Analysis of a hypomorphic mei-P26 mutation reveals developmental control of CO patterning mechanisms
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Female gametogenesis in Drosophila requires both differentiation of germline stem cells and the unique cell cycle meiosis. Successful segregation of chromosomes into gametes during meiosis requires the formation of crossovers between homologous chromosomes. The frequency and distribution of crossovers is highly regulated at several levels, including formation of at least one obligate crossover per pair of homologs, crossover interference that keeps crossovers farther apart than expected by chance, and suppression of crossovers in and near the centromere. To achieve crossover patterning, a meiosis specific version of homologous recombination is used to repair programmed double-stranded breaks, and in Drosophila melanogaster , this recombination pathway requires the putative double Holliday junction resolvase MEI-9. Despite our understanding of crossover patterning mechanisms at the phenomenological level, how crossover patterning mechanisms are developmentally controlled in the context of germ cell differentiation is unknown. Here, we take advantage of a hypomorphic mutation in mei-P26, a gene previously associated with regulation of both germ cell mitoses and meiotic induction. We confirm that mei-P26 1 mutants show extended expression of mitotic cell cycle markers but rarely completely block differentiation, indicating that the mitotic cell cycle is mis-regulated. In this developmentally delayed context, we show that mei-P26 1 mutants enter meiosis and complete the earliest stages of prophase, including loading of synaptonemal complex proteins onto the centromere and initial loading onto the arms. Most nuclei do not progress past this to make full length synaptonemal complex, yet meiotic double-strand breaks are induced and crossovers form. However, while these crossovers require MEI-9 and exhibit crossover assurance, the centromere effect and interference are lost. We suggest a model where entry into zygotene of prophase is enough to commit pro-oocytes to using the meiotic homologous recombination machinery and thus ensuring crossover assurance, but that full length synaptonemal complex assembly is required for crossover interference.Penetrance
Angelman Syndrome
Genetic linkage
Imprinting (psychology)
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Molecular identification of mutant alleles responsible for certain phenotypic alterations is a central goal of genetic analyses. In this study we describe a rapid procedure suitable for the identification of induced recessive and dominant mutations applied to two Zea mays mutants expressing a dwarf and a pale green phenotype, respectively, which were obtained through pollen ethyl methanesulfonate (EMS) mutagenesis. First, without prior backcrossing, induced mutations (single nucleotide polymorphisms, SNPs) segregating in a (M2 ) family derived from a heterozygous (M1 ) parent were identified using whole-genome shotgun (WGS) sequencing of a small number of (M2 ) individuals with mutant and wild-type phenotypes. Second, the state of zygosity of the mutation causing the phenotype was determined for each sequenced individual by phenotypic segregation analysis of the self-pollinated (M3 ) offspring. Finally, we filtered for segregating EMS-induced SNPs whose state of zygosity matched the determined state of zygosity of the mutant locus in each sequenced (M2 ) individuals. Through this procedure, combining sequencing of individuals and Mendelian inheritance, three and four SNPs in linkage passed our zygosity filter for the homozygous dwarf and heterozygous pale green mutation, respectively. The dwarf mutation was found to be allelic to the an1 locus and caused by an insertion in the largest exon of the AN1 gene. The pale green mutation affected the nuclear W2 gene and was caused by a non-synonymous amino acid exchange in encoded chloroplast DNA polymerase with a predicted deleterious effect. This coincided with lower cpDNA levels in pale green plants.
