Insights Into Evolution and Adaptation Using Computational Methods and Next Generation ...

279 Pages·2016·6.52 MB·English

by  Alexander G. Shanku

Insights Into Evolution and Adaptation Using
Computational Methods and Next Generation
Sequencing
BYAlexanderG.Shanku
Adissertationsubmittedtothe
GraduateSchool—NewBrunswick
Rutgers,TheStateUniversityofNewJersey
inpartialfulfillmentoftherequirements
forthedegreeof
DoctorofPhilosophy
GraduatePrograminComputationalBiologyandMolecularBiophysics
Writtenunderthedirectionof
AndrewD.Kern
andapprovedby
NewBrunswick,NewJersey
May,2016
(cid:13)c 2016
Alexander G. Shanku
ALL RIGHTS RESERVED
ABSTRACT OF THE DISSERTATION
Insights Into Evolution and Adaptation Using
Computational Methods and Next Generation
Sequencing
by Alexander G. Shanku
Dissertation Director: Andrew D. Kern
Historically, much of the research in evolutionary biology and population ge-
neticshasinvolvedanalysisatthelevelofeitherasinglelocusorafewnumber
thereof. However, “Next Generation” sequencing technology has opened the
floodgates with respect to both the sheer volume and quality of sequence data
that researchers have long needed to address and answer long-standing ques-
tions in their fields. Scientists are now, by and large, no longer hampered in
their efforts by technological hurdles to obtain data, but are in fact facing the
problem of how best to use the vast amount of data that are accumulating at
anever-increasingrate. Thisisagoodproblemtohave.
The following research described in this dissertation is an attempt to de-
riveanswerstoquestionsinthefieldsofpopulationgeneticsandevolutionary
biology that, until recently, have been either intractable or, at best, extremely
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difficult to address. In the first chapter I provide an introduction and a brief
historicallookattheresearcheffortsthathaveproceededmyown.
In the second chapter I describe how modern sequencing methods and
computationalanalysiscanbeusedtostudy,analyze,andanswerevolutionary
questionsaboutthenon-modelorganism,Enallagmahageni,inorderto1)deter-
mine this organism’s phylogenetic position within Arthropoda, 2) provide an-
swers and insight into the evolutionary history of the protein-encoding genes
in the Enallagma transcriptome, and 3) give functional annotation to these ex-
pressedproteins.
InthethirdchapterIexaminehownaturalselectionactsonthegenomeand
derive a method that can accurately determine the evolutionary cause of nu-
cleotide fixations, having occurred either through positive selection or neutral
processes. I then apply the methodology to North American populations of
Drosophila melanogaster, providing further evidence as to how adaptive evolu-
tionproceedsinanewlyestablishedpopulation. Thisisanimportantquestion,
for though there have been multiple approaches devised to determine the tar-
gets and modes of evolution in the genome, to date there has not emerged a
definitive method which can determine both the location and type of a selec-
tive process, and as a result, the picture of how and where adaptive evolution
proceedsinthegenomehasremainedopaque.
In the forth chapter I examine how levels of natural selection within the
genome have the potential to inhibit the ability to accurately learn popula-
tion demographic history. Using a number of modern algorithms and exten-
sivesimulations,Ifirstexaminewhetherornotdemographichistoriesthatare
learned under simple biological assumptions will yield accurate results when
the actual data itself does not adhere to these assumptions. Further, I go on
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to examine more complicated models of demographic history, looking specif-
ically at how positive selection biases inference, which directions these biases
occur,andatwhatlevelsofselectiondoinferencemethodsfailtoberobust. Fi-
nally, I describe potential evolutionary scenarios where these inference meth-
ods may be more prone to fail, as well as methods which might mitigate posi-
tiveselection’seffects,thusallowingformoreaccuratehistoriestobeinferred.
Theworkcontainedinthisdissertation,atthebroadestscale,isaneffortto
marry state-of-the-art techniques in statistics, computer science, and machine
learning algorithms to the technological advances of next generation sequenc-
ing; the potent combination of these technologies has provided a means with
which to derive answers to multiple, long-standing questions in population
geneticsandevolutionarybiology.
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Preface
The time will come when diligent research over long periods will
bring to light things which now lie hidden. A single lifetime, even
though entirely devoted to the sky, would not be enough for the
investigation of so vast a subject... And so this knowledge will be
unfoldedonlythroughlongsuccessiveages. Therewillcomeatime
whenourdescendantswillbeamazedthatwedidnotknowthings
that are so plain to them... Many discoveries are reserved for ages
stilltocome,whenmemoryofuswillhavebeeneffaced.
—Seneca,NaturalQuestions
Portionsofthisdissertationarebasedonworkpreviouslypublishedorsubmittedfor
