A Bayesian Framework for Inferring the Influence of Sequence Context on Point Mutations
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A Bayesian Framework for Inferring the Influence of Sequence Context on Point Mutations. / Ling, Guy; Miller, Danielle; Nielsen, Rasmus; Stern, Adi.
I: Molecular Biology and Evolution, Bind 37, Nr. 3, 2020, s. 893-903.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A Bayesian Framework for Inferring the Influence of Sequence Context on Point Mutations
AU - Ling, Guy
AU - Miller, Danielle
AU - Nielsen, Rasmus
AU - Stern, Adi
N1 - Publisher Copyright: © 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
PY - 2020
Y1 - 2020
N2 - The probability of point mutations is expected to be highly influenced by the flanking nucleotides that surround them, known as the sequence context. This phenomenon may be mainly attributed to the enzyme that modifies or mutates the genetic material, because most enzymes tend to have specific sequence contexts that dictate their activity. Here, we develop a statistical model that allows for the detection and evaluation of the effects of different sequence contexts on mutation rates from deep population sequencing data. This task is computationally challenging, as the complexity of the model increases exponentially as the context size increases. We established our novel Bayesian method based on sparse model selection methods, with the leading assumption that the number of actual sequence contexts that directly influence mutation rates is minuscule compared with the number of possible sequence contexts. We show that our method is highly accurate on simulated data using pentanucleotide contexts, even when accounting for noisy data. We next analyze empirical population sequencing data from polioviruses and HIV-1 and detect a significant enrichment in sequence contexts associated with deamination by the cellular deaminases ADAR 1/2 and APOBEC3G, respectively. In the current era, where next-generation sequencing data are highly abundant, our approach can be used on any population sequencing data to reveal context-dependent base alterations and may assist in the discovery of novel mutable sites or editing sites.
AB - The probability of point mutations is expected to be highly influenced by the flanking nucleotides that surround them, known as the sequence context. This phenomenon may be mainly attributed to the enzyme that modifies or mutates the genetic material, because most enzymes tend to have specific sequence contexts that dictate their activity. Here, we develop a statistical model that allows for the detection and evaluation of the effects of different sequence contexts on mutation rates from deep population sequencing data. This task is computationally challenging, as the complexity of the model increases exponentially as the context size increases. We established our novel Bayesian method based on sparse model selection methods, with the leading assumption that the number of actual sequence contexts that directly influence mutation rates is minuscule compared with the number of possible sequence contexts. We show that our method is highly accurate on simulated data using pentanucleotide contexts, even when accounting for noisy data. We next analyze empirical population sequencing data from polioviruses and HIV-1 and detect a significant enrichment in sequence contexts associated with deamination by the cellular deaminases ADAR 1/2 and APOBEC3G, respectively. In the current era, where next-generation sequencing data are highly abundant, our approach can be used on any population sequencing data to reveal context-dependent base alterations and may assist in the discovery of novel mutable sites or editing sites.
KW - evolutionary model
KW - MCMC
KW - mutation rates
KW - population genetics
KW - sequence context
U2 - 10.1093/molbev/msz248
DO - 10.1093/molbev/msz248
M3 - Journal article
C2 - 31651955
AN - SCOPUS:85081100928
VL - 37
SP - 893
EP - 903
JO - Molecular Biology and Evolution
JF - Molecular Biology and Evolution
SN - 0737-4038
IS - 3
ER -
ID: 336610192