Ohno's hypothesis and Muller's paradox: Sex chromosome dosage compensation may serve collective gene functions

Muller found halving gene dosage, as in males with one X chromosome, did not affect specific gene function. Why then was dosage “compensated?” This paradox was solved by invoking collective gene functions such as self/not self discrimination afforded by protein aggregation pressure. This predicts female susceptibility to autoimmune disease. “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.” Thinking in terms of individual, rather than of collective, gene functions, Ohno supposed that as, one by one, genes disappeared from the original proto-Y in males, there would have been pressure for males to increase the output from the corresponding allelic genes encoded by their solitary X. This would have sorted out the males, but the poor females that inherited such hyperactive X chromosomes would have had to find a way to decrease the output (since they had two X chromosomes) on a gene-by-gene basis. Females seemed to have solved the problem by turning off one of the X's. “The effects of individual genes, whether on the X or other chromosomes, are so near their saturation levels as to make direct [functional] discrimination between one and two doses impossible. Should not the very fact that most of these genes are so near their saturation level make dosage compensation unnecessary? Why should there be a perceptible advantage in going through the motions of equalizing them still further?” Dose–response curve showing a measure of conventional phenotype plotted against the quantity of a gene product that contributes to that phenotype. The thick vertical arrow indicates the normal concentration (Y) of a non-rate-limiting gene product in a diploid homozygous cell. If gene product concentration is directly proportional to gene dosage, halving gene dosage will halve gene product dosage (Y → Y'). This does not affect phenotype because concentrations corresponding to the plateau of the dose–response curve are not rate limiting (do not change phenotype value). X and X' indicate the corresponding points for a rate-limiting gene product (big change in corresponding phenotype value). Also shown is the hierarchical flow from gene to phenotype. Reproduced from 25 with permission of McGill-Queen's University Press. “The compensation mechanism must be concerned with the equalization of exceedingly minute differences. Dosage compensation has in fact become established because of its advantage in regulating more precisely the grade of characters whose variations in grade, even without it, would be exceedingly minute. … The selective forces that established it must depend on such minute advantages”[Muller's italics]. Thus, while appearing haplosufficient, the genes were actually haploinsufficient. Emphasizing his focus on specific gene function, Muller entitled his paper “Evidence on the precision of genetic adaptation.” But why, given that specific functions barely change, should differences in protein doses revealed by some modern technologies, matter? To answer this we must recall that genes have both specific and collective functions. For example, it has been known for nearly a century that cytosolic proteins collectively affect the distribution of ions across the cell membrane (“Donnan equilibrium”) 10, 11. While decreases in doses of the products of a few genes might only marginally affect collective functions, the progressive loss of genes from the degenerating Y chromosome would be expected eventually to evoke compensatory adaptations to maintain collective functions. The genes responsible for such adaptations need not necessarily be the same as the genes that were lost. Indeed, highly expressed genes – expected to best maintain collective functions – would be selected on this basis 12, 13. Thus, having lost a set of genes from the shrinking proto-Y chromosome, males would not necessarily have to increase the output from the same set of X-borne allelic genes. To maintain overall protein concentrations, it would suffice marginally to increase the output of some X-borne genes, perhaps by tinkering with some global output-controlling mechanism. 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 either be ignored by males or compensated by a marginal tweak of some or all of A–Z on their solitary X. The actual concentration of the A gene product (already halved) would scarcely change. This X chromosome would be handed on to females, who could progressively adapt using a similar global mechanism. “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].” “Monosomy or trisomy for a whole large chromosome usually presents a major problem; in humans, for example, either is usually lethal. This is probably because differences over a large genomic segment are more likely to involve differences in dose of critical hub genes. The more hub genes involved, the larger the problem. ... This view suggests that the reduction in dose of a minority of X genes drove the selection of complex molecular mechanisms to adjust X dosage in one sex or the other.” Unwilling to explain their results in such terms, Lin et al. 7 now repeat their laboratory's call for a “reopening” of “the search for the evolutionary force driving the origin of chromosome-wide X inactivation in female mammals”. Collective gene functions could provide such a force, highly expressed genes playing a major role. In particular, there is aggregation pressure. In the crowded cytosol, individual protein species are held to both contribute to, and be acted upon by, this pressure, to which their concentrations have been fine-tuned over evolutionary time 13, 16, 17. To resolve “Muller's paradox”, in 1994 I proposed that, if aggregation pressure is excessive, individual proteins would more readily approach their solubility limit and their specific peptides would then become available for presentation as MHC complexes to T lymphocytes 18. Normally, susceptibility to differential aggregation would aid the intracellular detection of either abnormal self, or foreign (not-self), proteins. New studies of the role of X chromosomes in the high susceptibility of females to autoimmune disease have cast fresh light on this 19. Evidence that failure to inactive an X chromosome predisposes both XX females and XXY males to autoimmune disease (reactivity with normal self), suggests that aggregation pressure could have been a major selective force driving the evolution of dosage compensation 20-26. The failure would have created an excess of X-linked proteins, so increasing aggregation pressure beyond acceptable limits. Because the initiating factor is construed as degeneration of genes on the proto-Y chromosome, it is convenient to suppose, like Ohno, that the male adapted first and then the female was forced to counter-adapt. In males the collective function would slowly decrease (because of a fall in protein concentration). If this collective function were aggregation pressure, then the resulting immunological impairment would force males to adapt by increasing protein concentration. By the same token, females receiving adapted chromosomes from males would tend to have had excessive protein concentrations, which would have provoked autoimmune disease. We do not know which of these selective forces would have been more powerful in achieving the dosage balance that we see today. But we should note that if it is concentration, rather than absolute dosage, of protein that is important, then other means of upward adjustment – such as slightly decreasing cell volume – might suffice in males. If such a volume adjustment were transferred to females, then the primary onus for adjusting protein dosage, in this case downwards, would rest with them. New technologies for determination of gene expression levels have been used to examine the evolutionary basis of mammalian sex chromosome dosage compensation 1-7. Muller's invocation of “exceedingly minute differences” in specific gene functions as the evolutionary force driving X chromosome dosage compensation in fruit flies 9, and Ohno's hypothesis in mammals 8, combine to confuse those who seek to understand seemingly conflicting results. Instead of specific gene functions, perhaps we should think more in terms of collective gene functions. New work on the enhanced susceptibility of females to autoimmune disease suggests that a dimly recognized collective function – aggregation pressure – may have played a major role in the evolution of dosage compensation 16-26. Two apparently disparate areas – dosage compensation and immunology – may be profoundly related. For over a decade Queen's University has hosted my dosage compensation educational web-pages: http://post.queensu.ca/∼forsdyke/xchromos.htm. The author has declared no conflict of interest.

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