the role of x inactivation and cellular mosaicism in women's health and sex-specific diseases

SPECIAL COMMUNICATION

The Role of X Inactivation andCellular Mosaicism in Women’s Healthand Sex-Specific DiseasesBarbara R. Migeon, MD

A PERUSAL OF PUBLICATIONS DE-voted to women’s healthissues suggests that wom-en’s diseases are those dis-

eases affecting the breast and ovaries,menstrual disorders, pregnancy, infer-tility, menopause, postmenopausalosteoporosis, and other disorders at-tributable to sex differences in the re-productive apparatus. Recently, the listhas broadened to recognize that menand women differ in response to theirdiseases. Such sex-specific responsesmay impede the ability of physicians todiagnose and appropriately treat a hostof diseases, including cardiovasculardisorders, infectious diseases, and psy-chiatric disorders. Also included are thedifferences in response to pharmaceu-ticals based on the documented sex dif-ferences in the kinetics of drug metabo-lism. Nonetheless, this expanded viewof what constitutes a sexual dimor-phism in the expression of disease of-ten fails to consider biological reasonsfor the sex-specific manifestations otherthan hormones or lack of them.

Certainly, gonadal and hormonal dif-ferences, testosterone in men and es-trogen in women, are responsible forsome sex differences in disease. How-ever, although hormones should not beignored, neither should they domi-nate the view of sex differences. Evenwhen environmental and hormonal dif-ferences between the sexes are notprominent, it is clear that mortality and

morbidity are greater in males. TABLE 1shows that more males than females diein infancy and preschool periods. Theinfant mortality is greater in males (av-eraging about 20% higher), irrespec-tive of the length of gestation. Based onstudies of recognized fetal loss, thegreater loss of males is also observed inutero.

Vulnerability of Males Leadsto Sex-Specific DiseaseWhat then is responsible for the greaterbiological vulnerability of males? Atleast some of the sex difference in vul-nerability is due to males having a singleX chromosome and females having 2X chromosomes; compensatory mecha-nisms having arisen to equalize the sexdifference in the number of X chromo-somes; and females being mosaics.

The sex chromosomes in femalesconsist of a pair of X chromosomes,

whereas males have a single X chro-mosome partnered with a Y chromo-some. The Y chromosome carries thecritical determinants of maleness. How-ever, it carries little else, having lostmost of its genetic content during mam-malian evolution. Whereas more thana thousand genes reside on the X chro-mosome (X-linked genes), the Y chro-mosome carries very few functionalgenes (probably �100) and lacks work-ing copies of most of the X-linkedgenes.1 It is likely that many of the sexdifferences in disease manifestations areattributable to the sex differences in thenumber of X chromosomes. Having

Author Affiliations: The McKusick-Nathans Instituteof Genetic Medicine and Department of Pediatrics,Johns Hopkins University School of Medicine, Balti-more, Md.Corresponding Author: Barbara R. Migeon, MD, TheMcKusick-Nathans Institute of Genetic Medicine, 459Broadway Research Bldg, 733 N Broadway, Balti-more, MD 21205 ([email protected]).

Sex-specific manifestations of disease are most often attributed to differ-ences in the reproductive apparatus or in life experiences. However, a gooddeal of sex differences in health issues have their origins in the genes on thesex chromosomes themselves and in X inactivation—the developmental pro-gram that equalizes their expression in males and females. Most females aremosaics, having a mixture of cells expressing either their mother’s or father’sX-linked genes. Often, cell mosaicism is advantageous, ameliorating the del-eterious effects of X-linked mutations and contributing to physiological di-versity. As a consequence, most X-linked mutations produce male-only dis-eases. Yet, in some cases the dynamic interactions between cells in mosaicfemales lead to female-specific disease manifestations.JAMA. 2006;295:1428-1433 www.jama.com

1428 JAMA, March 22/29, 2006—Vol 295, No. 12 (Reprinted) ©2006 American Medical Association. All rights reserved.

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only 1 copy of X-linked genes (1 al-lele) makes males more vulnerable todeleterious mutations that adverselyaffect the function encoded by thesegenes, certainly more vulnerable thanfemales with 2 copies (2 alleles). If hismutated allele is defective, a male can-not perform the function encoded bythat gene. Yet the same mutated alleleis usually less deleterious to a female,because she has a normal functioningcopy (on the other X chromosome).This is why so many male-only dis-eases are attributable to defective geneson the X chromosome.

