scholarly journals Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes

2019 ◽  
Vol 116 (36) ◽  
pp. 17916-17924 ◽  
Author(s):  
Ipsita Agarwal ◽  
Molly Przeworski
Keyword(s):  
X Chromosome ◽  
Rare Variants ◽  
Low Frequency ◽  
Replication Timing ◽  
Double Strand Breaks ◽  
X Chromosomes ◽  
Strand Breaks ◽  
Biochemical Processes ◽  
Males And Females ◽  
Mutational Processes

The sources of human germline mutations are poorly understood. Part of the difficulty is that mutations occur very rarely, and so direct pedigree-based approaches remain limited in the numbers that they can examine. To address this problem, we consider the spectrum of low-frequency variants in a dataset (Genome Aggregation Database, gnomAD) of 13,860 human X chromosomes and autosomes. X-autosome differences are reflective of germline sex differences and have been used extensively to learn about male versus female mutational processes; what is less appreciated is that they also reflect chromosome-level biochemical features that differ between the X and autosomes. We tease these components apart by comparing the mutation spectrum in multiple genomic compartments on the autosomes and between the X and autosomes. In so doing, we are able to ascribe specific mutation patterns to replication timing and recombination and to identify differences in the types of mutations that accrue in males and females. In particular, we identify C > G as a mutagenic signature of male meiotic double-strand breaks on the X, which may result from late repair. Our results show how biochemical processes of damage and repair in the germline interact with sex-specific life history traits to shape mutation patterns on both the X chromosome and autosomes.

scholarly journals Signatures of replication timing, recombination and sex in the spectrum of rare variants on the human X chromosome and autosomes

2019 ◽  
Author(s):  
Ipsita Agarwal ◽  
Molly Przeworski
Keyword(s):  
X Chromosome ◽  
Rare Variants ◽  
Low Frequency ◽  
Replication Timing ◽  
Double Strand Breaks ◽  
X Chromosomes ◽  
Strand Breaks ◽  
Biochemical Processes ◽  
Males And Females ◽  
Mutational Processes

AbstractThe sources of human germline mutations are poorly understood. Part of the difficulty is that mutations occur very rarely, and so direct pedigree-based approaches remain limited in the numbers that they can examine. To address this problem, we consider the spectrum of low frequency variants in a dataset (gnomAD) of 13,860 human X chromosomes and autosomes. X-autosome differences are reflective of germline sex differences, and have been used extensively to learn about male versus female mutational processes; what is less appreciated is that they also reflect chromosome-level biochemical features that differ between the X and autosomes. We tease these components apart by comparing the mutation spectrum in multiple genomic compartments on the autosomes and between the X and autosomes. In so doing, we are able to ascribe specific mutation patterns to replication timing and recombination, and to identify differences in the types of mutations that accrue in males and females. In particular, we identify C>G as a mutagenic signature of male meiotic double strand breaks on the X, which may result from late repair. Our results show how biochemical processes of damage and repair in the germline interact with sex-specific life history traits to shape mutation patterns on both the X chromosome and autosomes.

scholarly journals Illegitimate Recombination Induced by Overproduction of DnaB Helicase in Escherichia coli

1999 ◽  
Vol 181 (15) ◽  
pp. 4549-4553 ◽  
Author(s):  
Teruhito Yamashita ◽  
Katsuhiro Hanada ◽  
Mihoko Iwasaki ◽  
Hirotaka Yamaguchi ◽  
Hideo Ikeda
Keyword(s):  
Escherichia Coli ◽  
Dna Damage ◽  
Low Frequency ◽  
Double Strand Breaks ◽  
Illegitimate Recombination ◽  
Replication Forks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Damaging Agents ◽  
Dnab Helicase

ABSTRACT Illegitimate recombination that usually takes place at a low frequency is greatly enhanced by treatment with DNA-damaging agents. It is thought that DNA double-strand breaks induced by this DNA damage are important for initiation of illegitimate recombination. Here we show that illegitimate recombination is enhanced by overexpression of the DnaB protein in Escherichia coli. The recombination enhanced by DnaB overexpression occurred between short regions of homology. We propose a model for the initiation of illegitimate recombination in which DnaB overexpression may excessively unwind DNA at replication forks and induce double-strand breaks, resulting in illegitimate recombination. The defect in RecQ has a synergistic effect on the increased illegitimate recombination in cells containing the overproduced DnaB protein, implying that DnaB works in the same pathway as RecQ does but that they work at different steps.

