Ohno’s Hypothesis of X Chromosome Dosage Compensation Refuted

Contributed by: Jianzhi Zhang

 

The X and Y chromosomes of humans originated from a pair of autosomes in the common ancestor of placental and marsupial mammals.  In his classic book entitled “Sex Chromosomes and Sex-Linked Genes”, Susumu Ohno (1967) (1) wrote, “During the course of evolution, an ancestor to placental mammals must have escaped a peril resulting from the hemizygous existence of all the X-linked genes in the male by doubling the rate of product output of each X-linked gene,” (p. 99).  This presumed doubling of expression on X would cause X tetraploidy in females, which is believed to be the driving force behind the evolution of the random inactivation of one X chromosome in females.  As a result, the expressions of X-linked genes become equalized between males and females.  

The prevailing evolutionary model of sex chromosome dosage compensation.  Each arrowhead represents the expression of one allele, with the height of the arrowhead indicating the expression level of the allele. Two recent studies found no upregulation of X-linked genes, thus rejecting Ohno’s hypothesis.

So, are expressions of X-linked genes doubled to compensate the loss of their Y homologs, as Ohno hypothesized 45 years ago?  In the last few years, a number of groups tested Ohno’s hypothesis indirectly by comparing the expressions of X-linked and autosomal genes in humans or mice (2-11).  These authors reached different conclusions either supporting or refuting Ohno’s hypothesis, depending on the transcriptome data used and the genes compared.  This controversy is now resolved by a direct comparison of the expression levels of human X-linked genes with those of their one-to-one orthologs in chicken. 

Julien et al. (12) and Lin et al. (13) analyzed the same RNA-Seq data published last year.  They found that the expression ratio between a human X-linked gene and its one-to-one ortholog in the “proto-X” chromosome in chicken has a median of ~0.5.  That is, the per-allele expression level of X-linked genes is on average unchanged!  This finding conclusively refutes Ohno’s hypothesis.

Does this finding imply that a two-fold change in gene expression has such a small fitness effect that dosage compensation is hardly needed?  The answer appears different for different genes.  First, following a recent analysis (14), Lin et al. found that proto-X genes that encode members of large protein complexes did experience an on average two-fold up-regulation during sex chromosome evolution, likely because of the high dose sensitivity of large protein complex members.  But these genes constitute only ~5% of all X-linked genes and therefore do not show up in the chromosome-wide analysis.  Second, there are X-linked genes that have now migrated to autosomes, which may have been a strategy to avoid a dose change.  Third, a genome-wide study showed that haploinsufficiency is rare in yeast.  It is possible that the same is true in mammals.  Fourth, even for one-to-one orthologous genes in autosomes, a two-fold expression difference between human and chicken is not uncommon, suggesting that perhaps expression levels need not be so finely regulated and conserved.  Together, the analyses suggest that, for most genes on the proto-X, a 50% expression reduction is quite tolerable and need not be compensated.

Because Ohno’s hypothesis is the basis of the current model of male:female X chromosome dosage compensation, its invalidation opens the research for a new evolutionary explanation of X inactivation in female mammals. 

References

1. Ohno S (1967) Sex Chromosomes and Sex-Linked Genes. New York: Springer-Verlag.

2. Gupta V, Parisi M, Sturgill D, Nuttall R, Doctolero M, et al. (2006) Global analysis of X-chromosome dosage compensation. J Biol 5: 3.

3. Nguyen DK, Disteche CM (2006) Dosage compensation of the active X chromosome in mammals. Nat Genet 38: 47-53.

4. Lin H, Gupta V, Vermilyea MD, Falciani F, Lee JT, O'Neill LP, and Turner, BM (2007) Dosage compensation in the mouse balances up-regulation and silencing of X-linked genes. PLoS Biol 5: e326.

5. Xiong Y, Chen X, Chen Z, Wang X, Shi S, Wang X, Zhang J, and He X (2010) RNA sequencing shows no dosage compensation of the active X-chromosome. Nat Genet 42: 1043-1047.

6. Deng X, Hiatt JB, Nguyen DK, Ercan S, Sturgill D, Hillier L, Schlesinger F, Davis C, Reinke VJ, Gingeras TR, Shendure J, Waterston RH, Oliver B, Lieb JD, and Disteche CM (2011) Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nat Genet 43: 1179-1185.

7. Kharchenko PV, Xi R, Park PJ (2011) Evidence for dosage compensation between the X chromosome and autosomes in mammals. Nat Genet 43: 1167-1169.

8. Lin H, Halsall JA, Antczak P, O'Neill LP, Falciani F, and Turner BM (2011) Relative overexpression of X-linked genes in mouse embryonic stem cells is consistent with Ohno's hypothesis. Nat Genet 43: 1169-1170.

9. Yildirim E, Sadreyev RI, Pinter SF, Lee JT (2012) X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription. Nat Struct Mol Biol 19: 56-61.

10. He X, Chen X, Xiong Y, Chen Z, Wang X, Shi S, Wang X, and Zhang J (2011) He et al. reply. Nat Genet 43: 1171-1172.

11. Castagne R, Rotival M, Zeller T, Wild PS, Truong V, Tregouet DA, Munzel T, Ziegler A, Cambien F, Blankenberg S, and Tiret L (2011) The choice of the filtering method in microarrays affects the inference regarding dosage compensation of the active X-chromosome. PLoS One 6: e23956.

12. Julien P, Brawand D, Soumillon M, Necsulea A, Liechti A, Schutz F, Daish T, Grutzner F, and Kaessmann H (2012) Mechanisms and evolutionary patterns of mammalian and avian dosage compensation. PLoS Biol 10: e1001328.

