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Human Mutation Feb 2022Runs of long homozygous (ROH) stretches are considered to be the result of consanguinity and usually contain recessive deleterious disease-causing mutations. Several...
Runs of long homozygous (ROH) stretches are considered to be the result of consanguinity and usually contain recessive deleterious disease-causing mutations. Several algorithms have been developed to detect ROHs. Here, we developed a simple alternative strategy by examining X chromosome non-pseudoautosomal region to detect the ROHs from next-generation sequencing data utilizing the genotype probabilities and the hidden Markov model algorithm as a tool, namely ROHMM. It is implemented purely in java and contains both a command line and a graphical user interface. We tested ROHMM on simulated data as well as real population data from the 1000G Project and a clinical sample. Our results have shown that ROHMM can perform robustly producing highly accurate homozygosity estimations under all conditions thereby meeting and even exceeding the performance of its natural competitors.
Topics: Algorithms; Consanguinity; Genotype; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Polymorphism, Single Nucleotide
PubMed: 34923717
DOI: 10.1002/humu.24316 -
Journal of Evolutionary Biology Dec 2022Evolution of a non-recombining sex-specific region on the Y (or W) chromosome (NRY) is a key step in sex chromosome evolution, but how recombination suppression evolves...
Evolution of a non-recombining sex-specific region on the Y (or W) chromosome (NRY) is a key step in sex chromosome evolution, but how recombination suppression evolves is not well understood. Studies in many different organisms indicated that NRY evolution often involves several expansion steps. Why such NRY expansions occur remains unclear, although it is though that they are likely driven by sexually antagonistic selection. This paper describes a recent NRY expansion due to shift of the pseudoautosomal boundary on the sex chromosomes of a dioecious plant Silene latifolia. The shift resulted in inclusion of at least 16 pseudoautosomal genes into the NRY. This region is pseudoautosomal in closely related Silene dioica and Silene diclinis, indicating that the NRY expansion occurred in S. latifolia after it speciated from the other species ~120 thousand years ago. As S. latifolia and S. dioica actively hybridise across Europe, interspecific gene flow could blur the PAR boundary in these species. The pseudoautosomal genes have significantly elevated genetic diversity (π ~ 3% at synonymous sites), which is consistent with balancing selection maintaining diversity in this region. The recent shift of the PAR boundary in S. latifolia offers an opportunity to study the process of on-going NRY expansion.
Topics: Silene; Chromosomes, Plant; Genes, Plant; Recombination, Genetic; Sex Chromosomes; Evolution, Molecular
PubMed: 35834179
DOI: 10.1111/jeb.14063 -
Genes Dec 2022Transmission ratio distortion (TRD), or significant deviations from Mendelian inheritance, is a well-studied phenomenon on autosomal chromosomes, but has not yet...
Transmission ratio distortion (TRD), or significant deviations from Mendelian inheritance, is a well-studied phenomenon on autosomal chromosomes, but has not yet received attention on sex chromosomes. TRD was analyzed on 3832 heterosomal single nucleotide polymorphisms (SNPs) and 400 pseudoautosomal SNPs spanning the length of the X-chromosome using 436,651 genotyped Holstein cattle. On the pseudoautosomal region, an opposite sire-TRD pattern between male and female offspring was identified for 149 SNPs. This finding revealed unique SNPs linked to a specific-sex (Y- or X-) chromosome and describes the accumulation of recombination events across the pseudoautosomal region. On the heterosomal region, 13 SNPs and 69 haplotype windows were identified with dam-TRD. Functional analyses for TRD regions highlighted relevant biological functions responsible to regulate spermatogenesis, development of Sertoli cells, homeostasis of endometrium tissue and embryonic development. This study uncovered the prevalence of different TRD patterns across both heterosomal and pseudoautosomal regions of the X-chromosome and revealed functional candidate genes for bovine reproduction.
Topics: Animals; Male; Cattle; Female; X Chromosome; Genotype; Sex Chromosomes; Fertility; Recombination, Genetic
PubMed: 36553588
DOI: 10.3390/genes13122322 -
BioMed Research International 2020Translocations involving X and Y chromosomes rarely occur in humans and may affect reproductive function. We investigated an Xp:Yq unbalanced translocation with...
Translocations involving X and Y chromosomes rarely occur in humans and may affect reproductive function. We investigated an Xp:Yq unbalanced translocation with pseudoautosomal region (PAR) aberrations in a natural two-generation transmission. We report the case of an azoospermic male and his fertile mother without any other abnormal clinical phenotypes, except for short stature. Cytogenetic methods, including karyotyping and fluorescence hybridization (FISH), revealed the translocation. Chromosomal microarray comparative genomic hybridization (array-CGH) was used to investigate the regions of Xp partial deletion and Yq partial duplication. Final chromosome karyotypes in the peripheral blood of the infertile male and his mother were 46,Y,der(X)t(X;Y)(p22.33;q11.22) and 46,X,der(X)t(X;Y)(p22.33;q11.22), respectively. Short-stature-homeobox gene deletion was responsible for the short stature in both subjects. PAR aberrations and AZFc duplication may be a direct genetic risk factor for spermatogenesis. This report further supports the use of routine karyotype analysis, FISH-based technology, and array-CGH analysis to identify derivative chromosomes in a complex rearrangement.
