natural mosaic with regard to the activity of X-linked genes. It will be shown that the development of this particular form of dosage compensation is one of the reasons why the original X of a common ancestor was not fragmented into separate pieces during extensive speciation. Most of the X-autosome translocations disrupt the dosage compensation mechanism."


Thinking in terms of individual gene, rather than of collective gene, functions, Ohno supposed that as, one by one, genes disappeared from the original proto-Y in males, there would be pressure for males to increase the output from the corresponding allelic genes encoded by the remaining solitary X. This would sort out the males, but the poor females that inherited such potentially hyperactive X chromosomes, would have to find some way to decrease the output (since they had two X chromosomes) on a gene-by-gene basis.  Despite the slow, progressive, loss of X functions in the Y, females seem ingeniously to have solved the problem in one fell swoop, by turning one of the X's completely off.

    But, from the collective function perspective, the males would not necessarily have to increase the output from a corresponding X-borne allelic gene. To maintain overall protein concentrations, it would suffice to marginally increase the output of all the X-borne genes (the most highly expressed genes being the most important) by tinkering with some global output-controlling mechanism. Thus, if we label X chromosome genes A to Z, a loss of A from the proto-Y (halving the concentration of the A gene product) could be compensated by a marginal tweak of A-Z on the solitary X, so the actual concentration of the A gene product (halved) would scarcely change. This X would be handed on to females, who could progressively adapt using a similar global mechanism.

   Lin et al. (2012) used the autosomes as a yardstick against which to compare sex chromosome expression levels, on the assumption that prior to the degeneration of the Y chromosome the average outputs of all chromosome pairs were comparable. They provide "unambiguous evidence for expression halving (i.e. no change in per-allele expression level) of X-linked genes during evolution." Thinking in terms of individual gene functions, they further note:

"A natural question is how such chromosome-wide expression halving has been tolerated, given that autosomal monosomy [loss of one chromosome of a pair] is lethal in humans? Because Y degeneration is stepwise, expression reduction happened gradually to more and more X-linked genes during evolution. Thus, a possible explanation is that, at any time in evolution, an organism is faced with the expression halving of only one additional gene, which might have been slightly deleterious and thus can be fixed. This evolutionary process contrasts the sudden loss of an entire chromosome in monosomy that causes a large fitness reduction at once. Consistent with the above explanation is the observation that up to 97% of yeast genes have no detectable fitness effect when one allele [at a time] is deleted from a diploid cell. Although haplosufficiency has not been systematically examined in mammals, it is probable that, for most genes, expression halving has little fitness effect [by virtue of loss of an individual gene-encoded function]."

Thus, they suppose haploinsufficiency not to be a problem in mammals (for dose-response theory click here), and they call for a "reopening" of "the search for the evolutionary force driving the origin of chromosome-wide X inactivation in female mammals."

Lin et al. (2012) Expression reduction in mammalian X chromosome evolution refutes Ohno's hypothesis of dosage compensation. Proceedings of the National Academy of Sciences, USA 109, 11752-11757.

Ohno, S (1967) Sex Chromosomes and Sex-linked Genes. Springer-Verlag, Berlin, p. 3.

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This page was established in May 2009 by Donald Forsdyke and was last edited 29 May 2014