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Evolution-based strategies to elucidate genotype-phenotype relationships in traits relevant to human health

Kowalczyk, Amanda Elizabeth (2021) Evolution-based strategies to elucidate genotype-phenotype relationships in traits relevant to human health. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Understanding the link between genotype and phenotype is a key question in biological research. In other words, how do changes in DNA sequence give rise to the enormous diversity of life on Earth? In this work, we address that question by focusing on the genomics of convergent phenotypes, or phenotypes that have evolved independently in unrelated species. These natural biological replicates of phenotype evolution allow us to identify genomic regions, either regulatory or protein coding, that have experienced convergent evolution in concordance with convergent evolution of phenotypes, thus linking genomic regions to phenotypes.
In this work, we calculate evolutionary rates throughout the mammalian phylogeny for numerous genomic sequences to find concordance between species phenotype and evolutionary rate of sequences to link genomic regions to phenotypes. Chapter one describes three methods associated with quantifying the connection between genomic region evolution and phenotype evolution. First, RERconverge connects genomic regions to phenotypes in a linear regression-based framework. Second, permulations are a statistical extension to RERconverge that allow for rigorous calculation of confidence in associations from RERconverge. Third, proper implementation of branch-site models for convergent positive selection allows for identification of genes potentially driving convergent evolution.
Chapter two describes implementation of methods from chapter one to longevity phenotypes in 61 mammal species. We found increased evolutionary constraint in cancer control genes in large, long-lived species, thus likely conferring additional protection from cancer. Species exceptionally long-lived given their size showed increased evolutionary constraint on DNA repair pathways, indicating that efficient DNA repair is important to evolution of extreme lifespan independent of body size. This work provided insight into pan-mammalian genomic mechanisms underlying lifespan.
Chapter three describes further implementation of chapter one methods to the hairlessness phenotype in 61 mammal species. Although all mammals have some hair at some developmental time point, several mammals, such as cetaceans, naked mole-rats, armadillos, and humans, have relatively little hair. Many genomic elements we identified were known to be hair-related, and many more are valuable candidates for further testing into hair-related functions. This work for the first time provided insights to the natural evolution of mammalian hairlessness.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kowalczyk, Amanda
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorClark, Nathannclark@utah.edunclark
Thesis AdvisorChikina, Mariamchikina@pitt.edumchikina
Committee ChairKostka, Denniskostka@pitt.edukostka
Committee MemberAndreas,
Committee MemberLeah, Byrnelctbyrne@pitt.edulctbyrne
Date: 8 September 2021
Date Type: Publication
Defense Date: 17 May 2021
Approval Date: 8 September 2021
Submission Date: 15 June 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 188
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Computational and Systems Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: evolution, convergent evolution, genomics, comparative genomics, bioinformatics, longevity
Date Deposited: 08 Sep 2021 19:54
Last Modified: 08 Sep 2021 19:54


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