Dynamics of mitochondrial heteroplasmy in three families investigated via a repeatable re-sequencing study

• Type of Material: Article
• Authors: Hiroki Goto, Penn State University; Benjamin Dickins, Penn State University; Enis Afgan, Emory University; Ian M. Paul, Penn State College of Medicine; James Taylor, Emory University; Kateryna D. Makova, Penn State University; Anton Nekrutenko, Penn State University
• Language: English
• Date: 2011-06-23
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Goto et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://genomebiology.com/2011/12/6/R59
• Title of Journal or Parent Work: Genome Biology
• ISSN: 1465-6906
• Volume: 12
• Issue: R59
• Start Page: 1
• End Page: 16
• Grant/Funding Information: This work was funded by an NIH grant GM07226405S2 to KDM, a Beckman Foundation Young Investigator Award to AN, NSF grant DBI 0543285 and NIH grant HG004909 to AN and JT, NIH grants HG005133 and HG005542 to JT and AN, as well as funds from Penn State University and the Huck Institutes for the Life Sciences to AN and KDM and from Emory University to JT. Additional funding is provided, in part, under a grant with the Pennsylvania Department of Health using Tobacco Settlement Funds. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions.
• Research Categories: Biology, Microbiology; Chemistry, Biochemistry

Abstract

Background Originally believed to be a rare phenomenon, heteroplasmy - the presence of more than one mitochondrial DNA (mtDNA) variant within a cell, tissue, or individual - is emerging as an important component of eukaryotic genetic diversity. Heteroplasmies can be used as genetic markers in applications ranging from forensics to cancer diagnostics. Yet the frequency of heteroplasmic alleles may vary from generation to generation due to the bottleneck occurring during oogenesis. Therefore, to understand the alterations in allele frequencies at heteroplasmic sites, it is of critical importance to investigate the dynamics of maternal mtDNA transmission. Results Here we sequenced, at high coverage, mtDNA from blood and buccal tissues of nine individuals from three families with a total of six maternal transmission events. Using simulations and re-sequencing of clonal DNA, we devised a set of criteria for detecting polymorphic sites in heterogeneous genetic samples that is resistant to the noise originating from massively parallel sequencing technologies. Application of these criteria to nine human mtDNA samples revealed four heteroplasmic sites. Conclusions Our results suggest that the incidence of heteroplasmy may be lower than estimated in some other recent re-sequencing studies, and that mtDNA allelic frequencies differ significantly both between tissues of the same individual and between a mother and her offspring. We designed our study in such a way that the complete analysis described here can be repeated by anyone either at our site or directly on the Amazon Cloud. Our computational pipeline can be easily modified to accommodate other applications, such as viral re-sequencing.