Skip to main content
Duke University Libraries
DukeSpace Scholarship by Duke Authors
  • Login
  • Ask
  • Menu
  • Login
  • Ask a Librarian
  • Search & Find
  • Using the Library
  • Research Support
  • Course Support
  • Libraries
  • About
View Item 
  •   DukeSpace
  • Theses and Dissertations
  • Duke Dissertations
  • View Item
  •   DukeSpace
  • Theses and Dissertations
  • Duke Dissertations
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Mechanistic and Genetic Biases in Human Immunoglobulin Heavy Chain Development

Thumbnail
View / Download
763.5 Kb
Date
2008-04-23
Author
Volpe, Joseph M
Advisor
Kepler, Thomas B
Repository Usage Stats
408
views
652
downloads
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
Dissertation
Department
Computational Biology and Bioinformatics
Subject
Biology, Bioinformatics
Health Sciences, Immunology
immunoglobulin
heavy chain
V(D)J recombination
autoreactivity
antibodies
Permalink
https://hdl.handle.net/10161/607
Citation
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
  • Duke Dissertations
More Info
Show full item record
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

Rights for Collection: Duke Dissertations


Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info

Make Your Work Available Here

How to Deposit

Browse

All of DukeSpaceCommunities & CollectionsAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit DateThis CollectionAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit Date

My Account

LoginRegister

Statistics

View Usage Statistics
Duke University Libraries

Contact Us

411 Chapel Drive
Durham, NC 27708
(919) 660-5870
Perkins Library Service Desk

Digital Repositories at Duke

  • Report a problem with the repositories
  • About digital repositories at Duke
  • Accessibility Policy
  • Deaccession and DMCA Takedown Policy

TwitterFacebookYouTubeFlickrInstagramBlogs

Sign Up for Our Newsletter
  • Re-use & Attribution / Privacy
  • Harmful Language Statement
  • Support the Libraries
Duke University