Imprint switching for non-random X-chromosome inactivation during mouse oocyte growth

Development ◽  
2000 ◽  
Vol 127 (14) ◽  
pp. 3101-3105 ◽  
Author(s):  
T. Tada ◽  
Y. Obata ◽  
M. Tada ◽  
Y. Goto ◽  
N. Nakatsuji ◽  
...  
Keyword(s):  
X Chromosome ◽  
Replication Timing ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Nuclear Transplantation ◽  
Chromosome X ◽  
Oocyte Growth ◽  
X Chromosomes ◽  
Embryonic Tissues ◽  
Extraembryonic Tissues

In mammals, X-chromosome inactivation occurs in all female cells, leaving only a single active X chromosome. This serves to equalise the dosage of X-linked genes in male and female cells. In the mouse, the paternally derived X chromosome (X(P)) is imprinted and preferentially inactivated in the extraembryonic tissues whereas in the embryonic tissues inactivation is random. To investigate how X(P) is chosen as an inactivated X chromosome in the extraembryonic cells, we have produced experimental embryos by serial nuclear transplantation from non-growing (ng) oocytes and fully grown (fg) oocytes, in which the X chromosomes are marked with (1) an X-linked lacZ reporter gene to assay X-chromosome activity, or (2) the Rb(X.9)6H translocation as a cytogenetic marker for studying replication timing. In the extraembryonic tissues of these ng/fg embryos, the maternal X chromosome (X(M)) derived from the ng oocyte was preferentially inactivated whereas that from the fg oocyte remained active. However, in the embryonic tissues, X inactivation was random. This suggests that (1) a maternal imprint is set on the X(M) during oocyte growth, (2) the maternal imprint serves to render the X(M) resistant to inactivation in the extraembryonic tissues and (3) the X(M) derived from an ng oocyte resembles a normal X(P).

Review Lecture: Mechanisms and evolutionary origins of variable X-chromosome activity in mammals

1974 ◽  
Vol 187 (1088) ◽  
pp. 243-268 ◽  
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Gene Dosage ◽  
Control Mechanisms ◽  
Compensation Mechanism ◽  
X Chromosomes ◽  
Animal Group ◽  
Evolutionary Origins ◽  
Genetic Activity ◽  
Males And Females

The X-chromosome of mammals is remarkable for its variable genetic activity. In somatic cells only a single X-chromosome is active, no matter how many are present, thus providing a dosage compensation mechanism by which males and females effectively have the same gene dosage of X-linked genes. In germ cells, however, it appears that all X-chromosomes present are active. Female germ cells require the presence of two X-chromosomes for normal survival, whereas male germ cells die if they have more than one X-chromosome. This system is found in all eutherian mammals and in marsupials, but is not known in any other animal group. In marsupials the X-chromosome derived from the father seems to be preferentially inactivated, whereas in eutherian mammals that from either parent may be so in different cells of the same animal. The differentiation of a particular X-chromosome as active or inactive is initiated in early embryogeny, and thereafter maintained through all further cell divisions in that individual. The mechanisms by which this is achieved are of great interest in relation to genetic control mechanisms in general. Various recent hypotheses concerning these mechanisms are discussed.

scholarly journals FITNESS EFFECTS OF EMS-INDUCED MUTATIONS ON THE X CHROMOSOME OF DROSOPHILA MELANOGASTER. I. VIABILITY EFFECTS AND HETEROZYGOUS FITNESS EFFECTS

Genetics ◽  
1977 ◽  
Vol 87 (4) ◽  
pp. 763-774
Author(s):  
Joyce A Mitchell
Keyword(s):  
Drosophila Melanogaster ◽  
X Chromosome ◽  
Strongly Correlated ◽  
Induced Mutations ◽  
X Chromosomes ◽  
Heterozygous Condition ◽  
Fitness Effects ◽  
Sucrose Solutions ◽  
Discrete Generation ◽  
Males And Females

