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X Chromosome Dosage Compensation ANRV361-GE42-30 ARI 11 October 2008 11:16 ANNUAL X Chromosome Dosage REVIEWS Further Click here for quick links to Annual Reviews content online, Compensation: How including: • Other articles in this volume Mammals Keep the Balance • Top cited articles • Top downloaded articles • Our comprehensive search Bernhard Payer and Jeannie T. Lee Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114; email: [email protected], [email protected] Annu. Rev. Genet. 2008. 42:733–72 Key Words The Annual Review of Genetics is online at X chromosome inactivation, epigenetics, imprinting, evolution, genet.annualreviews.org chromatin, noncoding RNA by Reed College on 03/06/13. For personal use only. This article’s doi: 10.1146/annurev.genet.42.110807.091711 Abstract Copyright c 2008 by Annual Reviews. The development of genetic sex determination and cytologically dis- All rights reserved tinct sex chromosomes leads to the potential problem of gene dosage Annu. Rev. Genet. 2008.42:733-772. Downloaded from www.annualreviews.org 0066-4197/08/1201-0733$20.00 imbalances between autosomes and sex chromosomes and also between males and females. To circumvent these imbalances, mammals have developed an elaborate system of dosage compensation that includes both upregulation and repression of the X chromosome. Recent ad- vances have provided insights into the evolutionary history of how both the imprinted and random forms of X chromosome inactivation have come about. Furthermore, our understanding of the epigenetic switch at the X-inactivation center and the molecular aspects of chromosome-wide silencing has greatly improved recently. Here, we review various facets of the ever-expanding field of mammalian dosage compensation and discuss its evolutionary, developmental, and mechanistic components. 733 ANRV361-GE42-30 ARI 11 October 2008 11:16 INTRODUCTION dosage compensation might have been estab- lished during the evolution of sex chromo- “All things are poison and nothing is with- somes. We then summarize what is known Sex chromosomes: out poison, only the dose permits something about the different types of mammalian dosage Specialized not to be poisonous.” This quotation attributed compensation and focus on recent advances in chromosomes which to Theophrastus Bombastus von Hohenheim determine the sex of our understanding of the underlying mecha- (better known as Paracelsus, 1493–1541) de- an individual with nisms. For more in-depth information on each scribes a fundamental principle valid not only genetically determined topic, we refer the reader to the more special- sex for his field of toxicology but also for how cells ized review literature cited here. need to keep the dosage of gene expression in check. While diploid organisms usually can cope with variations in copy number of single ONE DOES NOT FIT ALL: genes, this does not hold true to larger portions THE VARIOUS MODES OF of the genome like entire chromosomes. Ane- DOSAGE COMPENSATION uploidies during human development, for ex- AND THEIR EVOLUTION ample, usually result in abortion, with the The Development of Sex remaining survivors displaying birth defects Chromosomes and Dosage such as developmental abnormalities and men- Compensation is Linked tal retardation (75). The few live-born babies with aneuploidies (0.3%) have either abnor- Sex determination in the animal kingdom is mal numbers of one of the four gene-poorest achieved by surprisingly diverse ways and can chromosomes Y (344 genes), 21 (386 genes), be dependent either on chromosomal consti- 18 (480 genes), or 13 (611 genes), or of tution or environmental factors (Figure 1). the relatively gene-rich (1529 genes) X chro- In some fish and reptile species, e.g., tur- mosome (75) (gene counts retrieved from tles or crocodiles, sex is determined by the NCBI MapViewer, Build 36.3: http://www. egg incubation temperature after fertilization ncbi.nlm.nih.gov/mapview/). In addition, X (see Reference 42 for a review). This envi- chromosome aneuploidies like those in XO fe- ronmental sex determination has the advan- males (Turnersyndrome) or XXY males (Kline- tage that offspring of the better-adapted sex felter syndrome) show considerably milder phe- can be preferentially produced if conditions like notypes than autosomal aneuploidies do. What temperature favor the reproductive fitness of sets the X chromosome apart from autosomes either sons or daughters (26, 254). As males by Reed College on 03/06/13. For personal use only. such that abnormal numbers of it are sometimes and females are chromosomally identical and tolerated, despite its high gene content? no specific sex chromosomes exist, this system The answer can be found in the diverse does not need any form of dosage compen- Annu. Rev. Genet. 