Among the proteins encoded by theX chromosome are antibodies that pro-tect against infections. A deficiency ofthese proteins causes many X-linkedimmunological diseases (for example,Bruton agammaglobulinemia andWiskott-Aldrich syndrome) (TABLE 2).2

Clearly, mutations that compromise thefunction of such proteins contribute tothe sex differences in the incidence ofsepticemia and meningitis of the new-born.3,4 Males, with only 1 allele, arecompromised more than females, whoare protected by their second copy ofthe gene. Although mutations leadingto a severe antibody deficiency may notpermit survival past childhood, less le-thal reductions in the immunoglobu-lin levels could increase susceptibilityto bacterial infections in adults.

Immunodeficiencies are not the onlycause of male vulnerability. Single mu-tations in many of the 1100 X-linkedgenes can generate a deficiency of a hostof essential proteins in males. For manyof the eclectic group of disorders causedby X-linked mutations (some shown inTable 2), males usually have a more se-vere form of the disease than females.Males in constrast with females mani-fest full-blown Duchenne muscular dys-trophy, hemophilia, and Lesch-Nyhan syndrome, and they die in uteroor in early infancy of hyperammone-mia (ornithine transcarbamylase defi-ciency) and incontinentia pigmenti. Incontrast, females with the same mu-tant alleles may have no recognizableclinical abnormalities (like most fe-males who carry Lesch-Nyhan syn-

drome or Duchenne mutations). Alter-natively, females may have mildersymptoms than their male relatives (likefemale carriers of ornithine transcar-bamylase deficiency and incontinen-tia pigmenti). This female advantage isdue to their having a normal copy ofthe gene, along with the mutated copy.

The opportunity to carry 2 alleles atthe same locus provides an advantagefor females, even though both alleles donot function in the same cell. In fact,like males, females effectively have asingle X chromosome as they have only1 working copy of a gene in each of theircells. Because of X inactivation—themechanism that equalizes the sex dif-ferences in numbers of X chromo-somes—the number of working X chro-mosomes in normal females is reducedfrom 2 to 1 during embryogenesis.5,6

Yet, having only a single functional Xchromosome in each cell has differentimplications for the health of males andfemales, because normally only fe-males are mosaics.

Females Are MosaicsFemales are mosaics because X inacti-vation creates 2 populations of cells dif-fering in the parental origin of the ac-tive X (discussed in Migeon6). As theactive X is usually chosen randomly,either chromosome has a chance to bethe working X. Therefore, a female hasa mixture of cells in all her tissues, somecells expressing the alleles on the X in-herited from her mother, the other cellsexpressing the paternal alleles. The ra-tio of one cell population to the othermay differ among individuals, and evenamong tissues of the same individual,due to stochastic events or rare muta-tions affecting the choice process.7,8

However, most females are in fact mo-saics, at least during early embryogen-esis when X inactivation occurs.

For the human female, cellular mo-saicism is not an abstract concept. Be-cause many X-linked genes have mul-tiple alleles, the alleles on a female’s 2X chromosomes are likely to differ.When a deleterious mutation in 1 al-lele disables the cells expressing it, fe-males have normal cells to perform the

compromised function. Although thedistribution of the 2 cell populationsand intermingling of these cells mayvary, the mosaic patches are smallenough so that a female usually has agreater variety of gene products in allher tissues than a male does. The bot-tom line is that although females haveonly a single working set of X-linkedgenes in each cell, they have a backupcopy in reserve.

