FireProtASR: A Web Server for Fully Automated Ancestral Sequence Reconstruction

Musil, Miloš; Khan, Rayyan Tariq; Beier, Andy; Štourač, Jan; Konegger, Hannes; Damborský, Jiřı́; Bednář, David

doi:10.1093/bib/bbaa337

Cited by 52 publications

(39 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Insertions and deletions at branch points introduce a major source of variation in sequence. Not all reconstruction tools model indels, but several consider each sequence position independently and infer “gaps” in ancestors through parsimony (PAML/LAZARUS [ 23 ]) or by probability based on the presence of gaps in descendants (GASP [ 24 ], FireProt ASR [ 25 ]). By referencing extant and ancestor sequences in a multiple sequence alignment, extended gaps are accounted for by simple indel coding (SIC) that regards deletions as equivalent if they start and end at the same positions [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

Engineering indel and substitution variants of diverse and ancient enzymes using Graphical Representation of Ancestral Sequence Predictions (GRASP)

Foley

Mora²,

Ross³

et al. 2022

PLoS Comput Biol

View full text Add to dashboard Cite

Ancestral sequence reconstruction is a technique that is gaining widespread use in molecular evolution studies and protein engineering. Accurate reconstruction requires the ability to handle appropriately large numbers of sequences, as well as insertion and deletion (indel) events, but available approaches exhibit limitations. To address these limitations, we developed Graphical Representation of Ancestral Sequence Predictions (GRASP), which efficiently implements maximum likelihood methods to enable the inference of ancestors of families with more than 10,000 members. GRASP implements partial order graphs (POGs) to represent and infer insertion and deletion events across ancestors, enabling the identification of building blocks for protein engineering. To validate the capacity to engineer novel proteins from realistic data, we predicted ancestor sequences across three distinct enzyme families: glucose-methanol-choline (GMC) oxidoreductases, cytochromes P450, and dihydroxy/sugar acid dehydratases (DHAD). All tested ancestors demonstrated enzymatic activity. Our study demonstrates the ability of GRASP (1) to support large data sets over 10,000 sequences and (2) to employ insertions and deletions to identify building blocks for engineering biologically active ancestors, by exploring variation over evolutionary time.

show abstract

Section: Resultsmentioning

confidence: 99%

Engineering indel and substitution variants of diverse and ancient enzymes using Graphical Representation of Ancestral Sequence Predictions (GRASP)

Foley

Mora²,

Ross³

et al. 2022

PLoS Comput Biol

View full text Add to dashboard Cite

show abstract

“…Insertions and deletions at branch points introduce a major source of variation in sequence. Not all reconstruction tools model indels, but several consider each sequence position independently and infer “gaps” in ancestors through parsimony (PAML/LAZARUS 21 ) or by probability based on the presence of gaps in descendants (GASP 22 , FireProt ASR 23 ). Extended gaps are accounted for by simple indel coding (SIC) that regards deletions in aligned sequences as equivalent if they start and end at the same positions 24 .…”

Section: Resultsmentioning

confidence: 99%

Engineering indel and substitution variants of diverse and ancient enzymes using Graphical Representation of Ancestral Sequence Predictions (GRASP)

Foley

Mora

Ross

et al. 2019

Preprint

View full text Add to dashboard Cite

We developed Graphical Representation of Ancestral Sequence Predictions (GRASP) to infer and explore ancestral variants of protein families with more than 10,000 members. GRASP uses partial order graphs to represent homology in very large datasets, which are intractable with current inference tools and may, for example, be used to engineer proteins by identifying ancient variants of enzymes. We demonstrate that (1) across three distinct enzyme families, GRASP predicts ancestor sequences, all of which demonstrate enzymatic activity, (2) within-family insertions and deletions can be used as building blocks to support the engineering of biologically active ancestors via a new source of ancestral variation, and (3) generous inclusion of sequence data encompassing great diversity leads to less variance in ancestor sequence.GRASP is the central tool in the GRASP-suite, which is freely available at

show abstract

“…Selection tests for the entire cspZ gene included Tajima’s neutrality test in MEGA-X (102) and all tests available in DnaSP v5 with 10,000 coalescent simulations (108), all at default settings. The ancestor state for the entire B. burgdorferi ingroup was reconstructed using the LG model in GRASP 2020.05.05 (109, 110), as well as FireProt-ASR with default settings (111) using both full and haplotype phylogenies, a multitaxon outgroup and solely B. bissettii as outgroup. Divergence dating was carried out in BEAST v1.10.4 (112) using the HKY+Γ 4 substitution model(113, 114), a coalescent Bayesian skyline coalescent model, and a strict clock with a uniform prior on the substitution rate using a previously determined rate of 4.75e-06 substitutions/site/year(42).…”

Section: Methodsmentioning

confidence: 99%

Structural evolution of an immune evasion determinant shapes Lyme borreliae host tropism

Marcinkiewicz

Brangulis

Dupuis

et al. 2022

Preprint

View full text Add to dashboard Cite

Lyme disease presents a suitable model for the investigation of host tropism – a pathogen’s ability to colonize and survive in different host species – since its causative agent, the spirochete Borrelia burgdorferi (Bb) is transmitted by ticks and maintained in rodent and bird reservoir hosts. In order to survive in vertebrates and escape from killing by complement, a first-line host immune defense, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to promote infection. Protein sequence conservation seems to be linked to FH-binding activity divergence, raising the hypothesis that even minor variation can confer host-specific, FH-binding-mediated infectivity. Our work shows that that this minor variation is located in a loop in the CspZ protein localized in the CspZ-FH binding interface. Our functional experiments prove that this loop promotes bird- or rodent-specific FH-binding activity and infectivity. Swapping loops between rodent- and bird-associated CspZ variants alters their capability to confer host-specific dissemination. We further investigated the evolutionary mechanisms driving the emergence of the CspZ loop-mediated, host-dependent complement evasion. This multifaceted work demonstrates how a single, short protein motif can significantly impact host tropism.

show abstract

FireProtASR: A Web Server for Fully Automated Ancestral Sequence Reconstruction

Cited by 52 publications

References 49 publications

Engineering indel and substitution variants of diverse and ancient enzymes using Graphical Representation of Ancestral Sequence Predictions (GRASP)

Engineering indel and substitution variants of diverse and ancient enzymes using Graphical Representation of Ancestral Sequence Predictions (GRASP)

Engineering indel and substitution variants of diverse and ancient enzymes using Graphical Representation of Ancestral Sequence Predictions (GRASP)

Structural evolution of an immune evasion determinant shapes Lyme borreliae host tropism

Contact Info

Product

Resources

About