Review Lecture: Mechanisms and evolutionary origins of variable X-chromosome activity in mammals

1974 ◽  
Vol 187 (1088) ◽  
pp. 243-268 ◽  
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Gene Dosage ◽  
Control Mechanisms ◽  
Compensation Mechanism ◽  
X Chromosomes ◽  
Animal Group ◽  
Evolutionary Origins ◽  
Genetic Activity ◽  
Males And Females

The X-chromosome of mammals is remarkable for its variable genetic activity. In somatic cells only a single X-chromosome is active, no matter how many are present, thus providing a dosage compensation mechanism by which males and females effectively have the same gene dosage of X-linked genes. In germ cells, however, it appears that all X-chromosomes present are active. Female germ cells require the presence of two X-chromosomes for normal survival, whereas male germ cells die if they have more than one X-chromosome. This system is found in all eutherian mammals and in marsupials, but is not known in any other animal group. In marsupials the X-chromosome derived from the father seems to be preferentially inactivated, whereas in eutherian mammals that from either parent may be so in different cells of the same animal. The differentiation of a particular X-chromosome as active or inactive is initiated in early embryogeny, and thereafter maintained through all further cell divisions in that individual. The mechanisms by which this is achieved are of great interest in relation to genetic control mechanisms in general. Various recent hypotheses concerning these mechanisms are discussed.

Genetic activity of sex chromosomes in somatic cells of mammals

1970 ◽  
Vol 259 (828) ◽  
pp. 41-52 ◽  
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Chromosome Region ◽  
Somatic Cells ◽  
X Inactivation ◽  
X Chromosomes ◽  
Animal Group ◽  
Inactive X Chromosome ◽  
Genetic Activity ◽  
Partial Inactivation

Mammals are thought to have a type of dosage compensation not so far known in any other animal group: however many X chromosomes are present, only one remains genetically active in somatic cells. Considerable evidence for this idea exists, in spite of criticism; the greatest difficulty is presented by the abnormalities in human individuals with X chromosome aberrations. Possible explanations for these abnormalities include: wrong X chromosome dosage in early development before X inactivation, reversal of inactivation, partial inactivation of both X chromosomes, activity of the X while in the condensed inactive state, and the presence of a homologous non-inactivated region of the human X and Y. In female germ cells X inactivation apparently does not occur, but the situation in male germ cells is less clear. The Y chromosome is probably also inactive in somatic cells of adults, but again its function in germ cells is not yet clear. Some species have a presumed doubly inactive X chromosome region, as well as the singly active one. The origins and functions of this region are unknown; it may have a role in female germ cells.

X-chromosome activity in foetal germ cells of the mouse

Development ◽  
1981 ◽  
Vol 63 (1) ◽  
pp. 75-84
Author(s):  
Marilyn Monk ◽  
Anne McLaren
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Germ Line ◽  
Gene Dosage ◽  
The Other ◽  
X Chromosomes ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Other Hand

A cycle of inactivation and reactivation of one X chromosome in the female (XX) germ line is shown by analysis of gene dosage effects on activity of an X-linked enzyme. The ratio of activities of the X-linked enzyme HPRT and an autosomal enzyme APRT are determined in XX and XY germ cells from embryonic gonads from the 12th to the 17th day of pregnancy. Mitotic stages of XX and XY germ cells on the 12th day have similar HPRT: APRT ratios, but on the 13th day the ratios are significantly higher in XX than XY germ cells. As the XX germ cells enter meiosis they show a marked increase in HPRT:APRT ratio which is primarily due to a rise in X-linked HPRT activity. Comparisons are made with XO germ cells on the 12th and 14th day. On the 12th day, XO do not differ from XX and XY germ cells, suggesting that only one X chromosome is active in XX germ cells at this stage. On the 14th day, on the other hand, the HPRT:APRT ratios in XO and XY germ cells are similar but in XX germ cells the ratio is significantly higher. The twofold difference between the ratio in XX and XO germ cells suggests that by this stage both X chromosomes are active in XX germ cells. The subsequent large increase of the ratio in XX relative to XY germ cells is thought to reflect their differing cell states.

scholarly journals Absence of X-chromosome dosage compensation in the primordial germ cells of Drosophila embryos

