title: Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck.
abstract: With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in ∼1:5000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in the severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limited observations and with no direct comparisons, it is not clear whether these observations simply reflect pedigree ascertainment and publication bias. To address this issue, we studied 577 mother-child pairs transmitting the m.11778G>A, m.3460G>A, m.8344A>G, m.8993T>G/C and m.3243A>G mtDNA mutations. Our analysis controlled for inter-assay differences, inter-laboratory variation and ascertainment bias. We found no evidence of selection during transmission but show that different mtDNA mutations segregate at different rates in human pedigrees. m.8993T>G/C segregated significantly faster than m.11778G>A, m.8344A>G and m.3243A>G, consistent with a tighter mtDNA genetic bottleneck in m.8993T>G/C pedigrees. Our observations support the existence of different genetic bottlenecks primarily determined by the underlying mtDNA mutation, explaining the different inheritance patterns observed in human pedigrees transmitting pathogenic mtDNA mutations.
authors.affiliation: Institute of Genetic Medicine.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Wilson
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research and.
authors.forename: Phillipa J
authors.initials: PJ
authors.lastname: Carling
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research and Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, Cambridge, UK, Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Vasileios I
authors.initials: VI
authors.lastname: Floros
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research and.
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research and.
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.affiliation: Department of Clinical Genetics, Research Schools GROW/CARIM, Maastricht University Medical Center, Maastricht, Netherlands.
authors.forename: Suzanne C E H
authors.initials: SC
authors.lastname: Sallevelt
authors.affiliation: Division of Molecular Neurogenetics, National Neurological Institute 'C. Besta', Milano, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy, Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway, Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.affiliation: Vanderbilt Genetics Institute, Department of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, TN, USA and.
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.affiliation: Department of Genetics, Faculty of Science, Kasetsart University, Bangkok, Thailand.
authors.forename: Passorn
authors.initials: P
authors.lastname: Wonnapinij
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, Cambridge, UK, Division of Molecular Neurogenetics, National Neurological Institute 'C. Besta', Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research and Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of Clinical Genetics, Research Schools GROW/CARIM, Maastricht University Medical Center, Maastricht, Netherlands.
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research and.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research and Medical Research Council Mitochondrial Biology Unit, Cambridge, UK, Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK, pfc25@medschl.cam.ac.uk.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D001499:Bayes Theorem; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D040582:Inheritance Patterns; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D008957:Models, Genetic; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D017594:Publication Bias
chemical_list: D004272:DNA, Mitochondrial