Sharing Gene Productsby Metabolic CooperationAlthough the 2 clonal cell populationsappear discrete, cells interact with eachother in myriad ways. Such interac-tions usually foster a kind of meta-bolic cooperation between them.9,10 Be-cause of metabolic cooperation, womenwith 1 copy of the mutant allele that isharmful or even lethal for their sons of-ten show no deleterious effects. Theirnormal cells may provide enough of theessential gene product to correct the de-fect in the mutant cells, or at leastenough to circumvent the lethality ofthe mutation. Cell-to-cell transfer ofgene products masks the genotype, be-cause the mutant cells are not really de-ficient. This occurs in the X-linked ly-sosomal diseases like Hunter and Fabrysyndromes caused by the deficiency oflysosomal enzymes involved in the me-tabolism of large intracellular pro-teins11,12 (Table 2). Such enzymes freelyenter and exit the lysosomes, the siteof their digestive activity, and are trans-ferred from one cell to another by man-

Table 1. Sex Ratios for Mortality at VariousAges in the United States for 1998*

Age, y Males/Females

0-1 1.25/11-4 1.25/15-14 1.51/1

15-24 2.87/125-34 2.20/135-44 1.80/145-54 1.68/155-64 1.50/165-74 1.30/175-84 0.96/1�85 0.48/1

*Data from Demographic Tables 1998 United Nations,Table 19. Available at: http://unstats.un.org/unsd/demographic/products/dyb/dybnat.htm. AccessedJanuary 10, 2005.

X INACTIVATION, CELLULAR MOSAICISM, AND WOMEN’S HEALTH

©2006 American Medical Association. All rights reserved. (Reprinted) JAMA, March 22/29, 2006—Vol 295, No. 12 1429


nose-6-phosphate–mediated endocy-tosis. When the enzyme is deficient, theundigested products accumulate andplug up or otherwise disrupt the nor-mal function of the lysosomes. Iduro-nate sulfatase, the enzyme defective inHunter syndrome, is synthesized insome cells of carrier females but not inothers. The cells that make and se-crete this enzyme transfer it to the cellsthat cannot; in this way, the defect inthe mutant cells is corrected. This trans-fer also occurs in carriers of Fabry dis-ease, but because �-galactosidase A isa lower-uptake enzyme, it is trans-ferred less efficiently than iduronate sul-fatase. As a consequence, Fabry het-erozygotes may manifest some of thedeleterious effects of this mutation; eventhen, their disease is usually muchmilder than that of affected males.12

Metabolic cooperation also occurs inmany tissues of Lesch-Nyhan hetero-

zygotes, who benefit from the transferof small nucleotides from normal tomutant cells via gap junctions9,10

(Table 2).

Cellular InterferenceNot all interactions are favorable to fe-males. Sometimes the products in cellsexpressing the mutant allele interferewith the function of the cells express-ing the normal allele. This kind of in-teraction occurs in the craniofrontona-sal syndrome, a developmental disorderthat leads to premature fusion of thecoronal suture of the skull.13 During em-bryonic development, cells in one lin-eage may induce function in another lin-eage or may actually repel the physicalmovement of the other. This happens inthe development of the skull, where thegrowth of bones must be constrained insome way so that they do not prema-turely fuse with one another, constrict-

ing the growth of the brain. Craniofron-tonasal syndrome is caused by adeficiency of ephrin B1 (EPNB1), an Xchromosome–encoded member of theephrin family of transmembrane pro-teins, which are very important signal-ing molecules in many developmentalprocesses.13 The role of EPNB1 is to de-fine the position of the coronal sutureof the skull, and it is thought that thisis done by inhibiting cells from cross-ing the normally sharp neural crest-mesoderm tissue boundary.

