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1.
PLoS Genet ; 16(2): e1008300, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32092051

RESUMO

Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies and is caused by mutations in EFNB1. Heterozygous females are more severely affected by CFNS than hemizygous males, a phenomenon called cellular interference that results from EPHRIN-B1 mosaicism. In Efnb1 heterozygous mice, mosaicism for EPHRIN-B1 results in cell sorting and more severe phenotypes than Efnb1 hemizygous males, but how craniofacial dysmorphology arises from cell segregation is unknown and CFNS etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques with temporal and spatial interrogation of embryonic cell segregation in mouse mutant models to elucidate mechanisms underlying CFNS pathogenesis. By generating EPHRIN-B1 mosaicism at different developmental timepoints and in specific cell populations, we find that EPHRIN-B1 regulates cell segregation independently in early neural development and later in craniofacial development, correlating with the emergence of quantitative differences in face shape. Whereas specific craniofacial shape changes are qualitatively similar in Efnb1 heterozygous and hemizygous mutant embryos, heterozygous embryos are quantitatively more severely affected, indicating that Efnb1 mosaicism exacerbates loss of function phenotypes rather than having a neomorphic effect. Notably, neural tissue-specific disruption of Efnb1 does not appear to contribute to CFNS craniofacial dysmorphology, but its disruption within neural crest cell-derived mesenchyme results in phenotypes very similar to widespread loss. EPHRIN-B1 can bind and signal with EPHB1, EPHB2, and EPHB3 receptor tyrosine kinases, but the signaling partner(s) relevant to CFNS are unknown. Geometric morphometric analysis of an allelic series of Ephb1; Ephb2; Ephb3 mutant embryos indicates that EPHB2 and EPHB3 are key receptors mediating Efnb1 hemizygous-like phenotypes, but the complete loss of EPHB1-3 does not fully recapitulate the severity of CFNS-like Efnb1 heterozygosity. Finally, by generating Efnb1+/Δ; Ephb1; Ephb2; Ephb3 quadruple knockout mice, we determine how modulating cumulative receptor activity influences cell segregation in craniofacial development and find that while EPHB2 and EPHB3 play an important role in craniofacial cell segregation, EPHB1 is more important for cell segregation in the brain; surprisingly, complete loss of EPHB1-EPHB3 does not completely abrogate cell segregation. Together, these data advance our understanding of the etiology and signaling interactions underlying CFNS dysmorphology.


Assuntos
Movimento Celular/genética , Anormalidades Craniofaciais/genética , Efrina-B1/genética , Crista Neural/embriologia , Crânio/anormalidades , Animais , Anormalidades Craniofaciais/diagnóstico , Modelos Animais de Doenças , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Efrina-B1/metabolismo , Feminino , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Mosaicismo , Mutação , Crista Neural/citologia , Fenótipo , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Índice de Gravidade de Doença , Fatores Sexuais , Crânio/embriologia , Cromossomo X/genética
3.
Anim Genet ; 51(1): 122-126, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31691328

RESUMO

A GWAS was performed for inborn X-linked facial dysmorphia with severe growth retardation in Labrador Retrievers. This lethal condition was mapped on the X chromosome at 17-21 Mb and supported by eight SNPs in complete LD. Dams of affected male puppies were heterozygous for the significantly associated SNPs and male affected puppies carried the associated alleles hemizygously. In the near vicinity to the associated region, RPS6KA3 was identified as a candidate gene causing facial dysmorphia in humans and mice known as Coffin-Lowry syndrome. Haplotype analysis showed significant association with the phenotypes of all 18 animals under study. This haplotype was validated through normal male progeny from a dam with the not-associated haplotype on both X chromosomes but male affected full-sibs with the associated haplotype.


Assuntos
Craniossinostoses/veterinária , Doenças do Cão/genética , Cães/genética , Genes Letais , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Animais , Craniossinostoses/genética , Feminino , Estudos de Associação Genética/veterinária , Haplótipos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Cromossomo X/genética
4.
PLoS Genet ; 15(11): e1008421, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31697682

RESUMO

Balancer chromosomes are multiply inverted and rearranged chromosomes that are widely used in Drosophila genetics. First described nearly 100 years ago, balancers are used extensively in stock maintenance and complex crosses. Recently, the complete molecular structures of several commonly used balancers were determined by whole-genome sequencing. This revealed a surprising amount of variation among balancers derived from a common progenitor, identified genes directly affected by inversion breakpoints, and cataloged mutations shared by balancers. These studies emphasized that it is important to choose the optimal balancer, because different inversions suppress meiotic recombination in different chromosomal regions. In this review, we provide a brief history of balancers in Drosophila, discuss how they are used today, and provide examples of unexpected recombination events involving balancers that can lead to stock breakdown.