13. Lin F, Xing K, Zhang J, He X (2012) Expression reduction in mammalian X chromosome evolution refutes Ohno's hypothesis of dosage compensation. Proc Natl Acad Sci U S A 109: 11752-11757.

14. Pessia E, Makino T, Bailly-Bechet M, McLysaght A, Marais GA (2012) Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome. Proc Natl Acad Sci U S A 109: 5346-5351.

Dawn of Molecular Biology of Infrared Vision

Contributed by: Shozo Yokoyama

Humans visualize a narrow range, 400-700 nanometer (nm), of electromagnetic radiation (light), which is reflected from the surfaces of various objects in nature.  In addition to the photochemical detection of light, certain animals and insects have acquired infrared (IR) vision during evolution.  IR is electromagnetic radiation with longer wavelength (750 nm - 1 mm) than those of the visible light.  Much of the energy we receive from the sun is IR radiation, but the IR radiation also includes the thermal radiation emitted by animals.  Organisms with IR vision detect the thermal radiation (750-1,200 nm) for hunting and thermoregulation. 

Fig. 1. Pit viper pit organ.

Only four vertebrates (pit vipers, boas, pythons, and vampire bats) are known to detect and localize sources of infrared (IR) radiation.  Their infrared “eyes” can be one pair (pit vipers and vampire bats) or as many as 13 pairs (boas and pythons) of deep cavities located beneath their eyes, called pit organs (Fig. 1).  In the rattlesnake, the pit organs contain an inner chamber that is separated by a thin (15 mm), concave IR-sensitive membrane (Fig. 2) (1).  The IR and visible-light information are integrated in the brain to yield a unique wide-spectrum picture of the world (2).  Since the postulation that such pit organs can be capable of detecting subtle environmental stimuli (3), the anatomy of the pit organs and the behavioural consequences of IR vision have been extensively studied.  Having no IR receptors in hand, however, little is known about the molecular basis of IR vision.  Thanks to the discovery of the IR receptors by David Julius and his colleagues at UCSF (4, 5), this 80-year stalemate is going to be overcome.  Before these papers were published, it had been suspected that IR receptors operate on a thermal principle rather than photochemical principle (e.g. (6)), suggesting that the transient receptor potential (TRP) ion channels may be involved.

      Fig. 2. Rattlesnake pit organ, (1).                  

 

The TRP ion channels are involved in a diverse range of biological processes, including calcium and magnesium homeostasis, neuronal growth, temperature sensation, and pain sensation (7, 8).  Based on sequence similarity, the TRP superfamily can be divided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPN (NOMPC), TRPP (polycystin), and TRPML (mucolipin) (Fig. 3).  The total numbers of TRP channels in worm (C. elegans), fruit fly (D. melanogaster), mouse (M. musculus), and human vary between 13 and 28 (8).  So, which TRP receptor is involved in the IR vision? 

Fig. 3. Some examples of TRP receptors, (8).

The best candidates for the IR receptors are TRPVs because of their sensitivities to body-heat and external temperatures.  For example, TRPV1, 2, 3, and 4 are activated at 43, 52, 39, and 27-34 ^oC, respectively.  However, in the first paper (4), Gracheva et al. have shown that the IR receptors isolated from the western diamondback rattlesnake (Crotalus atrox), ball python (Python regius), and garden tree boa (Corallus hortulanus) are TRPA1s.  Many people may have personally experienced the fiery sensation caused by wasabi when eating sushi.  This sensation is initiated by our TRPA1 receptors.  The paper contains an enormous amount of data on the molecular cloning and expression of TRPA1s, omics, and some molecular evolution not only of the three evolutionarily distantly related rattlesnake, python, and boa but also of the Texas rat snake (Pantherophis obsoletus lindheimeri) without IR vision.  Interestingly, the rattlesnake is evolutionarily more closely related to the rat snake than to the python or the boa, suggesting the independent origin of IR vision among the snakes.

Knowing that the snakes use TRPA1 for their IR vision, we might now think that vampire bats (Desmodus rotundus) also modified TRPA1 to detect IR.  We are wrong again!  The second and equally wonderful paper (5) reveals that the vampire bat after all uses one of the TRPVs, TRPV1, for its IR vision.  One fascinating feature is that the bat IR-detection has been achieved through alternative splicing of the TRPV1 transcript that produces a truncated receptor, which is caused by a newly acquired extra exon of 29 nucleotides.

The discoveries of the IR receptors in the snakes and vampire bat will open an exciting new chapter in the molecular analyses of signal transduction underlying IR detection.  Molecular evolutionary studies of the two sets of IR-sensitive and other TRP receptors will be helpful not only in understanding the mechanisms of IR vision but also in elucidating the mechanisms of phenotypic differentiation of diverse TRP superfamily members. 

References

1.  E. A. Newman, P. H. Hartline, The infrared 'vision' of snakes. Sci. Amer. 20, 116 (1982).

2.  E. A. Newman, P. H. Hartline, Integration of visual and infrared information in bimodal neurons in the rattlesnake optic tectum. Science 213, 789 (Aug 14, 1981).

3.  W. G. Lynn, The structure and function of the facial pit of the pit vipers. American Journal of Anatomy 49, 97 (1931).

4.  E. O. Gracheva et al., Molecular basis of infrared detection by snakes. Nature 464, 1006 (Apr 15, 2010).

5.  E. O. Gracheva et al., Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. Nature 476, 88 (Aug 4, 2011).

6.  J. F. Harris, R. I. Gamow, Snake infrared receptors: thermal or photochemical mechanism? Science 172, 1252 (Jun 18, 1971).

7.  R. Gaudet, A primer on ankyrin repeat function in TRP channels and beyond. Mol Biosyst 4, 372 (May, 2008).

8.  K. Venkatachalam, C. Montell, TRP channels. Annu Rev Biochem 76, 387 (2007).