Aberrant chromosomal sex-determining mechanisms in mammals, with special reference to species with XY females

Both mouse and man have the common XX/XY sex chromosome mechanism. The X chromosome is of original size (5-6% of female haploid set) and the Y is one of the smallest chromosomes of the complement. But there are species, belonging to a variety of orders, with composite sex chromosomes and multiple sex chromosome systems: XX/XY1Y2 and X1X1X2X2/X1X2Y. The original X or the Y, respectively, have been translocated on to an autosome. The sex chromosomes of these species segregate regularly at meiosis; two kinds of sperm and one kind of egg are produced and the sex ratio is the normal 1:1. Individuals with deviating sex chromosome constitutions (XXY, XYY, XO or XXX) have been found in at least 16 mammalian species other than man. The phenotypic manifestations of these deviating constitutions are briefly discussed. In the dog, pig, goat and mouse exceptional XX males and in the horse XY females attract attention. Certain rodents have complicated mechanisms for sex determination: Ellobius lutescens and Tokudaia osimensis have XO males and females. Both sexes of Microtus oregoni are gonosomic mosaics (male OY/XY, female XX/XO). The wood lemming, Myopus schisticolor, the collared lemming, Dirostonyx torquatus, and perhaps also one or two species of the genus Akodon have XX and XY females and XY males. The XX, X*X and X*Y females of Myopus and Dicrostonyx are discussed in some detail. The wood lemming has proved to be a favourable natural model for studies in sex determination, because a large variety of sex chromosome aneuploids are born relatively frequently. The dosage model for sex determination is not supported by the wood lemming data. For male development, genes on both the X and the Y chromosomes are necessary.     

Cytological identification of two X-chromosome types in the wood lemming (Myopus schisticolor)

In the wood lemming (Myopus schisticolor) three genetic types of sex chromosome constitution in females are postulated: XX, X^*X and X^*Y (X^*=X with a mutation inactivating the male determining effect of the Y chromosome). Males are all XY. It is shown in the present paper that the two types of X chromosomes, X and X^*, exhibit differences in the G-band patterns of their short arms. In addition, it was demonstrated in unbanded chromosomes that the short arm in X^* is shorter than in X. The origin of these differences is still obscure; but they allow to identify and to distinguish the individual types of sex chromosome constitution, as of XX versus X^*X females and of X^*Y females versus XY males, on the basis of G-banded chromosome preparations from somatic cells.     

Characterization of the Xp21-23 region in the wood lemming, a region involved in XY sex reversal.

The wood lemming (Myopus schisticolor) harbors two types of X chromosome, a normal X and a variant X, designated X*. The X* chromosome contains a mutation that causes XY sex reversal. We have previously demonstrated that the Xp21-23 region is deleted from X* and is associated with XY sex reversal. To further analyze the deleted region, we have constructed and characterized seven X chromosome- and region-specific recombinant DNA libraries. Further, we have screened mouse fetal gonad cDNA libraries with the microdissected Xp21-23 DNA as a probe in an attempt to identify homologous and expressed sequences from the deletion. Fourteen positive clones were isolated, and sequence analyses showed that ten of these contained identical sequences homologous to mouse gamma-satellite sequences. One of the remaining four was perfectly homologous to the mouse gene Ccth (chaperonin containing t-complex polypeptide 1, eta subunit). Southern blot indicated that the Ccth cDNA was located on the X chromosome, not deleted from the X* but closely linked to the deletion region. Although the role of the Ccth containing region in sex determination of the wood lemming requires additional studies, the isolation of the mouse Ccth gene by the deletion Xp21-23 probe could be important since this gene is mainly expressed in testis.     

