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Assigning and visualizing germline genes in antibody repertoires.

Frost SD, Murrell B, Hossain AS, Silverman GJ, Pond SL - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

Bottom Line: We also develop an interactive web application for viewing the results, allowing the user to explore the frequency distribution of sequence assignments and CDR3 region length statistics, which is useful for summarizing repertoires, as well as a detailed viewer of rearrangements and region alignments for individual query sequences.We demonstrate the accuracy and utility of our method compared with sequence similarity-based approaches and other non-phylogenetic model-based approaches, using both simulated data and a set of evaluation datasets of human immunoglobulin heavy chain sequences.IgSCUEAL demonstrates the highest accuracy of V and J assignment amongst existing approaches, even when the reassorted sequence is highly mutated, and can successfully cluster sequences on the basis of shared V/J germline alleles.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, Cambridgeshire CB3 0ES, UK.

ABSTRACT
Identifying the germline genes involved in immunoglobulin rearrangements is an essential first step in the analysis of antibody repertoires. Based on our prior work in analysing diverse recombinant viruses, we present IgSCUEAL (Immunoglobulin Subtype Classification Using Evolutionary ALgorithms), a phylogenetic approach to assign V and J regions of immunoglobulin sequences to their corresponding germline alleles, with D regions assigned using a simple pairwise alignment algorithm. We also develop an interactive web application for viewing the results, allowing the user to explore the frequency distribution of sequence assignments and CDR3 region length statistics, which is useful for summarizing repertoires, as well as a detailed viewer of rearrangements and region alignments for individual query sequences. We demonstrate the accuracy and utility of our method compared with sequence similarity-based approaches and other non-phylogenetic model-based approaches, using both simulated data and a set of evaluation datasets of human immunoglobulin heavy chain sequences. IgSCUEAL demonstrates the highest accuracy of V and J assignment amongst existing approaches, even when the reassorted sequence is highly mutated, and can successfully cluster sequences on the basis of shared V/J germline alleles.

No MeSH data available.


Related in: MedlinePlus

IgSCUEAL classification results for AF262201 from the PW57 dataset. Based on ≈20 000 phylogenetic attachment models examined by IgSCUEAL, the best-supported rearrangement is V4-34*04 (D3-10*01) J3*02. Alternative rearrangements, all involving V4-34 and J3 alleles are shown in panel (a). The inferred model-averaged support for attaching the J and V regions of AF262201 to various branches in the reference trees (most of the V tree has been collapsed for clarity) are shown as branch colours in panels (b) and (c), respectively.
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RSTB20140240F4: IgSCUEAL classification results for AF262201 from the PW57 dataset. Based on ≈20 000 phylogenetic attachment models examined by IgSCUEAL, the best-supported rearrangement is V4-34*04 (D3-10*01) J3*02. Alternative rearrangements, all involving V4-34 and J3 alleles are shown in panel (a). The inferred model-averaged support for attaching the J and V regions of AF262201 to various branches in the reference trees (most of the V tree has been collapsed for clarity) are shown as branch colours in panels (b) and (c), respectively.

Mentions: A maximum-likelihood phylogeny of unique functional (F and ORF) germline V genes. Individual family clades have been collapsed to represent the tree more compactly, while showing the diversity encompassed by the clade. The counts of unique family members (*01 alleles) and total allelic variants are shown as the first and second numbers following family names, respectively. The clade for the V5 family is shown in the enlarged inset, and demonstrates some conventions used for assigning labels to internal nodes in the tree. For example, the internal node V5-51*01 inherits its label from a child node with a branch length of zero. In the context of phylogenetic likelihood, this implies that the sequence at the internal node is identical to that of the descendant node, justifying label propagation. The parent of the V5-51*01 internal node is labelled V5, because it is the most fully resolved label shared by all of its descendants (V5-51*xx and V5-10*xx alleles), and none of its children have branch lengths of zero. The main body of this figure, as well as of figures 2 and 4, were generated using an interactive web application used to view IgSCUEAL results.