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryoma Ota ◽  
Makoto Hayashi ◽  
Shumpei Morita ◽  
Hiroki Miura ◽  
Satoru Kobayashi
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Dosage Compensation ◽  
Sex Chromosome ◽  
Primordial Germ Cells ◽  
Histone H4 ◽  
X Chromosomes ◽  
Essential Components ◽  
Msl Complex ◽  
Male Specific

AbstractDosage compensation is a mechanism that equalizes sex chromosome gene expression between the sexes. In Drosophila, individuals with two X chromosomes (XX) become female, whereas males have one X chromosome (XY). In males, dosage compensation of the X chromosome in the soma is achieved by five proteins and two non-coding RNAs, which assemble into the male-specific lethal (MSL) complex to upregulate X-linked genes twofold. By contrast, it remains unclear whether dosage compensation occurs in the germline. To address this issue, we performed transcriptome analysis of male and female primordial germ cells (PGCs). We found that the expression levels of X-linked genes were approximately twofold higher in female PGCs than in male PGCs. Acetylation of lysine residue 16 on histone H4 (H4K16ac), which is catalyzed by the MSL complex, was undetectable in these cells. In male PGCs, hyperactivation of X-linked genes and H4K16ac were induced by overexpression of the essential components of the MSL complex, which were expressed at very low levels in PGCs. Together, these findings indicate that failure of MSL complex formation results in the absence of X-chromosome dosage compensation in male PGCs.

scholarly journals Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

2021 ◽  
Vol 22 (3) ◽  
pp. 1114
Author(s):  
Ali Youness ◽  
Charles-Henry Miquel ◽  
Jean-Charles Guéry
Keyword(s):  
Autoimmune Diseases ◽  
X Chromosome ◽  
Gene Dosage ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Female Sex Hormones ◽  
Inactive X Chromosome ◽  
Immune Related Genes ◽  
Female Specific

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

Random X-chromosome inactivation in female primordial germ cells in the mouse

Development ◽  
1981 ◽  
Vol 64 (1) ◽  
pp. 251-258
Author(s):  
Andy McMahon ◽  
Mandy Fosten ◽  
Marilyn Monk
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Germ Line ◽  
Primordial Germ Cells ◽  
Phosphoglycerate Kinase ◽  
X Chromosome Inactivation ◽  
Yolk Sac ◽  
Chromosome Inactivation ◽  
X Chromosomes

The pattern of expression of the two X chromosomes was investigated in pre-meiotic germ cells from 12½-day-old female embryos heterozygous for the variant electrophoretic forms of the X-linked enzyme phosphoglycerate kinase (PGK-1). If such germ cells carry the preferentially active Searle's translocated X chromosome (Lyon, Searle, Ford & Ohno, 1964), then only the Pgk-1 allele on this chromosome is expressed. This confirms Johnston's evidence (1979,1981) that Pgk-1 expression reflects a single active X chromosome at this time. Extracts of 12½-day germ cells from heterozygous females carrying two normal X chromosomes show both the A and the B forms of PGK; since only one X chromosome in each cell is active, different alleles must be expressed in different cells, suggesting that X-chromosome inactivation is normally random in the germ line. This result makes it unlikely that germ cells are derived from the yolk-sac endoderm where the paternally derived X chromosome is preferentially inactivated. In their pattern of X-chromosome inactivation, germ cells evidently resemble other tissues derived from the epiblast.

scholarly journals Visualization of X chromosome reactivation in mouse primordial germ cells in vivo

Biology Open ◽  
2021 ◽  
Vol 10 (4) ◽  
Author(s):  
Yoshikazu Haramoto ◽  
Mino Sakata ◽  
Shin Kobayashi
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Primordial Germ Cells ◽  
Embryonic Cell ◽  
Epigenetic Memory ◽  
Genital Ridge ◽  
X Chromosomes ◽  
Hprt Locus ◽  
Mouse System

