10.1371/journal.pgen.1005306
Jun Ding
Jun
Ding
Carlo Sidore
Carlo
Sidore
Thomas J. Butler
Thomas
J. Butler
Mary Kate Wing
Mary
Kate Wing
Yong Qian
Yong
Qian
Osorio Meirelles
Osorio
Meirelles
Fabio Busonero
Fabio
Busonero
Lam C. Tsoi
Lam
C. Tsoi
Andrea Maschio
Andrea
Maschio
Andrea Angius
Andrea
Angius
Hyun Min Kang
Hyun
Min Kang
Ramaiah Nagaraja
Ramaiah
Nagaraja
Francesco Cucca
Francesco
Cucca
Gonçalo R. Abecasis
Gonçalo
R. Abecasis
David Schlessinger
David
Schlessinger
Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of ~2,000 Sardinians Using Tailored Sequencing Analysis Tools
Public Library of Science
2015
association
body mass index
heteroplasmie
Assessing Mitochondrial DNA Variation
heteroplasmy
homoplasmie
mtDNA copy numbers
copy number
mtDNA copy number
sequencing error rates
Tailored Sequencing Analysis Tools DNA sequencing
variant
2015-07-14 03:37:42
Dataset
https://plos.figshare.com/articles/dataset/_Assessing_Mitochondrial_DNA_Variation_and_Copy_Number_in_Lymphocytes_of_2_000_Sardinians_Using_Tailored_Sequencing_Analysis_Tools_/1482884
<div><p>DNA sequencing identifies common and rare genetic variants for association studies, but studies typically focus on variants in nuclear DNA and ignore the mitochondrial genome. In fact, analyzing variants in mitochondrial DNA (mtDNA) sequences presents special problems, which we resolve here with a general solution for the analysis of mtDNA in next-generation sequencing studies. The new program package comprises 1) an algorithm designed to identify mtDNA variants (i.e., homoplasmies and heteroplasmies), incorporating sequencing error rates at each base in a likelihood calculation and allowing allele fractions at a variant site to differ across individuals; and 2) an estimation of mtDNA copy number in a cell directly from whole-genome sequencing data. We also apply the methods to DNA sequence from lymphocytes of ~2,000 SardiNIA Project participants. As expected, mothers and offspring share all homoplasmies but a lesser proportion of heteroplasmies. Both homoplasmies and heteroplasmies show 5-fold higher transition/transversion ratios than variants in nuclear DNA. Also, heteroplasmy increases with age, though on average only ~1 heteroplasmy reaches the 4% level between ages 20 and 90. In addition, we find that mtDNA copy number averages ~110 copies/lymphocyte and is ~54% heritable, implying substantial genetic regulation of the level of mtDNA. Copy numbers also decrease modestly but significantly with age, and females on average have significantly more copies than males. The mtDNA copy numbers are significantly associated with waist circumference (p-value = 0.0031) and waist-hip ratio (p-value = 2.4×10<sup>-5</sup>), but not with body mass index, indicating an association with central fat distribution. To our knowledge, this is the largest population analysis to date of mtDNA dynamics, revealing the age-imposed increase in heteroplasmy, the relatively high heritability of copy number, and the association of copy number with metabolic traits.</p></div>