Meiotic behavior of gonosomically variant females of Akodon azarae (Rodentia, Cricetidae)

The meiotic behavior of sex chromosomes has been investigated in variant females of Akodon azarae, both in pachytene oocytes and metaphase I. In somatic cells, these females have a heteromorphic sex pair, in which the minor chromosome has been previously interpreted as a major deletion of the long arm of the X chromosome (dX). After microspreading for synaptonemal complex analysis, pachytene oocytes show two axes of very different lengths (100:17.1), which correspond to the sex chromosomes X and dX. True synapsis is abnormally restricted (43.3%) between these sex chromosomes; on the other hand, self-synapsis of both the X and dX chromosomes is frequent (60%). Single, nonsynapsed axes or axial segments are thickened. Strong chromatin condensation occurs around nonsynapsed axes or axial segments, giving many of these sex pairs an appearance similar to an XY body ("sex vesicle"). The minor gonosome axis differs from that of the Y chromosome of male meiosis, as the former is shorter (relative to the X) and has a different synaptic behavior. In 17 metaphases I from XdX variant females, only heteromorphic, end-to-end joined sex pairs were observed. These variant females differ from the variant females of the wood lemming Myopus schisticolor in several respects, but a similar mechanism seems to be prevalent in other species of the genus Akodon. Self-synapsis of unequal gonosomes in oocytes is assumed as an escape from functional deterioration, following the hypothesis put forward by others.     

Why females are mosaics,x-chromosome inactivation,and sex differences in disease

At every age, males have a higher risk of mortality than do females. This sex difference is most often attributed to the usual suspects: differences in hormones and life experiences. However, the fact that XY males have only one X chromosome undoubtedly contributes to this vulnerability, as any mutation that affects a gene on their X chromosome will affect their only copy of that gene. On the other hand, cellular mosaicism created by X inactivation provides a biologic advantage to females. There are 1100 genes on the X chromosome, and most of them are not expressed from the Y chromosome. Therefore, sex differences in the expression of these genes are likely to underlie many sex differences in the expression of diseases affected by these genes. In fact, this genetic biology should be considered for any disease or phenotype that occurs in one sex more than the other, because the disease mechanism may be influenced directly by an X-linked gene or indirectly through the consequences of X inactivation.     

X-linked genes of the H-Y antigen system in the wood lemming (Myopus schisticolor)

Summary H-Y antigen was investigated in 18 specimens representing six different sex chromosome constitutions of the wood lemming (Myopus schisticolor). The control range of H-Y antigen was defined by the sex difference between normal XX females (H-Y negativeper definitionem) and normal XY males (H-Y positive, full titer). H-Y antigen titers of the X^*Y and X^*0 females were in the male control range, while in the X^*X and X0 females the titers were intermediary. Data were obtained with two different H-Y antigen assays: the Raji cell cytotoxicity test and the peroxidase-antiperoxidase (PAP) method. Fibroblasts, gonadal cells, and spleen cells were checked. Presence of full titers of H-Y antigen in the absence of testis differentiation is readily explained by the assumption of a deficiency of the gonadspecific receptor of H-Y antigen. Since sex reversal is inherited as an X-linked trait, genes for this receptor are most likely X-linked. The implications of our findings are discussed in connection with earlier findings concerning H-Y antigen in XY gonadal dysgenesis in man and the X0 situation in man and mouse.     

Sex-chromosome aberrations in wood lemmings (Myopus schisticolor)

The wood lemming displays certain peculiar features: (1) The sex ratio shows a prevalence of females (FRANK, 1966; KALELA and OKSALA, 1966), and some females produce only female offspring (KALELA and OKSALA, 1966). (2) In a considerable proportion (in the present material, slightly less than half) of the females, an XY chromosome complement is found in the somatic tissues, but the Y is absent in the germ line of those studied (Fredga et al., 1976). Therefore, (3) a mechanism of double nondisjunction in early fetal life of XY females has to be postulated, which replaces the Y in the germ line by duplication of the X. It is assumed (4) that the X of XY females bears a sex-reversal factor that affects the male determining action of the Y (Fredga et al., 1977). There is (5) a strong presumption that in most cases the XY females are those that produce daughters only, but (6) a few exceptions may occur (FRANK, unpublished observations), suggesting that the regulation according to assumption 3 (perhaps also to 4) is incomplete in XY females. In the present report, four females are described with a 31,XO karyotype, two females with 33,XYY or 32,XY/33,XYY, respectively, two males with a 33,XXY, and one male with a 32,XX/33,XXY karyotype, as observed in a consecutive series of 502 wood lemmings. The incidence of sex-chromosome anomalies in liveborn and adult animals was 2.3%; the overall incidence, including embryos, was 1.79%. Neither the somatic XO constitution nor the existence of an extra Y in females precludes fertility. However, the XXY condition in the male results in sterility. There is certain evidence that an instability of the proposed mechanism for double mitotic nondisjunction of the sex chromosomes in oogonia accounts for the high rate of sex-chromosome aberrations in wood lemmings, at least when the mother is XY.     