ABSTRACT X chromosome inactivation (XCI), determined during development, remains stable after embryonic cell divisions. However, primordial germ cells (PGCs) are exceptions in that XCI is reprogrammed and inactivated X chromosomes are reactivated. Although interactions between PGCs and somatic cells are thought to be important for PGC development, little is known about them. Here, we performed imaging of X chromosome reactivation (XCR) using the ‘Momiji’ mouse system, which can monitor the X chromosome's inactive and active states using two color fluorescence reporter genes, and investigated whether interactions would affect XCR in PGCs. Based on their expression levels, we found that XCR of the Pgk1 locus began at embryonic day (E)10.5 and was almost complete by E13.5. During this period, PGCs became distributed uniformly in the genital ridge, proliferated, and formed clusters; XCR progressed accordingly. In addition, XCR of the Pgk1 locus preceded that of the Hprt locus, indicating that the timing of epigenetic memory erasure varied according to the locus of each of these X-linked genes. Our results indicate that XCR proceeds along with the proliferation of PGCs clustered within the genital ridge. This article has an associated First Person interview with the first author of the paper.

scholarly journals Distinct mechanisms mediate X chromosome dosage compensation in Anopheles and Drosophila

2021 ◽  
Vol 4 (9) ◽  
pp. e202000996
Author(s):  
Claudia Isabelle Keller Valsecchi ◽  
Eric Marois ◽  
M Felicia Basilicata ◽  
Plamen Georgiev ◽  
Asifa Akhtar
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Gene Dosage ◽  
Histone H4 ◽  
Ecological Constraints ◽  
Evolutionary Trajectory ◽  
X Chromosomes ◽  
Deleterious Gene ◽  
Msl Complex ◽  
High Degree

Sex chromosomes induce potentially deleterious gene expression imbalances that are frequently corrected by dosage compensation (DC). Three distinct molecular strategies to achieve DC have been previously described in nematodes, fruit flies, and mammals. Is this a consequence of distinct genomes, functional or ecological constraints, or random initial commitment to an evolutionary trajectory? Here, we study DC in the malaria mosquito Anopheles gambiae. The Anopheles and Drosophila X chromosomes evolved independently but share a high degree of homology. We find that Anopheles achieves DC by a mechanism distinct from the Drosophila MSL complex–histone H4 lysine 16 acetylation pathway. CRISPR knockout of Anopheles msl-2 leads to embryonic lethality in both sexes. Transcriptome analyses indicate that this phenotype is not a consequence of defective X chromosome DC. By immunofluorescence and ChIP, H4K16ac does not preferentially enrich on the male X. Instead, the mosquito MSL pathway regulates conserved developmental genes. We conclude that a novel mechanism confers X chromosome up-regulation in Anopheles. Our findings highlight the pluralism of gene-dosage buffering mechanisms even under similar genomic and functional constraints.

scholarly journals Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes

2019 ◽  
Vol 116 (36) ◽  
pp. 17916-17924 ◽  
Author(s):  
Ipsita Agarwal ◽  
Molly Przeworski
Keyword(s):  
X Chromosome ◽  
Rare Variants ◽  
Low Frequency ◽  
Replication Timing ◽  
Double Strand Breaks ◽  
X Chromosomes ◽  
Strand Breaks ◽  
Biochemical Processes ◽  
Males And Females ◽  
Mutational Processes

The sources of human germline mutations are poorly understood. Part of the difficulty is that mutations occur very rarely, and so direct pedigree-based approaches remain limited in the numbers that they can examine. To address this problem, we consider the spectrum of low-frequency variants in a dataset (Genome Aggregation Database, gnomAD) of 13,860 human X chromosomes and autosomes. X-autosome differences are reflective of germline sex differences and have been used extensively to learn about male versus female mutational processes; what is less appreciated is that they also reflect chromosome-level biochemical features that differ between the X and autosomes. We tease these components apart by comparing the mutation spectrum in multiple genomic compartments on the autosomes and between the X and autosomes. In so doing, we are able to ascribe specific mutation patterns to replication timing and recombination and to identify differences in the types of mutations that accrue in males and females. In particular, we identify C > G as a mutagenic signature of male meiotic double-strand breaks on the X, which may result from late repair. Our results show how biochemical processes of damage and repair in the germline interact with sex-specific life history traits to shape mutation patterns on both the X chromosome and autosomes.

