In humans, deletion of any one of three Y-chromosomal regions- AZFa, AZFb or AZFc-disrupts spermatogenesis, causing infertility in otherwise healthy men. Although candidate genes have been identified ...in all three regions, no case of spermatogenic failure has been traced to a point mutation in a Y-linked gene, or to a deletion of a single Y-linked gene. We sequenced the AZFa region of the Y chromosome and identified two functional genes previously described: USP9Y (also known as DFFRY) and DBY (refs 7,8). Screening of the two genes in 576 infertile and 96 fertile men revealed several sequence variants, most of which appear to be heritable and of little functional consequence. We found one de novo mutation in USP9Y: a 4-bp deletion in a splice-donor site, causing an exon to be skipped and protein truncation. This mutation was present in a man with nonobstructive azoospermia (that is, no sperm was detected in semen), but absent in his fertile brother, suggesting that the USP9Y mutation caused spermatogenic failure. We also identified a single-gene deletion associated with spermatogenic failure, again involving USP9Y, by re-analysing a published study.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We identified the gene carrying the juvenile spermatogonial depletion mutation (jsd), a recessive spermatogenic defect mapped to mouse chromosome 1 (refs. 1,2). We localized jsd to a 272-kb region ...and resequenced this area to identify the underlying mutation: a frameshift that severely truncates the predicted protein product of a 2.3-kb genomic open reading frame. This gene, Utp14b, evidently arose through reverse transcription of an mRNA from an X-linked gene and integration of the resulting cDNA into an intron of an autosomal gene, whose promoter and 5′ untranslated exons are shared with Utp14b. To our knowledge, Utp14b is the first protein-coding retrogene to be linked to a recessive mammalian phenotype. The X-linked progenitor of Utp14b is the mammalian ortholog of yeast Utp14, which encodes a protein required for processing of pre-rRNA and hence for ribosome assembly. Our findings substantiate the hypothesis that mammalian spermatogenesis is supported by autosomal retrogenes that evolved from X-linked housekeeping genes to compensate for silencing of the X chromosome during male meiosis. We find that Utp14b-like retrogenes arose independently and were conserved during evolution in at least four mammalian lineages. This recurrence implies a strong selective pressure, perhaps to enable ribosome assembly in male meiotic cells.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Amplicons – large, nearly identical repeats in direct or inverted orientation – are abundant in the male-specific region of the human Y chromosome (MSY) and provide targets for intrachromosomal ...non-allelic homologous recombination (NAHR). Thus far, NAHR events resulting in deletions, duplications, inversions, or isodicentric chromosomes have been reported only for amplicon pairs located exclusively on the short arm (Yp) or the long arm (Yq). Here we report our finding of four men with Y chromosomes that evidently formed by intrachromosomal NAHR between inverted repeat pairs comprising one amplicon on Yp and one amplicon on Yq. In two men with spermatogenic failure, sister-chromatid crossing-over resulted in pseudoisoYp chromosome formation and loss of distal Yq. In two men with normal spermatogenesis, intrachromatid crossing-over generated pericentric inversions. These findings highlight the recombinogenic nature of the MSY, as intrachromosomal NAHR occurs for nearly all Y-chromosome amplicon pairs, even those located on opposing chromosome arms.
•We molecularly characterize four structural rearrangements of the human Y chromosome.•Rearrangements arise by ectopic homologous recombination between Y chromosome arms.•Repeat pairs located on opposing arms of the Y chromosome can undergo recombination.•Fifty such rearrangements are predicted to arise on common Y chromosome structures.
We compared the human and mouse X chromosomes to systematically test Ohno’s law, which states that the gene content of X chromosomes is conserved across placental mammals
1
. First, we improved the ...accuracy of the human X-chromosome reference sequence through single-haplotype sequencing of ampliconic regions. This closed gaps in the reference sequence, corrected previously misassembled regions, and identified new palindromic amplicons. Our subsequent analysis led us to conclude that the evolution of human and mouse X chromosomes was bimodal. In accord with Ohno’s law, 94–95% of X-linked single-copy genes are shared between human and mouse; most are expressed in both sexes. Strikingly, most X-ampliconic genes are exceptions to Ohno’s law: only 31% of human and 22% of mouse X-ampliconic genes share orthologs. X-ampliconic genes are expressed predominantly in testicular germ cells, and many were independently acquired since the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genome‐wide recombination is essential for genome stability, evolution, and speciation. Mouse Tex11, an X‐linked meiosis‐specific gene, promotes meiotic recombination and chromosomal synapsis. Here, ...we report that TEX11 is mutated in infertile men with non‐obstructive azoospermia and that an analogous mutation in the mouse impairs meiosis. Genetic screening of a large cohort of idiopathic infertile men reveals that TEX11 mutations, including frameshift and splicing acceptor site mutations, cause infertility in 1% of azoospermic men. Functional evaluation of three analogous human TEX11 missense mutations in transgenic mouse models identified one mutation (V748A) as a potential infertility allele and found two mutations non‐causative. In the mouse model, an intronless autosomal Tex11 transgene functionally substitutes for the X‐linked Tex11 gene, providing genetic evidence for the X‐to‐autosomal retrotransposition evolution phenomenon. Furthermore, we find that TEX11 protein levels modulate genome‐wide recombination rates in both sexes. These studies indicate that TEX11 alleles affecting expression level or substituting single amino acids may contribute to variations in recombination rates between sexes and among individuals in humans.