Assuntos
Inversão Cromossômica/genética , Cromossomos de Insetos/genética , Heterocromatina/genética , Recombinação Homóloga/genética , Animais , Centrômero/genética , Drosophila melanogaster/genética , Genoma de Inseto/genética , Fenótipo , Deleção de Sequência/genética , Cromossomo X/genética
5.
PLoS Genet ; 15(11): e1008502, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738748

RESUMO

Male Drosophila typically have achiasmatic meiosis, and fusions between autosomes and the Y chromosome have repeatedly created non-recombining neo-Y chromosomes that degenerate. Intriguingly, Drosophila nasuta males recombine, but their close relative D. albomicans reverted back to achiasmy after evolving neo-sex chromosomes. Here we use genome-wide polymorphism data to reconstruct the complex evolutionary history of neo-sex chromosomes in D. albomicans and examine the effect of recombination and its cessation on the initiation of neo-Y decay. Population and phylogenomic analyses reveal three distinct neo-Y types that are geographically restricted. Due to ancestral recombination with the neo-X, overall nucleotide diversity on the neo-Y is similar to the neo-X but severely reduced within neo-Y types. Consistently, the neo-Y chromosomes fail to form a monophyletic clade in sliding window trees outside of the region proximal to the fusion. Based on tree topology changes, we inferred the recombination breakpoints that produced haplotypes specific to each neo-Y type. We show that recombination became suppressed at different time points for the different neo-Y haplotypes. Haplotype age correlates with onset of neo-Y decay, and older neo-Y haplotypes show more fixed gene disruption via frameshift indels and down-regulation of neo-Y alleles. Genes are downregulated independently on the different neo-Ys, but are depleted of testes-expressed genes across all haplotypes. This indicates that genes important for male function are initially shielded from degeneration. Our results offer a time course of the early progression of Y chromosome evolution, showing how the suppression of recombination, through the reversal to achiasmy in D. albomicans males, initiates the process of degeneration.


Assuntos
Evolução Molecular , Meiose/genética , Recombinação Genética , Cromossomo Y/genética , Alelos , Animais , Drosophila/genética , Feminino , Haplótipos , Masculino , Filogenia , Cromossomo X/genética
7.
Nat Struct Mol Biol ; 26(10): 963-969, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31582851

RESUMO

Ohno's hypothesis postulates that upregulation of X-linked genes rectifies their dosage imbalance relative to autosomal genes, which are present in two active copies per cell. Here we have dissected X-chromosome upregulation into the kinetics of transcription, inferred from allele-specific single-cell RNA sequencing data from somatic and embryonic mouse cells. We confirmed increased X-chromosome expression levels in female and male cells and found that the X chromosome achieved upregulation by elevated burst frequencies. By monitoring transcriptional kinetics in differentiating female mouse embryonic stem cells, we found that increased burst frequency was established on the active X chromosome when X inactivation took place on the other allele. Thus, our study provides mechanistic insights into X-chromosome upregulation.


Assuntos
Ativação Transcricional , Regulação para Cima , Cromossomo X/genética , Alelos , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Ligados ao Cromossomo X , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inativação do Cromossomo X
8.
PLoS Genet ; 15(9): e1008333, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31537017

RESUMO

In mammals, dosage compensation of sex chromosomal genes between females (XX) and males (XY) is achieved through X-chromosome inactivation (XCI). The X-linked X-inactive-specific transcript (Xist) long noncoding RNA is indispensable for XCI and initiates the process early during development by spreading in cis across the X chromosome from which it is transcribed. During XCI, Xist RNA triggers gene silencing, recruits a plethora of chromatin modifying factors, and drives a major structural reorganization of the X chromosome. Here, we review our knowledge of the multitude of epigenetic events orchestrated by Xist RNA to allow female mammals to survive through embryonic development by establishing and maintaining proper dosage compensation. In particular, we focus on recent studies characterizing the interaction partners of Xist RNA, and we discuss how they have affected the field by addressing long-standing controversies or by giving rise to new research perspectives that are currently being explored. This review is dedicated to the memory of Denise Barlow, pioneer of genomic imprinting and functional long noncoding RNAs (lncRNAs), whose work has revolutionized the epigenetics field and continues to inspire generations of scientists.


