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Orphanet Journal of Rare Diseases Jul 2022Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every...
Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.
Topics: Adult; Chromosomes, Human, X; Diabetes Mellitus, Type 2; Female; Humans; Karyotype; Karyotyping; Turner Syndrome
PubMed: 35821070
DOI: 10.1186/s13023-022-02423-5 -
Nature Sep 2023The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date and led to its systematic omission from genomic...
The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.
Topics: Humans; Male; Chromosomes, Human, Y; Genome, Human; Genomics; Mutation Rate; Phenotype; Evolution, Molecular; Euchromatin; Pseudogenes; Genetic Variation; Chromosomes, Human, X; Pseudoautosomal Regions
PubMed: 37612510
DOI: 10.1038/s41586-023-06425-6 -
Cytogenetic and Genome Research 2015The pseudoautosomal region (PAR) is a unique segment of sequence homology between differentiated sex chromosomes where recombination occurs during meiosis. Molecular and... (Review)
Review
The pseudoautosomal region (PAR) is a unique segment of sequence homology between differentiated sex chromosomes where recombination occurs during meiosis. Molecular and functional properties of the PAR are distinctive from the autosomes and the remaining regions of the sex chromosomes. These include a higher rate of recombination than genome average, bias towards GC-substitutions and increased interindividual nucleotide divergence and mutations. As yet, the PAR has been physically demarcated in only 28 eutherian species representing 6 mammalian orders. Murid rodents have the smallest, gene-poorest and most diverged PARs. Other eutherian PARs are largely homologous but differ in size and gene content, being the smallest in equids and human/simian primates and much larger in other eutherians. Because pseudoautosomal genes escape X inactivation, their dosage changes with sex chromosome aneuploidies, whereas phenotypic effects of the latter depend on the size and gene content of the PAR. Thus, X monosomy is more viable in mice, humans and horses than in species with larger PARs. Presently, little is known about the functions of PAR genes in individual species, though human studies suggest their involvement in early embryonic development. The PAR is, thus, of evolutionary, genetic and biomedical significance and a 'research hotspot' in eutherian genomes.
Topics: Animals; Evolution, Molecular; Female; Humans; Mammals; Placenta; Pregnancy; Recombination, Genetic; Sex Chromosome Aberrations; Sex Chromosomes
PubMed: 26730606
DOI: 10.1159/000443157 -
Genome Biology Oct 2022The pseudoautosomal region 1 (PAR1) is a 2.7 Mb telomeric region of human sex chromosomes. PAR1 has a crucial role in ensuring proper segregation of sex chromosomes...
BACKGROUND
The pseudoautosomal region 1 (PAR1) is a 2.7 Mb telomeric region of human sex chromosomes. PAR1 has a crucial role in ensuring proper segregation of sex chromosomes during male meiosis, exposing it to extreme recombination and mutation processes. We investigate PAR1 evolution using population genomic datasets of extant humans, eight populations of great apes, and two archaic human genome sequences.
RESULTS
We find that PAR1 is fast evolving and closer to evolutionary nucleotide equilibrium than autosomal telomeres. We detect a difference between substitution patterns and extant diversity in PAR1, mainly driven by the conflict between strong mutation and recombination-associated fixation bias at CpG sites. We detect excess C-to-G mutations in PAR1 of all great apes, specific to the mutagenic effect of male recombination. Despite recent evidence for Y chromosome introgression from humans into Neanderthals, we find that the Neanderthal PAR1 retained similarity to the Denisovan sequence. We find differences between substitution spectra of these archaics suggesting rapid evolution of PAR1 in recent hominin history. Frequency analysis of alleles segregating in females and males provided no evidence for recent sexual antagonism in this region. We study repeat content and double-strand break hotspot regions in PAR1 and find that they may play roles in ensuring the obligate X-Y recombination event during male meiosis.
