Comparative mapping and sequencing show that turnover of sex determining genes and chromosomes, and sex chromosome rearrangements, accompany speciation in many vertebrates. Here I review the evidence and propose that the evolution of therian mammals was precipitated by evolution of the male‐determining SRY gene, defining a novel XY sex chromosome pair, and interposing a reproductive barrier with the ancestral population of synapsid reptiles 190 million years ago (MYA). Divergence was reinforced by multiple translocations in monotreme sex chromosomes, the (...) first of which supplied a novel sex determining gene. A sex chromosome‐autosome fusion may have separated eutherians (placental mammals) from marsupials 160 MYA. Another burst of sex chromosome change and speciation is occurring in rodents, precipitated by the degradation of the Y. And although primates have a more stable Y chromosome, it may be just a matter of time before the same fate overtakes our own lineage. (shrink)

A combination of cytogenetic and molecular analyses has shown that several different transposable elements are involved in the restructuring of Drosophila chromosomes. Two kinds of elements, P and hobo, are especially prone to induce chromosome rearrangements. The mechanistic details of this process are unclear, but, at least some of the time, it seems to involve ectopic recombination between elements inserted at different chromosomal sites; the available data suggest that these ectopic recombination events are much more likely to occure between (...) elements in the same chromosome than between elements in different chromosomes. Other Drosophila transposons also appear to mediate chromosome restructuring by ectopic recombination; these include the retrotransposons BEL, roo, Docand I and the foldback element FB. In addition, two retrotransposons, HeT‐A and TART, have been found to be associated specifically with the ends of Drosophila chromosomes. Very limited data indicate that transposon‐mediated chromosome restructuring is occurring in natural populations of Drosophila. This suggests that transposable elements may help to shape the structure of the Drosophila genome and implies that they may have a similar role in other organisms. (shrink)

Telomeres play a vital role in protecting the ends of chromosomes and preventing chromosome fusion. The failure of cancer cells to properly maintain telomeres can be an important source of the chromosome instability involved in cancer cell progression. Telomere loss results in sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/B) cycles, leading to extensive DNA amplification and large deletions. These B/F/B cycles end primarily when the unstable chromosome acquires a new telomere by translocation of the ends of other (...) chromosomes. Many of these translocations are nonreciprocal, resulting in the loss of the telomere from the donor chromosome, providing a mechanism for transfer of instability from one chromosome to another until a chromosome acquires a telomere by a mechanism other than nonreciprocal translocation. B/F/B cycles can also result in other forms of chromosome rearrangements, including double‐minute chromosomes and large duplications. Thus, the loss of a single telomere can result in instability in multiple chromosomes, and generate many of the types of rearrangements commonly associated with human cancer. BioEssays 26:1164–1174, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Mammalian sex chromosomes exhibit marked sexual dimorphism in behavior during gametogenesis. During oogenesis, the X chromosomes pair and participate in unrestricted recombination; both are transcriptionally active. However, during spermatogenesis the X and Y chromosomes experience spatial restriction of pairing and recombination, are transcriptionally inactive, and form a chromatin domain that is markedly different from that of the autosomes. Thus the male germ cell has to contend with the potential loss of X‐encoded gene products, and it appears that coping strategies have (...) evolved. Genetic control of sex‐chromosome inactivation during spermatogenesis does not involve pairing or the presence of the Y chromosome or an intact X chromosome, and may therefore be under exogenous control by the gonad. Sex‐chromosome reactivation during oogenesis and inactivation during spermatogenesis probably reflect specific meiotic events such as recombination. Understanding these phenomena may help explain other sex‐related differences in genetic recombination. (shrink)

Recent studies have revealed an astonishing diversity of sex chromosomes in many vertebrate lineages, prompting questions about the mechanisms of sex chromosome turnover. While there is considerable population genetic theory about the evolutionary forces promoting sex chromosome replacement, this theory has not yet been integrated with our understanding of the molecular and developmental genetics of sex determination. Here, we review recent data to examine four questions about how the structure of gene networks influences the evolution of sex determination. (...) We argue that patterns of epistasis, arising from the structure of genetic networks, may play an important role in regulating the rates and patterns of sex chromosome replacement. (shrink)