Defining regions and rearrangements of the Silene latifolia Y chromosome

We combine data from published marker genotyping of three sets of S. latifolia Y chromosome deletion mutants with changed sex phenotypes and add genotypes for several new genic markers to refine the deletion map of the Y chromosome and compare it with the X chromosome genetic map. We conclude that the Y chromosome of this species has been derived through multiple rearrangements of the ancestral gene arrangement and that none of the rearrangements so far detected was involved in stopping X-Y recombination. Different Y genotypes may also differ in their gene content and possibly arrangements, suggesting that mapping the Y-linked sex-determining genes will be difficult, even if many further genic markers are obtained. Even in determining the map of Y chromosome markers to discover all the rearrangements, physical mapping by FISH or other experiments will be essential. Future deletion mapping work should ensure that markers are studied in the parents of deletion mutants and should probably include additional deletions that were not ascertained by causing mutant sex phenotypes.     

THE CONTRIBUTION OF GENE MOVEMENT TO THE “TWO RULES OF SPECIATION”

The two “rules of speciation”—the Large X‐effect and Haldane's rule—hold throughout the animal kingdom, but the underlying genetic mechanisms that cause them are still unclear. Two predominant explanations—the “dominance theory” and faster male evolution—both have some empirical support, suggesting that the genetic basis of these rules is likely multifarious. We revisit one historical explanation for these rules, based on dysfunctional genetic interactions involving genes recently moved between chromosomes. We suggest that gene movement specifically off or onto the X chromosome is another mechanism that could contribute to the two rules, especially as X chromosome movements can be subject to unique sex‐specific and sex chromosome specific consequences in hybrids. Our hypothesis is supported by patterns emerging from comparative genomic data, including a strong bias in interchromosomal gene movements involving the X and an overrepresentation of male reproductive functions among chromosomally relocated genes. In addition, our model indicates that the contribution of gene movement to the two rules in any specific group will depend upon key developmental and reproductive parameters that are taxon specific. We provide several testable predictions that can be used to assess the importance of gene movement as a contributor to these rules in the future.     

Sex determination and phenotype in wood lemmings with XXY and related karyotypic anomalies

Summary The wood lemming, Myopus schisticolor, possesses a unique sex determining system comprising both XX and XY females. Normal female development in the presence of XY is guaranteed by a mutation on the X, apparently associated with a structural rearrangement in Xp. This mutation inactivates the testis-inducing and male-determining factor on the Y and distinguishes X^* from X, and X^*Y females from XY males. Normal fertility of X^*Y females is ensured by a mitotic (double) nondisjunction mechanism which, at an early fetal stage, eliminates the Y from the germ line and replaces it by a copy of the X^*.Numerical sex chromosome aberrations are not infrequent and the trisomics XXY and X^*XY are relatively common. XXY individuals are sterile males with severe suppression of spermatogenesis. Among X^*XY animals, both males and females, as well as a true lateral hermaphrodite have been observed. Primary deficiency of germ cells, impairment of spermatogenesis and sterility are characteristic traits of the X^*XY males, whereas X^*XY females have normal oogenesis and are fertile. Both these extremes (except female fertility) coexist in the true hermaphrodite described in the present study. These apparently contradictory observations are explainable under the assumption that X^* and X in X^*XY individuals are inactivated non-randomly or that the cells are distributed unequally. Inactivation of the X or X^* determines whether or not the H-Y antigen will be expressed. When comparing conditions in Myopus and in man, an additional assumption has to be made in relation to the gene(s) involved in sex determination, located in Xp:In Myopus they do not escape inactivation, whereas in man they have been claimed to remain active.     

