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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.


Total sequence entropy partitioned into its various elementary contributions for the two individuals. The bottom three horizontal bars in each stack display the partitioning of the entropy of the probability distribution of recombination scenarios. Because multiple scenarios can generate the same sequence, the nucleotide sequence entropy of the sequences directly produced by recombination is smaller than the recombination scenario entropy. Out of those, productivity of the sequence further restricts the diversity by constraining frame and forbidding stop codons appearing, as depicted in the smaller bar above. Finally, as seen in the topmost bar, the initial selection process itself significantly reduces the diversity of those productive sequences. It is worth noticing that while the initial diversity of both individuals is different, consistent with their different CDR3 length distributions, the reduction effect of the selection is quite similar, keeping the same difference in entropy.
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RSTB20140243F8: Total sequence entropy partitioned into its various elementary contributions for the two individuals. The bottom three horizontal bars in each stack display the partitioning of the entropy of the probability distribution of recombination scenarios. Because multiple scenarios can generate the same sequence, the nucleotide sequence entropy of the sequences directly produced by recombination is smaller than the recombination scenario entropy. Out of those, productivity of the sequence further restricts the diversity by constraining frame and forbidding stop codons appearing, as depicted in the smaller bar above. Finally, as seen in the topmost bar, the initial selection process itself significantly reduces the diversity of those productive sequences. It is worth noticing that while the initial diversity of both individuals is different, consistent with their different CDR3 length distributions, the reduction effect of the selection is quite similar, keeping the same difference in entropy.

Mentions: The diversity of the immune repertoire is one of its key characteristics. The rearrangement and selection models enable us to precisely quantify this diversity and identify its sources. Repertoire diversity is an inherently dynamic property. Upon random rearrangement, the initial diversity is established, but initial selection will modify it. Those changes can be demonstrated by looking at the entropy of the different distributions, calculated from the models we infer. Entropy gives a measure of the number of different sequences we can expect to find at different stages of B-cell development (figure 8). The generation entropy can be broken down into contributions from the different events that make up the recombination scenario. Most of the diversity comes from insertions. Note that the entropy of rearranged sequences is smaller than the entropy of recombination events. This is due to convergent recombination—the fact that a given sequence can be produced by different recombination scenarios. Individual B has larger generation entropy than individual A, primarily because it has more insertions. The entropy of productive sequences is further reduced (by two bits) by keeping only the in-frame sequences. Subsequent action of selection reduces the diversity of the repertoire by about 10 bits. This reduction is true for both individuals, regardless of their different generation entropy, and follows from the correlation between Ppre and Q (figure 7b), which concentrates the distribution towards the most probable rearrangements, thus reducing diversity in the selected repertoire.Figure 8.


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)

Total sequence entropy partitioned into its various elementary contributions for the two individuals. The bottom three horizontal bars in each stack display the partitioning of the entropy of the probability distribution of recombination scenarios. Because multiple scenarios can generate the same sequence, the nucleotide sequence entropy of the sequences directly produced by recombination is smaller than the recombination scenario entropy. Out of those, productivity of the sequence further restricts the diversity by constraining frame and forbidding stop codons appearing, as depicted in the smaller bar above. Finally, as seen in the topmost bar, the initial selection process itself significantly reduces the diversity of those productive sequences. It is worth noticing that while the initial diversity of both individuals is different, consistent with their different CDR3 length distributions, the reduction effect of the selection is quite similar, keeping the same difference in entropy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSTB20140243F8: Total sequence entropy partitioned into its various elementary contributions for the two individuals. The bottom three horizontal bars in each stack display the partitioning of the entropy of the probability distribution of recombination scenarios. Because multiple scenarios can generate the same sequence, the nucleotide sequence entropy of the sequences directly produced by recombination is smaller than the recombination scenario entropy. Out of those, productivity of the sequence further restricts the diversity by constraining frame and forbidding stop codons appearing, as depicted in the smaller bar above. Finally, as seen in the topmost bar, the initial selection process itself significantly reduces the diversity of those productive sequences. It is worth noticing that while the initial diversity of both individuals is different, consistent with their different CDR3 length distributions, the reduction effect of the selection is quite similar, keeping the same difference in entropy.
Mentions: The diversity of the immune repertoire is one of its key characteristics. The rearrangement and selection models enable us to precisely quantify this diversity and identify its sources. Repertoire diversity is an inherently dynamic property. Upon random rearrangement, the initial diversity is established, but initial selection will modify it. Those changes can be demonstrated by looking at the entropy of the different distributions, calculated from the models we infer. Entropy gives a measure of the number of different sequences we can expect to find at different stages of B-cell development (figure 8). The generation entropy can be broken down into contributions from the different events that make up the recombination scenario. Most of the diversity comes from insertions. Note that the entropy of rearranged sequences is smaller than the entropy of recombination events. This is due to convergent recombination—the fact that a given sequence can be produced by different recombination scenarios. Individual B has larger generation entropy than individual A, primarily because it has more insertions. The entropy of productive sequences is further reduced (by two bits) by keeping only the in-frame sequences. Subsequent action of selection reduces the diversity of the repertoire by about 10 bits. This reduction is true for both individuals, regardless of their different generation entropy, and follows from the correlation between Ppre and Q (figure 7b), which concentrates the distribution towards the most probable rearrangements, thus reducing diversity in the selected repertoire.Figure 8.

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.