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Biochimica Et Biophysica Acta.... Apr 2022ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of... (Review)
Review
ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of individuals dying early on and the majority having good prognosis if they survive the first year of life. The reasons for this variability remain unclear. Two genes have been shown to cause ARPKD when mutated, PKHD1, mutations in which lead to most of ARPKD cases and DZIP1L, which is associated with moderate ARPKD. This mini review will explore the genetics of ARPKD and discuss potential genetic modifiers and phenocopies that could affect diagnosis.
Topics: Adaptor Proteins, Signal Transducing; Animals; Humans; Polycystic Kidney, Autosomal Recessive; Polymorphism, Genetic; Prognosis; Receptors, Cell Surface; Signal Transduction; Transcription Factors
PubMed: 35032595
DOI: 10.1016/j.bbadis.2022.166348 -
Trends in Genetics : TIG Nov 2019X inactivation presents two longstanding puzzles: the counting and choice of X chromosomes. Here, we consider counting and choice in the context of pairing, both of the...
X inactivation presents two longstanding puzzles: the counting and choice of X chromosomes. Here, we consider counting and choice in the context of pairing, both of the X and of the autosomes.
Topics: Animals; Chromosome Pairing; Chromosomes; Humans; Mammals; Mice; Models, Genetic; X Chromosome; X Chromosome Inactivation
PubMed: 31521404
DOI: 10.1016/j.tig.2019.07.010 -
Cell Dec 2023Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a...
Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.
Topics: Humans; Fragile X Syndrome; Trinucleotide Repeat Expansion; DNA Methylation; Mutation; Fragile X Mental Retardation Protein
PubMed: 38134876
DOI: 10.1016/j.cell.2023.11.019 -
Cell Jan 2024X chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X chromosome...
X chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X chromosome in cis to mediate gene silencing chromosome-wide. In female naive human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration, and XCI does not occur, raising questions about XIST's function. We found that XIST spreads across the X chromosome and induces dampening of X-linked gene expression in naive hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences in autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting.
Topics: Animals; Female; Humans; Male; Mice; Gene Silencing; Genes, X-Linked; RNA, Long Noncoding; X Chromosome; Pluripotent Stem Cells
PubMed: 38181737
DOI: 10.1016/j.cell.2023.11.033 -
BMC Biology Jul 2022Sex chromosomes are typically viewed as having originated from a pair of autosomes, and differentiated as the sex-limited chromosome (e.g. Y) has degenerated by losing... (Review)
Review
Sex chromosomes are typically viewed as having originated from a pair of autosomes, and differentiated as the sex-limited chromosome (e.g. Y) has degenerated by losing most genes through cessation of recombination. While often thought that degenerated sex-limited chromosomes primarily affect traits involved in sex determination and sex cell production, accumulating evidence suggests they also influence traits not sex-limited or directly involved in reproduction. Here, we provide an overview of the effects of sex-limited chromosomes on non-reproductive traits in XY, ZW or UV sex determination systems, and discuss evolutionary processes maintaining variation at sex-limited chromosomes and molecular mechanisms affecting non-reproductive traits.
Topics: Biological Evolution; Phenotype; Reproduction; Sex Chromosomes
PubMed: 35794589
DOI: 10.1186/s12915-022-01357-5 -
Genes Mar 2021Frogs are ideal organisms for studying sex chromosome evolution because of their diversity in sex chromosome differentiation and sex-determination systems. We review 222... (Review)
Review
Frogs are ideal organisms for studying sex chromosome evolution because of their diversity in sex chromosome differentiation and sex-determination systems. We review 222 anuran frogs, spanning ~220 Myr of divergence, with characterized sex chromosomes, and discuss their evolution, phylogenetic distribution and transitions between homomorphic and heteromorphic states, as well as between sex-determination systems. Most (~75%) anurans have homomorphic sex chromosomes, with XY systems being three times more common than ZW systems. Most remaining anurans (~25%) have heteromorphic sex chromosomes, with XY and ZW systems almost equally represented. There are Y-autosome fusions in 11 species, and no W-/Z-/X-autosome fusions are known. The phylogeny represents at least 19 transitions between sex-determination systems and at least 16 cases of independent evolution of heteromorphic sex chromosomes from homomorphy, the likely ancestral state. Five lineages mostly have heteromorphic sex chromosomes, which might have evolved due to demographic and sexual selection attributes of those lineages. Males do not recombine over most of their genome, regardless of which is the heterogametic sex. Nevertheless, telomere-restricted recombination between ZW chromosomes has evolved at least once. More comparative genomic studies are needed to understand the evolutionary trajectories of sex chromosomes among frog lineages, especially in the ZW systems.
