Please use this identifier to cite or link to this item: https://doi.org/10.21256/zhaw-3886
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dc.contributor.authorMirsky, Alexander-
dc.contributor.authorAnisimova, Maria-
dc.contributor.authorKazandjian, Linda-
dc.date.accessioned2018-07-17T15:12:28Z-
dc.date.available2018-07-17T15:12:28Z-
dc.date.issued2014-
dc.identifier.issn0737-4038de_CH
dc.identifier.issn1537-1719de_CH
dc.identifier.urihttps://digitalcollection.zhaw.ch/handle/11475/8270-
dc.description.abstractAntibodies are glycoproteins produced by the immune system as a dynamically adaptive line of defense against invading pathogens. Very elegant and specific mutational mechanisms allow B lymphocytes to produce a large and diversified repertoire of antibodies, which is modified and enhanced throughout all adulthood. One of these mechanisms is somatic hypermutation, which stochastically mutates nucleotides in the antibody genes, forming new sequences with different properties and, eventually, higher affinity and selectivity to the pathogenic target. Since somatic hypermutation involves fast mutation of antibody sequences, this process can be described using a Markov substitution model of molecular evolution. Here, using large sets of antibody sequences from mice and humans, we infer an empirical amino acid substitution model AB, which is specific to antibody sequences. Compared to existing general amino acid models, we show that the AB model provides significantly better description for the somatic evolution of mice and human antibody sequences, as demonstrated on large next generation sequencing (NGS) antibody data. General amino acid models are reflective of conservation at the protein level due to functional constraints, with most frequent amino acids exchanges taking place between residues with the same or similar physicochemical properties. In contrast, within the variable part of antibody sequences we observed an elevated frequency of exchanges between amino acids with distinct physicochemical properties. This is indicative of a sui generis mutational mechanism, specific to antibody somatic hypermutation. We illustrate this property of antibody sequences by a comparative analysis of the network modularity implied by the AB model and general amino acid substitution models. We recommend using the new model for computational studies of antibody sequence maturation, including inference of alignments and phylogenetic trees describing antibody somatic hypermutation in large NGS data sets. The AB model is implemented in the open-source software CodonPhyML (http://sourceforge.net/projects/codonphyml) and can be downloaded and supplied by the user to ProGraphMSA (http://sourceforge.net/projects/prographmsa) or other alignment and phylogeny reconstruction programs that allow for user-defined substitution models.de_CH
dc.language.isoende_CH
dc.publisherOxford University Pressde_CH
dc.relation.ispartofMolecular Biology and Evolutionde_CH
dc.rightshttp://creativecommons.org/licenses/by/4.0/de_CH
dc.subjectMarkov modelde_CH
dc.subjectAmino acid substitutionde_CH
dc.subjectAlignmentde_CH
dc.subjectEvolutionde_CH
dc.subjectAntibodyde_CH
dc.subjectSomatic hypermutationde_CH
dc.subjectAntibody genealogyde_CH
dc.subject.ddc572: Biochemiede_CH
dc.titleAntibody-specific model of amino acid substitution for immunological inferences from alignments of antibody sequencesde_CH
dc.typeBeitrag in wissenschaftlicher Zeitschriftde_CH
dcterms.typeTextde_CH
zhaw.departementLife Sciences und Facility Managementde_CH
zhaw.organisationalunitInstitut für Computational Life Sciences (ICLS)de_CH
dc.identifier.doi10.21256/zhaw-3886-
dc.identifier.doi10.1093/molbev/msu340de_CH
zhaw.funding.euNode_CH
zhaw.issue3de_CH
zhaw.originated.zhawYesde_CH
zhaw.pages.end819de_CH
zhaw.pages.start806de_CH
zhaw.publication.statuspublishedVersionde_CH
zhaw.volume32de_CH
zhaw.publication.reviewPeer review (Publikation)de_CH
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