Chromosomes that harbor dominant sex determination loci are predicted to erode over time—losing genes, accumulating transposable elements, degenerating into a functional wasteland and ultimately becoming extinct. The Drosophila melanogaster Y chromosome is fairly far along this path to oblivion. The few genes on largely heterochromatic Y chromosome are required for spermatocyte‐specific functions, but have no role in other tissues. Surprisingly, a recent paper shows that divergent Y chromosomes can substantially influence gene expression throughout the D. melanogaster genome.1 These (...) results show that variation on Y has an important influence on the deployment of the genome. BioEssays 30:409–411, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The creeping vole Microtus oregoni exhibits remarkably transformed sex chromosome biology, with complete chromosome drive/drag, X‐Y fusions, sex reversed X complements, biased X inactivation, and X chromosome degradation. Beginning with a selfish X chromosome, I propose a series of adaptations leading to this system, each compensating for deleterious consequences of the preceding adaptation: (1) YY embryonic inviability favored evolution of a selfish feminizing X chromosome; (2) the consequent Y chromosome transmission disadvantage favored X‐Y fusion (...) (“XP”); (3) Xist‐based silencing of Y‐derived XP genes favored a second X‐Y fusion (“XM”); (4) X chromosome dosage‐related costs in XPXM males favored the evolution of XM loss during spermatogenesis; (5) X chromosomal dosage‐related costs in XM0 females favored the evolution of XM drive during oogenesis; and (6) degradation of the non‐recombining XP favored the evolution of biased X chromosome inactivation. I discuss recurrent rodent sex chromosome transformation, and selfish genes as a constructive force in evolution. (shrink)

Sex chromosomes can differ between species as a result of evolutionary turnover, a process that can be driven by evolution of the sex determination pathway. Canonical models of sex chromosome turnover hypothesize that a new master sex determining gene causes an autosome to become a sex chromosome or an XY chromosome pair to switch to a ZW pair (or vice versa). Here, a novel paradigm for the evolution of sex determination and sex chromosomes is presented, in which (...) there is an evolutionary transition in the master sex determiner, but the X chromosome remains unchanged. There are three documented examples of the novel paradigm, and it is hypothesized that a similar process could happen in a ZW sex chromosome system. Three other taxa are also identified where the novel paradigm may have occurred, and how it could be distinguished from canonical trajectories in these and additional taxa is also described. (shrink)

It has become increasingly evident that gene content of the sex chromosomes is markedly different from that of the autosomes. Both sex chromosomes appear enriched for genes related to sexual differentiation and reproduction; but curiously, the human X chromosome also seems to bear a preponderance of genes linked to brain and muscle functions. In this review, we will synthesize several evolutionary theories that may account for this nonrandom assortment of genes on the sex chromosomes, including 1) asexual degeneration, 2) (...) sexual antagonism, 3) constant selection, and 4) hemizygous exposure. Additionally, we will speculate on how the evolution of sex‐chromosome gene content might have impacted on the phenotypic evolution of mammals and particularly humans. Our discussion will focus on the mammalian sex chromosomes, but will cross reference other species where appropriate. BioEssays 26:159–169, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Graphical AbstractSquamates may be an attractive group in which to study the influence of sex chromosomes on speciation rates because of the repeated evolution of heterogamety (both XY and ZW), as well as an apparently large number of taxa with environmental sex-determination.

Graphical AbstractOn the Black Swans of conventional sex determination theory: There aren't many, but when an exception to the standard model of sex determination (evolutionary turnover of genes playing the role of “master sex determiner”) arises, it certainly screams out for an explanation. In this issue, a novel one is put forward. It now awaits testing, particularly at the population level.

Loss of the Y‐chromosome is a common feature of species with chromosomal sex determination. However, our understanding of why some lineages frequently lose Y‐chromosomes while others do not is limited. The fragile Y hypothesis proposes that in species with chiasmatic meiosis the rate of Y‐chromosome aneuploidy and the size of the recombining region have a negative correlation. The fragile Y hypothesis provides a number of novel insights not possible under traditional models. Specifically, increased rates of Y aneuploidy may (...) impose positive selection for (i) gene movement off the Y; (ii) translocations and fusions which expand the recombining region; and (iii) alternative meiotic segregation mechanisms (achiasmatic or asynaptic). These insights as well as existing evidence for the frequency of Y‐chromosome aneuploidy raise doubt about the prospects for long‐term retention of the human Y‐chromosome despite recent evidence for stable gene content in older non‐recombining regions. (shrink)