Recombination is suppressed over a large region of the rainbow trout Y chromosome

The previous genetic mapping data have suggested that most of the rainbow trout sex chromosome pair is pseudoautosomal, with very small X-specific and Y-specific regions. We have prepared an updated genetic and cytogenetic map of the male rainbow trout sex linkage group. Selected sex-linked markers spanning the X chromosome of the female genetic map have been mapped cytogenetically in normal males and genetically in crosses between the OSU female clonal line and four different male clonal lines as well as in outcrosses involving outbred OSU and hybrids between the OSU line and the male clonal lines. The cytogenetic maps of the X and Y chromosomes were very similar to the female genetic map for the X chromosome. Five markers on the male maps are genetically very close to the sex determination locus ( SEX ), but more widely spaced on the female genetic map and on the cytogenetic map, indicating a large region of suppressed recombination on the Y chromosome surrounding the SEX locus. The male map is greatly extended at the telomere. A BAC clone containing the SCAR (sequence characterized amplified region) Omy - 163 marker, which maps close to SEX , was subjected to shotgun sequencing. Two carbonyl reductase genes and a gene homologous to the vertebrate skeletal ryanodine receptor were identified. Carbonyl reductase is a key enzyme involved in production of trout ovarian maturation hormone. This brings the number of type I genes mapped to the sex chromosome to six and has allowed us to identify a region on zebrafish chromosome 10 and medaka chromosome 13 which may be homologous to the distal portion of the long arm of the rainbow trout Y chromosome.     

Testis-determining H-Y antigen in XO males of the mole-vole (Ellobius lutescens)

The XO sex chromosome constitution has been found in both sexes of the mole-vole (Ellobius lutescens) belonging to the rodent family Microtinae. This enigmatic species has apparently been enduring a 50% zygotic lethality. The current serological study revealed the presence in XO males and the absence from XO females of H-Y (histocompatibility Y) antigen. In all the mammalian species studied thus far, the expression of H-Y antigen strictly coincided with the presence of testicular tissue and not necessarily with the presence of the Y chromosome. The testis-organizing function of the H-Y gene appears to have been confirmed.In the mole-vole, X linkage of the testis-organizing H-Y gene is favored over its autosomal inheritance. Only X linkage of the H-Y gene creates a compelling evolutionary need to change the female sex chromosome constitution from XX to XO, and to abandon the dosage compensation by an X inactivation mechanism, so that the nonproductive X^H-YX zygote can be eliminated as an embryonic lethal. With regard to the electrophoretic mobilities of three X-linked marker enzymes, however, a genetic difference between the male-specific X^H-Y and the female-specific X was not detected. This might reflect a relatively recent speciation.     

Dynamic gene order on the <Emphasis Type="Italic">Silene latifolia</Emphasis> Y chromosome

Dioecious Silene latifolia evolved heteromorphic sex chromosomes within the last ten million years, making it a species of choice for studies of the early stages of sex chromosome evolution in plants. About a dozen genes have been isolated from its sex chromosomes and basic genetic and deletion maps exist for the X and Y chromosomes. However, discrepancies between Y chromosome maps led to the proposal that individual Y chromosomes may differ in gene order. Here, we use an alternative approach, with fluorescence in situ hybridization (FISH), to locate individual genes on S. latifolia sex chromosomes. We demonstrate that gene order on the Y chromosome differs between plants from two populations. We suggest that dynamic gene order may be a general property of Y chromosomes in species with XY systems, in view of recent work demonstrating that the gene order on the Y chromosomes of humans and chimpanzees are dramatically different.     

Differences in recombination frequencies during female and male meioses of the sex chromosomes of the medaka, Oryzias latipes

In the medaka, Oryzias latipes, sex is determined chromosomally. The sex chromosomes differ from those of mammals in that the X and Y chromosomes are highly homologous. Using backcross panels for linkage analysis, we mapped 21 sequence tagged site (STS) markers on the sex chromosomes (linkage group 1). The genetic map of the sex chromosome was established using male and female meioses. The genetic length of the sex chromosome was shorter in male than in female meioses. The region where male recombination is suppressed is the region close to the sex-determining gene y, while female recombination was suppressed in both the telomeric regions. The restriction in recombination does not occur uniformly on the sex chromosome, as the genetic map distances of the markers are not proportional in male and female recombination. Thus, this observation seems to support the hypothesis that the heterogeneous sex chromosomes were derived from suppression of recombination between autosomal chromosomes. In two of the markers, Yc-2 and Casp6, which were expressed sequence-tagged (EST) sites, polymorphisms of both X and Y chromosomes were detected. The alleles of the X and Y chromosomes were also detected in O. curvinotus, a species related to the medaka. These markers could be used for genotyping the sex chromosomes in the medaka and other species, and could be used in other studies on sex chromosomes.     

