scholarly journals Frequency of mosaicism points towards mutation-prone early cleavage cell divisions in cattle

2016 ◽  
Author(s):  
Chad Harland ◽  
Carole Charlier ◽  
Latifa Karim ◽  
Nadine Cambisano ◽  
Manon Deckers ◽  
...  
Keyword(s):  
Sperm Cell ◽  
De Novo ◽  
Germ Line ◽  
High Rate ◽  
De Novo Mutation ◽  
Whole Genome ◽  
Early Cleavage ◽  
Cell Divisions ◽  
Premeiotic Clusters ◽  
Males And Females

It has recently become possible to directly estimate the germ-line de novo mutation (dnm) rate by sequencing the whole genome of father-mother-offspring trios, and this has been conducted in human1–5, chimpanzee6, mice7, birds8 and fish9. In these studies dnm’s are typically defined as variants that are heterozygous in the offspring while being absent in both parents. They are assumed to have occurred in the germ-line of one of the parents and to have been transmitted to the offspring via the sperm cell or oocyte. This definition assumes that detectable mosaïcism in the parent in which the mutation occurred is negligible. However, instances of detectable mosaïcism or premeiotic clusters are well documented in humans and other organisms, including ruminants10–12. We herein take advantage of cattle pedigrees to show that as much as ∼30% to ∼50% of dnm’s present in a gamete may occur during the early cleavage cell divisions in males and females, respectively, resulting in frequent detectable mosaïcism and a high rate of sharing of multiple dnm’s between siblings. This should be taken into account to accurately estimate the mutation rate in cattle and other species.

Infection of the germ line by retroviral particles produced in the follicle cells: a possible mechanism for the mobilization of the gypsy retroelement of Drosophila

Development ◽  
1997 ◽  
Vol 124 (14) ◽  
pp. 2789-2798 ◽  
Author(s):  
S.U. Song ◽  
M. Kurkulos ◽  
J.D. Boeke ◽  
V.G. Corces
Keyword(s):  
High Frequency ◽  
Cytoplasmic Membrane ◽  
De Novo ◽  
Germ Line ◽  
High Rate ◽  
Follicle Cells ◽  
Nurse Cells ◽  
Perivitelline Space ◽  
Viral Particles ◽  
Secretory Apparatus

The gypsy retroelement of Drosophila moves at high frequency in the germ line of the progeny of females carrying a mutation in the flamenco (flam) gene. This high rate of de novo insertion correlates with elevated accumulation of full-length gypsy RNA in the ovaries of these females, as well as the presence of an env-specific RNA. We have prepared monoclonal antibodies against the gypsy Pol and Env products and found that these proteins are expressed in the ovaries of flam females and processed in the manner characteristic of vertebrate retroviruses. The Pol proteins are expressed in both follicle and nurse cells, but they do not accumulate at detectable levels in the oocyte. The Env proteins are expressed exclusively in the follicle cells starting at stage 9 of oogenesis, where they accumulate in the secretory apparatus of the endoplasmic reticulum. They then migrate to the inner side of the cytoplasmic membrane where they assemble into viral particles. These particles can be observed in the perivitelline space starting at stage 10 by immunoelectron microscopy using anti-Env antibodies. We propose a model to explain flamenco-mediated induction of gypsy mobilization that involves the synthesis of gypsy viral particles in the follicle cells, from where they leave and infect the oocyte, thus explaining gypsy insertion into the germ line of the subsequent generation.

Characterizing mutagenic effects of recombination through a sequence-level genetic map

Science ◽  
2019 ◽  
Vol 363 (6425) ◽  
pp. eaau1043 ◽  
Author(s):  
Bjarni V. Halldorsson ◽  
Gunnar Palsson ◽  
Olafur A. Stefansson ◽  
Hakon Jonsson ◽  
Marteinn T. Hardarson ◽  
...  
Keyword(s):  
Genetic Map ◽  
Meiotic Recombination ◽  
De Novo ◽  
Sequence Data ◽  
Mutagenic Effect ◽  
Whole Genome Sequence ◽  
De Novo Mutation ◽  
Base Pairs ◽  
Males And Females ◽  
Mutagenic Effects

Genetic diversity arises from recombination and de novo mutation (DNM). Using a combination of microarray genotype and whole-genome sequence data on parent-child pairs, we identified 4,531,535 crossover recombinations and 200,435 DNMs. The resulting genetic map has a resolution of 682 base pairs. Crossovers exhibit a mutagenic effect, with overrepresentation of DNMs within 1 kilobase of crossovers in males and females. In females, a higher mutation rate is observed up to 40 kilobases from crossovers, particularly for complex crossovers, which increase with maternal age. We identified 35 loci associated with the recombination rate or the location of crossovers, demonstrating extensive genetic control of meiotic recombination, and our results highlight genes linked to the formation of the synaptonemal complex as determinants of crossovers.

