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\documentclass[11pt,twoside,openright,letterpaper]{memoir}
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% graphics:
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% glossary:
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\title{Patterns of crossing over and gene conversion in meiotic recombination}
\author{Christopher L Campbell}
%Albert Einstein College of Medicine}
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% \setcounter{tocdepth}{5}
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& \\
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\textbf{Thesis Advisor:} \\
\vspace{1.5cm} \hrule width 0.9\textwidth \smallskip Signature
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Adam Auton, D.Phil. \\
\small \smallskip
Assistant Professor, Department of Genetics \\
Assistant Professor, Department of Epidemiology \& Population Health \\
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\vspace{1cm}
&
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\textbf{Co-advisor:} \\
\vspace{1.5cm} \hrule width 0.9\textwidth \smallskip Signature
\begin{flushleft}
Bernice E. Morrow, Ph.D. \\
\small \smallskip
Professor, Department of Genetics \\
Professor, Department of Obstetrics \& Gynecology and Women's Health \\
Professor, Department of Pediatrics (Cardiology) \\
Sidney L. and Miriam K. Olson Chair in Cardiology \\
Director, Division of Translational Genetics, Department of Genetics \\
\end{flushleft}
\end{minipage}\\
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%%%
\vfill
Submitted in partial fulfillment of the requirements for the Degree of Doctor of
Philosophy in the Graduate Division of Medical Sciences.
\vspace{0.5cm}
\\ Albert Einstein College of Medicine
\\ Yeshiva University
\\ New York
\\ May 31, 2016
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% Abstract: The abstract of the Dissertation is to include: a hypothesis, the procedures followed, the
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\begin{centering} ABSTRACT \\ \vspace{10pt} %\end{centering}
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\Author \\
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\DoubleSpacing
Recombination during meiosis is an essential process to the generation of gametes.
It acts to shuffle genetic variation within the genome, generating new combination of alleles that can be subject to natural selection.
Failures of the chromosomes to synapse and recombine can result in aneuploidy, while improper repair of double strand breaks can cause chromosome rearrangements, both of which are highly deleterious.
% In humans and other mammals, recombination has been studied using a wide variety of approaches, including molecular methods such as sperm typing, and inferential methods, such as linkage disequilibrium modeling and pedigree analysis.
Recombination has two outcomes: crossover and gene conversion.
In crossover, there is an equal exchange of genetic material between homologous chromosomes, while gene conversion is the non-reciprocal transfer of genetic information between homologues that is limited to smaller intervals.
Most research has focused on crossover, which varies widely in frequency and placement within the genome, and between individuals, sexes, populations, and species.
This variation is controlled by multiple factors, including the protein PRDM9, which drives crossovers to concentrated areas of recombination known as hotspots.
In addition, crossover interference acts to inhibit crossovers in close proximity.
Crossover properties also vary greatly by sex, and it has been suggested that these change with age, a possible cause of chromosomal aneuploidy.
% chapter 2
In order to better understand recombination in humans I have employed statistical methods to identify sex specific differences in recombination in detail.
In Chapter \ref{ch:cointEsc}, I performed a pedigree analysis using data derived from over 18,000 meioses.
% Using this data, I characterized sex differences in human recombination in detail.
% , and created sex-specific maps of recombination in the human genome.
% These results extend previous work showing that females have a higher recombination rate than males, by a ratio of 1.6 in the autosomes, and that male recombination tends to be focused towards the telomeres.
I find that males and females had different hotspot usage, with males having a higher hotspot overlap proportion than females, by 4.6\%.
I measure crossover interference, which affects the spatial positioning of crossovers, finding that older mothers had a steep increase in crossovers that escape regulation by interference.
These crossovers appear closely spaced, pointing to a possible deregulation of recombination that increases with maternal age.
In Chapter \ref{ch:cointExtras}, I present an extension to Chapter \ref{ch:cointEsc}, which confirms the age effect using samples from older individuals.
I include a re-analysis of public data from single cell sperm and oocytes, showing that interference varies widely on an individual basis.
In Chapter \ref{ch:dogPed}, I focused on crossover patterns using a complex pedigree of inbred domestic dogs, consisting of 408 meioses.
Dogs are unique in that their PRDM9 ortholog has accumulated mutations, rendering it inactive, and raising question as to how crossovers are placed without this regulatory mechanism.
I found that dog recombination is broadly similar to humans: females have a higher recombination rate than males, and male recombination strongly prefers telomeric regions.
Despite the absence of PRDM9, dog recombination appears to be more concentrated to a smaller proportion of sequence when compared to humans, suggesting the existence of hotspots.
Finally, I show evidence for positive crossover interference acting in the dog genome with a similar mechanism to that observed in humans.
In Chapter \ref{ch:geneConv}, I developed a novel computational approach using a hidden Markov model to detect gene conversion events in admixed population genetic data.
The model uses two divergent ancestral reference populations in order to predict the location of gene conversion events on an admixed haplotype.
Simulation results show that the model can plausibly be used to detect gene conversion.
% , however the complexity is high, with a large number of states at each site.
Overall, I have performed three separate but interrelated studies of recombination that expand on existing studies.
First, my work expands on the current knowledge of recombination variation and provides evidence for sexual dimorphism in crossover modifying properties, including placement and frequency.
Second, my work has further investigated the effects of the loss of PRDM9 on the recombination landscape in dogs, and through comparison to humans, provided insight into recombination in both species.
Finally, I developed a novel computational approach for investigating gene conversion.
These studies come together to enable further understanding of the properties of genetic recombination as a whole.