CONCLUSIONS
Our study provides an unprecedented quantification of population genetic forces governing PAR1 biology across extant and extinct hominids. PAR1 evolutionary dynamics are predominantly governed by recombination processes with a strong impact on mutation patterns across all species.
Topics: Animals; Female; Hominidae; Humans; Male; Nucleotides; Pseudoautosomal Regions; Receptor, PAR-1; Y Chromosome
PubMed: 36253794
DOI: 10.1186/s13059-022-02784-x -
Oncotarget Nov 2016Cytogenetic aberrations, such as chromosomal translocations, aneuploidy, and amplifications, are frequently detected in hematological malignancies. For many of the... (Review)
Review
Cytogenetic aberrations, such as chromosomal translocations, aneuploidy, and amplifications, are frequently detected in hematological malignancies. For many of the common autosomal aberrations, the mechanisms underlying their roles in cancer development have been well-characterized. On the contrary, although loss of a sex chromosome is observed in a broad range of hematological malignancies, how it cooperates in disease development is less understood. Nevertheless, it has been postulated that tumor suppressor genes reside on the sex chromosomes. Although the X and Y sex chromosomes are highly divergent, the pseudoautosomal regions are homologous between both chromosomes. Here, we review what is currently known about the pseudoautosomal region genes in the hematological system. Additionally, we discuss implications for haploinsufficiency of critical pseudoautosomal region sex chromosome genes, driven by sex chromosome loss, in promoting hematological malignancies. Because mechanistic studies on disease development rely heavily on murine models, we also discuss the challenges and caveats of existing models, and propose alternatives for examining the involvement of pseudoautosomal region genes and loss of a sex chromosome in vivo. With the widespread detection of loss of a sex chromosome in different hematological malignances, the elucidation of the role of pseudoautosomal region genes in the development and progression of these diseases would be invaluable to the field.
Topics: Chromosome Deletion; Chromosomes, Human, X; Chromosomes, Human, Y; Genes, Tumor Suppressor; Hematologic Neoplasms; Humans; Proto-Oncogenes; Pseudoautosomal Regions; RNA, Untranslated; Sex Chromosome Aberrations
PubMed: 27655702
DOI: 10.18632/oncotarget.12050 -
Cell & Bioscience 2020Sex differences are prevalent in normal development, physiology and disease pathogeneses. Recent studies have demonstrated that mosaic loss of Y chromosome and aberrant... (Review)
Review
Sex differences are prevalent in normal development, physiology and disease pathogeneses. Recent studies have demonstrated that mosaic loss of Y chromosome and aberrant activation of its genes could modify the disease processes in male biased manners. This mini review discusses the nature of the genes on the human Y chromosome and identifies two general categories of genes: those sharing dosage-sensitivity functions with their X homologues and those with testis-specific expression and functions. Mosaic loss of the former disrupts the homeostasis important for the maintenance of health while aberrant activation of the latter promotes pathogenesis in non-gonadal tissues, thereby contributing to genetic predispositions to diseases in men.
PubMed: 32817785
DOI: 10.1186/s13578-020-00452-w -
Sexual Development : Genetics,... 2012The pseudoautosomal region (PAR) is a unique and specialized segment on the mammalian sex chromosomes with known functions in male meiosis and fertility. Detailed... (Review)
Review
The pseudoautosomal region (PAR) is a unique and specialized segment on the mammalian sex chromosomes with known functions in male meiosis and fertility. Detailed molecular studies of the region in human and mouse show dramatic differences between the 2 PARs. Recent mapping efforts in horse, dog/cat, cattle/ruminants, pig and alpaca indicate that the PAR also varies in size and gene content between other species. Given that PAR genes escape X inactivation, these differences might critically affect the genetic consequences, such as embryonic survival and postnatal phenotypes of sex chromosome aneuploidies. The aim of this review is to combine the available information about the organization of the PAR in domestic species with the cytogenetic data on sex chromosome aneuploidies. We show that viable XO individuals are relatively frequently found in species with small PARs, such as horses, humans and mice but are rare or absent in species in which the PAR is substantially larger, like in cattle/ruminants, dogs, pigs, and alpacas. No similar correlation can be detected between the PAR size and the X chromosome trisomy in different species. Recent evidence about the likely involvement of PAR genes in placenta formation, early embryonic development and genomic imprinting are presented.