Assuntos
Compensação de Dosagem (Genética)/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Compensação de Dosagem (Genética)/fisiologia , Epigênese Genética/genética , Feminino , Inativação Gênica/fisiologia , Humanos , Masculino , Mamíferos/genética , RNA Longo não Codificante/fisiologia , Cromossomo X/genética , Inativação do Cromossomo X/genética
9.
J Dairy Sci ; 102(11): 10100-10104, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31447157

RESUMO

Freemartinism is the most common type of disorder of sex development in cattle. It leads to sterility in the female co-twin in heterosexual twin pregnancy, and is thus a serious problem in cattle production. The incidence of freemartin syndrome is directly dependent on the prevalence of twinning, which has increased in dairy cattle populations in recent years. Thus, early and rapid identification of freemartins is needed to reduce economic loss. Of the various methods used to diagnose this condition, identifying the XX and XY cell lines in blood samples using cytogenetic techniques is the gold standard; however, this technique is time consuming. Faster and more reliable techniques are thus being sought. Droplet digital PCR (ddPCR) is a third-generation PCR method and it has not previously been used to detect XX/XY leukocyte chimerism in cattle. The aim of the present study was to verify the usefulness of ddPCR to detect and quantify leukocyte chimerism in this species. The X and Y copy numbers were estimated by identifying the copy numbers of 2 genes located on the sex chromosomes: amelogenin X-linked (AMELX) on the X chromosome and amelogenin Y-linked (AMELY) on the Y chromosome. In the first step, we performed ddPCR on samples prepared from female DNA mixed with male DNA in serially diluted proportions. We determined that the sensitivity of this method was sufficient to detect a low-frequency (<5%) cell line. In the next step, ddPCR was used to analyze 22 Holstein Friesian freemartins. Cytogenetic evaluation of these cases revealed leukocyte chimerism; the proportion of XX and XY metaphase spreads varied over a wide range, from XX (98%)/XY (2%) to XX (4%)/XY (96%). The use of ddPCR facilitated the precise estimation of the ratio of the copy number of X to Y sex chromosomes. In all cases, the XX/XY chimerism detected by cytogenetic analysis was confirmed using ddPCR. The method turned out to be very simple, accurate, and sensitive. In conclusion, we recommend the ddPCR method for fast and reliable detection of XX/XY leukocyte chimerism in cattle.


Assuntos
Amelogenina/genética , Quimerismo/veterinária , Freemartinismo/diagnóstico , Reação em Cadeia da Polimerase/veterinária , Cromossomos Sexuais/genética , Animais , Bovinos , Feminino , Freemartinismo/genética , Leucócitos , Masculino , Reação em Cadeia da Polimerase/métodos , Gravidez , Sensibilidade e Especificidade , Cromossomo X/genética , Cromossomo Y/genética
10.
PLoS Genet ; 15(8): e1008337, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31449519

RESUMO

The synaptonemal complex (SC) is a proteinaceous scaffold required for synapsis and recombination between homologous chromosomes during meiosis. Although the SC has been linked to differences in genome-wide crossover rates, the genetic basis of standing variation in SC structure remains unknown. To investigate the possibility that recombination evolves through changes to the SC, we characterized the genetic architecture of SC divergence on two evolutionary timescales. Applying a novel digital image analysis technique to spermatocyte spreads, we measured total SC length in 9,532 spermatocytes from recombinant offspring of wild-derived mouse strains with differences in this fundamental meiotic trait. Using this large dataset, we identified the first known genomic regions involved in the evolution of SC length. Distinct loci affect total SC length divergence between and within subspecies, with the X chromosome contributing to both. Joint genetic analysis of MLH1 foci-immunofluorescent markers of crossovers-from the same spermatocytes revealed that two of the identified loci also confer differences in the genome-wide recombination rate. Causal mediation analysis suggested that one pleiotropic locus acts early in meiosis to designate crossovers prior to SC assembly, whereas a second locus primarily shapes crossover number through its effect on SC length. One genomic interval shapes the relationship between SC length and recombination rate, likely modulating the strength of crossover interference. Our findings pinpoint SC formation as a key step in the evolution of recombination and demonstrate the power of genetic mapping on standing variation in the context of the recombination pathway.