Paradoxically, EPNB1 mutations pro-duce more severe defects in heterozy-gous females than in hemizygousmales.13 Males have few, if any, abnor-malities in contrast with the carrier fe-males who have full-blown craniosyn-ostosis and other cranial abnormalities(Table 2). Why do mutations in EFNB1produce cranial abnormalities only infemales? The prevailing thought is that

Table 2. Sex Differences in Clinical Manifestations of Diseases Due to Mutations in a Single X-Linked Allele

DiseaseOMIM Reference

Number*Mutated

Gene Males Females

Adrenoleukodystrophy 300100 ABCD1/ALD Early onset of lethal cerebraldemyelinization

OrLate onset of spastic paraplegia and

peripheral neuropathy

AsymptomaticOrLate-onset spastic paraplegia and

peripheral neuropathy(adrenomyeloneuropathy)

Bruton (X-linked)agammaglobulinemia

300300 BTK Severe immunodeficiency, absence of allmature B cells

Usually unaffected, absence ofmutant B cells

Craniofrontonasal syndrome 304110 EPNB1 Asymptomatic or mildly dysmorphicfacial features

Craniostenosis, hypertelorism,severe facial asymmetry

Duchenne muscular dystrophy 310200 DMD Gradual destruction of muscles anddeath in teenagers

Usually unaffected

Fabry disease 301500 �GLA Episodic pain, renal and heart failure,premature death

Milder disease, if any

Fragile X syndrome 309550 FMR1 Severe mental retardation Usually normal or mild retardation

Glucose-6-phosphatedehydrogenase deficiency

305900 G6PD Severe hemolytic anemia Usually unaffected

Hemophilia 306700 F8 Bruising, prolonged bleeding withtrauma, hemorrhage into joints

Usually unaffected

Hunter syndrome 309900 IS Dwarfing, abnormal bones, mentalretardation

Usually unaffected

Incontinentia pigmenti 308300 IP (Nemo) Usually death in utero Abnormalities of skin, hair, teeth

Lesch-Nyhan syndrome 300322 HPRT Gout, cerebral palsy, mental retardation,self-mutilation

Usually unaffected

Otopalatodigital syndrome 300017 FLN A Severe skeletal osteodysplasia, often diein utero or stillborn

Mild-severe skeletal dysplasia

Ornithine transcarbamylasedeficiency

311250 OTC Usually death from hyperammonemia ininfancy

Usually mild or moderatehyperammonemia

Rett syndrome 312750 MeCP2 Usually death in utero Autism, ataxia, and progressivedementia

Wiskott-Aldrich syndrome 301000 WAS Severe immunodeficiency; no T cells andplatelets

Usually unaffected

Abbreviation: OMIM, Online Mendelian Inheritance in Man.*For details about the clinical manifestations and molecular basis of the diseases discussed, consult the reference number for each disease in the OMIM database.2




the mixture of mutant and normal cellsin some way perturbs the signaling pro-cess required for the formation of thefuture coronal suture and, as a conse-quence of faulty signaling, the bonesprematurely fuse. To explain why maleswith the mutation are so minimally af-fected, it has been suggested that otherfunctionally redundant members of theephrin family substitute for EFNB1 incompletely deficient cells, but cannotdo so in the female because of the ad-mixture of mutant and wild-type cells.Although relatively rare, cellular inter-ference of this kind may cause prob-lems in females that are not observedin hemizygous males. Craniofrontona-sal syndrome might be considered a fe-male-only disorder because of the sexdifferences in pathogenesis and clini-cal manifestations.