ABSTRACT Drosophila melanogaster X chromosomes were mutagenized by feeding males sucrose solutions containing ethyl methanesulfonate (EMS); the concentrations of EMS in the food were 2.5 mm, 5.0 mm, and 10.0 mm. Chromosomes were exposed to the mutagen up to three times by treating males in succeeding generations. After treatment, the effective exposures were 2.5, 5.0, 7.5, 10.0, 15.0, and 30.0 mm EMS. X chromosomes treated in this manner were tested for effects on fitness in both hemizygous and heterozygous conditions, and for effects on viability in hemizygous and homozygous conditions. In addition, untreated X chromosomes were available for study. The viability and heterozygous fitness effects are presented in this paper, and the hemizygous fitness effects are discussed in the accompanying one (Mitchell and Simmons 1977). Hemizygous and homozygous viability effects were measured by segregation tests in vial cultures. For hemizygous males, viability was reduced 0.5 percent per mm EMS treatment; for homozygous females, it was reduced 0.7 percent per mm treatment. The decline in viability appeared to be a linear function of EMS dose. The viabilities of males and females were strongly correlated. Heterozygous fitness effects were measured by monitoring changes in the frequencies of treated and untreated X chromosomes in discrete generation populations which, through the use of an X-Y translocation, maintained them only in heterozygous condition. Flies that were heterozygous for a treated chromosome were found to be 0.4 percent less fit per m m EMS than flies heterozygous for an untreated one.

scholarly journals Local and sex-specific biases in crossover vs. noncrossover outcomes at meiotic recombination hotspots in mouse

2015 ◽  
Author(s):  
Esther de Boer ◽  
Maria Jasin ◽  
Scott Keeney
Keyword(s):  
Meiotic Recombination ◽  
Chromosomal Location ◽  
Double Strand Breaks ◽  
Chromosome 1 ◽  
Female Meiosis ◽  
Strand Breaks ◽  
Recombination Hotspots ◽  
Cellular Context ◽  
Males And Females ◽  
Meiotic Recombination Hotspots

Meiotic recombination initiated by programmed double-strand breaks (DSBs) yields two types of interhomolog recombination products, crossovers and noncrossovers, but what determines whether a DSB will yield a crossover or noncrossover is not understood. In this study we analyze the influence of sex and chromosomal location on mammalian recombination outcomes by constructing fine-scale recombination maps in both males and females at two mouse hotspots located in different regions of the same chromosome. These include the most comprehensive maps of recombination hotspots in oocytes to date. One hotspot, located centrally on chromosome 1, behaved similarly in male and female meiosis: crossovers and noncrossovers formed at comparable levels and ratios in both sexes. In contrast, at a distal hotspot crossovers were recovered only in males even though noncrossovers were obtained at similar frequencies in both sexes. These findings reveal an example of extreme sex-specific bias in recombination outcome. We further find that estimates of relative DSB levels are surprisingly poor predictors of relative crossover frequencies between hotspots in males. Our results demonstrate that the outcome of mammalian meiotic recombination can be biased, that this bias can vary depending on location and cellular context, and that DSB frequency is not the only determinant of crossover frequency.

scholarly journals Delayed DNA replication in haploid human embryonic stem cells

2021 ◽  
Author(s):  
Matthew Micheal Edwards ◽  
Michael V. Zuccaro ◽  
Ido Sagi ◽  
Qiliang Ding ◽  
Dan Vershkov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Replication ◽  
Embryonic Stem Cells ◽  
X Chromosome ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Replication Timing ◽  
Genetic System ◽  
X Chromosomes ◽  
Genomic Regions