Although sexual antagonism may have played a role in forming some sex chromosome systems, there appears to be little empirical or theoretical justification in assuming that it is the driving force in all cases of sex chromosome evolution. In many species, sex chromosomes have diverged in size and shape through the accumulation of mutations in regions of suppressed recombination. It is commonly assumed that recombination is suppressed in sex chromosomes due to selection to resolve sexually antagonistic pleiotropy. However, (...) the requirement for a sex chromosome‐specific mechanism for suppressing recombination is questionable, since more general models of recombination suppression on autosomes also appear to be applicable to sex chromosomes. Direct tests of the predictions of the sexual antagonism hypothesis offer only limited support in specific sex chromosome systems and circumstantial evidence remains open to interpretation. (shrink)

In most discussions of the evolution of sex chromosomes, it is presumed that the morphological differences between the X and Y were initiated by genetic changes. An alternative possibility is that, in the early stages, a key role was played by epigenetic modifications of chromatin structure that did not depend directly on genetic changes. Such modifications could have resulted from spontaneous epimutations at a sex‐determining locus or, in mammals, from selection in females for the epigenetic silencing of imprinted regions of (...) the paternally derived sex chromosome. Other features of mammalian sex chromosomes that are easier to explain if the epigenetic dimension of chromosome evolution is considered include the relatively large number of X‐linked genes associated with human brain development, and the overrepresentation of spermatogenesis genes on the X. Both may be evolutionary consequences of dosage compensation through X‐inactivation. BioEssays 26:1327–1332, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Gradual degradation seems inevitable for non‐recombining sex chromosomes. This has been supported by the observation of degenerated non‐recombining sex chromosomes in a variety of species. The human Y chromosome has also degenerated significantly during its evolution, and theories have been advanced that the Y chromosome could disappear within the next ∼5 million years, if the degeneration rate it has experienced continues. However, recent studies suggest that this is unlikely. Conservative evolutionary forces such as strong purifying selection and intrachromosomal (...) repair through gene conversion balance the degeneration tendency of the Y chromosome and maintain its integrity after an initial period of faster degeneration. We discuss the evidence both for and against the extinction of the Y chromosome. We also discuss potential insights gained on the evolution of sex‐determining chromosomes by studying simpler sex‐determining chromosomal regions of unicellular and multicellular microorganisms. (shrink)

Graphical AbstractMuller found halving gene dosage, as in males with one X chromosome, did not affect specific gene function. Why then was dosage “compensated?” This paradox was solved by invoking collective gene functions such as self/not self discrimination afforded by protein aggregation pressure. This predicts female susceptibility to autoimmune disease.

Recent mutagenesis studies have demonstrated that the chemotherapeutic agent, chlorambucll (CHL), is highly mutagenic in male germ cells of the mouse. Post‐melotic germ cells, and especially early spermatids, are the most sensitive to the cytotoxic and mutagenic effects of this agent. Genetic, cytogenetic and molecular analyses of many induced mutations have shown that, in these germ‐cell stages, CHL induces predominantly chromosomal rearrangements (deletions and translocations), and mutation‐rate studies show that, in terms of tolerated doses, CHL is perhaps five to ten (...) times more efficient in inducing rearrangements than is radiation exposure. Appropriate breeding protocols, along with knowledge of the advantages and limitations associated with the use of CHL, can be used to expand the current resource of chromosomal rearrangements in the mouse and to provide new phenotype‐associated mutations amenable to positional‐cloning techniques. The analysis of CHL‐induced mutations has also contributed to understanding the factors that affect the yield and nature of chemically induced germline mutations in mammals. (shrink)

Sex‐specific transcriptional and epigenomic profiles are detectable in the embryo very soon after fertilization. I propose that in male (XY) and female (XX) pre‐implantation embryos sex chromosomes establish sexually dimorphic interactions with the autosomes, before overt differences become apparent and long before gonadogenesis. Lineage determination restricts expression biases between the sexes, but the epigenetic differences are less constrained and can be perpetuated, accounting for dimorphisms that arise later in life. In this way, sexual identity is registered in the epigenome very (...) early in development. As development progresses, sex‐specific regulatory modules are harbored within shared transcriptional networks that delineate common traits. In reviewing this field, I propose that analyzing the mechanisms for sexual dimorphisms at the molecular and biochemical level and incorporating developmental and environmental factors will lead to a greater understanding of sex differences in health and disease. (shrink)

