Pseudoautosomal Locus Research Articles

Recurrent allopolyploidization, Y-chromosome introgression and the evolution of sexual systems in the plant genus Mercurialis.

The plant genus Mercurialis includes dioecious, monoecious and androdioecious species (where males coexist with hermaphrodites). Its diversification involved reticulate evolution via hybridization and polyploidization. The Y chromosome of the diploid species Mercurialis annua shows only mild signs of degeneration. We used sequence variation at a Y-linked locus in several species and at multiple autosomal and pseudoautosomal loci to investigate the origin and evolution of the Y chromosome across the genus. Our study provides evidence for further cases of allopolyploid speciation. It also reveals that all lineages with separate sexes (with one possible exception) share the same ancestral Y chromosome. Surprisingly, males in androdioecious populations of hexaploid M. annua carry a Y chromosome that is not derived from either of its two putative progenitor lineages but from a more distantly related perennial dioecious lineage via introgression. These results throw new light on the evolution of sexual systems and polyploidy in Mercurialis and secure it as a promising model for further study of plant sex chromosomes.This article is part of the theme issue ‘Sex determination and sex chromosome evolution in land plants’.

A Novel and Mosaic WDR45 Nonsense Variant Causes Beta-Propeller Protein-Associated Neurodegeneration Identified Through Whole Exome Sequencing and X chromosome Heterozygosity Analysis.

Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked rare dominant disorder of autophagy. The role of WDR45 has been implicated in BPAN almost exclusively in females possibly due to male lethality. Characterization of distinctive clinical manifestations and potentially the complex genetic determinants in rare male patients remain crucial for deciphering BPAN and other X-linked dominant diseases. We performed whole exome sequencing (WES) followed by segregation analysis and identified a novel nonsense and mosaic variant in WDR45, namely NM_007075.3:c.873C>G; p.(Tyr291*) in an affected male at the age of 34. His biphasic medical history was compatible with BPAN, which was characterized by delayed psychomotor development, intellectual disability, and progression into dystonia parkinsonism in his twenties. The variant had an apparently mosaic pattern both in whole exome and Sanger sequencing findings. In order to figure out if mosaicism was restricted to this variant or related to a chromosomal level mosaicism, we used our in-house WES data from 129 unrelated individuals to calculate the threshold values of male and female X chromosome heterozygosity (XcHet) in WES data for our pipeline. A background level of heterozygous variants on X chromosome excluding the pseudoautosomal loci is an observed phenomenon in WES analysis and this level has been used as a quality measure. Herein, we suggest utilization of this measure for detection of digital anomalies of the X chromosome in males by potentially observing a higher XcHet value than the threshold value. This approach has revealed a variant level mosaicism in the affected male, which was further supported with cytogenetic analyses.

Recombination and Nucleotide Diversity in the Sex Chromosomal Pseudoautosomal Region of the Emu, Dromaius novaehollandiae

Pseudoautosomal regions (PARs) shared by avian Z and W sex chromosomes are typically small homologous regions within which recombination still occurs and are hypothesized to share the properties of autosomes. We capitalized on the unusual structure of the sex chromosomes of emus, Dromaius novaehollandiae, which consist almost entirely of PAR shared by both sex chromosomes, to test this hypothesis. We compared recombination, linkage disequilibrium (LD), GC content, and nucleotide diversity between pseudoautosomal and autosomal loci derived from 11 emu bacterial artificial chromosome (BAC) clones that were mapped to chromosomes by fluorescent in situ hybridization. Nucleotide diversity (pi = 4N(e)mu) was not significantly lower in pseudoautosomal loci (14 loci, 1.9 +/- 2.4 x 10(-3)) than autosomal loci (8 loci, 4.2 +/- 6.1 x 10(-3)). By contrast, recombination per site within BAC-end sequences (rho = 4Nc) (pseudoautosomal, 3.9 +/- 6.9 x 10(-2); autosomal, 2.3 +/- 3.7 x 10(-2)) was higher and average LD (D') (pseudoautosomal, 4.2 +/- 0.2 x 10(-1); autosomal, 4.7 +/- 0.5 x 10(-1)) slightly lower in pseudoautosomal sequences. We also report evidence of deviation from a simple neutral model in the PAR and in autosomal loci, possibly caused by departures from demographic equilibrium, such as population growth. This study provides a snapshot of the population genetics of avian sex chromosomes at an early stage of differentiation.