De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2905-2906 ◽  
Author(s):  
Johannes Oldenburg ◽  
Simone Rost ◽  
Osman El-Maarri ◽  
Marco Leuer ◽  
Klaus Olek ◽  
...  
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Mitotic Cell ◽  
De Novo Mutation ◽  
Female Carrier ◽  
Meiotic Cell ◽  
Cell Divisions ◽  
Intron 22 Inversion ◽  
Bivalent Formation

The intron 22 inversion represents the most prevalentfactor VIII gene defect in severe hemophilia A, accounting for about 40% of all mutations. It is hypothesized that the inversion mutations occur almost exclusively in germ cells during meiotic cell division by intrachromosomal recombination between 1 of 2 telomeric copies of the Int22h region and its intragenic homologue. The majority of inversion mutations originate in male germ cells, where the lack of bivalent formation may facilitate flipping of the telomeric end of the single X chromosome. This is the first intron 22 inversion that presents as a somatic mosaicism in a female, affecting only about 50% of lymphocyte and fibroblast cells of the proposita. Supposing a post-zygotic de novo mutation as the usual cause of somatic mosaicism, the finding would imply that the intron 22 inversion mutation is not restricted to meiotic cell divisions but can also occur during mitotic cell divisions, either in germ cell precursors or in somatic cells.

scholarly journals Direct estimation of de novo mutation rates in a chimpanzee parent-offspring trio by ultra-deep whole genome sequencing

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Shoji Tatsumoto ◽  
Yasuhiro Go ◽  
Kentaro Fukuta ◽  
Hideki Noguchi ◽  
Takashi Hayakawa ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
De Novo Mutation ◽  
Mutation Rates ◽  
Whole Genome ◽  
Direct Estimation

scholarly journals THE ABSENCE OF SOMATIC EFFECTS OF P-M HYBRID DYSGENESIS IN DROSOPHILA MELANOGASTER

Genetics ◽  
1986 ◽  
Vol 113 (4) ◽  
pp. 897-918
Author(s):  
M Catharine McElwain
Keyword(s):  
Drosophila Melanogaster ◽  
Size Distribution ◽  
De Novo ◽  
Germ Line ◽  
Adaptive Significance ◽  
Hybrid Dysgenesis ◽  
De Novo Mutation ◽  
Anatomical Distribution ◽  
Parallel Processes

ABSTRACT The wings and abdomens of dysgenic and nondysgenic control flies were scored for the presence of clones of cells mutant for first and third chromosome markers. These exceptional clones can arise from mitotic recombination, de novo mutation or deletion, and P-M hybrid dysgenesis has been shown to increase the frequency of parallel processes occurring in germ-line cells. Particular attention was given to careful genetic and molecular characterization of all stocks and to providing adequate and appropriate controls so that even very small increases in somatic clone frequency due to P-M hybrid dysgenesis would be detected. No difference was found in the frequency, size distribution or anatomical distribution of mutant somatic clones correlated to hybrid dysgenesis, confirming previous indications. The potential adaptive significance of a germ-line restriction of P-M hybrid dysgenesis is discussed.

scholarly journals Overlooked roles of DNA damage and maternal age in generating human germline mutations

2019 ◽  
Vol 116 (19) ◽  
pp. 9491-9500 ◽  
Author(s):  
Ziyue Gao ◽  
Priya Moorjani ◽  
Thomas A. Sasani ◽  
Brent S. Pedersen ◽  
Aaron R. Quinlan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Maternal Age ◽  
De Novo ◽  
Germline Mutations ◽  
Strand Break ◽  
De Novo Mutation ◽  
Substantial Contribution ◽  
Base Substitution ◽  
Induced Mutations ◽  
Cell Divisions

The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact that there are both more mutations and more cell divisions in the male than in the female germline. When analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that view into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental age. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C-to-G transversions and CpG transitions, which together constitute over one-fourth of all base substitution mutations, show genomic distributions and sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Moreover, we find evidence that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations in the embryo. These findings reveal underappreciated roles of DNA damage and maternal age in the genesis of human germline mutations.