Mammalian sex--Origin and evolution of the Y chromosome and SRY

Sex determination in vertebrates is accomplished through a highly conserved genetic pathway. But surprisingly, the downstream events may be activated by a variety of triggers, including sex determining genes and environmental cues. Amongst species with genetic sex determination, the sex determining gene is anything but conserved, and the chromosomes that bear this master switch subscribe to special rules of evolution and function. In mammals, with a few notable exceptions, female are homogametic (XX) and males have a single X and a small, heterochromatic and gene poor Y that bears a male dominant sex determining gene SRY. The bird sex chromosome system is the converse in that females are the heterogametic sex (ZW) and males the homogametic sex (ZZ). There is no SRY in birds, and the dosage-sensitive Z-borne DMRT1 gene is a credible candidate sex determining gene. Different sex determining switches seem therefore to have evolved independently in different lineages, although the complex sex chromosomes of the platypus offer us tantalizing clues that the mammal XY system may have evolved directly from an ancient reptile ZW system. In this review we will discuss the organization and evolution of the sex chromosomes across a broad range of mammals, and speculate on how the Y chromosome, and SRY, evolved.     

Evidence for degeneration of the Y chromosome in the dioecious plant Silene latifolia

The human Y--probably because of its nonrecombining nature--has lost 97% of its genes since X and Y chromosomes started to diverge [1, 2]. There are clear signs of degeneration in the Drosophila miranda neoY chromosome (an autosome fused to the Y chromosome), with neoY genes showing faster protein evolution [3-6], accumulation of unpreferred codons [6], more insertions of transposable elements [5, 7], and lower levels of expression [8] than neoX genes. In the many other taxa with sex chromosomes, Y degeneration has hardly been studied. In plants, many genes are expressed in pollen [9], and strong pollen selection may oppose the degeneration of plant Y chromosomes [10]. Silene latifolia is a dioecious plant with young heteromorphic sex chromosomes [11, 12]. Here we test whether the S. latifolia Y chromosome is undergoing genetic degeneration by analyzing seven sex-linked genes. S. latifolia Y-linked genes tend to evolve faster at the protein level than their X-linked homologs, and they have lower expression levels. Several Y gene introns have increased in length, with evidence for transposable-element accumulation. We detect signs of degeneration in most of the Y-linked gene sequences analyzed, similar to those of animal Y-linked and neo-Y chromosome genes.     

Gonadal development and birth weight in X*X and X*Y females of the wood lemming, Myopus schisticolor

A quantitative histological analysis of ovaries from 8- to 10-day-old wood lemmings revealed significant differences between females with X*Y and X*X sex chromosome constitutions. The ovarian volume of X*Y females was on average 57% of X*X, and the number of oocytes was less than half in X*Y compared to X*X. However, the frequency of growing oocytes in relation to the total number was 6.5% for X*Y compared to 3.0% for X*X. Oogenesis in X*Y wood lemmings resembles in many respects that of mice heterozygous for certain translocations and with tertiary trisomy (Ts31H), and those with X0 monosomy. The fertility in X*Y wood lemmings is not reduced. On the contrary, X*Y females have a higher reproductive fitness than X*X and XX. This is discussed in relation to the present findings. The body weight at birth was 8% higher in X*Y than in X*X.     

Gender in plants: sex chromosomes are emerging from the fog

Although most plants have flowers with both male and female sex organs, there are several thousands of plant species where male or female flowers form on different individuals. Surprisingly, the presence of well-established sex chromosomes in these dioecious plants is rare. The best-described example is white campion, for which large sex chromosomes have been identified and mapped partially. A recent study presented a comprehensive genetic and physical mapping of the genome of dioecious papaya. It revealed a short male specific region on the Y chromosome (MSY) that does not recombine with the X chromosome, providing strong evidence that the sex chromosomes originated from a regular pair of autosomes. The primitive papaya Y chromosome thus represents an early event in sex chromosome evolution. In this article, we review the current status of plant sex-chromosome research and discuss the advantages of different dioecious models.