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Evidence of genotype imputation differences when phasing population isolate participants with a cosmopolitan haplotype reference panel

Chiyka, Elizabeth A. (2022) Evidence of genotype imputation differences when phasing population isolate participants with a cosmopolitan haplotype reference panel. Master's Thesis, University of Pittsburgh. (Unpublished)

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Samoa is a population isolate that has generated a unique genetic profile by means of the founder effect and population bottlenecks. These differences make them more difficult to conduct genetic research on, as most resources are tailored around individuals with European ancestry. This is especially difficult when performing genetic imputation, which is the estimation of missing genotypes. Imputation typically involves a phasing step that assigns the two alleles of genotypes onto one of the two members of each pair of chromosomes. This allows researchers to better determine which variants are inherited together. I aim to discover if, when working with a population isolate, phasing with a cosmopolitan haplotype panel, such as the one generated through the Trans-Omics for Precision Medicine (TOPMed) Program, has the potential to change the imputation. The existing imputation used a reference panel of genotypes of 1000 Genomes Project Individuals and of Sa-moans, phased together, to impute into an Affymetrix scaffold. I conducted a new imputation using the same reference panel and scaffold but phased the reference panel along with the genotypes of 180,000 individuals from TOPMed. I compared imputation quality based on minor allele frequency (MAF) and two measures of imputation quality: R2 and ER2. When plotting the trendlines of R2 and ER2 versus MAF, the trendlines of the imputed genotypes phased with TOPMed exhibited higher imputation quality across MAF. Comparison of imputed MAF between the two imputations showed a positive linear trend with moderate variance. The R2 and ER2 distributions and means differed between both groups. This suggests that there are differences introduced by phasing with a cosmopolitan haplotype panel when working with a population isolate. Therefore, researchers should not use a cosmopolitan panel to phase population isolates, which will save time and computational resources in future studies. Advancing research in this population computationally will aid in public health outcomes downstream. Improved imputation will provide more accurate genotyping data in diverse populations, which will help genetic counselors and clinicians make more in-formed decisions when working with these groups.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Chiyka, Elizabeth A.eac96@pitt.edueac96
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMinster, Ryan L.rminster@pitt.eduRMINSTER0000-0001-7382-6717
Committee MemberWeeks, Daniel E.weeks@pitt.eduweeks0000-0001-9410-7228
Committee MemberCarlson, Jenna C.jnc35@pitt.edujnc350000-0001-5483-0833
Date: 10 May 2022
Date Type: Publication
Defense Date: 22 April 2022
Approval Date: 10 May 2022
Submission Date: 29 April 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 77
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: imputation, TOPMed, Samoa, phasing, 1000 Genomes
Date Deposited: 10 May 2022 20:53
Last Modified: 30 Jun 2022 15:14


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