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thesis.lyx
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\begin_layout Title
Bioinformatic analysis of complex, high-throughput genomic and epigenomic
data in the context of CD4
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T-cell differentiation and diagnosis and treatment of transplant rejection
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\begin_layout Author
A thesis presented
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by
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Ryan C.
Thompson
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to
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The Scripps Research Institute Graduate Program
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in partial fulfillment of the requirements for the degree of
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Doctor of Philosophy in the subject of Biology
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for
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The Scripps Research Institute
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La Jolla, California
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October 2019
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© 2019 by Ryan C.
Thompson
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All rights reserved.
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Thesis acceptance form page.
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For Dan, who helped me through the hard times again and again.
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He is fondly remembered and sorely missed.
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Acknowledgements
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My path through graduate school has been a long and winding one, and I am
grateful to all the mentors I have had through the years – Drs.
Terry Gaasterland, Daniel Salomon, and Andrew Su – all of whose encouragement
and support have been vital to my development into the scientist I am today.
I am also thankful for my collaborators in the Salomon lab: Drs.
Sarah Lamere, Sunil Kurian, Thomas Whisenant, Padmaja Natarajan, Katie
Podshivalova, and Heather Kiyomi Komori; as well as the many other lab
members I have worked with in small ways over the years.
In addition, Steven Head, Dr.
Phillip Ordoukhanian, and Terri Gelbart from the Scripps Genomics core
have also been instrumental in supporting my work.
And of course, I am thankful for the guidance and expertise provided by
my committee, Drs.
Nicholas Schork, Ali Torkamani, Michael Petrascheck, and Luc Teyton.
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Finally, I wish to thank my parents, for instilling in me a love of science
and learning from an early age and encouraging me to pursue that love as
a career as I grew up.
I am truly lucky to have such a loving and supportive family.
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It is included as an integral part of the thesis and should immediately
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Include accents and diacritical marks.
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Transplant rejection mediated by adaptive immune response is the major challenge
to long-term graft survival.
Rejection is treated with immune suppressive drugs, but early diagnosis
is essential for effective treatment.
Memory lymphocytes are known to resist immune suppression, but the precise
regulatory mechanisms underlying immune memory are still poorly understood.
High-throughput genomic assays such as microarrays, RNA-seq, and ChIP-seq
are heavily used in the study of immunology and transplant rejection.
Here we present 3 analyses of such assays in this context.
First, we re-analyze a large data set consisting of H3K4me2, H3K4me3, and
H3K27me3 ChIP-seq data and RNA-seq data in naïve and memory CD4
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T-cells using modern bioinformatics methods designed to address deficiencies
in the data and extend the analysis in several new directions.
All 3 histone marks are found to occur in broad regions and are enriched
near promoters, but the radius of promoter enrichment is found to be larger
for H3K27me3.
We observe that both gene expression and promoter histone methylation in
naïve and memory cells converges on a common signature 14 days after activation
, consistent with differentiation of naïve cells into memory cells.
The location of histone modifications within the promoter is also found
to be important, with asymmetric associations with gene expression for
peaks located the same distance up- or downstream of the TSS.
Second, we demonstrate the effectiveness of fRMA as a single-channel normalizat
ion for using expression arrays to diagnose transplant rejection in a clinical
diagnostic setting, and we develop a custom fRMA normalization for a previously
unsupported array platform.
For methylation arrays, we adapt methods designed for RNA-seq to improve
the sensitivity of differential methylation analysis by modeling the heterosked
asticity inherent in the data.
Finally, we present and validate a novel method for RNA-seq of cynomolgus
monkey blood samples using complementary oligonucleotides to prevent wasteful
over-sequencing of globin genes.
These results all demonstrate the usefulness of a toolbox full of flexible
and modular analysis methods in analyzing complex high-throughput assays
in contexts ranging from basic science to translational medicine.
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Notes to draft readers
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Thank you so much for agreeing to read my thesis and give me feedback on
it.
What you are currently reading is a rough draft, in need of many revisions.
You can always find the latest version at
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.
the PDF at this link is updated periodically with my latest revisions,
but you can just download the current version and give me feedback on that.
Don't worry about keeping up with the updates.
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As for what feedback I'm looking for, first of all, don't waste your time
marking spelling mistakes and such.
I haven't run a spell checker on it yet, so let me worry about that.
Also, I'm aware that many abbreviations are not properly introduced the
first time they are used, so don't worry about that either.
However, if you see any glaring formatting issues, such as a figure being
too large and getting cut off at the edge of the page, please note them.
In addition, if any of the text in the figures is too small, please note
that as well.
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Beyond that, what I'm mainly interested in is feedback on the content.
For example: does the introduction flow logically, and does it provide
enough background to understand the other chapters? Does each chapter make
it clear what work and analyses I have done? Do the figures clearly communicate
the results I'm trying to show? Do you feel that the claims in the results
and discussion sections are well-supported? There's no need to suggest
improvements; just note areas that you feel need improvement.
Additionally, if you notice any un-cited claims in any chapter, please
flag them for my attention.
Similarly, if you discover any factual errors, please note them as well.
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You can provide your feedback in whatever way is most convenient to you.
You could mark up this PDF with highlights and notes, then send it back
to me.
Or you could collect your comments in a separate text file and send that
to me, or whatever else you like.
However, if you send me your feedback in a separate document, please note
a section/figure/table number for each comment, and
\emph on
also
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send me the exact PDF that you read so I can reference it while reading
your comments, since as mentioned above, the current version I'm working
on will have changed by that point (which might include shuffling sections
and figures around, changing their numbers).
One last thing: you'll see a bunch of text in orange boxes throughout the
PDF.