Monoallelic gene expression has played a significant role in the evolution of mammals enabling the expansion of a vast repertoire of olfactory receptor types and providing increased sensitivity and diversity. Monoallelic expression of immune receptor genes has also increased diversity for antigen recognition, while the same mechanism that marks a single allele for preferential rearrangement also provides a distinguishing feature for directing hypermutations. Random monoallelic expression of the X chromosome is necessary to balance gene dosage across sexes. In (...) marsupials only the maternal X chromosome is expressed, while in eutherian mammals the paternal X genes are silenced in the developing placenta and early blastocyst. These examples of epigenetic gene regulation commonly employ asynchrony of replication, the binding of polycomb proteins and antisense RNA, and histone modifications to chromatin structure. The same is true for genomic imprinting which among vertebrates is unique to mammals and represents a special kind of epigenetic modification that is heritable according to parent of origin. Genomic imprinting pervades many aspects of mammalian growth and evolution but in particular has played a significant role in the co‐adaptive evolution of the mother and foetus. (shrink)

Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face (...) a special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy. (shrink)

Mammal sex determination depends on an XY chromosome system, a gene for testis development and a means of activating the X chromosome. The duckbill platypus challenges these dogmas.1,2 Gutzner et al.1 find no recognizable SRY sequence and question whether the mammalian X was even the original sex chromosome in the platypus. Instead they suggest that the original platypus sex chromosomes were derived from the ZW chromosome system of birds and reptiles. Unraveling the puzzles of sex determination (...) and dosage compensation in the platypus has been complicated by the fact that it has a surplus of sex chromosomes. Rather than a single X and Y chromosome, the male platypus has five Xs and five Ys. BioEssays 27:681–684, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

In Caenorhabditis elegans, sex is determined by the number of X chromosomes which, in turn, determines the expression of the X‐linked gene xol‐1. Recent work(1) has shown that xol‐1 expression is controlled by least two distinct regulatory mechanisms, one transcriptional and another post‐transcriptional. The transcriptional regulator is a repressor acting in XX embryos; although the specific gene has not been identified, the chromosome region has been defined. A previously defined regulator of xol‐1, known as fox‐1, maps to a different (...) region of the X chromosome and works post‐transcriptionally, consistent with the identification of the fox‐1 gene product as a putative RNA binding protein(2). (shrink)

Studies on Neurospora chromosome segment duplications (Dps) performed since the publication of Perkins's comprehensive review in 1997 form the focus of this article. We present a brief summary of Perkins's seminal work on chromosome rearrangements, specifically, the identification of insertional and quasiterminal translocations that can segregate Dp progeny when crossed with normal sequence strains (i.e., T × N). We describe the genome defense process called meiotic silencing by unpaired DNA that renders Dp‐heterozygous crosses (i.e., Dp × N) barren, (...) which provides a basis for identifying Dps, and discuss whether other processes also might contribute to the barren phenotype of Dp × N and Dp × Dp crosses. We then turn to studies suggesting that large Dps (i.e., >300 kbp) can allow smaller gene‐sized duplications to escape another genome defense process called repeat‐induced point mutation (RIP), possibly by titration of the RIP machinery. Finally, we assess whether in natural populations dominant RIP suppressor Dps provide an “RIP‐free” niche for evolution of new genes following the duplication of existing genes. (shrink)

Sex selection technologies have become increasingly prevalent and accessible. We can find them advertised widely across the Internet and discussed in the popular media—an entry for “sex selection services” on Google generated 859,000 sites in April 2004. The available services fall into three main types: preconception sperm sorting followed either by intrauterine insemination of selected sperm or by in vitro fertilization ; preimplantation genetic diagnosis, by which embryos created by IVF are tested and only those of the desired sex are (...) transferred to the woman's uterus; and prenatal testing of fetuses through ultrasound or chromosomal analysis, followed by selective abortion of fetuses detected to be of the undesired sex. (shrink)