Assuntos
Troca Genética , Variação Genética , Proteína 1 Homóloga a MutL/genética , Complexo Sinaptonêmico/genética , Cromossomo X/genética , Animais , Mapeamento Cromossômico/métodos , Evolução Molecular , Loci Gênicos , Ensaios de Triagem em Larga Escala/métodos , Processamento de Imagem Assistida por Computador , Masculino , Camundongos , Microscopia de Fluorescência , Proteína 1 Homóloga a MutL/metabolismo , Espermatócitos/metabolismo , Complexo Sinaptonêmico/metabolismo , Cromossomo X/metabolismo
11.
Nat Commun ; 10(1): 3219, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363093

RESUMO

The position, shape and number of transcription start sites (TSS) are critical determinants of gene regulation. Most methods developed to detect TSSs and study promoter usage are, however, of limited use in studies that demand quantification of expression changes between two or more groups. In this study, we combine high-resolution detection of transcription start sites and differential expression analysis using a simplified TSS quantification protocol, MAPCap (Multiplexed Affinity Purification of Capped RNA) along with the software icetea . Applying MAPCap on developing Drosophila melanogaster embryos and larvae, we detected stage and sex-specific promoter and enhancer activity and quantify the effect of mutants of maleless (MLE) helicase at X-chromosomal promoters. We observe that MLE mutation leads to a median 1.9 fold drop in expression of X-chromosome promoters and affects the expression of several TSSs with a sexually dimorphic expression on autosomes. Our results provide quantitative insights into promoter activity during dosage compensation.


Assuntos
Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Capuzes de RNA/isolamento & purificação , Sítio de Iniciação de Transcrição , Animais , Animais Geneticamente Modificados , Linhagem Celular , Proteínas Cromossômicas não Histona/genética , Cromossomos de Insetos/genética , Biologia Computacional/métodos , DNA Helicases/genética , Compensação de Dosagem (Genética) , Proteínas de Drosophila/genética , Drosophila melanogaster/crescimento & desenvolvimento , Embrião não Mamífero , Desenvolvimento Embrionário/genética , Perfilação da Expressão Gênica/métodos , Genes de Insetos , Larva/genética , Larva/crescimento & desenvolvimento , Mutação , Regiões Promotoras Genéticas , Capuzes de RNA/genética , Software , Fatores de Transcrição/genética , Cromossomo X/genética
12.
PLoS Genet ; 15(7): e1008251, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31329593

RESUMO

Y chromosomes often contain amplified genes which can increase dosage of male fertility genes and counteract degeneration via gene conversion. Here we identify genes with increased copy number on both X and Y chromosomes in various species of Drosophila, a pattern that has previously been associated with sex chromosome drive involving the Slx and Sly gene families in mice. We show that recurrent X/Y co-amplification appears to be an important evolutionary force that has shaped gene content evolution of sex chromosomes in Drosophila. We demonstrate that convergent acquisition and amplification of testis expressed gene families are common on Drosophila sex chromosomes, and especially on recently formed ones, and we carefully characterize one putative novel X/Y co-amplification system. We find that co-amplification of the S-Lap1/GAPsec gene pair on both the X and the Y chromosome occurred independently several times in members of the D. obscura group, where this normally autosomal gene pair is sex-linked due to a sex chromosome-autosome fusion. We explore several evolutionary scenarios that would explain this pattern of co-amplification. Investigation of gene expression and short RNA profiles at the S-Lap1/GAPsec system suggest that, like Slx/Sly in mice, these genes may be remnants of a cryptic sex chromosome drive system, however additional transgenic experiments will be necessary to validate this model. Regardless of whether sex chromosome drive is responsible for this co-amplification, our findings suggest that recurrent gene duplications between X and Y sex chromosomes could have a widespread effect on genomic and evolutionary patterns, including the epigenetic regulation of sex chromosomes, the distribution of sex-biased genes, and the evolution of hybrid sterility.


