TY - JOUR
T1 - Transmission of human mtDNA heteroplasmy in the genome of the Netherlands families
T2 - Support for a variable-size bottleneck
AU - Genome of the Netherlands Consortium
AU - Li, Mingkun
AU - Rothwell, Rebecca
AU - Vermaat, Martijn
AU - Wachsmuth, Manja
AU - Schröder, Roland
AU - Laros, Jeroen F.J.
AU - Van Oven, Mannis
AU - De Bakker, Paul I.W.
AU - Bovenberg, Jasper A.
AU - Van Duijn, Cornelia M.
AU - Van Ommen, Gert Jan B.
AU - Slagboom, P. Eline
AU - Swertz, Morris A.
AU - Wijmenga, Cisca
AU - Kayser, Manfred
AU - Boomsma, Dorret I.
AU - Zöllner, Sebastian
AU - De Knijff, Peter
AU - Stoneking, Mark
AU - De Craen, Anton J.M.
AU - Beekman, Marian
AU - Hofman, Albert
AU - Willemsen, Gonneke
AU - Wolffenbuttel, Bruce
AU - Platteel, Mathieu
AU - Du, Yuanping
AU - Chen, Ruoyan
AU - Cao, Hongzhi
AU - Cao, Rui
AU - Sun, Yushen
AU - Cao, Jeremy Sujie
AU - Van Dijk, Freerk
AU - Neerincx, Pieter B.T.
AU - Deelen, Patrick
AU - Dijkstra, Martijn
AU - Byelas, George
AU - Kanterakis, Alexandros
AU - Bot, Jan
AU - Ye, Kai
AU - Lameijer, Eric Wubbo
AU - Den Dunnen, Johan T.
AU - Karssen, Lennart C.
AU - Van Leeuwen, Elisa M.
AU - Amin, Najaf
AU - Koval, Vyacheslav
AU - Rivadeneira, Fernando
AU - Estrada, Karol
AU - Hehir-Kwa, Jayne Y.
AU - De Ligt, Joep
AU - Abdellaoui, Abdel
N1 - Publisher Copyright:
© 2016 Li et al.
PY - 2016/4
Y1 - 2016/4
N2 - Although previous studies have documented a bottleneck in the transmission of mtDNA genomes from mothers to offspring, several aspects remain unclear, including the size and nature of the bottleneck. Here, we analyze the dynamics of mtDNA heteroplasmy transmission in the Genomes of the Netherlands (GoNL) data, which consists of complete mtDNA genome sequences from 228 trios, eight dizygotic (DZ) twin quartets, and 10 monozygotic (MZ) twin quartets. Using a minor allele frequency (MAF) threshold of 2%, we identified 189 heteroplasmies in the trio mothers, of which 59% were transmitted to offspring, and 159 heteroplasmies in the trio offspring, of which 70% were inherited from the mothers. MZ twin pairs exhibited greater similarity in MAF at heteroplasmic sites than DZ twin pairs, suggesting that the heteroplasmy MAF in the oocyte is the major determinant of the heteroplasmy MAF in the offspring. We used a likelihood method to estimate the effective number of mtDNA genomes transmitted to offspring under different bottleneck models; a variable bottleneck size model provided the best fit to the data, with an estimated mean of nine individual mtDNA genomes transmitted. We also found evidence for negative selection during transmission against novel heteroplasmies (in which the minor allele has never been observed in polymorphism data). These novel heteroplasmies are enhanced for tRNA and rRNA genes, and mutations associated with mtDNA diseases frequently occur in these genes. Our results thus suggest that the female germ line is able to recognize and select against deleterious heteroplasmies.
AB - Although previous studies have documented a bottleneck in the transmission of mtDNA genomes from mothers to offspring, several aspects remain unclear, including the size and nature of the bottleneck. Here, we analyze the dynamics of mtDNA heteroplasmy transmission in the Genomes of the Netherlands (GoNL) data, which consists of complete mtDNA genome sequences from 228 trios, eight dizygotic (DZ) twin quartets, and 10 monozygotic (MZ) twin quartets. Using a minor allele frequency (MAF) threshold of 2%, we identified 189 heteroplasmies in the trio mothers, of which 59% were transmitted to offspring, and 159 heteroplasmies in the trio offspring, of which 70% were inherited from the mothers. MZ twin pairs exhibited greater similarity in MAF at heteroplasmic sites than DZ twin pairs, suggesting that the heteroplasmy MAF in the oocyte is the major determinant of the heteroplasmy MAF in the offspring. We used a likelihood method to estimate the effective number of mtDNA genomes transmitted to offspring under different bottleneck models; a variable bottleneck size model provided the best fit to the data, with an estimated mean of nine individual mtDNA genomes transmitted. We also found evidence for negative selection during transmission against novel heteroplasmies (in which the minor allele has never been observed in polymorphism data). These novel heteroplasmies are enhanced for tRNA and rRNA genes, and mutations associated with mtDNA diseases frequently occur in these genes. Our results thus suggest that the female germ line is able to recognize and select against deleterious heteroplasmies.
UR - http://www.scopus.com/inward/record.url?scp=84964010064&partnerID=8YFLogxK
U2 - 10.1101/gr.203216.115
DO - 10.1101/gr.203216.115
M3 - Article
C2 - 26916109
AN - SCOPUS:84964010064
SN - 1088-9051
VL - 26
SP - 417
EP - 426
JO - Genome Research
JF - Genome Research
IS - 4
ER -