2008.42:733-772. Downloaded from www.annualreviews.org dosage compensation mechanisms that mam- sation. A major disadvantage of environmen- mals and other organisms have developed tal sex determination is that the existence of a to equalize sex chromosome-linked gene ex- species can be threatened by sudden changes in pression between the sexes with unequal sex the environment such as global warming. Ac- chromosome constitution (120, 222). In most cording to one theory, climate changes caused model organisms studied thus far, dosage com- the extinction of the dinosaurs, because their pensation seems to be an essential require- temperature-dependent sex-determination sys- ment for successful development, and failure tem might have forced them to produce pre- in dosage compensation leads to embryonic dominantly male or female offspring (145). lethality. This review provides a general out- In contrast to environmental sex determi- line of the latest findings in vertebrate dosage nation stands genetic or chromosomal sex de- compensation and in particular of mammalian termination in which the adult sex is predeter- X-inactivation. We first explain why and how mined during fertilization. It has been proposed 734 Payer · Lee ANRV361-GE42-30 ARI 11 October 2008 11:16 that the ancestors of today’s reptiles, birds, and chromosomes (heterogametic sex). In the first Homogametic: the mammals initially determined sex by using en- system used by birds and some reptiles like member of any one vironmental cues (42). Sex chromosomes were snakes, females are heterogametic and have a species that makes then developed from a pair of autosomes by ac- Z and a W chromosome, whereas males are only one type of quisition of a sex-determining gene or muta- homogametic and have two Z chromosomes. gamete. In mammals, tion on one of the two autosomes (153, 170; The second system is the familiar XY-basedsys- it is the XX female; in birds, it is the ZZ male see References 25, 63 for reviews). That this tem, which most mammals employ with het- happened independently more than once dur- erogametic XY males and homogametic XX ing vertebrate evolution is apparent from the remarkably diverse sex chromosome constitu- a Environmental Dosage balance Dosage balance tions and sex-determination mechanisms in dif- sex determination between autosomes between sexes ferent species. Two major systems can be distin- and sex chromosomes guished depending on which of the two sexes AA PXY has two identical sex chromosomes (homoga- PXY PXY PXY metic sex) and which one has two different sex Cool −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ AA PXY Warm Figure 1 Simplified overview of the interlinked development of chromosomal sex determination and the need for b Development of dosage compensation mechanisms. (a) Initially males chromosomal sex determination and females are chromosomally indistinguishable AA PX PY and sex is determined by environmental cues such as PX PY breeding temperature. An autosomal pair is the PX PY PX PX predecessor of the future sex chromosomes (PXY, SRY Proto-XY). (b) The acquisition of a sex-determining gene (e.g., SRY ) on one copy of the Proto-XY pair PX PX AA PX PX establishes distinct sex chromosomes (PX, Proto-X and PY, Proto-Y) leading to a chromosomal sex-determination system. As PX and PY otherwise c Degradation of share most of the genes with each other, no gene Y-chromosome dosage imbalance yet exists. (c) Additional leads to dosage accumulation of male-specific genes on the PY leads imbalance X Y by Reed College on 03/06/13. For personal use only. to a suppression of meiotic recombination with PX X Y A A and to progressive degradation to the Y chromosome in its current form. Many X-linked X Y X X X genes are now present in only one copy in males Annu. Rev. Genet. 2008.42:733-772. Downloaded from www.annualreviews.org compared to two copies of genes on autosomes (A) X X AA X X creating a gene dosage imbalance between the X and the autosomes. Another imbalance emerges between the X-linked genes in males and females as females have two copies of X-linked genes. (d ) Tocounteract d Development these imbalances, mammals developed two dosage of dosage compensation mechanisms. Genes on the Xa (active compensation X) are upregulated about twofold by an unknown AA Xa Y mechanism, reestablishing the balance between the Xa Y X and autosomes in males. Xa upregulation in Xa Y Xa Xi females is counteracted by inactivation of the Xi (inactive X), to avoid imbalance with the autosomes AA Xa Xi and to create X chromosome balance between the Xa Xi sexes. Which mechanism (Xa-upregulation vs. Xi-inactivation) was developed first, or if the mechanisms coevolved, is unknown. www.annualreviews.org • Mammalian Dosage Compensation 735 ANRV361-GE42-30 ARI 11 October 2008 11:16 females. Over time the sex chromosomes di- their sex by measuring the ratio between X verge more and more from each other by ac- chromosomes and autosomes. In both species cumulating further sex-linked mutations and the molecules translating the X:A ratio into the Heterogametic: the member of any one genes.
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