Topics: Chromosome Aberrations; Chromosome Deletion; Chromosome Duplication; Chromosomes; Chromosomes, Human, X; Chromosomes, Human, Y; Comparative Genomic Hybridization; Cytogenetics; Gene Deletion; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Male; Metaphase; Oligonucleotide Array Sequence Analysis; Pseudoautosomal Regions; Risk Factors; Spermatogenesis; Translocation, Genetic; User-Computer Interface
PubMed: 33344636
DOI: 10.1155/2020/4976204 -
Genes Apr 2018Hybrid sterility is an important step in the speciation process. Hybrids between dwarf hamsters and provide a good model for studies in cytological and genetic...
Hybrid sterility is an important step in the speciation process. Hybrids between dwarf hamsters and provide a good model for studies in cytological and genetic mechanisms of hybrid sterility. Previous studies in hybrids detected multiple abnormalities of spermatogenesis and a high frequency of dissociation between the X and Y chromosomes at the meiotic prophase. In this study, we found that the autosomes of the hybrid males and females underwent paring and recombination as normally as their parental forms did. The male hybrids showed a significantly higher frequency of asynapsis and recombination failure between the heterochromatic arms of the X and Y chromosomes than the males of the parental species. Female hybrids as well as the females of the parental species demonstrated a high incidence of centromere misalignment at the XX bivalent and partial asynapsis of the ends of its heterochromatic arms. In all three karyotypes, recombination was completely suppressed in the heterochromatic arm of the X chromosome, where the pseudoautosomal region is located. We propose that this recombination pattern speeds up divergence of the X- and Y-linked pseudoautosomal regions between the parental species and results in their incompatibility in the male hybrids.
PubMed: 29693587
DOI: 10.3390/genes9050227 -
Andrology May 2017Testicular maturation arrest is characterized by interruption of germ cell development and differentiation. Genetic factors play important role in the causation of human...
Testicular maturation arrest is characterized by interruption of germ cell development and differentiation. Genetic factors play important role in the causation of human disease, including male infertility. The objective was to study copy number variations in testicular maturation arrest using single nucleotide polymorphism (SNP) microarray technique. Conventional cytogenetics, targeted fluorescence in situ hybridization (FISH) and sequence-tagged site (STS) polymerase chain reaction (PCR) were used to confirm some of the SNP microarray findings. SNP microarray on 68 cases of testicular maturation arrest detected copy number variations (CNVs) mostly on sex chromosomes involving pseudoautosomal regions (PAR) 1, 2 and 3 as well as azoospermic factors (AZFs) besides three cases of chromosomal abnormalities (two Klinefelter syndromes and one case of dicentric Y). The AZF deletion was observed in 14 (20.6%) cases and the AZFc gain was observed in 6 (8.8%) cases. PAR 1 and 2 CNVs was observed in 5 (7.3%) cases. PAR 3 CNVs was detected in 19 cases and 2 controls. The TSPY2 gene gain (within PAR 3 CNVs) was observed in 16 cases and 1 control. CNV containing autosomal genes possibly associated with male infertility in this study was SPATA31A2-A5 (9p12) in five cases. In this study, SNP microarray identified possible underlying aetiology in 55.9% (38/68) cases besides identifying minimal critical region of AZFc deletion as 0.51 mb (Y:24356128-24873665) involving TTY5, RBMY2FP, RBMY1F, RBMY1J, TTY6 and PRY genes. SNP microarray seems superior, sensitive, specific as well as cost-effective method and has potential to be the first tier investigations to explore underlying genomic factors of testicular maturation arrest. The present study is an attempt to find out probable genomic factors with idiopathic testicular maturation arrest.
Topics: Adolescent; Adult; Azoospermia; DNA Copy Number Variations; Humans; In Situ Hybridization, Fluorescence; Infertility, Male; Male; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Prospective Studies; Young Adult
PubMed: 28217965
DOI: 10.1111/andr.12330 -
The EMBO Journal Jul 2021Segregation of the largely non-homologous X and Y sex chromosomes during male meiosis is not a trivial task, because their pairing, synapsis, and crossover formation are...
Segregation of the largely non-homologous X and Y sex chromosomes during male meiosis is not a trivial task, because their pairing, synapsis, and crossover formation are restricted to a tiny region of homology, the pseudoautosomal region. In humans, meiotic X-Y missegregation can lead to 47, XXY offspring, also known as Klinefelter syndrome, but to what extent genetic factors predispose to paternal sex chromosome aneuploidy has remained elusive. In this issue, Liu et al (2021) provide evidence that deleterious mutations in the USP26 gene constitute one such factor.