Frequent independent origins of environmental sex determination (ESD) are assumed within amniotes. However, the phylogenetic distribution of sex‐determining modes suggests that ESD is likely very ancient and may be homologous across ESD groups. Sex chromosomes are demonstrated to be old and stable in endothermic (mammals and birds) and many ectothermic (non‐avian reptiles) lineages, but they are mostly non‐homologous between individual amniote lineages. The phylogenetic pattern may be explained by ancestral ESD with multiple transitions to later evolutionary stable genotypic sex determination. (...) It is pointed out here that amniote ESD shares several key aspects with sequential hermaphroditism of fishes such as a lack of sex differences in genomes, biased population sex ratios, and potentially also molecular mechanism related to general stress responses. Here, it is speculated that ESD evolves via a heterochronic shift of the sensitive period of sex change from the adult to the embryonic stage in a hermaphroditic amniote ancestor. Also see the video abstract here https://youtu.be/q2mjtlCefu4. (shrink)

DNA damage repair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms to repair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNA repair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also affect subtelomeric regions (...) that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long‐read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature. (shrink)

Why do the two sexes have different lifespans and rates of aging? Two hypotheses based on asymmetric inheritance of sex chromosomes (“unguarded X”) or mitochondrial genomes (“mother's curse”) explain sex differences in lifespan as sex‐specific maladaptation leading to increased mortality in the shorter‐lived sex. While asymmetric inheritance hypotheses equate long life with high fitness, considerable empirical evidence suggests that sexes resolve the fundamental tradeoff between reproduction and survival differently resulting in sex‐specific optima for lifespan. However, selection for sex‐specific values in (...) life‐history traits is constrained by intersexual genetic correlations resulting in intra‐locus sexual conflict over optimal lifespan. The available data suggest that the evolution of sexual dimorphism only partially resolves these conflicts. Sexual conflict over optimal trait values, which has been demonstrated in model organisms and in humans, is likely to play a key role in shaping the evolution of lifespan, as well as in maintaining genetic variation for sex‐specific diseases. (shrink)

Recent studies indicate that mammalian chromosomes contain discretecis‐acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non‐coding RNA gene ASAR6 results in late replication, an under‐condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono‐allelic expression and asynchronous (...) replication timing. Additional “chromosome engineering” studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain “inactivation/stability centers” that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types ofcis‐acting elements, origins, telomeres, centromeres, and “inactivation/stability centers”, all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes. (shrink)

Sex chromosomes in plants have been known for a century, but only recently have we begun to understand the mechanisms behind sex determination in dioecious plants. Here, we discuss evolution of sex determination, focusing on Silene latifolia, where evolution of separate sexes is consistent with the classic “two mutations” model—a loss of function male sterility mutation and a gain of function gynoecium suppression mutation, which turned an ancestral hermaphroditic population into separate males and females. Interestingly, the gynoecium suppression function in (...) S. latifolia evolved via loss of function in at least two sex‐linked genes and works via gene dosage balance between sex‐linked, and autosomal genes. This system resembles X/A‐ratio‐based sex determination systems in Drosophila and Rumex, and could represent a steppingstone in the evolution of X/A‐ratio‐based sex determination from an active Y system. (shrink)

The Y chromosome in the XY sex-determination system is often shorter than its X counterpart, a condition attributed to degeneration after Y recombination ceases. Contrary to the traditional view of continuous, gradual degeneration, our study reveals stabilization within large mating populations. In these populations, we demonstrate that both mutant and active alleles on the Y chromosome can reach equilibrium through a mutation-selection balance. However, the emergence of a new species, particularly through the founder effect, can disrupt this equilibrium. (...) Specifically, if the male founders of a new species carry only a mutant allele for a particular Y-linked gene, this allele becomes fixed, leading to the loss of the corresponding active gene on the Y chromosome. Our findings suggest that the rate of Y-chromosome degeneration may be linked to the frequency of speciation events associated with single-male founder events. (shrink)

