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Short-range template switching in great ape genomes explored using pair hidden Markov models

Many complex genomic rearrangements arise through template switch errors, which occur in DNA replication when there is a transient polymerase switch to an alternate template nearby in three-dimensional space. While typically investigated at kilobase-to-megabase scales, the genomic and evolutionary c...

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Autores principales: Walker, Conor R., Scally, Aylwyn, De Maio, Nicola, Goldman, Nick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954356/
https://www.ncbi.nlm.nih.gov/pubmed/33651813
http://dx.doi.org/10.1371/journal.pgen.1009221
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author Walker, Conor R.
Scally, Aylwyn
De Maio, Nicola
Goldman, Nick
author_facet Walker, Conor R.
Scally, Aylwyn
De Maio, Nicola
Goldman, Nick
author_sort Walker, Conor R.
collection PubMed
description Many complex genomic rearrangements arise through template switch errors, which occur in DNA replication when there is a transient polymerase switch to an alternate template nearby in three-dimensional space. While typically investigated at kilobase-to-megabase scales, the genomic and evolutionary consequences of this mutational process are not well characterised at smaller scales, where they are often interpreted as clusters of independent substitutions, insertions and deletions. Here we present an improved statistical approach using pair hidden Markov models, and use it to detect and describe short-range template switches underlying clusters of mutations in the multi-way alignment of hominid genomes. Using robust statistics derived from evolutionary genomic simulations, we show that template switch events have been widespread in the evolution of the great apes’ genomes and provide a parsimonious explanation for the presence of many complex mutation clusters in their phylogenetic context. Larger-scale mechanisms of genome rearrangement are typically associated with structural features around breakpoints, and accordingly we show that atypical patterns of secondary structure formation and DNA bending are present at the initial template switch loci. Our methods improve on previous non-probabilistic approaches for computational detection of template switch mutations, allowing the statistical significance of events to be assessed. By specifying realistic evolutionary parameters based on the genomes and taxa involved, our methods can be readily adapted to other intra- or inter-species comparisons.
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spelling pubmed-79543562021-03-22 Short-range template switching in great ape genomes explored using pair hidden Markov models Walker, Conor R. Scally, Aylwyn De Maio, Nicola Goldman, Nick PLoS Genet Research Article Many complex genomic rearrangements arise through template switch errors, which occur in DNA replication when there is a transient polymerase switch to an alternate template nearby in three-dimensional space. While typically investigated at kilobase-to-megabase scales, the genomic and evolutionary consequences of this mutational process are not well characterised at smaller scales, where they are often interpreted as clusters of independent substitutions, insertions and deletions. Here we present an improved statistical approach using pair hidden Markov models, and use it to detect and describe short-range template switches underlying clusters of mutations in the multi-way alignment of hominid genomes. Using robust statistics derived from evolutionary genomic simulations, we show that template switch events have been widespread in the evolution of the great apes’ genomes and provide a parsimonious explanation for the presence of many complex mutation clusters in their phylogenetic context. Larger-scale mechanisms of genome rearrangement are typically associated with structural features around breakpoints, and accordingly we show that atypical patterns of secondary structure formation and DNA bending are present at the initial template switch loci. Our methods improve on previous non-probabilistic approaches for computational detection of template switch mutations, allowing the statistical significance of events to be assessed. By specifying realistic evolutionary parameters based on the genomes and taxa involved, our methods can be readily adapted to other intra- or inter-species comparisons. Public Library of Science 2021-03-02 /pmc/articles/PMC7954356/ /pubmed/33651813 http://dx.doi.org/10.1371/journal.pgen.1009221 Text en © 2021 Walker et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Walker, Conor R.
Scally, Aylwyn
De Maio, Nicola
Goldman, Nick
Short-range template switching in great ape genomes explored using pair hidden Markov models
title Short-range template switching in great ape genomes explored using pair hidden Markov models
title_full Short-range template switching in great ape genomes explored using pair hidden Markov models
title_fullStr Short-range template switching in great ape genomes explored using pair hidden Markov models
title_full_unstemmed Short-range template switching in great ape genomes explored using pair hidden Markov models
title_short Short-range template switching in great ape genomes explored using pair hidden Markov models
title_sort short-range template switching in great ape genomes explored using pair hidden markov models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954356/
https://www.ncbi.nlm.nih.gov/pubmed/33651813
http://dx.doi.org/10.1371/journal.pgen.1009221
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