Topics: Aneuploidy; Cysteine Endopeptidases; Humans; Male; Meiosis; Risk Factors; Spermatozoa
PubMed: 34031897
DOI: 10.15252/embj.2021108552 -
Molecular Cytogenetics 2020Tourette syndrome (TS) is a complex neurodevelopmental disorder (NDD) characterized by multiple chronic involuntary motor and vocal tics with onset during childhood or...
BACKGROUND
Tourette syndrome (TS) is a complex neurodevelopmental disorder (NDD) characterized by multiple chronic involuntary motor and vocal tics with onset during childhood or adolescence. Most TS patients present with additional comorbidities, typically attention deficit hyperactivity disorder (ADHD), obsessive- compulsive disorder (OCD), autism spectrum disorder (ASD) and intellectual disability (ID). Both TS and ID are genetically complex disorders that likely occur as a result of the effects of multiple genes interacting with other environmental factors. In addition to single gene mutations and chromosomal disorders, copy number variations (CNVs) are implicated across many NDDs and ID and contribute to their shared genetic etiology. Screening of CNVs using microarray-based Comparative Genomic Hybridization (aCGH) is now routinely performed in all subjects with NDD and ID.
CASE PRESENTATION
We report a case of a 12-year-old girl diagnosed with Gilles de la Tourette Syndrome associated to behavior disorders and intellectual disability in particular with regard to language. Array-CGH analysis showed a CNV of a subtelomeric region Xq28 (gain of 260 kb) inherited from the healthy father. The duplication contains two genes, and of the PAR2 pseudoautosomal region. FISH analysis revealed that the duplicated segment is located on the short arm of a chromosome 13, resulting in a trisomy of the region. In the proband the expression levels of the genes evaluated in the peripheral blood sample are comparable both those of the mother and to those of female control subjects.
CONCLUSIONS
Although the trisomy of the 260 kb region from Xq28 identified in proband is also shared by the healthy father, it is tantalizing to speculate that, together with genetic risk factors inherited from the mother, it may play a role in the development of a form of Tourette syndrome with intellectual disability. This hypothesis is also supported by the fact that both genes present in the duplicated region ( and are expressed in the CNS and are implicated in neurotransmission and neurite growth and branching. In addition, similar CNVs have been identified in individuals whose phenotype is associated with autism spectrum disorders or intellectual disability.
PubMed: 32582378
DOI: 10.1186/s13039-020-00493-3 -
ELife Jan 2023Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in 'mutation intolerant' genes. We show how such observations can be...
Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in 'mutation intolerant' genes. We show how such observations can be interpreted in light of a model of mutation-selection balance and use the model to relate the pathogenic consequences of LOF mutations at present to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,318 autosomal and 679 X-linked genes from exome sequences in 56,855 individuals. Estimated fitness costs for the loss of a gene copy are typically above 1%; they tend to be largest for X-linked genes, whether or not they have a Y homolog, followed by autosomal genes and genes in the pseudoautosomal region. We compare inferred fitness effects for all possible de novo LOF mutations to those of de novo mutations identified in individuals diagnosed with one of six severe, complex diseases or developmental disorders. Probands carry an excess of mutations with estimated fitness effects above 10%; as we show by simulation, when sampled in the population, such highly deleterious mutations are typically only a couple of generations old. Moreover, the proportion of highly deleterious mutations carried by probands reflects the typical age of onset of the disease. The study design also has a discernible influence: a greater proportion of highly deleterious mutations is detected in pedigree than case-control studies, and for autism, in simplex than multiplex families and in female versus male probands. Thus, anchoring observations in human genetics to a population genetic model allows us to learn about the fitness effects of mutations identified by different mapping strategies and for different traits.
Topics: Humans; Male; Female; Mutation; Loss of Function Mutation; Autistic Disorder; Phenotype; Case-Control Studies
PubMed: 36648429
DOI: 10.7554/eLife.83172 -
G3 (Bethesda, Md.) May 2022Salmon lice have plagued the salmon farming industry and have negatively impacted salmon populations in the wild. In response, researchers have generated high density...
Salmon lice have plagued the salmon farming industry and have negatively impacted salmon populations in the wild. In response, researchers have generated high density genetic maps, genome assemblies, transcriptomes, and whole-genome resequencing data to better understand this parasite. In this study, we used long-read sequencing technology to update the previous genome assemblies of Atlantic Ocean salmon lice with a more contiguous assembly and a more comprehensive gene catalog of Pacific Ocean salmon lice. We were also able to further characterize genomic features previously identified from other studies by using published resequenced genomes of 25 Atlantic and 15 Pacific salmon lice. One example was further characterizing the ZW sex chromosomes. For both the Atlantic and Pacific Ocean salmon lice subspecies, we found that the female W-chromosome is only a small fraction of the Z-chromosome and that the vast majority of the W and Z-chromosome do not contain conserved regions (i.e. pseudoautosomal regions). However, conserved orthologous protein sequences can still be identified between the W- and Z-chromosomes.
Topics: Animals; Copepoda; Female; Fish Diseases; Pacific Ocean; Salmo salar; Salmon; Sequence Analysis, DNA; Transcriptome
PubMed: 35404448
DOI: 10.1093/g3journal/jkac087