Mechanistic and Genetic Biases in Human Immunoglobulin Heavy Chain Development
Abstract
Broadly neutralizing antibodies against HIV are rare; most patients never develop
them at detectable levels. The discovery of four such antibodies therefore warrants
research into their origins and their presumed unique characteristics. Such studies,
however, require baseline knowledge about commonalities and biases affecting human
immunoglobulin development. Obtaining that knowledge requires large sets of gene sequence
data and the appropriate statistical techniques and tools.
The Genbank repository provides a free and easily accessible source for such data.
Several large datasets cumulatively comprising over 10,000 human Ig heavy chain genes
were identified, downloaded, and carefully filtered. We then developed a special software
tool called SoDA, which employs a unique dynamic programming algorithm to provide
a statistical reconstruction of the events that led to a given antigen receptor gene.
Once developed, tested, and peer-reviewed, we used SoDA to provide initial data about
each downloaded gene with respect to gene segment usage, n-nucleotide addition, CDR3
length, and mutation frequency, thereby establishing the most precise estimates currently
available for human Ig heavy chain gene segment usage frequencies.
We compared data from productive non-autoreactive Ig to non-productive Ig and found
evidence for gene segment usage biases, D/J segment pairing preferences resulting
from multiple sequential D-to-J recombination events, and biases in TdT action between
the V-D and D-J. Further analysis of autoreactive Ig genes yielded evidence that n-nucleotide
addition comes at a cost: the higher the ratio of n-nucleotides to germline-encoded
nucleotides for a given CDR3 length, the greater the probability of autoreactivity.
These results suggest that the germline gene segments have been selected for lack
of autoreactivity.
It has previously been shown that human Ig gene segments have evolved efficient evolvability
under somatic hypermutation. We have now extended these results, showing that Ig
gene sequences are "tuned" to preferentially produce consequential mutations in the
antigen-binding domains, and synonymous mutations in the framework regions.
Together, these analyses provide new insights into the genetic and mechanistic biases
shaping the human Ig repertoire.
Type
DissertationDepartment
Computational Biology and BioinformaticsSubject
Biology, BioinformaticsHealth Sciences, Immunology
immunoglobulin
heavy chain
V(D)J recombination
autoreactivity
antibodies
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https://hdl.handle.net/10161/607Citation
Volpe, Joseph M (2008). Mechanistic and Genetic Biases in Human Immunoglobulin Heavy Chain Development. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/607.Collections
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