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%\chapter{Acknowledgements}
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% The Training Program in Cellular and Molecular Biology and Genetics, T32 GM007491.
\SingleSpacing
\clearpage
\tableofcontents
\clearpage
\listoffigures
\clearpage
\listoftables
\glsaddall
\clearpage\begingroup\let\newpage\relax
\printglossary[type=main,style=long,nonumberlist,title={List of Abbreviations}]
\addcontentsline{toc}{chapter}{List of Abbreviations}
\endgroup
\include{abbrv}
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\mainmatter
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\chapterstyle{ger}
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\chapter{Introduction} \label{ch:introduction}
\include{introduction/introduction}
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\begin{SingleSpace}
% \chapter[Title displayed in ToC][Title displayed in header]{Title}
\chapter[Escape from crossover interference increases with maternal age][Interference escape increases with maternal age]{Escape from crossover interference increases with maternal age} \label{ch:cointEsc}
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\noindent Christopher L. Campbell$^1$, Nicholas A. Furlotte$^2$, Nick Eriksson$^{2,\dagger}$, David Hinds$^2$, and Adam Auton$^1$
\vspace{0.5cm}
\noindent This manuscript has been published: \\
Campbell, C. L. et al. Escape from crossover interference increases with maternal age. Nat. Commun. 6:6260 doi: 10.1038/ncomms7260 (2015). \\
PMCID: PMC4335350
\vspace{0.5cm}
\noindent $^1$ Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA. \\
\noindent $^2$ 23andMe Inc., Mountain View, California 94043, USA. \\
\noindent $^\dagger$ Present address: Coursera, 381 East Evelyn Avenue, Mountain View, California 94041, USA. \\
\vspace{0.5cm}
\begin{centering}
Correspondence and requests for materials should be addressed to \\
A.A.\ (email: \texttt{[email protected]}). \\
\end{centering}
\end{SingleSpace}
\include{cointEscape/cointEscape}
\include{cointEscape/cointEscapeSupp}
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\begin{SingleSpace}
\chapter{Crossover interference varies by age and individual} \label{ch:cointExtras}
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\noindent Christopher L. Campbell$^1$ and Adam Auton$^{1*}$
\vspace{0.5cm}
\noindent This chapter contains unpublished data.\\
\vspace{0.5cm}
\noindent $^1$ Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA. \\
\noindent $^*$ Former affiliation.
\end{SingleSpace}
\include{cointExtras/cointExtras}
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\begin{SingleSpace}
\chapter[A pedigree-based map of recombination in the domestic dog genome][Recombination maps in the dog genome]{A pedigree-based map of recombination in the domestic dog genome} \label{ch:dogPed}
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\noindent Christopher L Campbell$^1$, Claude Bh\'{e}rer$^{1*,2}$, Bernice E Morrow$^1$, Adam R Boyko$^3$, and Adam Auton$^{1*}$
\vspace{0.5cm}
\noindent This manuscript is currently under review:
\vspace{0.5cm}
\noindent $^1$ Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA. \\
\noindent $^2$ New York Genome Center, New York, New York 10013, USA \\
\noindent $^3$ Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA \\
\noindent $^*$ Former affiliation.
\vspace{0.5cm}
\begin{centering}
Correspondence and requests for materials should be addressed to \\
A.A.\ (email: \texttt{[email protected]}). \\
\end{centering}
\end{SingleSpace}
\include{dogPed/dogPed}
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\begin{SingleSpace}
\chapter[Detection of gene conversion in human admixed population genetic data][A model for the detection of gene conversion]{Detection of gene conversion in human admixed population genetic data} \label{ch:geneConv}
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\noindent Christopher L. Campbell$^1$ and Adam Auton$^{1*}$
\vspace{0.5cm}
\noindent This chapter contains unpublished data.\\
\vspace{0.5cm}
\noindent $^1$ Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA. \\
\noindent $^*$ Former affiliation.
\end{SingleSpace}
\include{geneConv/geneConv}
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\chapter{Discussion} \label{ch:discussion}
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\include{discussion/discussion}
\backmatter
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\begin{SingleSpace}
\renewcommand{\thechapter}{A}
\chapter{Appendix A} \label{ch:appendixCB}
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\vspace{0.5cm}
Christopher L Campbell
\vspace{0.5cm}
\noindent Results presented within this appendix were extracted from a manuscript currently under review:
\vspace{0.5cm}
\noindent Refined genetic maps reveal sexual dimorphism in human meiotic recombination at multiple scales. \\
\noindent Claude Bh\'{e}rer$^{1*,2}$, Christopher L Campbell$^1$, and Adam Auton$^{1*}$.
\vspace{0.5cm}
\noindent $^1$ Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA. \\
\noindent $^2$ New York Genome Center, New York, New York 10013, USA \\
\noindent $^3$ Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA \\
\noindent $^*$ Former affiliation. \\
\noindent $^\#$ Present address.
\vspace{0.5cm}
\begin{centering}
Corresponding authors: \\
Adam Auton (\texttt{[email protected]}) \\
Claude Bh\'{e}rer (\texttt{[email protected]}) \\
\end{centering}
\end{SingleSpace}
\include{appendix_cb/appendix}
%\includepdf[pages=1-20]{appendix_papers/SexDimorphismRecombination_2016April8_maintext.pdf}
%\includepdf[pages=1-21]{appendix_papers/SexDimorphismRecombination_2016April8_SUPP.pdf}
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%\chapter{Appendix B}
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%\includepdf[pages=1-7]{appendix_papers/Campbell2015.pdf}
%\includepdf[pages=1-28]{appendix_papers/Campbell2015_supp.pdf}
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\end{document}
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