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nature genetics volume 20 september 1998 9

The war of the sex chromosomesNathan A. Ellis

Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. e-mail: n-ellis@ski.mskcc.org

With the publication of Ohno’s watershedmonograph1, molecular genetic characteri-zation of the mammalian sex chromo-somes has radically altered our view ofX-chromosome inactivation and the evo-lutionary conservation of synteny of themammalian X chromosome (Ohno’s law).X inactivation is the dosage compensationmechanism in mammals whereby duringembryogenesis of females a single X-chro-

mosome is genetically silenced. Althoughmost genes are subject to X inactivation,some escape. Moreover, during evolutionautosomal genes can be added to the Xchromosome and later incorporated to dif-ferent extents into the inactivation system.A recent report by Karin Jegalian andDavid Page shows that inactivation of indi-vidual X-linked genes can evolve indepen-dently in different mammalian lineages2.The general correlation between the pres-

ence of a functional Y homologue andescape from X inactivation is remarkable;these results confirm the prevailing theorythat Y deterioration is the driving evolu-tionary force behind the dosage compensa-tion mechanism.

The evolution of the dosage compensa-tion mechanism is inextricably interwovenwith the evolution of the mammalian sexdetermination system and the formation

of the Y chromosome (Fig. 1). The sexchromosomes started out as a pair of ordi-nary autosomes. Once the Y chromosomewas elected to accumulate factors con-tributing to male fitness, a series of eventswas initiated which culminated in a puny,anarchic Y chromosome and a tightlycontrolled, hierarchically regulated Xchromosome. Analogous to the Biblicalsequence in which order follows chaos, adosage compensation mechanism devel-

oped in response to the mass destructionof Y-encoded homologues. Genetic isola-tion of the Y led to the accumulation ofrecessive mutations (a process known asMüller’s ratchet) that, in aggregate,reduced male fitness; this in turn ‘pres-sured’ the X chromosome to increase itsexpression. Excessive X-gene expression ispresumed to have decreased female fitnessuntil the X-inactivation system evolved tosilence the doubly-dosed genes on one ofthe X chromosomes in females.

The process by which a single X chromo-some is selected for inactivation (Fig. 1) iscontrolled by a single locus known as XIST(ref. 3). Emanating from the XIST locus,an inactivation signal is established thatspreads along the X chromosome. It wasonce thought that almost every gene on theX is inactivated; but it is now known that asurprisingly large number (over 20, andpossibly many more) escape X inactiva-tion4,5. Thirty years ago, only one escapeegene had been localized to the distal tip ofthe short arm of the X chromosome. Today,we know of many such escapees, proximalas well as distal, and on the long arm as wellas on the short—which indicates thatspreading of inactivation is a process medi-ated on a regional or gene-by-gene basis.

During the course of evolution, an ancestor to placental mammals musthave escaped a peril resulting from the hemizygous existence of all theX-linked genes. Once this step was accomplished, the female no longerneeded two Xs in her somatic cells. Hence, the dosage compensationmechanism by random inactivation of one or the other X evolved.—Susumu Ohno

pair ofordinaryautosomes

allelic systemof

sex determination

testis-determininggene is combinedwith genes that increase male

fitness

proto X

recombinationsuppression

mutation double-dose

single-dose inactivated

Müller'sratchet

war between the sexchromosomes; increased

X-gene dosage and Y deterioration

dosagecompensation

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addition ofautosomalmaterial to

the PAR

PARPAR

XISTon

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X inactive XY PAR

proto Y

F M

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*XISToff

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X-autosome and Y-autosometranslocation that is