Following the tradition of feminist philosophers and scholars of science from the 1980s onward such as Evelyn Fox-Keller, Helen Longino, Anne Fausto-Sterling, and others who revealed how popular notions of masculinity and femininity infiltrated and shaped the content of scientific knowledge, Sarah S. Richardson's book Sex Itself: The Search for Male and Female in the Human Genome deserves a place on the shelf with this canonical literature. It addresses one of the most celebrated symbols of biological sex binary: the X (...) and Y chromosomes. The X and Y chromosomes, we learn, were not given the role of "sex chromosomes" upon their discovery in 1890 and 1905, respectively. Their transformation into the ultimate... (shrink)

In this paper, we hypothesize that X chromosome-associated mechanisms, which affect X-linked genes and are behind the immunological advantage of females, may also affect X-linked microRNAs. The human X chromosome contains 10% of all microRNAs detected so far in the human genome. Although the role of most of them has not yet been described, several X chromosome-located microRNAs have important functions in immunity and cancer. We therefore provide a detailed map of all described microRNAs located on human (...) and mouse X chromosomes, and highlight the ones involved in immune functions and oncogenesis. The unique mode of inheritance of the X chromosome is ultimately the cause of the immune disadvantage of males and the enhanced survival of females following immunological challenges. How these aspects influence X-linked microRNAs will be a challenge for researchers in the coming years, not only from an evolutionary point of view, but also from the perspective of disease etiology. (shrink)

Sex reversal, a mismatch between phenotypic and genetic sex, can be induced by chemical and thermal insults in ectotherms. Therefore, climate change and environmental pollution may increase sex‐reversal frequency in wild populations, with wide‐ranging implications for sex ratios, population dynamics, and the evolution of sex determination. We propose that reconsidering the half‐century old theory “Witschi's rule” should facilitate understanding the differences between species in sex‐reversal propensity and thereby predicting their vulnerability to anthropogenic environmental change. The idea is that sex reversal (...) should be asymmetrical: more likely to occur in the homogametic sex, assuming that sex‐reversed heterogametic individuals would produce new genotypes with reduced fitness. A review of the existing evidence shows that while sex reversal can be induced in both homogametic and heterogametic individuals, the latter seem to require stronger stimuli in several cases. We provide guidelines for future studies on sex reversal to facilitate data comparability and reliability. (shrink)

X‐chromosome inactivation refers to the coordinate regulation of almost all genes on the mammalian × chromosome. Most models for × chromosome inactivation suppose a role for methylation of × chromosome DNA sequences and/or the heterochromatinization of large «domains» of the × chromosome containing many genes.1 Some recent work concerning the expression of X‐linked transgenes, and parallels between regulated expression of sex‐linked genes in invertebrates and mammals, suggest that × chromosome inactivation may be a gene‐by‐gene (...) event mediated by the interaction between regulatory sequences common to all X‐linked genes and soluble activators and repressors. (shrink)

X chromosome inactivation (XCI) is an essential epigenetic process that ensures X‐linked gene dosage equilibrium between sexes in mammals. XCI is dynamically regulated during development in a manner that is intimately linked to differentiation. Numerous studies, which we review here, have explored the dynamics of X inactivation and reactivation in the context of development, differentiation and diseases, and the phenotypic and molecular link between the inactive status, and the cellular context. Here, we also assess whether XCI is a uniform (...) mechanism in mammals by analyzing epigenetic signatures of the inactive X (Xi) in different species and cellular contexts. It appears that the timing of XCI and the epigenetic signature of the inactive X greatly vary between species. Surprisingly, even within a given species, various Xi configurations are found across cellular states. We discuss possible mechanisms underlying these variations, and how they might influence the fate of the Xi. (shrink)

Not all vertebrates share the familiar system of XX:XY sex determination seen in mammals. In the chicken and other birds, sex is determined by a ZZ:ZW sex chromosome system. Gonadal development in the chicken has provided insights into the molecular genetics of vertebrate sex determination and how it has evolved. Such comparative studies show that vertebrate sex‐determining pathways comprise both conserved and divergent elements. The chicken embryo resembles lower vertebrates in that estrogens play a central role in gonadal sex (...) differentiation. However, several genes shown to be critical for mammalian sex determination are also expressed in the chicken, but their expression patterns differ, indicating functional plasticity. While the genetic trigger for sex determination in birds remains unknown, some promising candidate genes have recently emerged. The Z‐linked gene, DMRT1, supports the Z‐dosage model of avian sex determination. Two novel W‐linked genes, ASW and FET1, represent candidate female determinants. BioEssays 26:120–132, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