Cell Competition and SkewingSome X-linked mutations adverselyaffect the growth of cells, impeding theirability to utilize nutrients, or respondto growth signals. The presence of 2kinds of cells, differing in their prolif-erative capacities, sets up a competi-tion between them.7 Therefore, an-other interaction between the cellpopulations in the mosaic female isgrowth competition. The cells that re-produce faster will eventually out-grow the others; even small differ-ences in growth rate have an effect. Cellsexpressing mutant alleles that inter-fere with proliferation are likely to beeliminated in time by overgrowth of thecells expressing the normal allele. Therate of elimination can be rapid (eg, thedeath of mutant cells in incontinentiapigmenti or the failure of mutant T cellsto migrate to the marrow in Wiskott-Aldrich syndrome) or mutant cells canbe lost gradually (eg, the enzyme-deficient blood cells in Lesch-Nyhansyndrome).7

The elimination of mutant cells leadsto what is called unbalanced or skewedX inactivation. Approximately 10% offemales have skewing such that greaterthan 95% of their cells express the sameparental allele. The cells that are lost areoften mutant, but even normal cells may

be lost for stochastic reasons. Thisskewing may have no clinical signifi-cance for some of these females, as thereare no clinically relevant mutationsbeing expressed, or they may be maskedon the inactive X. However, in somecases the skewing, no matter its cause,will influence the expression of a ge-netic disease.

The Effect of Skewingon Clinical PhenotypeSkewing that favors the normal allelemay be caused by death or failure ofmutant cells to migrate to appropriatetissues and is associated with no clini-cal abnormalities. When mutant cellshave no proliferative disadvantage,clinical manifestations may occur if hav-ing only 50% normal cells is not suffi-cient, as in ornithine transcarbamy-lase deficiency or Rett syndromes(Table 2). In any case, the severity ofclinical symptoms in any X-linked het-erozygote will be influenced by skew-ing, no matter which allele is favoredor the cause of the skewing. Skewingthat favors the mutant gene will in-crease the manifestations, whereasskewing favoring the normal allele willdecrease the likelihood of symptoms.

Sex-Specific DiseasesIn some females, 1 mutant allele isenough to produce clinical symp-toms; however, their disease will be lesssevere than in males. For example, ifthe mutation is lethal to males in utero,females may have some clinical mani-festations. However, they were pro-tected against death in utero by theirnormal copy of the gene (Table 2).Clearly, these sex-specific diseases arean outgrowth of the sex difference innumbers of X chromosomes. Inconti-nentia pigmenti and Rett syndrome arefemale-only diseases because the dis-ease in males is usually lethal in uteroor has different manifestations. Suchdisorders are often thought to affectonly 1 sex, because the sex differencesin expression of X-linked mutations isnot always recognized. The practice ofdefining disorders by their syndromicphenotypes has proven to be enor-

mously misleading as to the cause of thedisease. The otopalatodigital syn-drome group of bone malformationswas considered as 4 independent X-linked diseases until the filamin A genewas shown to be mutant in all of them14

(Table 2). The manifestations differ ac-cording to the site in the gene that ismutated and the sex of the individualin whom it occurs. Rett syndrome wasthought to affect only females untilidentification of the methyl CpG pro-tein 2 gene (MeCP2) showed that thesame mutation had different manifes-tations in males. In fact, for most X-linked disorders, females and maleshave their own form of the disease,based on the presence or absence of cel-lular mosaicism.

Mosaicism itself contributes to dis-ease heterogeneity among females. Ifand how they manifest a disorder de-pends on the makeup of the mosaic cellpopulations and the nature of all theother alleles on their active X chromo-somes. The composition of the mosa-icism is determined initially by the ran-dom choice of active X during earlyembryogenesis.6 Only after X inactiva-tion creates the cellular mosaicism doesthe influence of all the alleles on the 2X chromosomes come into play. The ul-timate composition of the mosaic cellpopulations is determined by the dy-namic interaction between genes on the2 X chromosomes. The 2 populationsof cells, each one commandeered by adifferent active X chromosome, takepart in a virtual competition for pre-dominance. In most females, the re-sult of the competition ends in a deadheat, one gene canceling out any mi-nor selective advantage of another andboth populations are fairly equally rep-resented in every one of their tissues.

