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Quantifying evolutionary constraints on B-cell affinity maturation.

McCoy CO, Bedford T, Minin VN, Bradley P, Robins H, Matsen FA - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

Bottom Line: The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) mutation and selection.It has recently become possible to gain detailed information concerning this process through high-throughput sequencing.We find that the substitution process is conserved across individuals but varies significantly across gene segments.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

ABSTRACT
The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B-cell sequence data, and then apply them to a very deep short-read dataset of BCRs. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on BCRs using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions.

No MeSH data available.


Site-specific estimates of the selection coefficient ω. Violin plots show distribution of median ω estimates across V genes at each site. Bar plots show count of V genes classified as undergoing negative, neutral, or positive selection. Only sites with at least 100 productive and out-of-frame observed sequences aligned were considered. The sites with IMGT numbers less than or equal to 104 are traditionally designated ‘framework’.
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RSTB20140244F4: Site-specific estimates of the selection coefficient ω. Violin plots show distribution of median ω estimates across V genes at each site. Bar plots show count of V genes classified as undergoing negative, neutral, or positive selection. Only sites with at least 100 productive and out-of-frame observed sequences aligned were considered. The sites with IMGT numbers less than or equal to 104 are traditionally designated ‘framework’.

Mentions: We note extensive negative selection in the residues immediately preceding the third heavy chain complementarity-determining region (CDR3; figure 4). The amino acid profile for these sites shows a distinct preference for a tyrosine or rarely a phenylalanine two residues before the start of the CDR3 at site 102 (electronic supplementary material, figure S4). It shows a preference for a tyrosine or more rarely a phenylalanine or a histidine in the residue just before the start of the CDR3 at site 103. These aromatic positions likely play important structural roles in the antibody complex: site 102 is buried in the core of the heavy chain and makes extensive van der Waals interactions as well as a sidechain–backbone hydrogen bond, while site 103 forms part of the interface between the heavy and light chains (see further description of structural results below).Figure 4.


Quantifying evolutionary constraints on B-cell affinity maturation.

McCoy CO, Bedford T, Minin VN, Bradley P, Robins H, Matsen FA - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

Site-specific estimates of the selection coefficient ω. Violin plots show distribution of median ω estimates across V genes at each site. Bar plots show count of V genes classified as undergoing negative, neutral, or positive selection. Only sites with at least 100 productive and out-of-frame observed sequences aligned were considered. The sites with IMGT numbers less than or equal to 104 are traditionally designated ‘framework’.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528421&req=5

RSTB20140244F4: Site-specific estimates of the selection coefficient ω. Violin plots show distribution of median ω estimates across V genes at each site. Bar plots show count of V genes classified as undergoing negative, neutral, or positive selection. Only sites with at least 100 productive and out-of-frame observed sequences aligned were considered. The sites with IMGT numbers less than or equal to 104 are traditionally designated ‘framework’.
Mentions: We note extensive negative selection in the residues immediately preceding the third heavy chain complementarity-determining region (CDR3; figure 4). The amino acid profile for these sites shows a distinct preference for a tyrosine or rarely a phenylalanine two residues before the start of the CDR3 at site 102 (electronic supplementary material, figure S4). It shows a preference for a tyrosine or more rarely a phenylalanine or a histidine in the residue just before the start of the CDR3 at site 103. These aromatic positions likely play important structural roles in the antibody complex: site 102 is buried in the core of the heavy chain and makes extensive van der Waals interactions as well as a sidechain–backbone hydrogen bond, while site 103 forms part of the interface between the heavy and light chains (see further description of structural results below).Figure 4.

Bottom Line: The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) mutation and selection.It has recently become possible to gain detailed information concerning this process through high-throughput sequencing.We find that the substitution process is conserved across individuals but varies significantly across gene segments.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

ABSTRACT
The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B-cell sequence data, and then apply them to a very deep short-read dataset of BCRs. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on BCRs using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions.

No MeSH data available.