Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15474-9. doi: 10.1073/pnas.1409328111. Epub 2014 Oct 13.

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA.

Author information

1
Departments of Biochemistry and Molecular Biology.
2
Biology, and.
3
Forensic Science Program, Pennsylvania State University, University Park, PA 16802;
4
School of Science and Technology, Nottingham Trent University, Nottingham NG1 4BU, United Kingdom;
5
Department of Integrative Biology, University of California, Berkeley, CA 94720; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, DK-1350 Copenhagen, Denmark; and.
6
Statistics.
7
Department of Integrative Biology, University of California, Berkeley, CA 94720;
8
Department of Pediatrics, College of Medicine, Pennsylvania State University, Hershey, PA 17033.
9
Departments of Biochemistry and Molecular Biology, anton@bx.psu.edu kdm16@psu.edu.
10
Biology, and anton@bx.psu.edu kdm16@psu.edu.

Abstract

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother-child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30-35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10(-8) (interquartile range from 4.2 × 10(-9) to 4.1 × 10(-8)) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.

KEYWORDS:

heteroplasmy; mitochondria

PMID:
25313049
PMCID:
PMC4217420
DOI:
10.1073/pnas.1409328111
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center