Assuntos
Proteínas de Drosophila/genética , Drosophila/genética , Cromossomo X/genética , Cromossomo Y/genética , Animais , Biologia Computacional , Evolução Molecular , Amplificação de Genes , Duplicação Gênica , Masculino , Família Multigênica , Filogenia
13.
Nat Commun ; 10(1): 2950, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270318

RESUMO

X-chromosome inactivation triggers fusion of A/B compartments to inactive X (Xi)-specific structures known as S1 and S2 compartments. SMCHD1 then merges S1/S2s to form the Xi super-structure. Here, we ask how S1/S2 compartments form and reveal that Xist RNA drives their formation via recruitment of Polycomb repressive complex 1 (PRC1). Ablating Smchd1 in post-XCI cells unveils S1/S2 structures. Loss of SMCHD1 leads to trapping Xist in the S1 compartment, impairing RNA spreading into S2. On the other hand, depleting Xist, PRC1, or HNRNPK precludes re-emergence of S1/S2 structures, and loss of S1/S2 compartments paradoxically strengthens the partition between Xi megadomains. Finally, Xi-reactivation in post-XCI cells can be enhanced by depleting both SMCHD1 and DNA methylation. We conclude that Xist, PRC1, and SMCHD1 collaborate in an obligatory, sequential manner to partition, fuse, and direct self-association of Xi compartments required for proper spreading of Xist RNA.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Cromossomos de Mamíferos/genética , Complexo Repressor Polycomb 1/metabolismo , RNA Longo não Codificante/metabolismo , Cromossomo X/química , Cromossomo X/genética , Animais , Metilação de DNA/genética , Histonas/metabolismo , Lisina/metabolismo , Camundongos , Modelos Genéticos , Inativação do Cromossomo X/genética
14.
Nat Commun ; 10(1): 3129, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311937

RESUMO

Xist RNA, the master regulator of X chromosome inactivation, acts in cis to induce chromosome-wide silencing. Whilst recent studies have defined candidate silencing factors, their relative contribution to repressing different genes, and their relationship with one another is poorly understood. Here we describe a systematic analysis of Xist-mediated allelic silencing in mouse embryonic stem cell-based models. Using a machine learning approach we identify distance to the Xist locus and prior gene expression levels as key determinants of silencing efficiency. We go on to show that Spen, recruited through the Xist A-repeat, plays a central role, being critical for silencing of all except a subset of weakly expressed genes. Polycomb, recruited through the Xist B/C-repeat, also plays a key role, favouring silencing of genes with pre-existing H3K27me3 chromatin. LBR and the Rbm15/m6A-methyltransferase complex make only minor contributions to gene silencing. Together our results provide a comprehensive model for Xist-mediated chromosome silencing.


Assuntos
RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo , Inativação do Cromossomo X , Cromossomo X/genética , Animais , Linhagem Celular , Técnicas de Inativação de Genes , Inativação Gênica , Histonas/genética , Camundongos , Células-Tronco Embrionárias Murinas , Proteínas do Grupo Polycomb/metabolismo , Proteínas de Ligação a RNA/genética
15.
PLoS One ; 14(6): e0218565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220175

RESUMO

Testicular or ovotesticular disorders of sex development (DSD) in individuals with female karyotype (XX) lacking the SRY gene has been observed in several mammalian species, including dogs. A genetic background for this abnormality has been extensively sought, and the region harboring the SOX9 gene has often been considered key in canine DSD. Three types of polymorphism have been studied in this region to date: a) copy number variation (CNV) in a region about 400 kb upstream of SOX9, named CNVR1; b) duplication of SOX9; and c) insertion of a single G-nucleotide (rs852549625) approximately 2.2 Mb upstream of SOX9. The aim of this study was thus to comprehensively analyze these polymorphisms in a large multibreed case-control cohort containing 45 XX DSD dogs, representing 23 breeds. The control set contained 57 fertile females. Droplet digital PCR (ddPCR) was used to study CNVR1 and the duplication of SOX9. Fluorescent in situ hybridization (FISH) was used to visualize copy numbers on a cellular level. The Sanger sequencing approach was performed to analyze the region harboring the G-insertion. We confirmed that CNVR1 is highly polymorphic and that copy numbers varied between 0 and 7 in the case and control cohorts. Interestingly, the number of copies was significantly higher (P = 0.038) in XX DSD dogs (mean = 2.7) than in the control females (mean = 2.0) but not in all studied breeds. Duplication of the SOX9 gene was noted only in a single XX DSD dog (an American Bully), which had three copies of SOX9. Distribution of the G-nucleotide insertion was similar in the XX DSD (frequency 0.20) and control (frequency 0.14) cohorts. Concluding, our study showed that CNVR1, located upstream of SOX9, is associated with the XX DSD phenotype, though in a breed-specific manner. Duplication of the SOX9 gene is a rare cause of this disorder in dogs. Moreover, we did not observe any association of G-insertion with the DSD phenotype. We assume that the genetic background of XX DSD can be different in certain breeds.