scholarly journals FITNESS EFFECTS OF EMS-INDUCED MUTATIONS ON THE X CHROMOSOME OF DROSOPHILA MELANOGASTER. I. VIABILITY EFFECTS AND HETEROZYGOUS FITNESS EFFECTS

Genetics ◽  
1977 ◽  
Vol 87 (4) ◽  
pp. 763-774
Author(s):  
Joyce A Mitchell
Keyword(s):  
Drosophila Melanogaster ◽  
X Chromosome ◽  
Strongly Correlated ◽  
Induced Mutations ◽  
X Chromosomes ◽  
Heterozygous Condition ◽  
Fitness Effects ◽  
Sucrose Solutions ◽  
Discrete Generation ◽  
Males And Females

ABSTRACT Drosophila melanogaster X chromosomes were mutagenized by feeding males sucrose solutions containing ethyl methanesulfonate (EMS); the concentrations of EMS in the food were 2.5 mm, 5.0 mm, and 10.0 mm. Chromosomes were exposed to the mutagen up to three times by treating males in succeeding generations. After treatment, the effective exposures were 2.5, 5.0, 7.5, 10.0, 15.0, and 30.0 mm EMS. X chromosomes treated in this manner were tested for effects on fitness in both hemizygous and heterozygous conditions, and for effects on viability in hemizygous and homozygous conditions. In addition, untreated X chromosomes were available for study. The viability and heterozygous fitness effects are presented in this paper, and the hemizygous fitness effects are discussed in the accompanying one (Mitchell and Simmons 1977). Hemizygous and homozygous viability effects were measured by segregation tests in vial cultures. For hemizygous males, viability was reduced 0.5 percent per mm EMS treatment; for homozygous females, it was reduced 0.7 percent per mm treatment. The decline in viability appeared to be a linear function of EMS dose. The viabilities of males and females were strongly correlated. Heterozygous fitness effects were measured by monitoring changes in the frequencies of treated and untreated X chromosomes in discrete generation populations which, through the use of an X-Y translocation, maintained them only in heterozygous condition. Flies that were heterozygous for a treated chromosome were found to be 0.4 percent less fit per m m EMS than flies heterozygous for an untreated one.

scholarly journals sisterless A is required for the activation of Sex lethal in the germline

2019 ◽  
Author(s):  
Raghav Goyal ◽  
Ellen Baxter ◽  
Mark Van Doren
Keyword(s):  
Sex Determination ◽  
X Chromosome ◽  
Germ Cells ◽  
Specific Expression ◽  
Male Germ Cells ◽  
X Chromosomes ◽  
Dna Elements ◽  
Sex Lethal ◽  
Female Specific ◽  
Necessary And Sufficient

ABSTRACTIn Drosophila, sex determination in somatic cells has been well-studied and is under the control of the switch gene Sex lethal (Sxl), which is activated in females by the presence of two X chromosomes. Though sex determination is regulated differently in the germline versus the soma, Sxl is also necessary and sufficient for the female identity in germ cells. Loss of Sxl function in the germline results in ovarian germline tumors, a characteristic of male germ cells developing in a female soma. Further, XY (male) germ cells expressing Sxl are able to produce eggs when transplanted into XX (female) somatic gonads, demonstrating that Sxl is also sufficient for female sexual identity in the germline. As in the soma, the presence of two X chromosomes is sufficient to activate Sxl in the germline, but the mechanism for “counting” X chromosomes in the germline is thought to be different from the soma. Here we have explored this mechanism at both cis- and trans-levels. Our data support the model that the Sxl “establishment” promoter (SxlPE) is activated in a female-specific manner in the germline, as in the soma, but that the timing of SxlPE activation, and the DNA elements that regulate SxlPE are different from those in the soma. Nevertheless, we find that the X chromosome-encoded gene sisterless A (sisA), which helps activate Sxl in the soma, is also essential for Sxl activation in the germline. Loss of sisA function leads to loss of Sxl expression in the germline, and to ovarian tumors and germline loss. These defects can be rescued by the expression of Sxl, demonstrating that sisA lies upstream of Sxl in germline sex determination. We conclude that sisA acts as an X chromosome counting element in both the soma and the germline, but that additional factors that ensure robust, female-specific expression of Sxl in the germline remain to be discovered.

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