Transmission of human mtDNA heteroplasmy in the genome of the Netherlands families : Support for a variable-size bottleneck

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 offspr... Mehr ...

Verfasser: Li, Mingkun
Rothwell, Rebecca
Vermaat, Martijn
Wachsmuth, Manja
Schröder, Roland
Laros, Jeroen F J
Van Oven, Mannis
De Bakker, Paul I W
Bovenberg, Jasper A.
Van Duijn, Cornelia M.
Van Ommen, Gert Jan B
Slagboom, P. Eline
Swertz, Morris A.
Wijmenga, Cisca
Kayser, Manfred
Boomsma, Dorret I.
Zöllner, Sebastian
De Knijff, Peter
Stoneking, Mark
De Craen, Anton J M
Beekman, Marian
Hofman, Albert
Willemsen, Gonneke
Wolffenbuttel, Bruce
Platteel, Mathieu
Du, Yuanping
Chen, Ruoyan
Cao, Hongzhi
Cao, Rui
Sun, Yushen
Cao, Jeremy Sujie
Van Dijk, Freerk
Neerincx, Pieter B T
Deelen, Patrick
Dijkstra, Martijn
Byelas, George
Kanterakis, Alexandros
Bot, Jan
Ye, Kai
Lameijer, Eric Wubbo
Den Dunnen, Johan T.
Karssen, Lennart C.
Van Leeuwen, Elisa M.
Amin, Najaf
Koval, Vyacheslav
Rivadeneira, Fernando
Estrada, Karol
Hehir-Kwa, Jayne Y.
De Ligt, Joep
Abdellaoui, Abdel
Hottenga, Jouke Jan
Kattenberg, V. Mathijs
Van Enckevort, David
Mei, Hailiang
Santcroos, Mark
Van Schaik, Barbera D C
Handsaker, Robert E.
McCarroll, Steven A.
Eichler, Evan E.
Ko, Arthur
Sudmant, Peter
Francioli, Laurent C.
Kloosterman, Wigard P.
Nijman, Isaac J.
Guryev, Victor
Dokumenttyp: Artikel
Erscheinungsdatum: 2016
Schlagwörter: Genetics / Genetics(clinical) / Journal Article / Research Support / Non-U.S. Gov't / Twin Study
Sprache: Englisch
Permalink: https://search.fid-benelux.de/Record/base-26835349
Datenquelle: BASE; Originalkatalog
Powered By: BASE
Link(s) : https://dspace.library.uu.nl/handle/1874/346655

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.