fertile and viable

The Ys and wherefores of sX chromosome evolution. Model for the evolution of the mammalian sex chromosomes. a, Mammalian sex chromosomesevolved from a pair of ordinary autosomes. At first, sex was genetically determined by a simple diallelic system, F and M, in which the male was the heteroga-metic sex. b, Sex chromosome differentiation began when the proto-Y chromosome accrued at least one additional gene, that together with the M allele, con-ferred a selective advantage to males. Such combinations of syntenic genes in turn selected for a meiotic system in which recombination between sexchromosomes was suppressed (a region of suppression is represented by the yellow area on the Y). c, The inevitable consequence of recombination suppressionwas the additional accrual by the Y chromosome of recessive mutations (*) in the many genes unrelated to sexual development by a process known as Müller’sratchet. Recessive mutations in the recombination-suppressed segment are not effectively selected against, and patrilineal inheritance reduces the effective pop-ulation size of Y genes, resulting in increased genetic drift. The loss in fitness in males that resulted from hemizygosity of more and more X chromosome geneswas corrected by increasing the expression of the X genes, thus raising the level of X-gene expression in females. A region has been maintained that is shared bythe sex chromosomes (denoted PAR for pseudoautosomal region). Crossing-over is confined to this segment and is required for the segregation of the sex chro-mosomes in male meiosis. d, Inactivation of one X chromosome in females evolved. A single locus, XIST, was recruited to initiate and signal genetic silencing ofone X chromosome in females (indicated by the larger arrows alongside the X chromosome). PARs in most eutherians are small regions, and in certain circum-stances they can be dispensed with altogether (as in marsupials). On the other hand, PARs can be sites to which autosomal material can be translocated (e). Thenewly translocated material then becomes subject to Müller’s ratchet and the dosage compensation wars.

a b c d e

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news & views

10 nature genetics volume 20 september 1998

Paring PARsOn the human sex chromosomes, there is asegment of 2.6 million base pairs on thedistal tips of the short arms (PAR1) where,contrary to the usual prohibition, cross-ing-over during male meiosis is not onlyallowed but required for successful segre-gation of the X and the Y chromosomes.PAR1 genes are present in two doses inboth males and females, and they escapeX-inactivation. As such, it seems justifiablethat PAR genes are not subject to Ohno’slegendary law. Similarly, a second PAR(PAR2) exists on the distal tips of the longarms where at least one gene is known todisobey Ohno’s law. Even more illuminat-ing is the fact that a huge portion ofthe eutherian X chromosome originated aschromosome material that was translo-cated in several pieces from several dif-ferent autosomes sometime since theevolutionary paths of eutherians andmetatherians separated about 150 millionyears ago. The current human PAR1 is aremnant of what was once a much largerPAR (ref. 6). How did it shrink? As ever,the expression and integrity of the sex-chromosome genes provide a clue.

One formerly pseudoautosomal gene,human STS, is only partially X-inacti-vated, whereas its Y homologue hasbecome a non-functional pseudogene.Similarly, human PRKX escapes X inacti-vation; its Y homologue is intact but isexpressed at a lower level than the Xhomologue. Thus, the dual processes of Ydeterioration and X inactivation have todifferent extents integrated the formerlypseudoautosomal genes into the sex chro-mosome system. What remains are Xgenes in various intermediate evolution-ary states. At one end of the spectrum areX genes that are subject to inactivationand have lost their functional Y chromo-some counterparts, and at the other endare X genes that escape X inactivation andmaintain functional Y counterparts.

Jegalian and Page have studied the genesthat, at least in humans, have resisted thedual processes of Y deterioration and X

inactivation. As a suitable surrogate forinactivation status, they analysed themethylation levels in the promoter regionsof three genes, ZFX, RPS4X and SMCX, in19 eutherian species representing 11 orders(Table 1). The results were striking: ZFXescapes X-inactivation, and a functionalhomologue, ZFY, is maintained on the Ychromosome in all mammals exceptrodents. In rodents, ZFX is inactivated andthe expression level of ZFY is reduced andand restricted to germ cells. RPS4X escapesX inactivation only in the primate lineage;everywhere else, RPS4X is X-inactivated.Concomitantly, a functional RPS4Y homo-logue is maintained in the primate lineageonly. Finally, SMCX is X-inactivated insome species and escapes inactivation inothers. SMCY gene sequences are presentin many species, but the available evidencesuggests that in species in which the Xgene is inactivated, Y gene function isreduced. In mouse, inactivation of SMCXoccurs in embryogenesis but the gene par-tially reactivates during later stages ofdevelopment7. Mouse SMCX appears tobe in an intermediate state in which Yfunction is normal but X inactivation hasnot been completely successful.