scholarly journals De novo ZIC2 frameshift variant associated with frontonasal dysplasia in a Limousin calf

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Marina Braun ◽  
Annika Lehmbecker ◽  
Deborah Eikelberg ◽  
Maren Hellige ◽  
Andreas Beineke ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
De Novo Mutation ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Craniofacial Malformations ◽  
Frontonasal Dysplasia ◽  
Affected Calf

Abstract Background Bovine frontonasal dysplasias like arhinencephaly, synophthalmia, cyclopia and anophthalmia are sporadic congenital facial malformations. In this study, computed tomography, necropsy, histopathological examinations and whole genome sequencing on an Illumina NextSeq500 were performed to characterize a stillborn Limousin calf with frontonasal dysplasia. In order to identify private genetic and structural variants, we screened whole genome sequencing data of the affected calf and unaffected relatives including parents, a maternal and paternal halfsibling. Results The stillborn calf exhibited severe craniofacial malformations. Nose and maxilla were absent, mandibles were upwardly curved and a median cleft palate was evident. Eyes, optic nerve and orbital cavities were not developed and the rudimentary orbita showed hypotelorism. A defect centrally in the front skull covered with a membrane extended into the intracranial cavity. Aprosencephaly affected telencephalic and diencephalic structures and cerebellum. In addition, a shortened tail was seen. Filtering whole genome sequencing data revealed a private frameshift variant within the candidate gene ZIC2 in the affected calf. This variant was heterozygous mutant in this case and homozygous wild type in parents, half-siblings and controls. Conclusions We found a novel ZIC2 frameshift mutation in an aprosencephalic Limousin calf. The origin of this variant is most likely due to a de novo mutation in the germline of one parent or during very early embryonic development. To the authors’ best knowledge, this is the first identified mutation in cattle associated with bovine frontonasal dysplasia.

scholarly journals De Novo Mutation in an Enhancer of EBF3 in simplex autism

2020 ◽  
Author(s):  
Evin M. Padhi ◽  
Tristan J. Hayeck ◽  
Brandon Mannion ◽  
Sumantra Chatterjee ◽  
Marta Byrska-Bishop ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
De Novo Mutation ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Enhancer Activity ◽  
Protein Coding

AbstractPrevious research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of de novo protein-coding variants within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2,671 families with autism, with a specific focus on de novo variation in enhancers with previously characterized in vivo activity. We identified three independent de novo mutations limited to individuals with autism in the enhancer hs737. These mutations result in similar phenotypic characteristics, affect enhancer activity in vitro, and preferentially occur in AAT motifs in the enhancer with predicted disruptions of transcription factor binding. We also find that hs737 is enriched for copy number variation in individuals with NDDs, is dosage sensitive in the human population, is brain-specific, and targets the NDD gene EBF3 that is genome-wide significant for protein coding de novo variants, demonstrating the importance of understanding all forms of variation in the genome.One Sentence SummaryWhole-genome sequencing in thousands of families reveals variants relevant to simplex autism in a brain enhancer of the well-established neurodevelopmental disorder gene EBF3.

De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2905-2906 ◽  
Author(s):  
Johannes Oldenburg ◽  
Simone Rost ◽  
Osman El-Maarri ◽  
Marco Leuer ◽  
Klaus Olek ◽  
...  
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Mitotic Cell ◽  
De Novo Mutation ◽  
Female Carrier ◽  
Meiotic Cell ◽  
Cell Divisions ◽  
Intron 22 Inversion ◽  
Bivalent Formation

Abstract The intron 22 inversion represents the most prevalentfactor VIII gene defect in severe hemophilia A, accounting for about 40% of all mutations. It is hypothesized that the inversion mutations occur almost exclusively in germ cells during meiotic cell division by intrachromosomal recombination between 1 of 2 telomeric copies of the Int22h region and its intragenic homologue. The majority of inversion mutations originate in male germ cells, where the lack of bivalent formation may facilitate flipping of the telomeric end of the single X chromosome. This is the first intron 22 inversion that presents as a somatic mosaicism in a female, affecting only about 50% of lymphocyte and fibroblast cells of the proposita. Supposing a post-zygotic de novo mutation as the usual cause of somatic mosaicism, the finding would imply that the intron 22 inversion mutation is not restricted to meiotic cell divisions but can also occur during mitotic cell divisions, either in germ cell precursors or in somatic cells.

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