Assigning and visualizing germline genes in antibody repertoires.

Frost SD, Murrell B, Hossain AS, Silverman GJ, Pond SL - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

IgSCUEAL classification results for AF262201 from the PW57 dataset. Based on ≈20 000 phylogenetic attachment models examined by IgSCUEAL, the best-supported rearrangement is V4-34*04 (D3-10*01) J3*02. Alternative rearrangements, all involving V4-34 and J3 alleles are shown in panel (a). The inferred model-averaged support for attaching the J and V regions of AF262201 to various branches in the reference trees (most of the V tree has been collapsed for clarity) are shown as branch colours in panels (b) and (c), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528417&req=5

RSTB20140240F4: IgSCUEAL classification results for AF262201 from the PW57 dataset. Based on ≈20 000 phylogenetic attachment models examined by IgSCUEAL, the best-supported rearrangement is V4-34*04 (D3-10*01) J3*02. Alternative rearrangements, all involving V4-34 and J3 alleles are shown in panel (a). The inferred model-averaged support for attaching the J and V regions of AF262201 to various branches in the reference trees (most of the V tree has been collapsed for clarity) are shown as branch colours in panels (b) and (c), respectively.
Mentions: A maximum-likelihood phylogeny of unique functional (F and ORF) germline V genes. Individual family clades have been collapsed to represent the tree more compactly, while showing the diversity encompassed by the clade. The counts of unique family members (*01 alleles) and total allelic variants are shown as the first and second numbers following family names, respectively. The clade for the V5 family is shown in the enlarged inset, and demonstrates some conventions used for assigning labels to internal nodes in the tree. For example, the internal node V5-51*01 inherits its label from a child node with a branch length of zero. In the context of phylogenetic likelihood, this implies that the sequence at the internal node is identical to that of the descendant node, justifying label propagation. The parent of the V5-51*01 internal node is labelled V5, because it is the most fully resolved label shared by all of its descendants (V5-51*xx and V5-10*xx alleles), and none of its children have branch lengths of zero. The main body of this figure, as well as of figures 2 and 4, were generated using an interactive web application used to view IgSCUEAL results.

Bottom Line: We also develop an interactive web application for viewing the results, allowing the user to explore the frequency distribution of sequence assignments and CDR3 region length statistics, which is useful for summarizing repertoires, as well as a detailed viewer of rearrangements and region alignments for individual query sequences.We demonstrate the accuracy and utility of our method compared with sequence similarity-based approaches and other non-phylogenetic model-based approaches, using both simulated data and a set of evaluation datasets of human immunoglobulin heavy chain sequences.IgSCUEAL demonstrates the highest accuracy of V and J assignment amongst existing approaches, even when the reassorted sequence is highly mutated, and can successfully cluster sequences on the basis of shared V/J germline alleles.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, Cambridgeshire CB3 0ES, UK.

ABSTRACT
Identifying the germline genes involved in immunoglobulin rearrangements is an essential first step in the analysis of antibody repertoires. Based on our prior work in analysing diverse recombinant viruses, we present IgSCUEAL (Immunoglobulin Subtype Classification Using Evolutionary ALgorithms), a phylogenetic approach to assign V and J regions of immunoglobulin sequences to their corresponding germline alleles, with D regions assigned using a simple pairwise alignment algorithm. We also develop an interactive web application for viewing the results, allowing the user to explore the frequency distribution of sequence assignments and CDR3 region length statistics, which is useful for summarizing repertoires, as well as a detailed viewer of rearrangements and region alignments for individual query sequences. We demonstrate the accuracy and utility of our method compared with sequence similarity-based approaches and other non-phylogenetic model-based approaches, using both simulated data and a set of evaluation datasets of human immunoglobulin heavy chain sequences. IgSCUEAL demonstrates the highest accuracy of V and J assignment amongst existing approaches, even when the reassorted sequence is highly mutated, and can successfully cluster sequences on the basis of shared V/J germline alleles.

No MeSH data available.


Related in: MedlinePlus