These data demonstrate that the X-inac-tivation system has embraced these threegenes in some mammalian species but notin others, and, wherever X inactivation isobserved, the expression of the homologueon the Y chromosome is either reduced, orthe Y gene is lost entirely. If X inactivationwere driving these evolutionary events,functional Y genes with X-inactivatedhomologues would be more frequent.Functional human Y genes have been thor-oughly studied, and it is remarkable howconsistently their expression is either testis-specific or, alternatively, ubiquitous butwith a functional X homologue that escapesX-inactivation8. Many are the defunct Ygenes that have X homologues that escape Xinactivation, and many are the X-inactiva-tion escapees with no Y homologue at all.From all the available evidence, we can con-clude that, for the most part, Y deteriora-

tion is the driving evolutionary force. Themouse SMCX gene, however, tells a cau-tionary tale; it shows that X inactivation canbe the driving evolutionary force.

X-inactivation escapees RPS4X andSMCX were present on the X chromosomeancestral to eutherians and metatheriansand ZFX was one of those genes translo-cated in the eutherian lineage to the X chro-mosome from an autosome6. Most of theirformer colleagues were driven off the Ychromosome long ago. What makes thesegenes more resistant to the dual processesof Y deterioration and X inactivation? Per-haps they resist the turns of Müller’s ratchetbecause they are dosage-sensitive genes. Inother words, mutation or X inactivation ofone copy of these genes may result in nega-tive phenotypic effects (for example,growth or fertility defects). This hypothesiscould be testable by generating a mousedeficient of SMCX. Supporting it is the factthat somatic features resembling those ofpeople with Turner syndrome have beenobserved in females with XY gonadal dys-genesis who have deletions of ZFX andRPS4X, suggesting that these genes mayindeed be dosage sensitive. How Y de-terioration and X inactivation would cap-ture dosage-sensitive genes in somemammalian lineages but not others isunknown; perhaps the two processes occa-sionally pounce simultaneously on a gene,or perhaps modulations of autosomalgenes that control dosage sensitivity sud-denly confer dosage resistance.

The mammalian X inactivation systemhas turned out to be far more malleableand adaptive then originally imagined.Inactivation is controlled on both a chro-mosome-wide and a gene-regional basis,and X-inactivation status continues toevolve even today as new genes are shuf-fled into the PAR and later captured by thenon-recombining part of the Y chromo-some. Once capture has been effected,Müller’s ratchet proves to be an exception-ally strong force—to which the vast num-ber of Ohno-obedient X-inactivated genestestify. While the Y chromosome standsaccused of violence to many decent, hard-working genes, at least some of us can bethankful that, although it may not bemuch, it’s good at what it does. ■■

1. Ohno, S. (Springer-Verlag, Berlin, 1967).2. Jegalian, K. & Page, D.C. Nature 394, 776−780 (1998).3. Carrel, L. & Willard, H.F. Nature Genet. 19, 211−212

(1998).4. Disteche, C. Trends Genet. 11, 17−22 (1995).5. Brown, C., Carrel, L. & Willard, H.F. Am. J. Hum.

Genet. 60, 1333−1343 (1997).6. Graves, J.A.M., Disteche, C.M. & Toder, R. Cytogenet.

Cell Genet. 80, 94−103 (1998).7. Lingenfelter, P.A. et al. Nature Genet. 18, 212−213

(1998).8. Lahn, B.L. & Page, D.C. Science 278, 675−680 (1997).

Table 1 • X-chromosome inactivation and Y-chromosome deterioration

Gene Primates Domesticated mammals Rodents MarsupialsXCIa Y geneb XCI Y gene XCI Y gene XCI Y gene

ZFX no yes no yes yes noc autosomaldRPS4X no yes yes no yes no yesSMCX no yes yes noc no yes yes

no yesyes yese

aXCI, X-chromosome inactivation; yes, subject to X inactivation; no, escapes X inactivation;blank, not known. bY gene, functional homologue on the Y chromosome; yes, homologuepresent; no, homologue absent. cIn some cases, a Y gene may be present but either nonfunc-tional (no Y transcripts detected) or expression is reduced in level or restricted (the rodent Zfygenes, which are expressed in testis only, have reduced homology to the highly conserved Zfxgenes, suggesting perhaps an evolving gene function). dZFX is autosomal in marsupials and inmonotremes, as described in the text. eGene is present, but expression unknown.

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