In a number of females, the result ofthe competition produces a winner andone cell population becomes preemi-nent in the tissues in which the moreinfluential genes are expressed. In mostcases, the cellular selection mecha-nism weeds out the weaker cells.Whether or not cell selection occurs isdetermined by multiple factors. Somefactors have to do with the nature of the




mutation, such as the amount of pro-tein remaining in the mutant cells.Other factors include the ability of thegene product to be transferred fromwild-type to mutant cells, and the de-gree to which it affects cell prolifera-tion. Skewing is most apparent whenthe product of the mutant gene is non-transferable and has a strong influ-ence on cell proliferation. In addition,other genes can affect the result; eventhe strong influence of mutant allelesat one X-linked locus can be modifiedby those at another. Therefore, the out-come of the competition between the2 cell populations may differ from onetissue to another, depending on expres-sion patterns of relevant genes.

Females ManifestingMale-Only DiseasesSome females lose the biological ad-vantage. Occasionally, the mutationconfers a proliferative advantage ratherthan disadvantage and leads to cell se-lection favoring the mutant allele. Be-cause skewing favors their mutant cells,many heterozygotes for adrenoleuko-dystrophy (Table 2) manifest the dis-ease known as adrenomyeloneuropa-thy, a milder disorder that affects thespinal cord rather than the brain.15,16 Ifthe competition between cell popula-tions favors the mutant cells, femalesmay manifest diseases that are usuallyobserved only in males.17 Such fe-males are termed manifesting heterozy-gotes because they express the male ver-sion of the disease despite having only1 copy of the mutation. Other causesof manifesting heterozygotes includethe nature of the chromosome on whichthe mutation resides. In some fe-males, chromosome abnormalities in-volving the X chromosome eliminatethe cellular mosaicism and unmask mu-tant alleles on the X chromosome,which is consistently active, or masknormal alleles that are never ex-pressed.18 In rare cases, females are notmosaic because of mutations affectingthe initial process that chooses the ac-tive X chromosome; one parental chro-mosome had an edge over the other.19,20

Furthermore, some monozygotic twins

are prone to extreme skewing.21,22

Clearly, there are many determinantsof a female’s X-linked phenotype. Al-though mosaicism affords a signifi-cant biological advantage, the out-come is never certain. It depends onmany dynamic interactions that are in-fluenced by chance events as well as thevariations in the normal blueprint fordevelopment.

The Effect of X Inactivationon Non–X-Linked DiseasesUp to now the effect of the single ac-tive X and cellular mosaicism on themanifestations of X-linked diseases hasbeen considered. However, the influ-ence of X inactivation is not limited tothe X chromosome, as any disease pro-cess with an X-linked component mightbe influenced by patterns of X inacti-vation and this possibility should beconsidered for any disorder that oc-curs more frequently in one sex thanthe other, or has different manifesta-tions in one sex than the other.

Autoimmune DiseasesOne class of diseases that is muchmore prevalent in females than malesis autoimmune disease. These includearthritis and thyroiditis in which anti-bodies to the relevant tissues arefound in the blood of the affected indi-viduals. Whereas, type 1 diabetesmellitus is the only major organ-specific autoimmune disorder not toshow a strong female bias, diseaseslike thryroiditis, systemic lupus ery-thematosus, and scleroderma show 3-to 10-fold more affected females. Forexample, females comprise 90% ofthose individuals who develop sys-temic lupus erythematosus. Althoughthe female prevalence is often attrib-uted to the effect of estrogen, Stewart23

pointed out that other sex differencesmight have as much or more relevanceto autoimmune disease, for example,X inactivation.

A unique feature of autoimmune dis-orders is the apparent loss of immuno-logical tolerance to self-antigens. Infemales, the self-proteins expressed andpresented for tolerization differ in the 2

cell populations. Because this mosa-icismisalsopresent in the tolerizingcellsof the thymus, the sampling processinvolved in recognizing self might missthe antigens on one of the parental Xchromosomes.Theprobability thataself-antigen encoded by the X chromosomemight elude the recognition processwouldbe increased ifX inactivationwerehighly skewed, such that one of theparental X chromosomes was expressedin relatively few cells. The more extremethe skewin thymiccells (specifically, thedendritic cells that present antigen), themore likely it is that antigens will evadethe tolerizing process.