Topics: Animals; Anura; Evolution, Molecular; Female; Male; Phylogeny; Sex Chromosomes; Sex Determination Processes
PubMed: 33810524
DOI: 10.3390/genes12040483 -
Journal of Evolutionary Biology Dec 2022Sex chromosomes are common features of animal genomes, often carrying a sex determination gene responsible for initiating the development of sexually dimorphic traits.... (Review)
Review
Sex chromosomes are common features of animal genomes, often carrying a sex determination gene responsible for initiating the development of sexually dimorphic traits. The specific chromosome that serves as the sex chromosome differs across taxa as a result of fusions between sex chromosomes and autosomes, along with sex chromosome turnover-autosomes becoming sex chromosomes and sex chromosomes 'reverting' back to autosomes. In addition, the types of genes on sex chromosomes frequently differ from the autosomes, and genes on sex chromosomes often evolve faster than autosomal genes. Sex-specific selection pressures, such as sexual antagonism and sexual selection, are hypothesized to be responsible for sex chromosome turnovers, the unique gene content of sex chromosomes and the accelerated evolutionary rates of genes on sex chromosomes. Sex-specific selection has pronounced effects on sex chromosomes because their sex-biased inheritance can tilt the balance of selection in favour of one sex. Despite the general consensus that sex-specific selection affects sex chromosome evolution, most population genetic models are agnostic as to the specific sources of these sex-specific selection pressures, and many of the details about the effects of sex-specific selection remain unresolved. Here, I review the evidence that ecological factors, including variable selection across heterogeneous environments and conflicts between sexual and natural selection, can be important determinants of sex-specific selection pressures that shape sex chromosome evolution. I also explain how studying the ecology of sex chromosome evolution can help us understand important and unresolved aspects of both sex chromosome evolution and sex-specific selection.
Topics: Animals; Male; Female; Sex Chromosomes; Selection, Genetic; Sex Determination Processes; Inheritance Patterns; Phenotype; Evolution, Molecular
PubMed: 35950939
DOI: 10.1111/jeb.14074 -
Therapeutic Advances in Musculoskeletal... 2019Hypophosphatasia is a rare inherited disease caused by a loss of function mutations in the gene that codes for the tissue-nonspecific alkaline phosphatase enzyme. It is... (Review)
Review
Hypophosphatasia is a rare inherited disease caused by a loss of function mutations in the gene that codes for the tissue-nonspecific alkaline phosphatase enzyme. It is autosomally inherited and at least 388 different genetic defects have been identified. The clinical presentation is variable from a severe perinatal form, that is fatal if untreated, to adult-onset disease. This review covers the pathophysiology, diagnosis and current management option including the recently licensed enzyme replacement therapy asfotase alfa.
PubMed: 31413732
DOI: 10.1177/1759720X19863997 -
International Journal of Molecular... Feb 2023Primary ovarian insufficiency (POI) is a heterogeneous disease resulting from non-functional ovaries in women before the age of 40. It is characterized by primary... (Review)
Review
Primary ovarian insufficiency (POI) is a heterogeneous disease resulting from non-functional ovaries in women before the age of 40. It is characterized by primary amenorrhea or secondary amenorrhea. As regards its etiology, although many POI cases are idiopathic, menopausal age is a heritable trait and genetic factors play an important role in all POI cases with known causes, accounting for approximately 20% to 25% of cases. This paper reviews the selected genetic causes implicated in POI and examines their pathogenic mechanisms to show the crucial role of genetic effects on POI. The genetic factors that can be found in POI cases include chromosomal abnormalities (e.g., X chromosomal aneuploidies, structural X chromosomal abnormalities, X-autosome translocations, and autosomal variations), single gene mutations (e.g., newborn ovary homeobox gene (NOBOX), folliculogenesis specific bHLH transcription factor (FIGLA), follicle-stimulating hormone receptor (FSHR), forkhead box L2 (FOXL2), bone morphogenetic protein 15 (BMP15), etc., as well as defects in mitochondrial functions and non-coding RNAs (small ncRNAs and long ncRNAs). These findings are beneficial for doctors to diagnose idiopathic POI cases and predict the risk of POI in women.
Topics: Female; Humans; Infant, Newborn; Amenorrhea; Chromosome Aberrations; Mutation; Primary Ovarian Insufficiency
PubMed: 36901862
DOI: 10.3390/ijms24054423