scholarly journals The mutation rate in PIG-A is normal in patients with paroxysmal nocturnal hemoglobinuria (PNH)

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 734-736 ◽  
Author(s):  
David J. Araten ◽  
Lucio Luzzatto
Keyword(s):  
Cell Division ◽  
Cell Population ◽  
Mutation Rate ◽  
Genetic Instability ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Somatic Mutations ◽  
Intrinsic Rate ◽  
Large Cell ◽  
Normal Range ◽  
Hematopoietic System

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the presence in the patient's hematopoietic system of a large cell population with a mutation in the X-linked PIG-A gene. Although this abnormal cell population is often found to be monoclonal, it is not unusual that 2 or even several PIG-A mutant clones coexist in the same patient. Therefore, it has been suggested that the PIG-A gene may be hypermutable in PNH. By a method we have recently developed for measuring the intrinsic rate of somatic mutations (μ) in humans, in which PIG-A itself is used as a sentinel gene, we have found that in 5 patients with PNH, μ ranged from 1.24 × 10–7 to 11.2 × 10–7, against a normal range of 2.4 × 10–7 to 29.6 × 10–7 mutations per cell division. We conclude that genetic instability of the PIG-A gene is not a factor in the pathogenesis of PNH.

scholarly journals Allele Frequency Spectrum in a Cancer Cell Population

2017 ◽  
Author(s):  
H. Ohtsuki ◽  
H. Innan
Keyword(s):  
Population Genetics ◽  
Cell Division ◽  
Allele Frequency ◽  
Frequency Spectrum ◽  
Cancer Cell ◽  
Cell Population ◽  
Large Cell ◽  
Parental Cancer ◽  
Allele Frequency Spectrum ◽  
Cancer Cell Population

ABSTRACTA cancer grows from a single cell, thereby constituting a large cell population. In this work, we are interested in how mutations accumulate in a cancer cell population. We provided a theoretical framework of the stochastic process in a cancer cell population and obtained near exact expressions of allele frequency spectrum or AFS (only continuous approximation is involved) from both forward and backward treatments under a simple setting; all cells undergo cell division and die at constant rates, b and d, respectively, such that the entire population grows exponentially. This setting means that once a parental cancer cell is established, in the following growth phase, all mutations are assumed to have no effect on b or d (i.e., neutral or passengers). Our theoretical results show that the difference from organismal population genetics is mainly in the coalescent time scale, and the mutation rate is defined per cell division, not per time unit (e.g., generation). Except for these two factors, the basic logic are very similar between organismal and cancer population genetics, indicating that a number of well established theories of organismal population genetics could be translated to cancer population genetics with simple modifications.

scholarly journals Age-dependent branching processes and applications to the Luria-Delbrck experiment

2015 ◽  
Author(s):  
◽  
Hesam Oveys
Keyword(s):  
Cell Division ◽  
Probability Distribution ◽  
Cell Population ◽  
Mutation Rate ◽  
Branching Processes ◽  
Large Population ◽  
Probability Generating Function ◽  
Microbial Evolution ◽  
Darwinian Evolution ◽  
Microbial Populations

Microbial populations adapt to their environment by acquiring advantageous mutations, but in the early twentieth century, questions about how these organisms acquire mutations arose. The experiment of Salvador Luria and Max Delbruck that won them a Nobel Prize in 1969 confirmed that mutations don't occur out of necessity, but instead can occur many generations before there is a selective advantage, and thus organisms follow Darwinian evolution instead of Lamarckian. Since then, new areas of research involving microbial evolution has spawned as a result of their experiment. Determining the mutation rate of a cell is one such area. Probability distributions that determine the number of mutants in a large population have been derived by D. E. Lea, C. A. Coulson, and J. B. S. Haldane. However, not much work has been done when time of cell division is dependent on the cell age, and even less so when cell division is asymmetric, which is the case in most microbial populations. Using probability generating function methods, we rigorously construct a probability distribution for the cell population size given a life-span distribution for both mother and daughter cells, and then determine its asymptotic growth rate. We use this to construct a probability distribution for the number of mutants in a large cell population, which can be used with likelihood methods to estimate the cell mutation rate.

scholarly journals Nucleotide excision repair is impaired by binding of transcription factors to DNA

2015 ◽  
Author(s):  
Radhakrishnan Sabarinathan ◽  
Loris Mularoni ◽  
Jordi Deu-Pons ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Nucleotide Excision Repair ◽  
Mutation Rate ◽  
Binding Sites ◽  
Somatic Mutations ◽  
Excision Repair ◽  
Replication Timing ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Nucleotide Excision ◽  
Active Transcription

Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

scholarly journals Conformational Heterogeneity in Human Interphase Chromosome Organization Reconciles the FISH and Hi-C Paradox

2019 ◽  
Author(s):  
Guang Shi ◽  
D. Thirumalai
Keyword(s):  
Cell Population ◽  
Genome Organization ◽  
Large Cell ◽  
Spatial Distance ◽  
Chromosome Organization ◽  
Conformational Heterogeneity ◽  
Interphase Chromosome ◽  
Length Scales ◽  
Rouse Model ◽  
Contact Probability

AbstractHi-C experiments are used to infer the contact probabilities between loci separated by varying genome lengths. Contact probability should decrease as the spatial distance between two loci increases. However, studies comparing Hi-C and FISH data show that in some cases the distance between one pair of loci, with larger Hi-C readout, is paradoxically larger compared to another pair with a smaller value of the contact probability. Here, we show that the FISH-Hi-C paradox can be resolved using a theory based on a Generalized Rouse Model for Chromosomes (GRMC). The FISH-Hi-C paradox arises because the cell population is highly heterogeneous, which means that a given contact is present in only a fraction of cells. Insights from the GRMC is used to construct a theory, without any adjustable parameters, to extract the distribution of subpopulations from the FISH data, which quantitatively reproduces the Hi-C data. Our results show that heterogeneity is pervasive in genome organization at all length scales, reflecting large cell-to-cell variations.