Assuntos
Variações do Número de Cópias de DNA , Transtornos do Desenvolvimento Sexual/genética , Doenças do Cão/genética , Fatores de Transcrição SOX9/genética , Animais , Estudos de Casos e Controles , Cães , Feminino , Cromossomo X/genética
16.
Mol Ecol ; 28(8): 1863-1865, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31099463

RESUMO

Under XY sex determination, the Y chromosome is only inherited via males, whereas the X chromosome is predominantly found in females. Thus, it is favourable when alleles with high male fitness become associated with the Y chromosome and when alleles with high female fitness become associated with the X chromosome. These favourable associations can be strengthened through linkage. Rearrangements, such as inversions and sex chromosome-autosome fusions, can increase linkage and thereby become favoured (Charlesworth, 2017). In a From the Cover article in this issue of Molecular Ecology, Toups, Rodrigues, Perrin, and Kirkpatrick (2019) present the first genomic analysis of a sex chromosome reciprocal translocation, a particularly dramatic chromosomal rearrangement that modifies linkage with the sex chromosome. As a result of reciprocal translocation, one studied population of the common frog (Rana temporaria, Figure 1) displays a remarkable sex-determining system in which there are two physically unlinked sex chromosomes that are exclusively cotransmitted (Figure 2a).


Assuntos
Rana temporaria/genética , Cromossomos Sexuais/genética , Processos de Determinação Sexual , Translocação Genética/genética , Animais , Inversão Cromossômica/genética , Feminino , Ligação Genética , Cariotipagem , Masculino , Cromossomo X/genética , Cromossomo Y/genética
17.
Genetics ; 212(3): 729-742, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31123040

RESUMO

Condensins are evolutionarily conserved protein complexes that are required for chromosome segregation during cell division and genome organization during interphase. In Caenorhabditis elegans, a specialized condensin, which forms the core of the dosage compensation complex (DCC), binds to and represses X chromosome transcription. Here, we analyzed DCC localization and the effect of DCC depletion on histone modifications, transcription factor binding, and gene expression using chromatin immunoprecipitation sequencing and mRNA sequencing. Across the X, the DCC accumulates at accessible gene regulatory sites in active chromatin and not heterochromatin. The DCC is required for reducing the levels of activating histone modifications, including H3K4me3 and H3K27ac, but not repressive modification H3K9me3. In X-to-autosome fusion chromosomes, DCC spreading into the autosomal sequences locally reduces gene expression, thus establishing a direct link between DCC binding and repression. Together, our results indicate that DCC-mediated transcription repression is associated with a reduction in the activity of X chromosomal gene regulatory elements.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Compensação de Dosagem (Genética) , Código das Histonas , Complexos Multiproteicos/metabolismo , Sequências Reguladoras de Ácido Nucleico , Cromossomo X/genética , Adenosina Trifosfatases/genética , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Cromatina/metabolismo , Proteínas de Ligação a DNA/genética , Histonas/genética , Histonas/metabolismo , Complexos Multiproteicos/genética , Fatores de Transcrição/metabolismo , Cromossomo X/metabolismo
18.
Genetics ; 212(3): 801-813, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064822

RESUMO

Hybrid male progeny from interspecies crosses are more prone to sterility or inviability than hybrid female progeny, and the male sterility and inviability often demonstrate parent-of-origin asymmetry. However, the underlying genetic mechanism of asymmetric sterility or inviability remains elusive. We previously established a genome-wide hybrid incompatibility (HI) landscape between Caenorhabditis briggsae and C. nigoni by phenotyping a large collection of C. nigoni strains each carrying a C. briggsae introgression. In this study, we systematically dissect the genetic mechanism of asymmetric sterility and inviability in both hybrid male and female progeny between the two species. Specifically, we performed reciprocal crosses between C . briggsae and different C. nigoni strains that each carry a GFP-labeled C. briggsae genomic fragment referred to as introgression, and scored the HI phenotypes in the F1 progeny. The aggregated introgressions cover 94.6% of the C. briggsae genome, including 100% of the X chromosome. Surprisingly, we observed that two C. briggsae X fragments that produce C. nigoni male sterility as an introgression rescued hybrid F1 sterility in males fathered by C. briggsae Subsequent backcrossing analyses indicated that a specific interaction between the X-linked interaction and one autosome introgression is required to rescue the hybrid male sterility. In addition, we identified another two C. briggsae genomic intervals on chromosomes II and IV that can rescue the inviability, but not the sterility, of hybrid F1 males fathered by C. nigoni, suggesting the involvement of differential epistatic interactions in the asymmetric hybrid male fertility and inviability. Importantly, backcrossing of the rescued sterile males with C. nigoni led to the isolation of a 1.1-Mb genomic interval that specifically interacts with an X-linked introgression, which is essential for hybrid male fertility. We further identified three C. briggsae genomic intervals on chromosome I, II, and III that produced inviability in all F1 progeny, dependent on or independent of the parent-of-origin. Taken together, we identified multiple independent interacting loci that are responsible for asymmetric hybrid male and female sterility, and inviability, which lays a foundation for their molecular characterization.