Linkage disequilibrium between the pseudoautosomal PEPB-1 locus and the sex-determining region of chinook salmon.

Allele frequency differences between sexes and an excess of heterozygotes in males had suggested that the PEPB-1 locus is sex-linked in chinook salmon (Oncorhynchus tshawytscha). We here estimate less than 1% recombination between PEPB-1 and a growth hormone pseudogene known to be in the sex-determining region (SEX) in 374 progeny from eight experimental matings. We present modified maximum likelihood methods for estimating haplotype frequencies from population samples at a sex-linked locus in which functional alleles occur on both the X and Y chromosomes (pseudoautosomal loci). We find nearly complete linkage disequilibrium between PEPB-1 and SEX in 20 population samples from the Puget Sound region of Washington and southern British Columbia. However, allele frequencies at PEPB-1 were similar in males and females in 35 population samples from the coast of Washington and the Columbia River basin. Pseudoautosomal regions have been described in a broad taxonomic array of vertebrates and invertebrates, and they are likely candidate regions to find genes associated with differences in life history, morphology, or behavior between males and females.

A Recoding Scheme for X-Linked and Pseudoautosomal Loci to Be Used with Computer Programs for Autosomal LOD-Score Analysis

We present a recoding scheme that allows for a parametric multipoint X-chromosomal linkage analysis of dichotomous traits in the context of a computer program for autosomes that can use trait models with imprinting. Furthermore, with this scheme, it is possible to perform a joint multipoint analysis of X-linked and pseudoautosomal loci. It is required that (1) the marker genotypes of all female nonfounders are available and that (2) there are no male nonfounders who have daughters in the pedigree. The second requirement does not apply if the trait locus is pseudoautosomal. The X-linked marker loci are recoded by adding a dummy allele to the males’ hemizygous genotypes. For modelling an X-linked trait locus, five different liability classes are defined, in conjunction with a paternal imprinting model for male nonfounders. The formulation aims at the mapping of a diallelic trait locus relative to an arbitrary number of codominant markers with known genetic distances, in cases where a program for a genuine X-chromosomal analysis is not available.

Absence of Age Effect on Meiotic Recombination between Human X and Y Chromosomes

Recombination between the X and Y chromosomes is limited to the pseudoautosomal region and is necessary for proper segregation of the sex chromosomes during spermatogenesis. Failure of the sex chromosomes to disjoin properly during meiosis can result in individuals with a 47,XXY constitution, and approximately one-half of these result from paternal nondisjunction at meiosis I. Analysis of individuals with paternally derived 47,XXY has shown that the majority are the result of meiosis in which the X and Y chromosomes have failed to recombine. Our studies of sperm have demonstrated that aneuploid 24,XY sperm have a decreased recombination frequency, compared with that of normal sperm. Some studies have indicated a relationship of increased paternal age with 47,XXY offspring and with the production of XY disomic sperm, whereas others have failed to find such relationships. To determine whether there is a relationship between paternal age and recombination in the pseudoautosomal region, single-sperm genotyping was performed to measure the frequency of recombination between a sex-specific locus, STS/STS pseudogene, and a pseudoautosomal locus, DXYS15, in younger men (age < or =30 years) compared with older men (age > or =50 years). A total of 2,329 sperm cells were typed by single-sperm PCR in 20 men who were heterozygous for the DXYS15 locus (1,014 sperm from 10 younger men and 1,315 sperm from 10 older men). The mean recombination frequency was 39.2% in the younger men and 37.8% in the older men. There was no heterogeneity in the frequency of recombination rates. There was no significant difference between the recombination frequencies among the younger men and those among the older men, when analyzed by the clustered binomial Z test (Z=.69, P=.49). This result suggests that paternal age has no effect on the recombination frequency in the pseudoautosomal region.