Topics: Aneuploidy; Animals; Animals, Domestic; Chromosome Mapping; Female; Humans; Male; Mice; Sex Chromosome Aberrations; X Chromosome; Y Chromosome
PubMed: 21876343
DOI: 10.1159/000330627 -
GigaScience Dec 2022The swamp buffalo (Bubalus bubalis carabanesis) is an economically important livestock supplying milk, meat, leather, and draft power. Several female buffalo genomes...
BACKGROUND
The swamp buffalo (Bubalus bubalis carabanesis) is an economically important livestock supplying milk, meat, leather, and draft power. Several female buffalo genomes have been available, but the lack of high-quality male genomes hinders studies on chromosome evolution, especially Y, as well as meiotic recombination.
RESULTS
Here, a chromosome-level genome with a contig N50 of 72.2 Mb and a fine-scale recombination map of male buffalo were reported. We found that transposable elements (TEs) and structural variants (SVs) may contribute to buffalo evolution by influencing adjacent gene expression. We further found that the pseudoautosomal region (PAR) of the Y chromosome is subject to stronger purification selection. The meiotic recombination map showed that there were 2 obvious recombination hotspots on chromosome 8, and the genes around them were mainly related to tooth development, which may have helped to enhance the adaption of buffalo to inferior feed. Among several genomic features, TE density has the strongest correlation with recombination rates. Moreover, the TE subfamily, SINE/tRNA, is likely to play a role in driving recombination into SVs.
CONCLUSIONS
The male genome and sperm sequencing will facilitate the understanding of the buffalo genomic evolution and functional research.
Topics: Male; Female; Animals; Semen; Bison; Genomics; Buffaloes; Chromosomes
PubMed: 37589307
DOI: 10.1093/gigascience/giad063 -
Cellular and Molecular Life Sciences :... Sep 2023XY chromosome missegregation is relatively common in humans and can lead to sterility or the generation of aneuploid spermatozoa. A leading cause of XY missegregation in...
XY chromosome missegregation is relatively common in humans and can lead to sterility or the generation of aneuploid spermatozoa. A leading cause of XY missegregation in mammals is the lack of formation of double-strand breaks (DSBs) in the pseudoautosomal region (PAR), a defect that may occur in mice due to faulty expression of Spo11 splice isoforms. Using a knock-in (ki) mouse that expresses only the single Spo11β splice isoform, here we demonstrate that by varying the genetic background of mice, the length of chromatin loops extending from the PAR axis and the XY recombination proficiency varies. In spermatocytes of C57 mice, in which loops are relatively short, recombination/synapsis between XY is fairly normal. In contrast, in cells of C57/129 males where PAR loops are relatively long, formation of DSBs in the PAR (more frequently the Y-PAR) and XY synapsis fails at a high rate, and mice produce sperm with sex-chromosomal aneuploidy. However, if the entire set of Spo11 splicing isoforms is expressed by a wild type allele in the C57/129 background, XY recombination and synapsis is recovered. By generating a Spo11αki mouse model, we prove that concomitant expression of SPO11β and SPO11α isoforms, boosts DSB formation in the PAR. Based on these findings, we propose that SPO11 splice isoforms cooperate functionally in promoting recombination in the PAR, constraining XY asynapsis defects that may arise due to differences in the conformation of the PAR between mouse strains.
Topics: Animals; Humans; Male; Mice; Alleles; Protein Isoforms; Pseudoautosomal Regions; Recombination, Genetic; Semen; Endodeoxyribonucleases
PubMed: 37682311
DOI: 10.1007/s00018-023-04912-7