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The stem cell population of the human colon crypt: analysis via methylation patterns.

Nicolas P, Kim KM, Shibata D, Tavaré S - PLoS Comput. Biol. (2007)

Bottom Line: Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data.Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20.The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

View Article: PubMed Central - PubMed

Affiliation: Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr

ABSTRACT
The analysis of methylation patterns is a promising approach to investigate the genealogy of cell populations in an organism. In a stem cell-niche scenario, sampled methylation patterns are the stochastic outcome of a complex interplay between niche structural features such as the number of stem cells within a niche and the niche succession time, the methylation/demethylation process, and the randomness due to sampling. As a consequence, methylation pattern studies can reveal niche characteristics but also require appropriate statistical methods. The analysis of methylation patterns sampled from colon crypts is a prototype of such a study. Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data. In this paper we develop a more powerful method to analyze these data based on coalescent modelling and Bayesian inference. Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20. The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

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Posterior Distribution of τ, g, α, and ɛResults are obtained using the model with context-dependent methylation rate and ignoring data from patient X.(Row 1) Reports the posteriors of the parameters τ, the average depth of the genealogy of the stem cells (in years), and g, the length of cell differentiation in terms of number of cell generations. These two parameters control, together with N, the shape of the genealogy.(Row 2) Reports the results for the parameters α and ɛ, responsible, together with ν, for the polymorphism given the genealogy: α is the relative amount of methylation/demethylation events in the g generations of cell differentiation compared with the number of events in a stem cell lineage up to the most recent common ancestor of the stem cell population; ɛ is the sequencing error rate.
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pcbi-0030028-g006: Posterior Distribution of τ, g, α, and ɛResults are obtained using the model with context-dependent methylation rate and ignoring data from patient X.(Row 1) Reports the posteriors of the parameters τ, the average depth of the genealogy of the stem cells (in years), and g, the length of cell differentiation in terms of number of cell generations. These two parameters control, together with N, the shape of the genealogy.(Row 2) Reports the results for the parameters α and ɛ, responsible, together with ν, for the polymorphism given the genealogy: α is the relative amount of methylation/demethylation events in the g generations of cell differentiation compared with the number of events in a stem cell lineage up to the most recent common ancestor of the stem cell population; ɛ is the sequencing error rate.

Mentions: The marginal posterior of each parameter of the model with context-dependent methylation rate obtained after removing data from patient X is shown in Figure 5 (N and ν) and Figure 6 (τ, g, α, and ɛ). The posterior distribution of N, τ, and g give a clear picture of the main features of the shape of the genealogy. The posterior distribution of the number of stem cells, N, reaches its mode between 15 and 20, gives little support for values of N below 8, and seems to exclude any value of N smaller than 6. The posterior distribution of τ suggests that the actual value of this parameter, which corresponds approximately to the average time before the stem cell population finds its most recent common ancestor, is located between 15 and 40 years. Finally, there seems to be very little information on parameter g that accounts for the shape of the genealogy of the cells sampled from the progeny of the same stem cell: the posterior distribution of g closely matches its continuous uniform prior on (5,10).


The stem cell population of the human colon crypt: analysis via methylation patterns.

Nicolas P, Kim KM, Shibata D, Tavaré S - PLoS Comput. Biol. (2007)

Posterior Distribution of τ, g, α, and ɛResults are obtained using the model with context-dependent methylation rate and ignoring data from patient X.(Row 1) Reports the posteriors of the parameters τ, the average depth of the genealogy of the stem cells (in years), and g, the length of cell differentiation in terms of number of cell generations. These two parameters control, together with N, the shape of the genealogy.(Row 2) Reports the results for the parameters α and ɛ, responsible, together with ν, for the polymorphism given the genealogy: α is the relative amount of methylation/demethylation events in the g generations of cell differentiation compared with the number of events in a stem cell lineage up to the most recent common ancestor of the stem cell population; ɛ is the sequencing error rate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808490&req=5

pcbi-0030028-g006: Posterior Distribution of τ, g, α, and ɛResults are obtained using the model with context-dependent methylation rate and ignoring data from patient X.(Row 1) Reports the posteriors of the parameters τ, the average depth of the genealogy of the stem cells (in years), and g, the length of cell differentiation in terms of number of cell generations. These two parameters control, together with N, the shape of the genealogy.(Row 2) Reports the results for the parameters α and ɛ, responsible, together with ν, for the polymorphism given the genealogy: α is the relative amount of methylation/demethylation events in the g generations of cell differentiation compared with the number of events in a stem cell lineage up to the most recent common ancestor of the stem cell population; ɛ is the sequencing error rate.
Mentions: The marginal posterior of each parameter of the model with context-dependent methylation rate obtained after removing data from patient X is shown in Figure 5 (N and ν) and Figure 6 (τ, g, α, and ɛ). The posterior distribution of N, τ, and g give a clear picture of the main features of the shape of the genealogy. The posterior distribution of the number of stem cells, N, reaches its mode between 15 and 20, gives little support for values of N below 8, and seems to exclude any value of N smaller than 6. The posterior distribution of τ suggests that the actual value of this parameter, which corresponds approximately to the average time before the stem cell population finds its most recent common ancestor, is located between 15 and 40 years. Finally, there seems to be very little information on parameter g that accounts for the shape of the genealogy of the cells sampled from the progeny of the same stem cell: the posterior distribution of g closely matches its continuous uniform prior on (5,10).

Bottom Line: Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data.Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20.The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

View Article: PubMed Central - PubMed

Affiliation: Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr

ABSTRACT
The analysis of methylation patterns is a promising approach to investigate the genealogy of cell populations in an organism. In a stem cell-niche scenario, sampled methylation patterns are the stochastic outcome of a complex interplay between niche structural features such as the number of stem cells within a niche and the niche succession time, the methylation/demethylation process, and the randomness due to sampling. As a consequence, methylation pattern studies can reveal niche characteristics but also require appropriate statistical methods. The analysis of methylation patterns sampled from colon crypts is a prototype of such a study. Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data. In this paper we develop a more powerful method to analyze these data based on coalescent modelling and Bayesian inference. Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20. The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

Show MeSH