When and how does cell division order influence cell allocation to the inner cell mass of the mouse blastocyst?

Development ◽  
1987 ◽  
Vol 100 (2) ◽  
pp. 325-332
Author(s):  
C.L. Garbutt ◽  
M.H. Johnson ◽  
M.A. George
Keyword(s):  
Cell Division ◽  
Cell Population ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Lineage ◽  
The Other ◽  
Mouse Blastocyst ◽  
Short Term ◽  
Cell Stage ◽  
Cell Embryo

Aggregate 8-cell embryos were constructed from four 2/8 pairs of blastomeres, one of which was marked with a short-term cell lineage marker and was also either 4 h older (derived from an early-dividing 4-cell) or 4 h younger (derived from a late-dividing 4-cell) than the other three pairs. The aggregate embryos were cultured to the 16-cell stage, at which time a second marker was used to label the outside cell population. The embryos were then disaggregated and each cell was examined to determine its labelling pattern. From this analysis, we calculated the relative contributions to the inside cell population of the 16-cell embryo of older and younger cells. Older cells were found to contribute preferentially. However, if the construction of the aggregate 8-cell embryo was delayed until each of the contributing 2/8 cell pairs had undergone intercellular flattening and then had been exposed to medium low in calcium to reverse this flattening immediately prior to aggregation, the advantage possessed by the older cells was lost. These results support the suggestion that older cells derived from early-dividing 4-cell blastomeres contribute preferentially to the inner cell mass as a result of being early-flattening cells.

scholarly journals A phylogenomic approach reveals a low somatic mutation rate in a long-lived plant

2020 ◽  
Vol 287 (1922) ◽  
pp. 20192364
Author(s):  
Adam J. Orr ◽  
Amanda Padovan ◽  
David Kainer ◽  
Carsten Külheim ◽  
Lindell Bromham ◽  
...  
Keyword(s):  
Life History ◽  
Somatic Mutation ◽  
Mutation Rate ◽  
Somatic Mutations ◽  
Growing Body

Somatic mutations can have important effects on the life history, ecology, and evolution of plants, but the rate at which they accumulate is poorly understood and difficult to measure directly. Here, we develop a method to measure somatic mutations in individual plants and use it to estimate the somatic mutation rate in a large, long-lived, phenotypically mosaic Eucalyptus melliodora tree. Despite being 100 times larger than Arabidopsis, this tree has a per-generation mutation rate only ten times greater, which suggests that this species may have evolved mechanisms to reduce the mutation rate per unit of growth. This adds to a growing body of evidence that illuminates the correlated evolutionary shifts in mutation rate and life history in plants.

scholarly journals Somatic mutations substantially increase the per‐generation mutation rate in the conifer Picea sitchensis

2019 ◽  
Vol 3 (4) ◽  
pp. 348-358 ◽  
Author(s):  
Vincent C. T. Hanlon ◽  
Sarah P. Otto ◽  
Sally N. Aitken
Keyword(s):  
Mutation Rate ◽  
Somatic Mutations ◽  
Picea Sitchensis

Mutations Beget More Mutations—Rapid Evolution of Mutation Rate in Response to the Risk of Runaway Accumulation

2019 ◽  
Vol 37 (4) ◽  
pp. 1007-1019 ◽  
Author(s):  
Yongsen Ruan ◽  
Haiyu Wang ◽  
Bingjie Chen ◽  
Haijun Wen ◽  
Chung-I Wu
Keyword(s):  
Mutation Rate ◽  
Generation Time ◽  
Feedback Loop ◽  
Somatic Mutations ◽  
Rapid Evolution ◽  
Evolutionary Patterns ◽  
Positive Feedback Loop ◽  
Constant Rate ◽  
Time Changes ◽  
Runaway Process

Abstract The rapidity with which the mutation rate evolves could greatly impact evolutionary patterns. Nevertheless, most studies simply assume a constant rate in the time scale of interest (Kimura 1983; Drake 1991; Kumar 2005; Li 2007; Lynch 2010). In contrast, recent studies of somatic mutations suggest that the mutation rate may vary by several orders of magnitude within a lifetime (Kandoth et al. 2013; Lawrence et al. 2013). To resolve the discrepancy, we now propose a runaway model, applicable to both the germline and soma, whereby mutator mutations form a positive-feedback loop. In this loop, any mutator mutation would increase the rate of acquiring the next mutator, thus triggering a runaway escalation in mutation rate. The process can be initiated more readily if there are many weak mutators than a few strong ones. Interestingly, even a small increase in the mutation rate at birth could trigger the runaway process, resulting in unfit progeny. In slowly reproducing species, the need to minimize the risk of this uncontrolled accumulation would thus favor setting the mutation rate low. In comparison, species that starts and ends reproduction sooner do not face the risk and may set the baseline mutation rate higher. The mutation rate would evolve in response to the risk of runaway mutation, in particular, when the generation time changes. A rapidly evolving mutation rate may shed new lights on many evolutionary phenomena (Elango et al. 2006; Thomas et al. 2010, 2018; Langergraber et al. 2012; Besenbacher et al. 2019).

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