In this review, we focus on the evolutionary and biomedical aspects of the architecture of human chromosome 3 (HSA3) by analyzing chromosomal regions that have been conserved during the evolutionary process, compared to those that have been involved in the genomic restructuring of different placental lineages. Given that the organization of human chromosome 3 is derived when compared to the ancestral primate karyotype, and is an autosome that is commonly implicated in human tumour formation, we examined the patterns (...) of change and the genomic consequences that have resulted from its complex evolutionary history. The data show four discrete chromosomal regions that are frequently implicated in chromosomal rearrangements (3p25, 3p22, 3p12 and 3q21). These are rich in repetitive elements and are commonly implicated in structural rearrangements that underpin human genomic disorders and neoplasias. Additional Supporting Information may be found in the online version of this article. BioEssays 30:1126–1137, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In many species of reptiles, sex is determined at fertilization by zygotic sex chromosome composition. In other species, including all crocodilians, most turtles and some lizards, sex is determined by temperature during the earlier stages of gonadal differentiation. The effects of exogenous estrogens, antiestrogens and aromatase inhibitors at different temperatures have unambiguously demonstrated the involvement of estrogens in sexual differentiation of the gonads. Aromatase is the enzyme that converts androgens to estrogens. Gonadal aromatase activity is well correlated with gonadal (...) structure. It increases exponentially in differentiating ovaries, whereas it remains low in differentiating testes. Moreover, there is a high correlation between the thermosensitive periods for both ovary differentiation and increase in aromatase activity. We suggest that a thermosensitive factor intervenes, directly or indirectly, in the transcriptional regulation of the aromatase gene in reptiles with temperature‐dependent sex determination. (shrink)

The sex‐determining genes of fungi reside at one or two specialised regions of the chromosome known as the mating type (MAT) loci. The genes are sufficient to determine haploid cell identity, enable compatible mating partners to attract each other, and prepare cells for sexual reproduction after fertilisation. How conserved are these genes in different fungal groups? New work1 seeks an answer to this question by identifying the sex‐determining regions of an early diverged fungus. These regions bear remarkable similarity to (...) those described in other fungi, but the sex proteins they encode belong to only a single class of transcription factor, the high mobility group (HMG), indicating that these are likely to be ancestral to other proteins recruited for fungal sex. BioEssays 30:711–714, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Nucleotide diversity of the human Y chromosome is much lower than that in the rest of the genome. A new hypothesis postulates that this invariance may result from mutations in maternally inherited mitochondrial DNA (mtDNA), leading to impaired reproduction among males and lowered male effective population size. If correct, we should expect to see low levels of polymorphism in the male‐specific Y chromosome of many organisms but not necessarily in the female‐specific W chromosome in organisms with female (...) heterogamety. However, recent observations from birds suggest that the avian W chromosome is very low in nucleotide diversity. This indicates that mtDNA mutations cannot broadly explain the evolution of the sex‐limited chromosome. Other work has suggested that sexual selection at loci involved in sex determination or secondary sexual characteristics might reduce levels of genetic variability on Y through hitch‐hiking effects. Although the W chromosome does not seen to play a dominant role for sex determination in birds, it cannot be excluded that selective sweeps arising from natural or sexual selection contribute to the low levels of genetic variability seen on this chromosome. BioEssays 25:163–167, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Many organisms face a dilemma rooted in the unequal numbers of X chromosomes carried by the two sexes and the need to maintain equivalent expression of X‐linked genes. Several strategies have arisen to cope with this problem. All rely on accurately targeting epigenetic modifications to entire chromosomes. Targeting results from the action of recognition elements that attract modification and may rely on spreading of modification in cis along the affected chromosome. A recent report describing the first X chromosome (...) recognition element from C. elegans opens the way to defining the relative contributions of these factors to the compensation of X‐linked gene expression in worms.1 Extrachromosomal arrays composed of a C. elegans recognition element attract proteins that modify the C. elegans X chromosomes and interact genetically with mutations disrupting compensation. Moreover, examination of X:A translocations provides the first evidence for spreading of modification along C. elegans X chromosomes. BioEssays 26:707–710, 2004. © 2004 Wiley Periodicals, Inc. (shrink)