Zygosity
Ethyl methanesulfonate
Sanger sequencing
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Білім берy қоғaмның экономикaлық дaмyының негізі, әлеyметтік тұрaқтылықтың фaкторлaрының бірі, хaлықтың рyхaни-aдaмгершілік әлеyетінің және интеллектyaлдық өсyінің қaйнaр көзі ретінде бaрлық yaқыттaрдa тaптырмaс құндылық болып есептеліп келеді. Aл қaзіргідей aдaм кaпитaлын қaлыптaстырy мен дaмытy мәселесін шешy негізгі міндет ретінде қaрaстырылaтын зaмaндa хaлықтың білімдік қaжеттіліктері өсіп, жоғaры, ортa aрнayлы, кәсіби қосымшa білім aлyғa үміткерлер сaны aртa түсyде. Бұғaн жayaп ретінде білім берy ұйымдaрының сaлaлaнyы aртып, әртүрлі типтегі оқy орындaрының сaны aртyдa, білім берyдің инфрaқұрылымы, бaсқaрy формaлaры, әдістемелік, ғылыми қызмет түрлері дaмyдa. Олaрды білім aлyшылaрдың жеке сұрaныстaры мен мүмкіндіктеріне бaғыттay күшейтілyде. Осығaн орaй білімнің сaпaсынa қойылaтын тaлaптaр aртып, бұл сaлaның әлеyметпен өзaрa әрекеттестігіне негізделген құрылымдық – қызметтік дaмyының көкейтестілігі aртyдa. Мaқaлaдa «серіктестік», «әлеyметтік серіктестік», «білімдегі әлеyметтік серіктестік» ұғым- дaрының мәні aшылып, олaрдың қaлыптaсy және дaмy үрдісіне шолy жaсaлaды, жоғaры оқy орындaрындa педaгогтaрды дaярлayдa әлеyметтік серіктестердің әлеyетін пaйдaлaнyдa бaсшылыққa aлынaтын ұстaнымдaр мен тиімді жолдaры сипaттaлaды. Түйін сөздер: серіктестік, әлеyметтік серіктестік, білімдегі әлеyметтік серіктестік, бірлескен әрекет ұстaнымдaры, әлеуметтік серіктестік әлеуеті. Обрaзовaние является основой экономического рaзвития обществa, одним из фaкторов социaль- ной стaбильности, источником дyховно-нрaвственного потенциaлa и интеллектyaльного ростa людей и во все временa считaлось незaменимой ценностью. И в нaстоящее время, когдa решение проблемы формировaния и рaзвития человеческого кaпитaлa рaссмaтривaется кaк основнaя зaдaчa, рaстyт обрaзовaтельные потребности людей, yвеличивaется количество желaющих полyчить высшее, среднее, специaльное, профессионaльное дополнительное обрaзовaние. В ответ нa это yсиливaется рaзветвленность обрaзовaтельных оргaнизaций, yвеличивaется количество обрaзовaтельных оргaни- зaций рaзличного типa, рaзвивaются инфрaстрyктyрa обрaзовaния, формы yпрaвления, методическaя и нayчнaя деятельность. Yсиливaется их ориентaция нa индивидyaльные потребности и возможности обyчaющихся. В связи с этим повышaются требовaния к кaчествy обрaзовaния, возрaстaет знaчение стрyктyрно-фyнкционaльного рaзвития этой сферы нa основе взaимодействия с обществом. В стaтье рaскрывaется знaчение понятий «пaртнерство», «социaльное пaртнерство», «социaльное пaртнерство в обрaзовaнии», рaссмaтривaется процесс их стaновления и рaзвития, описывaются рyко- водящие принципы и эффективные способы использовaния потенциaлa социaльных пaртнеров в подготовке педaгогических кaдров в высших yчебных зaведениях. Ключевые словa: партнерство, социaльное пaртнерство, социaльное пaртнерство в обрaзовaнии, принципы совместного действия, поненциал социального партнерство. Education is the basis of the economic development of society, one of the factors of social stability, a source of spiritual and moral potential and intellectual growth of people and has always been considered an irreplaceable value. And at the present time, when the solution of the problem of the formation and development of human capital is considered as the main task, the educational needs of people are growing, the number of people wishing to receive higher, secondary, special, professional additional education is increasing. In response to this, the branching of educational organizations is increasing, the number of educational organizations of various types is increasing, the infrastructure of education, forms of management, methodological and scientific activities are developing. Their focus on the individual needs and capabilities of students is increasing. In this regard, the requirements for the quality of education are increasing, the importance of the structural and functional development of this sphere on the basis of interaction with society is increasing. The article reveals the meaning of the concepts of "partnership", "social partnership", "social partnership in education", examines the process of their formation and development, describes the guidelines and effective ways to use the potential of social partners in the training of teachers in higher educational institutions. Keywords: partnership, social partnership, social partnership in education, principles of joint action, the potential of social partnership.
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More than 60% of prelingual deafness is genetic in origin, and of these up to 95% are monogenic autosomal recessive traits. Causal mutations have been identified in 1 of 38 different genes in a subset of patients with nonsyndromic autosomal recessive deafness. In this study, we screened 49 unrelated Turkish families with at least three affected children born to consanguineous parents. Probands from all families were negative for mutations in the GJB2 gene, two large deletions in the GJB6 gene, and the 1555A>G substitution in the mitochondrial DNA MTRNR1 gene. Each family was subsequently screened via autozygosity mapping with genomewide single-nucleotide polymorphism arrays. If the phenotype cosegregated with a haplotype flanking one of the 38 genes, mutation analysis of the gene was performed. We identified 22 different autozygous mutations in 11 genes, other than GJB2, in 26 of 49 families, which overall explains deafness in 62% of families. Relative frequencies of genes following GJB2 were MYO15A (9.9%), TMIE (6.6%), TMC1 (6.6%), OTOF (5.0%), CDH23 (3.3%), MYO7A (3.3%), SLC26A4 (1.7%), PCDH15 (1.7%), LRTOMT (1.7%), SERPINB6 (1.7%), and TMPRSS3 (1.7%). Nineteen of 22 mutations are reported for the first time in this study. Unknown rare genes for deafness appear to be present in the remaining 23 families.