A physical map of the human Y chromosome Page, David C; Tilford, Charles A; Kuroda-Kawaguchi, Tomoko ...
Nature (London),
02/2001, Letnik:
409, Številka:
6822
Journal Article
Recenzirano
Odprti dostop
The non-recombining region of the human Y chromosome (NRY), which comprises 95% of the chromosome, does not undergo sexual recombination and is present only in males. An understanding of its ...biological functions has begun to emerge from DNA studies of individuals with partial Y chromosomes, coupled with molecular characterization of genes implicated in gonadal sex reversal, Turner syndrome, graft rejection and spermatogenic failure. But mapping strategies applied successfully elsewhere in the genome have faltered in the NRY, where there is no meiotic recombination map and intrachromosomal repetitive sequences are abundant. Here we report a high-resolution physical map of the euchromatic, centromeric and heterochromatic regions of the NRY and its construction by unusual methods, including genomic clone subtraction and dissection of sequence family variants. Of the map's 758 DNA markers, 136 have multiple locations in the NRY, reflecting its unusually repetitive sequence composition. The markers anchor 1,038 bacterial artificial chromosome clones, 199 of which form a tiling path for sequencing.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Y chromosome deletions arise frequently in human populations, where they cause sex reversal and Turner syndrome and predispose individuals to infertility and germ cell cancer. Knowledge of the ...nucleotide sequence of the male-specific region of the Y chromosome (MSY) makes it possible to precisely demarcate such deletions and the repertoires of genes lost, offering insights into mechanisms of deletion and the molecular etiologies of associated phenotypes. Such deletion mapping is usually conducted using polymerase chain reaction (PCR) assays for the presence or absence of a series of Y-chromosomal DNA markers, or sequence-tagged sites (STSs). In the course of mapping intact and aberrant Y chromosomes during the past two decades, we and our colleagues have developed robust PCR assays for 1287 Y-specific STSs. These PCR assays amplify 1698 loci at an average spacing of <14 kb across the MSY euchromatin. To facilitate mapping of deletions, we have compiled a database of these STSs, MSY Breakpoint Mapper (http://breakpointmapper.wi.mit.edu/). When queried, this online database provides regionally targeted catalogs of STSs and nearby genes. MSY Breakpoint Mapper is useful for efficiently and systematically defining the breakpoint(s) of virtually any naturally occurring Y chromosome deletion.
The DAZ genes are candidate fertility factors that lie within the human Y chromosome's AZFc region, whose deletion is a common cause of spermatogenic failure. The number of DAZ genes has been ...difficult to determine, in part because the nucleotide sequences of the DAZ genes are nearly identical. Here, fluorescence in situ hybridization and characterization of BAC clones revealed four full-length DAZ genes on the human Y chromosome. They exist in two clusters, each comprising an inverted pair of DAZ genes (3′ ← 5′::5′ → 3′). Analysis of genomic sequences and testicular transcripts suggested that three or four DAZ genes are translated. Each gene contains at least seven tandem copies of a previously described, 2.4-kb repeat unit that encodes 24 amino acids. In addition, two DAZ genes contain tandem copies of a 10.8-kb repeat unit that encodes the RNA-binding domain, which appears to be multimerized in some DAZ proteins. Combining our present results with previous studies, we can reconstruct several steps in the evolution of the DAZ genes on the Y chromosome. In the ancestral Y-chromosomal DAZ gene, amplification of both intragenic repeats began before the human and cynomolgus (Old World) monkey lineages diverged. During subsequent evolution, an inverted duplication of this modified gene occurred. Finally, the resulting two-gene cluster was duplicated, generating the two-cluster/four-gene arrangement found on modern human Y chromosomes.
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