Stochastic simulations of normal aging and Werner's syndrome.

Handle URI:
http://hdl.handle.net/10754/596817
Title:
Stochastic simulations of normal aging and Werner's syndrome.
Authors:
Qi, Qi; Wattis, Jonathan A D; Byrne, Helen M
Abstract:
Human cells typically consist of 23 pairs of chromosomes. Telomeres are repetitive sequences of DNA located at the ends of chromosomes. During cell replication, a number of basepairs are lost from the end of the chromosome and this shortening restricts the number of divisions that a cell can complete before it becomes senescent, or non-replicative. In this paper, we use Monte Carlo simulations to form a stochastic model of telomere shortening to investigate how telomere shortening affects normal aging. Using this model, we study various hypotheses for the way in which shortening occurs by comparing their impact on aging at the chromosome and cell levels. We consider different types of length-dependent loss and replication probabilities to describe these processes. After analyzing a simple model for a population of independent chromosomes, we simulate a population of cells in which each cell has 46 chromosomes and the shortest telomere governs the replicative potential of the cell. We generalize these simulations to Werner's syndrome, a condition in which large sections of DNA are removed during cell division and, amongst other conditions, results in rapid aging. Since the mechanisms governing the loss of additional basepairs are not known, we use our model to simulate a variety of possible forms for the rate at which additional telomeres are lost per replication and several expressions for how the probability of cell division depends on telomere length. As well as the evolution of the mean telomere length, we consider the standard deviation and the shape of the distribution. We compare our results with a variety of data from the literature, covering both experimental data and previous models. We find good agreement for the evolution of telomere length when plotted against population doubling.
Citation:
Qi Q, Wattis JAD, Byrne HM (2014) Stochastic Simulations of Normal Aging and Werner’s Syndrome. Bull Math Biol 76: 1241–1269. Available: http://dx.doi.org/10.1007/s11538-014-9952-8.
Publisher:
Springer Science + Business Media
Journal:
Bulletin of Mathematical Biology
KAUST Grant Number:
KUK-C1-013-04
Issue Date:
26-Apr-2014
DOI:
10.1007/s11538-014-9952-8
PubMed ID:
24771273
PubMed Central ID:
PMC4048474
Type:
Article
ISSN:
0092-8240; 1522-9602
Sponsors:
This work was initiated following several fruitful conversations with Professor Richard Faragher of Brighton University for which we are extremely grateful. QQ is grateful to the University of Nottingham for funding her PhD studies. The work of HMB was supported in part by Award No. KUK-C1-013-04, made by King Abdullah University of Science and Technology (KAUST). We thank the referees for making helpful comments.
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Full metadata record

DC FieldValue Language
dc.contributor.authorQi, Qien
dc.contributor.authorWattis, Jonathan A Den
dc.contributor.authorByrne, Helen Men
dc.date.accessioned2016-02-21T08:51:15Zen
dc.date.available2016-02-21T08:51:15Zen
dc.date.issued2014-04-26en
dc.identifier.citationQi Q, Wattis JAD, Byrne HM (2014) Stochastic Simulations of Normal Aging and Werner’s Syndrome. Bull Math Biol 76: 1241–1269. Available: http://dx.doi.org/10.1007/s11538-014-9952-8.en
dc.identifier.issn0092-8240en
dc.identifier.issn1522-9602en
dc.identifier.pmid24771273en
dc.identifier.doi10.1007/s11538-014-9952-8en
dc.identifier.urihttp://hdl.handle.net/10754/596817en
dc.description.abstractHuman cells typically consist of 23 pairs of chromosomes. Telomeres are repetitive sequences of DNA located at the ends of chromosomes. During cell replication, a number of basepairs are lost from the end of the chromosome and this shortening restricts the number of divisions that a cell can complete before it becomes senescent, or non-replicative. In this paper, we use Monte Carlo simulations to form a stochastic model of telomere shortening to investigate how telomere shortening affects normal aging. Using this model, we study various hypotheses for the way in which shortening occurs by comparing their impact on aging at the chromosome and cell levels. We consider different types of length-dependent loss and replication probabilities to describe these processes. After analyzing a simple model for a population of independent chromosomes, we simulate a population of cells in which each cell has 46 chromosomes and the shortest telomere governs the replicative potential of the cell. We generalize these simulations to Werner's syndrome, a condition in which large sections of DNA are removed during cell division and, amongst other conditions, results in rapid aging. Since the mechanisms governing the loss of additional basepairs are not known, we use our model to simulate a variety of possible forms for the rate at which additional telomeres are lost per replication and several expressions for how the probability of cell division depends on telomere length. As well as the evolution of the mean telomere length, we consider the standard deviation and the shape of the distribution. We compare our results with a variety of data from the literature, covering both experimental data and previous models. We find good agreement for the evolution of telomere length when plotted against population doubling.en
dc.description.sponsorshipThis work was initiated following several fruitful conversations with Professor Richard Faragher of Brighton University for which we are extremely grateful. QQ is grateful to the University of Nottingham for funding her PhD studies. The work of HMB was supported in part by Award No. KUK-C1-013-04, made by King Abdullah University of Science and Technology (KAUST). We thank the referees for making helpful comments.en
dc.publisherSpringer Science + Business Mediaen
dc.rightsThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.en
dc.subject.meshModels, Biologicalen
dc.titleStochastic simulations of normal aging and Werner's syndrome.en
dc.typeArticleen
dc.identifier.journalBulletin of Mathematical Biologyen
dc.identifier.pmcidPMC4048474en
dc.contributor.institutionCentre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham , NG7 2RD, UK, qi.qi@live.co.uk.en
kaust.grant.numberKUK-C1-013-04en
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