publicationbytheauthor[1].
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Acknowledgements
This dissertation is based upon the research undertaken as a Ph.D. student
whileattendingDartmouthCollegeandRutgersUniversityfrom2010through
2016. These five and a half years have been divided between my research, the
classroom, and ultimately, the creation of this document. However, none of
these things would have been possible without the help, guidance, and assis-
tance of the many other people that I have had the good fortune of meeting
alongmyacademicpath.
Accordingly, I must first acknowledge and express my gratitude to my ad-
visor and mentor, Andrew D. Kern. Our first meeting was over a pint while
we talked science, and I’m fortunate to say that five years later our meetings
oftentakethesameform. ThescopeofwhatI’velearnedunderyourdirection
isimmense,andforthataloneIamgrateful. Yourloveforscience,andinquiry
ingeneral,permeatedthelabandwasmotivatingandinspiring. Yourpatience
andunderstandingneverwentunnoticed. Iamalsohappytosaythatinaddi-
tiontotheacademicrelationshipwehavecultivated,Ialsoamabletocallyou
afriend. Andy,thankyousomuchforeverything.
IwouldliketothankmyDissertationCommittee: JinchuanXing,IsaacEd-
ery, and Kevin Chen - your guidance, suggestions, and the wealth of your
combined experiences is something that I will benefit from my entire career.
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Having the chance to interact with you, be it in journal club, the classroom,
or as part of a collaboration has been an extremely valuable experience and I
thankeachoneofyouforit.
Ihavebeenfortunatetoworkalongsidearemarkablecolleagueandfriend,
DanielSchrider. Dan,Icertainlyoweyouquiteabit. You’vetaughtmeagreat
deal and shared so much of what you know, and for that I must thank you.
Your energy and passion for science are truly motivating. Along with A.D.K,
we’ve made a point to keep mind and body strong - shouting “ALL MEAT
MAN!!” willnowonlybringstares.
Iwouldcertainlynothavemadeitthisfar,letalonesubmitthisdissertation,
if I weren’t so fortunate to have known the Associate Director of my graduate
program - a confidant, motivator, and friend Gail Ferstandig Arnold. Thank
yousomuch,Gail. Iamsoappreciativeofeverythingyou’vedoneforme.
Icouldn’tleavethe4th floorwithoutthankingmyfriendKathleenMcDon-
ald and recalling the many hours we’ve spent talking in your office. Being
able to vent about the “RUt” to each other and about the daily happenings in
Nelson was often needed and very cathartic. You certainly helped to keep my
spirits up. So, Kathleen, I say thank you for all of your help, your friendship,
andgreatconversations.
This dissertation starts in Tennessee and finishes in New Jersey, with stops
in New Hampshire and Brooklyn along the way. During those transitions,
serendipity led to a close relationship with the Cline and Cutraro families.
Clayton, Allison, Andy, and Erin, your kindness and support mean the world
to us. Watching our families grow together during these past five years has
beenveryspecial.
TothehardestDevilDogsaround-NathanielE.Allen,PatrickJ.Belmonte,
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and Craig H. Strohl - Semper Fidelis, and REPORT!! I’m especially fortunate
for the time I’ve spent with you, Nat, over the past twenty years. You’ve kept
me engaged with the world, and I treasure every one of our late night conver-
sations,debates,andarguments.
Not everyone is a fortunate as I am to have such wonderful in-laws. Your
support, care, and love will always be remembered during this time. Kathy
andDavidCrosslin,andHalandKimberlyDanson-thankyousoverymuch.
In the same light, I am grateful for my whole family’s support and here
mustspecificallyacknowledgemysisterandbrother-in-law,JennieandPatrick
Osman. Your love and support have been crucial, your encouragement has
always kept my spirits up, and knowing that you have always been in my
corner means a great deal. Thank you both so much. I am excited for the
chancetoliveclosetoyoubothagain,orforthefirsttime!
My mother, Carol Shanku - your faith in me never faltered, even during
thosetimeswhenmyowndid. Youhavegivenselflesslytomeforsolongand
have supported me in all of my endeavors. I am forever grateful. I could not
askforabettermother,mother-in-lawtomywife,andgrandmothertomyson.
Iloveyouverymuch.
Benjamin, my son, maybe one day you will read this and discover what I
wasworkingonthefirst5yearsofyourlife. Maybenotthough,it’salongread.
I am lucky that whenever I will think back about my Ph.D., I’ll be thinking
about you, too. I love you, I am very proud of you, and I am excited for our
nextadventure.
Most importantly, I have to acknowledge my wife, Bethany. This has cer-
tainlybeensomeadventure. Beth,we’vebeensidebysidethisentiretime,and
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throughalltheupsanddowns,yourlove,kindness,andpatience-immeasur-
ableasitis-haveneverwavered. Yourendlesssupporthasmeantsomuchto
me. I could never have made it without you. I love you very much and am so
luckytosharemylifewithyou.
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