Recent studies lend support to thisconjecture. Scleroderma is an autoim-mune disease of connective tissuewhose etiology is unknown and notthought to be X-linked, or even to havea strong genetic component. There-fore, it is surprising that nearly half ofa group of 55 females with sclero-derma have extremely skewed X inac-tivation in their blood cells.24 It is likelythat scleroderma is the consequenceand not the cause of the skewing. Ifskewing occurs for stochastic or otherreasons, the chance is increased for an-tigens expressed on the minor popula-tion of cells to escape recognition. Onewould not expect all affected individu-als to show skewing, as it is likely thatthere are other risk factors for this dis-ease. Also, evidence is accumulatingthat a third or more of individuals withthe kind of thyroid disease associatedwith thyroid antibodies show skewedpatterns of inactivation.25,26 On the otherhand, in the scleroderma study, skew-ing in blood cells was not observed inindividuals with rheumatoid arthritis,so this may not be a factor in all auto-immune diseases.

Role of Cell Mosaicismin HealthMost of our knowledge of human bi-ology has been acquired by viewing itthrough the window of disease or del-eterious mutations. However, it is likelythat the contribution of cellular mosa-icism to sex differences is not limitedto disease. Studies of educational per-




formance show that from the first daysof school, girls outperform boys, aremore attentive, and are more persis-tent at tasks.27 Recent studies haveshown that sex affects the way a per-son’s brain responds to humor.28 It doesnot seem far-fetched to think that cel-lular mosaicism may have a role in someof these sex differences in behavior.Even in absence of disease alleles, a fe-male is a composite of 2 interminglingcell populations that are sharing geneproducts with one another. Clearly, mo-saicism based on X inactivation has thepotential to generate cellular diversityfor many physiological processes. Basedon observations of color vision, Small-wood et al29 pointed out that cellulardiversity is advantageous as a generalstrategy for enhancing the efficiency ofsignal processing and transmission. Forexample, in new world monkeys, thesingle X-linked pigment gene has 3 al-leles, each encoding a pigment with adifferent spectral sensitivity. Males and

homozygous females have dichro-matic color vision, whereas heterozy-gous females have trichromatic color vi-sion, and this is associated withenhanced chromatic discrimination.29

Just as the ability to express a varietyof normal color vision alleles en-hances the way that color is per-ceived, having cells that collaborate onthe elaboration of a protein may resultin novel molecules, and such mol-ecules may enhance the function beingperformed. The diversity provided byexpressing 2 different alleles simulta-neously, yet in different cells, is cer-tain to lead to novel effects.

In conclusion, many sex-specificmanifestations of disease are the con-sequence of both sexes having a singleworking X chromosome. Mutations ofan X-linked gene in males leads to male-only diseases, because they have onlythe defective copy of the gene, whereasfemales have a normal copy in re-serve. Mosaicism for the X chromo-

some proteome plays a large role in de-termining a female’s disease response.Most often, mosaicism is advanta-geous, mediating transfer of essentialgene products from normal to mutantcells, or elimination of deleterious cells.Some females will completely avoidclinical manifestations. Other femalesmust pay some price for surviving ges-tation. For this reason, males and fe-males have their own unique manifes-tations of identical mutations, and thefemale-only diseases are most often lesssevere than their male counterparts. Oc-casionally, however, females may mani-fest male-only diseases, either becauseloss of the mosaicism exposes delete-rious genes or because the interac-tions have harmful effects. In addi-tion, cellular mosaicism contributes tophysiological diversity, because it pro-vides an increased repertoire of ex-pressed X-linked genes.

Financial Disclosures: None reported.

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the role of x inactivation and cellular mosaicism in women's health and sex-specific diseases

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