Haploid human embryonic stem cells (ESCs) provide a powerful genetic system but diploidize at high rates. We hypothesized that diploidization results from aberrant DNA replication. To test this, we profiled DNA replication timing in isogenic haploid and diploid ESCs. The greatest difference was the earlier replication of the X chromosome in haploids, consistent with the lack of X chromosome inactivation. Surprisingly, we also identified 21 autosomal regions that had dramatically delayed replication in haploids, extending beyond the normal S phase and into G2/M. Haploid-delays comprised a unique set of quiescent genomic regions that are also under-replicated in polyploid placental cells. The same delays were observed in female ESCs with two active X chromosomes, suggesting that increased X chromosome dosage may cause delayed autosomal replication. We propose that incomplete replication at the onset of mitosis could prevent cell division and result in re-entry into the cell cycle and whole genome duplication.

scholarly journals Delayed DNA replication in haploid human embryonic stem cells

2021 ◽  
Author(s):  
Matthew M. Edwards ◽  
Michael V. Zuccaro ◽  
Ido Sagi ◽  
Qiliang Ding ◽  
Dan Vershkov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Replication ◽  
Embryonic Stem Cells ◽  
X Chromosome ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Replication Timing ◽  
Genetic System ◽  
X Chromosomes ◽  
Genomic Regions

Haploid human embryonic stem cells (ESCs) provide a powerful genetic system but diploidize at high rates. We hypothesized that diploidization results from aberrant DNA replication. To test this, we profiled DNA replication timing in isogenic haploid and diploid ESCs. The greatest difference was the earlier replication of the X Chromosome in haploids, consistent with the lack of X-Chromosome inactivation. We also identified 21 autosomal regions that had delayed replication in haploids, extending beyond the normal S phase and into G2/M. Haploid-delays comprised a unique set of quiescent genomic regions that are also underreplicated in polyploid placental cells. The same delays were observed in female ESCs with two active X Chromosomes, suggesting that increased X-Chromosome dosage may cause delayed autosomal replication. We propose that incomplete replication at the onset of mitosis could prevent cell division and result in re-entry into the cell cycle and whole genome duplication.

Effect of low-frequency ultrasound on double-strand breaks in giant DNA molecules

2013 ◽  
Vol 103 (6) ◽  
pp. 063705 ◽  
Author(s):  
Kenji Yoshida ◽  
Naoki Ogawa ◽  
Yukihiro Kagawa ◽  
Hiraku Tabata ◽  
Yoshiaki Watanabe ◽  
...  
Keyword(s):  
Low Frequency ◽  
Double Strand Breaks ◽  
Dna Molecules ◽  
Strand Breaks ◽  
Low Frequency Ultrasound ◽  
Frequency Ultrasound

scholarly journals Late Replication of the Inactive X Chromosome Is Independent of the Compactness of Chromosome Territory in Human Pluripotent Stem Cells

Acta Naturae ◽  
2013 ◽  
Vol 5 (2) ◽  
pp. 54-61
Author(s):  
A. V. Panova ◽  
E. D. Nekrasov ◽  
M. A. Lagarkova ◽  
S. L. Kiselev ◽  
A. N. Bogomazova
Keyword(s):  
Stem Cells ◽  
X Chromosome ◽  
Pluripotent Stem Cells ◽  
Replication Timing ◽  
Chromosome Territory ◽  
Late Replication ◽  
Facultative Heterochromatin ◽  
X Chromosomes ◽  
Inactive X Chromosome ◽  
The Status

Dosage compensation of the X chromosomes in mammals is performed via the formation of facultative heterochromatin on extra X chromosomes in female somatic cells. Facultative heterochromatin of the inactivated X (Xi), as well as constitutive heterochromatin, replicates late during the S-phase. It is generally accepted that Xi is always more compact in the interphase nucleus. The dense chromosomal folding has been proposed to define the late replication of Xi. In contrast to mouse pluripotent stem cells (PSCs), the status of X chromosome inactivation in human PSCs may vary significantly. Fluorescence in situ hybridization with a whole X-chromosome-specific DNA probe revealed that late-replicating Xi may occupy either compact or dispersed territory in human PSCs. Thus, the late replication of the Xi does not depend on the compactness of chromosome territory in human PSCs. However, the Xi reactivation and the synchronization in the replication timing of X chromosomes upon reprogramming are necessarily accompanied by the expansion of X chromosome territory.

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