Failure to support a pseudoautosomal locus for schizophrenia

Evidence for a pseudoautosomal locus for schizophrenia was sought through an assessment of the psychiatric status of the uncles and aunts ( n = 30) of schizophrenic patients. The proportion of affected paternal uncles did not differ from that of affected paternal aunts. Likewise, the proportion of affected maternal aunts did not differ from that of affected maternal uncles. The research design used in this study failed to support the pseudoautosomal hypothesis of schizophrenia.

Pseudoautosomal region in schizophrenia: Linkage analysis of seven loci by sib-pair and lod-score methods

In a previous study, we reported a nonrandom segregation between schizophrenia and the pseudoautosomal locus DXYS14 in a sample of 33 sibships. That study has been extended by the addition of 16 new sibships from 16 different families. Data from six other loci of the pseudoautosomal region and of the immediately adjacent part of the X specific region have also been analyzed. Two methods of linkage analysis were used: the affected sibling pair (ASP) method and the lod-score method. Lod-score analyses were performed on the basis of three different models—A, B, and C—all shown to be consistent with the epidemiological data on schizophrenia. No clear evidence for linkage was obtained with any of these models. However, whatever the genetic model and the disease classification, maximum lod scores were positive with most of the markers, with the highest scores generally being obtained for the DXYS14 locus. When the ASP method was used, the earlier finding of nonrandom segregation between schizophrenia and the DXYS14 locus was still supported in this larger data set, at an increased level of statistical significance. Findings of ASP analyses were not significant for the other loci. Thus, findings obtained from analyses using the ASP method, but not the lod-score method, were consistent with the pseudoautosomal hypothesis for schizophrenia.

An Examination of Linkage of Schizophrenia and Schizoaffective Disorder to the Pseudoautosomal Region (Xp22.3)

We investigated linkage between schizophrenia and the loci DXYS14, DXYS17, and MIC2 within the pseudoautosomal region in 85 families with two or more siblings suffering from schizophrenia or schizoaffective disorder. A maximum lod score of 2.44 was reached at MIC2, with a dominant model of inheritance at a recombination fraction of 0.367 in females and 0.046 in males (a F:M sex ratio > 1, i.e. opposite to that expected with a pseudoautosomal locus). Evidence consistent with linkage (P = 0.01) was also obtained with a sibling pair analysis at the MIC2 locus. These data do not support (although they do not definitively exclude) a locus within the pseudoautosomal region; they are consistent with the presence of a gene that predisposes to schizophrenia in the sex-specific regions of the X and Y chromosomes.

Pseudoautosomal locus for schizophrenia excluded in 12 pedigrees.

A pseudoautosomal locus for schizophrenia has been proposed based on observations of an excess of same-sex affected sibling pairs over opposite-sex pairs when the transmitting parent is the father. Such a pattern of partial concordance by sex related to paternal transmission would be difficult to explain by any biologic mechanism other than pseudoautosomal transmission of schizophrenia. To test the pseudoautosomal hypothesis, 37 sibling pairs concordant for the schizophrenia spectrum were identified from 24 nuclear pedigrees. No significant difference in concordance for sex was found between sibships of paternal and maternal transmission of schizophrenia. Next, a linkage analysis was performed in 12 informative pedigrees, examining seven marker loci spanning the pseudoautosomal region. Both strict schizophrenia and a broader schizophrenia spectrum were analyzed as the affected phenotype, and both autosomal dominant and autosomal recessive models were tested. None of the markers supported linkage to either schizophrenia or the schizophrenia spectrum. Lod scores of less than -4 were obtained across the entire pseudoautosomal region by means of multipoint linkage analyses in the autosomal dominant model. In the autosomal recessive model, the respective lod scores were less than -2. We conclude that there is no evidence of a pseudoautosomal locus for schizophrenia in our pedigrees in any of the genetic models we tested.

Meiotic abnormalities in hybrid mice of the C57BL/6J x Mus spretus cross suggest a cytogenetic basis for Haldane's rule of hybrid sterility.

