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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.


(a) Comparison of non-synonymous (λN) and synonymous (λS) rates in productive and out-of-frame sequences. (b) ω estimates using unproductive rearrangements as a proxy for the neutral process. Both panels use data from IGHV3-23*01, the most frequent V gene/allele combination.
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RSTB20140244F3: (a) Comparison of non-synonymous (λN) and synonymous (λS) rates in productive and out-of-frame sequences. (b) ω estimates using unproductive rearrangements as a proxy for the neutral process. Both panels use data from IGHV3-23*01, the most frequent V gene/allele combination.

Mentions: IGHV3-23*01 is the most frequent V gene/allele combination in our dataset, and it displays patterns that are consistent with the other genes. Specifically, we see significant variation in the synonymous substitution rate (right panels, figure 3a) even in out-of-frame sequences, which is presumably because of motif-driven mutation. Thus, if we had directly applied traditional means of estimating selection by comparing the rate of non-synonymous and synonymous substitutions, we would have falsely identified sites as being under strong selection. By contrast, the selection inferences made using out-of-frame sequences stay much closer to neutral (figure 3b).Figure 3.


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)

(a) Comparison of non-synonymous (λN) and synonymous (λS) rates in productive and out-of-frame sequences. (b) ω estimates using unproductive rearrangements as a proxy for the neutral process. Both panels use data from IGHV3-23*01, the most frequent V gene/allele combination.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSTB20140244F3: (a) Comparison of non-synonymous (λN) and synonymous (λS) rates in productive and out-of-frame sequences. (b) ω estimates using unproductive rearrangements as a proxy for the neutral process. Both panels use data from IGHV3-23*01, the most frequent V gene/allele combination.
Mentions: IGHV3-23*01 is the most frequent V gene/allele combination in our dataset, and it displays patterns that are consistent with the other genes. Specifically, we see significant variation in the synonymous substitution rate (right panels, figure 3a) even in out-of-frame sequences, which is presumably because of motif-driven mutation. Thus, if we had directly applied traditional means of estimating selection by comparing the rate of non-synonymous and synonymous substitutions, we would have falsely identified sites as being under strong selection. By contrast, the selection inferences made using out-of-frame sequences stay much closer to neutral (figure 3b).Figure 3.

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.