Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation
Somatic hypermutation (SHM) plays a critical role in the maturation of antibodies, optimizing recognition initiated by recombination of V(D)J genes. Previous studies have shown that the propensity to mutate is modulated by the context of surrounding nucleotides and that SHM machinery generates biase...
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| Format: | Article |
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Frontiers Media S.A.
2017-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00537/full |
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| author | Zizhang Sheng Zizhang Sheng Chaim A. Schramm Chaim A. Schramm Chaim A. Schramm Rui Kong NISC Comparative Sequencing Program James C. Mullikin John R. Mascola Peter D. Kwong Peter D. Kwong Lawrence Shapiro Lawrence Shapiro Lawrence Shapiro |
| author_facet | Zizhang Sheng Zizhang Sheng Chaim A. Schramm Chaim A. Schramm Chaim A. Schramm Rui Kong NISC Comparative Sequencing Program James C. Mullikin John R. Mascola Peter D. Kwong Peter D. Kwong Lawrence Shapiro Lawrence Shapiro Lawrence Shapiro |
| author_sort | Zizhang Sheng |
| collection | DOAJ |
| description | Somatic hypermutation (SHM) plays a critical role in the maturation of antibodies, optimizing recognition initiated by recombination of V(D)J genes. Previous studies have shown that the propensity to mutate is modulated by the context of surrounding nucleotides and that SHM machinery generates biased substitutions. To investigate the intrinsic mutation frequency and substitution bias of SHMs at the amino acid level, we analyzed functional human antibody repertoires and developed mGSSP (method for gene-specific substitution profile), a method to construct amino acid substitution profiles from next-generation sequencing-determined B cell transcripts. We demonstrated that these gene-specific substitution profiles (GSSPs) are unique to each V gene and highly consistent between donors. We also showed that the GSSPs constructed from functional antibody repertoires are highly similar to those constructed from antibody sequences amplified from non-productively rearranged passenger alleles, which do not undergo functional selection. This suggests the types and frequencies, or mutational space, of a majority of amino acid changes sampled by the SHM machinery to be well captured by GSSPs. We further observed the rates of mutational exchange between some amino acids to be both asymmetric and context dependent and to correlate weakly with their biochemical properties. GSSPs provide an improved, position-dependent alternative to standard substitution matrices, and can be utilized to developing software for accurately modeling the SHM process. GSSPs can also be used for predicting the amino acid mutational space available for antigen-driven selection and for understanding factors modulating the maturation pathways of antibody lineages in a gene-specific context. The mGSSP method can be used to build, compare, and plot GSSPs1; we report the GSSPs constructed for 69 common human V genes (DOI: 10.6084/m9.figshare.3511083) and provide high-resolution logo plots for each (DOI: 10.6084/m9.figshare.3511085). |
| first_indexed | 2024-12-12T05:07:57Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T05:07:57Z |
| publishDate | 2017-05-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-9a95ccfe3d4b48bf82d151153d8360a02022-12-22T00:37:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-05-01810.3389/fimmu.2017.00537262457Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic HypermutationZizhang Sheng0Zizhang Sheng1Chaim A. Schramm2Chaim A. Schramm3Chaim A. Schramm4Rui Kong5NISC Comparative Sequencing Program6James C. Mullikin7John R. Mascola8Peter D. Kwong9Peter D. Kwong10Lawrence Shapiro11Lawrence Shapiro12Lawrence Shapiro13Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, United StatesDepartment of Systems Biology, Columbia University, New York, NY, United StatesDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, United StatesDepartment of Systems Biology, Columbia University, New York, NY, United StatesVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United StatesNIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United StatesVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, United StatesVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, United StatesDepartment of Systems Biology, Columbia University, New York, NY, United StatesVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesSomatic hypermutation (SHM) plays a critical role in the maturation of antibodies, optimizing recognition initiated by recombination of V(D)J genes. Previous studies have shown that the propensity to mutate is modulated by the context of surrounding nucleotides and that SHM machinery generates biased substitutions. To investigate the intrinsic mutation frequency and substitution bias of SHMs at the amino acid level, we analyzed functional human antibody repertoires and developed mGSSP (method for gene-specific substitution profile), a method to construct amino acid substitution profiles from next-generation sequencing-determined B cell transcripts. We demonstrated that these gene-specific substitution profiles (GSSPs) are unique to each V gene and highly consistent between donors. We also showed that the GSSPs constructed from functional antibody repertoires are highly similar to those constructed from antibody sequences amplified from non-productively rearranged passenger alleles, which do not undergo functional selection. This suggests the types and frequencies, or mutational space, of a majority of amino acid changes sampled by the SHM machinery to be well captured by GSSPs. We further observed the rates of mutational exchange between some amino acids to be both asymmetric and context dependent and to correlate weakly with their biochemical properties. GSSPs provide an improved, position-dependent alternative to standard substitution matrices, and can be utilized to developing software for accurately modeling the SHM process. GSSPs can also be used for predicting the amino acid mutational space available for antigen-driven selection and for understanding factors modulating the maturation pathways of antibody lineages in a gene-specific context. The mGSSP method can be used to build, compare, and plot GSSPs1; we report the GSSPs constructed for 69 common human V genes (DOI: 10.6084/m9.figshare.3511083) and provide high-resolution logo plots for each (DOI: 10.6084/m9.figshare.3511085).http://journal.frontiersin.org/article/10.3389/fimmu.2017.00537/fullantibodyomicsB cell ontogenybroadly neutralizing antibodymutation frequencyrepertoire diversity |
| spellingShingle | Zizhang Sheng Zizhang Sheng Chaim A. Schramm Chaim A. Schramm Chaim A. Schramm Rui Kong NISC Comparative Sequencing Program James C. Mullikin John R. Mascola Peter D. Kwong Peter D. Kwong Lawrence Shapiro Lawrence Shapiro Lawrence Shapiro Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation Frontiers in Immunology antibodyomics B cell ontogeny broadly neutralizing antibody mutation frequency repertoire diversity |
| title | Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation |
| title_full | Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation |
| title_fullStr | Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation |
| title_full_unstemmed | Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation |
| title_short | Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation |
| title_sort | gene specific substitution profiles describe the types and frequencies of amino acid changes during antibody somatic hypermutation |
| topic | antibodyomics B cell ontogeny broadly neutralizing antibody mutation frequency repertoire diversity |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00537/full |
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