Light- and electron-microscopic analyses of chromosomal pairing and recombination in F1 and first-backcross generation mice of the C57BL/6J x Mus spretus cross revealed a variety of meiotic irregularities that could contribute to meiocyte loss and infertility. Pachytene anomalies included univalency, partially paired bivalents, homolog-length inequalities, nonhomologous pairing, and associations of asynapsed autosomal segments with the X chromosome. These phenomena were most prevalent in F1 males, which are invariably sterile. Although F1 females were qualitatively fertile, breeding data indicated significant reproductive impairment. Molecular analyses of X-linked and pseudoautosomal loci in sterile and fertile backcross males revealed that the failure of X-Y pairing and recombination is correlated with heterozygosity within the pseudoautosomal regions of the X and Y chromosomes. In addition to impairing fertility, the synaptic disturbances (such as localized asynapsis and nonhomologous pairing) observed in F1 individuals can potentially alter recombinational patterns, thereby contributing to the genetic-map distortion observed with this interspecific cross. Together, the cytogenetic and reproductive data suggest that sex-related differences in the gametogenic process, quantitative differences in the incidence of synaptic irregularities in female and male meiosis, and phenomena associated with the X and Y chromosomes comprise the etiological basis of the sex-biased F1 sterility. The differential gender-related effects of these cytogenetic phenomena may constitute the underlying basis of Haldane's rule in mammals.

The human pseudoautosomal GM-CSF receptor alpha subunit gene is autosomal in mouse.

The gene encoding the granulocyte macrophage colony stimulating factor receptor alpha subunit (CSF2RA) has previously been mapped to the pseudoautosomal region of the human sex chromosomes. In contrast, we report that the murine locus, Csf2ra, maps to an autosome in the laboratory mouse. By in situ hybridization and genetic mapping, Csf2ra maps at telomeric band D2 of mouse chromosome 19. This first instance of a pseudoautosomal locus in human being autosomal in mouse, indicates incomplete conservation between the human and mouse X chromosomes and suggests that the genetic content of the pseudoautosomal region may differ between species of eutherian mammals due to chromosomal rearrangements.

No evidence for a pseudoautosomal locus for schizophrenia. Linkage analysis of multiply affected families.

Evidence for a pseudoautosomal locus for a schizophrenia susceptibility gene was sought by two forms of analysis of 25 multiply affected families. Firstly, in the sample as a whole there was an excess of same-sex over mixed-sex siblings compared with that expected. Secondly, linkage analysis was performed in six of the families. The genotypes were studied for DXYS14, a highly polymorphic marker in the telomeric pseudoautosomal region. No evidence for positive linkage was found with two-point analysis under eight different genetic models for the mode of transmission. A non-parametric, sibling-pair analysis also failed to detect linkage. Our findings provide no evidence for linkage within the pseudoautosomal region; same-sex concordance must arise from some other mechanism.

Evidence for a Pseudo-autosomal Locus for Schizophrenia Using the Method of Affected Sibling Pairs

A susceptibility locus for schizophrenia in the 'pseudo-autosomal' region has been proposed on the basis of the reported excess of sex-chromosome aneuploidies (e.g. XXY and XXX) among patients with schizophrenia and the finding that schizophrenic sib-pairs are more often of the same than of the opposite sex. This hypothesis has been tested in 83 sibships with two or more siblings fulfilling Research Diagnostic Criteria for schizophrenia or schizoaffective disorder. Alleles at the pseudo-autosomal telomeric locus DXYS14, which is unlinked with sex, were analysed using the method of affected sib-pairs. Affected sibs shared alleles at DXYS14 more frequently than expected by random Mendelian assortment, supporting genetic linkage between DXYS14 and schizophrenia.

Unsound Methodology in Investigating a Pseudoautosomal Locus in Schizophrenia

We have reservations about accepting the conclusions made by Crow et al (1989), namely that there is evidence that susceptibility to schizophrenia may be transmitted by a pseudoautosomal locus. In our view the methodology of the study is unsound. Additionally the data presented by the authors, when analysed correctly, do not support their hypothesis.

Y chromosome and aggression in strains of laboratory mice

Intermale attack behavior differences in laboratory strains of inbred mice have Y chromosome correlates in a small number of strain comparisons. Moreover, the Y correlates interact with autosomal or pseudoautosomal genes. Recent data on the genetics of the Y do not contradict these conclusions. The discovery of several polymorphic loci of the Y could pave the way for a direct confirmation of Y correlates of attack behavior by linkage detection. The involvement of the Y in this behavior has been put forward. Plasmatic testosterone concentration reactivity of some target organs to exogeneous testosterone appears to be correlated with two independent loci of the Y acting in an additive or interactive manner with autosomal or pseudoautosomal loci. However, the association between testosterone action and attack behavior in males needs further evidence, and in any case this association does not underline linear mechanisms.