Assuntos
Caenorhabditis/genética , Infertilidade Masculina/genética , Cromossomo X/genética , Animais , Caenorhabditis/fisiologia , Epistasia Genética , Feminino , Hibridização Genética , Masculino
19.
Mol Cell ; 74(5): 1069-1085.e11, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31000436

RESUMO

Orderly segregation of chromosomes during meiosis requires that crossovers form between homologous chromosomes by recombination. Programmed DNA double-strand breaks (DSBs) initiate meiotic recombination. We identify ANKRD31 as a key component of complexes of DSB-promoting proteins that assemble on meiotic chromosome axes. Genome-wide, ANKRD31 deficiency causes delayed recombination initiation. In addition, loss of ANKRD31 alters DSB distribution because of reduced selectivity for sites that normally attract DSBs. Strikingly, ANKRD31 deficiency also abolishes uniquely high rates of recombination that normally characterize pseudoautosomal regions (PARs) of X and Y chromosomes. Consequently, sex chromosomes do not form crossovers, leading to chromosome segregation failure in ANKRD31-deficient spermatocytes. These defects co-occur with a genome-wide delay in assembling DSB-promoting proteins on autosome axes and loss of a specialized PAR-axis domain that is highly enriched for DSB-promoting proteins in wild type. Thus, we propose a model for spatiotemporal patterning of recombination by ANKRD31-dependent control of axis-associated DSB-promoting proteins.


Assuntos
Proteínas de Transporte/genética , Quebras de DNA de Cadeia Dupla , Recombinação Homóloga/genética , Meiose/genética , Animais , Proteínas de Transporte/química , Segregação de Cromossomos/genética , Masculino , Camundongos , Regiões Pseudoautossômicas/genética , Espermatócitos/crescimento & desenvolvimento , Espermatócitos/metabolismo , Cromossomo X/genética , Cromossomo Y/genética
20.
Genetics ; 212(2): 469-487, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31028113

RESUMO

Faithful segregation of homologous chromosomes at meiosis requires pairing and recombination. In taxa with dimorphic sex chromosomes, pairing between them in the heterogametic sex is limited to a narrow interval of residual sequence homology known as the pseudoautosomal region (PAR). Failure to form the obligate crossover in the PAR is associated with male infertility in house mice (Mus musculus) and humans. Yet despite this apparent functional constraint, the boundary and organization of the PAR is highly variable in mammals, and even between subspecies of mice. Here, we estimate the genetic map in a previously documented expansion of the PAR in the M. musculus castaneus subspecies and show that the local recombination rate is 100-fold higher than the autosomal background. We identify an independent shift in the PAR boundary in the M. musculus musculus subspecies and show that it involves a complex rearrangement, but still recombines in heterozygous males. Finally, we demonstrate pervasive copy-number variation at the PAR boundary in wild populations of M. m. domesticus, M. m. musculus, and M. m. castaneus Our results suggest that the intensity of recombination activity in the PAR, coupled with relatively weak constraints on its sequence, permit the generation and maintenance of unusual levels of polymorphism in the population of unknown functional significance.


Assuntos
Mapeamento Cromossômico , Regiões Pseudoautossômicas/genética , Recombinação Genética/genética , Cromossomo X/genética , Cromossomo Y/genética , Animais , Evolução Molecular , Feminino , Masculino , Meiose/genética , Camundongos , Regiões Pseudoautossômicas/metabolismo , Especificidade da Espécie
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