IgTree: creating Immunoglobulin variable region gene lineage trees.

Lineage trees describe the microevolution of cells within an organism. They have been useful in the study of B cell affinity maturation, which is based on somatic hypermutation of immunoglobulin genes in germinal centers and selection of the resulting mutants. Our aim was to create and implement an algorithm that can generate lineage trees from immunoglobulin variable region gene sequences. The IgTree program implements the algorithm we developed, and generates lineage trees. Original sequences found in experiments are assigned to either leaves or internal nodes of the tree. Each tree node represents a single mutation separating the sequences. The mutations that separate the sequences from each other can be point mutations, deletions or insertions. The program can deal with gaps and find potential reversion mutations. The program also enumerates mutation frequencies and sequence motifs around each mutation, on a per-tree basis. The algorithm has proven useful in several studies of immunoglobulin variable region gene mutations.

[1]  Rodrigo Lopez,et al.  Clustal W and Clustal X version 2.0 , 2007, Bioinform..

[2]  T. Manser,et al.  Evolution of antibody structure during the immune response. The differentiative potential of a single B lymphocyte , 1989, The Journal of experimental medicine.

[3]  A. Dispenzieri,et al.  Quantitative analysis of clonal bone marrow CD19+ B cells: use of B cell lineage trees to delineate their role in the pathogenesis of light chain amyloidosis. , 2006, Clinical immunology.

[4]  Ramit Mehr,et al.  Immunoglobulin variable-region gene mutational lineage tree analysis: application to autoimmune diseases. , 2006, Autoimmunity reviews.

[5]  Anat Hutzler,et al.  Lineage tree analysis of immunoglobulin variable-region gene mutations in autoimmune diseases: chronic activation, normal selection. , 2006, Cellular immunology.

[6]  R Mehr,et al.  Reconciling repertoire shift with affinity maturation: the role of deleterious mutations. , 1999, Journal of immunology.

[7]  A. Dispenzieri,et al.  Novel Analysis of Clonal Diversification in Blood B Cell and Bone Marrow Plasma Cell Clones in Immunoglobulin Light Chain Amyloidosis , 2006, Journal of Clinical Immunology.

[8]  David S. Johnson,et al.  The computational complexity of inferring rooted phylogenies by parsimony , 1986 .

[9]  M. Gorfine,et al.  Antigen-driven selection in germinal centers as reflected by the shape characteristics of immunoglobulin gene lineage trees: a large-scale simulation study. , 2008, Journal of theoretical biology.

[10]  David G. Schatz,et al.  Targeting of somatic hypermutation , 2006, Nature Reviews Immunology.

[11]  Ramit Mehr,et al.  Immune system learning and memory quantified by graphical analysis of B-lymphocyte phylogenetic trees. , 2004, Bio Systems.

[12]  I. Barshack,et al.  B‐cell clonal diversification and gut‐lymph node trafficking in ulcerative colitis revealed using lineage tree analysis , 2008, European journal of immunology.

[13]  N. Saitou,et al.  The neighbor-joining method: a new method for reconstructing phylogenetic trees. , 1987, Molecular biology and evolution.

[14]  Tamir Tuller,et al.  Maximum Likelihood of Evolutionary Trees Is Hard , 2005, RECOMB.

[15]  Ramit Mehr,et al.  Age‐ and tissue‐specific differences in human germinal center B cell selection revealed by analysis of IgVH gene hypermutation and lineage trees , 2002, European journal of immunology.

[16]  R Mehr,et al.  Effects of age on antibody affinity maturation. , 2003, Biochemical Society transactions.

[17]  Ramit Mehr,et al.  The Dynamics of Germinal Centre Selection as Measured by Graph-Theoretical Analysis of Mutational Lineage Trees , 2002, Developmental immunology.

[18]  Emden R. Gansner,et al.  An open graph visualization system and its applications to software engineering , 2000 .

[19]  W. Li,et al.  Simple method for constructing phylogenetic trees from distance matrices. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Klaus Rajewsky,et al.  Intraclonal generation of antibody mutants in germinal centres , 1991, Nature.

[21]  C. Kocks,et al.  Stepwise intraclonal maturation of antibody affinity through somatic hypermutation. , 1988, Proceedings of the National Academy of Sciences of the United States of America.