Concordance by sex in sibling pairs with schizophrenia is paternally inherited. Evidence for a pseudoautosomal locus.

The hypothesis that the gene for schizophrenia is located in the pseudoautosomal region of the sex chromosomes predicts that same-sex concordance will occur in paternally rather than maternally derived pairs. In 120 families that included at least one sibling pair with schizophrenia, affected members were significantly more likely to be of the same sex when there was a history of illness on the paternal than on the maternal side, the difference remaining significant when parent of origin was assessed by three different methods. The finding is as predicted by the pseudoautosomal hypothesis: therefore a search for the gene should be focused on this small (three megabase) region of the genome. The ratio of same to mixed sex pairs in paternally-derived cases (approximately 3:1) suggests the gene is located in the centromeric one-third of the pseudoautosomal region.

Sex vesicle “entrapment”: Translocation or nonhomologous recombination of misaligned Yp and Xp as alternative mechanisms for abnormal inheritance of the sex‐determining region

Abnormal inheritance of the sex determining region, normally located on Yp, results in about 1 in 20,000 phenotypic males with a 46,XX genotype. Studies to date indicate that many 46,XX males apparently arise due to a balanced, yet abnormal, nonhomologous interchange of Xp and Yp termini. However, 2 of the 5 XX males we report here have 3 copies of the pseudoautosomal locus, MIC2. Thus, they appear to have inherited the sex determining region as a result of Yp sequences being added onto the X pseudoautosomal region. Such an unequal, extremely nonhomologous interchange could alternatively be considered to arise from an unbalanced translocation of Yp to Xp. Our results suggest that very unequal interchange or translocation of Yp sequences onto the X pseudoautosomal region is not as rare a mechanism for XX males as originally thought. We also suggest that sex vesicle "entrapment" favors the association of a Yp fragment to the X pseudoautosomal region over a translocation to either Xq or an autosome.

Exchange of terminal portions of X- and Y-chromosomal short arms in human XY females.

Human Y(+) XX maleness has been shown to result from an abnormal terminal Xp-Yp interchange that can occur during paternal meiosis. To test whether human XY females are produced by the same mechanism, we followed the inheritance of paternal pseudoautosomal loci and Xp22.3-specific loci in two XY female patients. Y-specific sequences and the whole pseudoautosomal region of the Y chromosome of their fathers were absent in these patients. However, the entire pseudoautosomal region and the X-specific part of Xp22.3 distal to the STS locus had been inherited from the X chromosome of the respective father. This Xp transfer to Yp was established by in situ hybridization experiments showing an Xp22.3-specific locus on Yp in both cases. Such results demonstrate that an abnormal and terminal X-Y interchange generated the rearranged Y chromosome of these two XY females; they appear to be the true countertype of Y(+) XX males. In these patients, who also display some Turner stigmata, the Y gene(s) involved in this phenotype is (are) localized to interval 1 or 2. If the loss of such gene(s) affects fetal viability, their proximity to TDF would account for the underrepresentation of interchange 46,XY females compared with Y(+) XX males.

X-Y crossing over in the chimpanzee.

Single-copy DNA sequences defining several pseudoautosomal loci on the human sex chromosomes are shown to be highly conserved in the genome of the chimpanzee. Segregation analysis of polymorphic pseudoautosomal probes in a chimpanzee pedigree revealed that the transmission of the paternal alleles was not strictly sex-linked. In situ hybridization localized the pseudoautosomal probe 29C1 specifically to Xp22-Xpter and to Yq12.2-Yqter on the chimpanzee sex chromosomes. Thus, our results demonstrate the existence of homologous segments on the chimpanzee X and Y chromosomes, which regularly undergo recombinatory exchange in male meiosis. The chimpanzee is now the third mammalian species, besides man and mouse, in which there is genetic evidence for a pseudoautosomal segment on the sex chromosomes.