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

View ORCID ProfileConor R. Walker, View ORCID ProfileAylwyn Scally, View ORCID ProfileNicola De Maio, View ORCID ProfileNick Goldman
doi: https://doi.org/10.1101/2020.11.09.374694
Conor R. Walker
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, CB10 1SD, United Kingdom
2Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
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Aylwyn Scally
2Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
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Nicola De Maio
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, CB10 1SD, United Kingdom
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Nick Goldman
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, CB10 1SD, United Kingdom
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  • For correspondence: goldman@ebi.ac.uk
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Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 10, 2020.
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Short-range template switching in great ape genomes explored using a pair hidden Markov model
Conor R. Walker, Aylwyn Scally, Nicola De Maio, Nick Goldman
bioRxiv 2020.11.09.374694; doi: https://doi.org/10.1101/2020.11.09.374694
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Short-range template switching in great ape genomes explored using a pair hidden Markov model
Conor R. Walker, Aylwyn Scally, Nicola De Maio, Nick Goldman
bioRxiv 2020.11.09.374694; doi: https://doi.org/10.1101/2020.11.09.374694

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