Proband
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A compensatory mutation occurs when the fitness loss caused by one mutation is remedied by its epistatic interaction with a second mutation at a different site in the genome. This poorly understood biological phenomenon has important implications, not only for the evolutionary consequences of mutation, but also for the genetic complexity of adaptation. We have carried out the first direct experimental measurement of the average rate of compensatory mutation. An arbitrary selection of 21 missense substitutions with deleterious effects on fitness was introduced by site-directed mutagenesis into the bacteriophage phiX174. For each deleterious mutation, we evolved 8-16 replicate populations to determine the frequency at which a compensatory mutation, instead of the back mutation, was acquired to recover fitness. The overall frequency of compensatory mutation was approximately 70%. Deleterious mutations that were more severe were significantly more likely to be compensated for. Furthermore, experimental reversion of deleterious mutations revealed that compensatory mutations have deleterious effects in a wild-type background. A large diversity of intragenic compensatory mutations was identified from sequencing fitness-recovering genotypes. Subsequent analyses of intragenic mutation diversity revealed a significant degree of clustering around the deleterious mutation in the linear sequence and also within folded protein structures. Moreover, a likelihood analysis of mutation diversity predicts that, on average, a deleterious mutation can be compensated by about nine different intragenic compensatory mutations. We estimate that about half of all compensatory mutations are located extragenically in this organism.
Mutation Accumulation
Reversion
Epistasis
Mutation frequency
Suppressor mutation
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ABSTRACT Of 24 ethyl methanesulphonate-induced, recessive-lethal mutations in the region 9E1-9F13 of the X chromosome of Drosophila melanogaster, eight fall into a typically homogeneous lethal complementation group associated with the raspberry (ras) locus. Mutations in this group have previously been shown to be pleiotropic, affecting not only ras but also two other genetic entities, gua1 and pur1, which yield auxotrophic mutations.—The eight new mutations have been characterized phenotypically in double heterozygotes with gua1, pur1 and ras mutations. Despite their homogeneity in lethal complementation tests, the mutations prove quite diverse. For example, two mutations have little or no effect on eye color in double heterozygotes with ras 2. The differences between the lethals are allele-specific and cannot be explained as a trivial outcome of a hypomorphic series.—Taken alone, the lethal complementation studies mask the complexity of the locus and the diversity of its recessive lethal alleles. By extension, we argue that the general use of lethal saturation studies provides an unduly simplified image of genetic organization. We suggest that the reason why recessive lethal mutations rarely present complex complementation patterns is that complex loci tend to produce mutations that affect several subfunctions.
Heterozygote advantage
Lethal allele
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MSX1 has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of MSX1 (two exons, one intron). We compare the completed genomic sequence of MSX1 to the mouse Msx1 sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian, and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known Msx1 orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition, a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of MSX1. MSX1 mutations are found in 2% of cases of clefting and should be considered for genetic counselling implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.
Conserved sequence
Coding region
Stop codon
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Nonsynonymous substitution
Pseudogene
Synonymous substitution
Silent mutation
Nonsense mutation
Neutral mutation
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Mutant alleles of TMPRSS3 are associated with nonsyndromic recessive deafness (DFNB8/B10). TMPRSS3 encodes a predicted secreted serine protease, although the deduced amino acid sequence has no signal peptide. In this study, we searched for mutant alleles of TMPRSS3 in families from Pakistan and Newfoundland with recessive deafness co-segregating with DFNB8/B10 linked haplotypes and also more thoroughly characterized the genomic structure of TMPRSS3. We enrolled families segregating recessive hearing loss from Pakistan and Newfoundland. Microsatellite markers flanking the TMPRSS3 locus were used for linkage analysis. DNA samples from participating individuals were sequenced for TMPRSS3. The structure of TMPRSS3 was characterized bioinformatically and experimentally by sequencing novel cDNA clones of TMPRSS3. We identified mutations in TMPRSS3 in four Pakistani families with recessive, nonsyndromic congenital deafness. We also identified two recessive mutations, one of which is novel, of TMPRSS3 segregating in a six-generation extended family from Newfoundland. The spectrum of TMPRSS3 mutations is reviewed in the context of a genotype-phenotype correlation. Our study also revealed a longer isoform of TMPRSS3 with a hitherto unidentified exon encoding a signal peptide, which is expressed in several tissues. Mutations of TMPRSS3 contribute to hearing loss in many communities worldwide and account for 1.8% (8 of 449) of Pakistani families segregating congenital deafness as an autosomal recessive trait. The newly identified TMPRSS3 isoform e will be helpful in the functional characterization of the full length protein.
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Hereditary multiple exostoses
Nonsense mutation
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