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Inferring processes underlying B-cell repertoire diversity.

Elhanati Y, Sethna Z, Marcou Q, Callan CG, Mora T, Walczak AM - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

Bottom Line: Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality.We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection).Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de physique théorique, UMR8549, CNRS and École normale supérieure, 24, rue Lhomond, 75005 Paris, France.

ABSTRACT
We quantify the VDJ recombination and somatic hypermutation processes in human B cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

No MeSH data available.


Related in: MedlinePlus

Heat plot of the inferred amino acid selection factors qi;L for each amino acid, ordered by length L of the CDR3 region (ordinate) and position i within that region (abscissa). The CDR3 region is bounded on the left by a Cys residue and by a Trp residue on the right. There is a clear pattern of amino acid preference (or anti-preference) within a few positions of these boundaries, independent of overall CDR3 length L.
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RSTB20140243F5: Heat plot of the inferred amino acid selection factors qi;L for each amino acid, ordered by length L of the CDR3 region (ordinate) and position i within that region (abscissa). The CDR3 region is bounded on the left by a Cys residue and by a Trp residue on the right. There is a clear pattern of amino acid preference (or anti-preference) within a few positions of these boundaries, independent of overall CDR3 length L.

Mentions: Selection acting on the rearranged sequences is quantified by position-dependent selection factors qi;L(a) that capture the positive or negative effect that each amino acid at each position has on the functionality of the entire sequence, and in addition by gene-dependent selection factors qVJ (figure 1b). We show the amino acid selection factors averaged over both individuals in figure 5 and show the gene-dependent selection factors in electronic supplementary material, figure S12. The qi;L factors are reasonably consistent between the two individuals (figure 6a), even though their sequence repertoires show slightly different CDR3 length distributions (figure 4). Residue selection patterns show a dependence on the position and length of the CDR3—some patterns are related to either the V or J side of the junction, while other effects are localized in the bulk. This is related to the conserved motifs just outside of the CDR3, which function as anchors for the variable area. Thus, the role of an amino acid is different whether it is close to the V gene conserved motif, the J conserved motif, or far from both.Figure 5.


Inferring processes underlying B-cell repertoire diversity.

Elhanati Y, Sethna Z, Marcou Q, Callan CG, Mora T, Walczak AM - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

Heat plot of the inferred amino acid selection factors qi;L for each amino acid, ordered by length L of the CDR3 region (ordinate) and position i within that region (abscissa). The CDR3 region is bounded on the left by a Cys residue and by a Trp residue on the right. There is a clear pattern of amino acid preference (or anti-preference) within a few positions of these boundaries, independent of overall CDR3 length L.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528420&req=5

RSTB20140243F5: Heat plot of the inferred amino acid selection factors qi;L for each amino acid, ordered by length L of the CDR3 region (ordinate) and position i within that region (abscissa). The CDR3 region is bounded on the left by a Cys residue and by a Trp residue on the right. There is a clear pattern of amino acid preference (or anti-preference) within a few positions of these boundaries, independent of overall CDR3 length L.
Mentions: Selection acting on the rearranged sequences is quantified by position-dependent selection factors qi;L(a) that capture the positive or negative effect that each amino acid at each position has on the functionality of the entire sequence, and in addition by gene-dependent selection factors qVJ (figure 1b). We show the amino acid selection factors averaged over both individuals in figure 5 and show the gene-dependent selection factors in electronic supplementary material, figure S12. The qi;L factors are reasonably consistent between the two individuals (figure 6a), even though their sequence repertoires show slightly different CDR3 length distributions (figure 4). Residue selection patterns show a dependence on the position and length of the CDR3—some patterns are related to either the V or J side of the junction, while other effects are localized in the bulk. This is related to the conserved motifs just outside of the CDR3, which function as anchors for the variable area. Thus, the role of an amino acid is different whether it is close to the V gene conserved motif, the J conserved motif, or far from both.Figure 5.

Bottom Line: Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality.We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection).Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de physique théorique, UMR8549, CNRS and École normale supérieure, 24, rue Lhomond, 75005 Paris, France.

ABSTRACT
We quantify the VDJ recombination and somatic hypermutation processes in human B cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

No MeSH data available.


Related in: MedlinePlus