title: Fine Time Scaling of Purifying Selection on Human Nonsynonymous mtDNA Mutations Based on the Worldwide Population Tree and Mother-Child Pairs.
abstract: A high-resolution mtDNA phylogenetic tree allowed us to look backward in time to investigate purifying selection. Purifying selection was very strong in the last 2,500 years, continuously eliminating pathogenic mutations back until the end of the Younger Dryas (∼11,000 years ago), when a large population expansion likely relaxed selection pressure. This was preceded by a phase of stable selection until another relaxation occurred in the out-of-Africa migration. Demography and selection are closely related: expansions led to relaxation of selection and higher pathogenicity mutations significantly decreased the growth of descendants. The only detectible positive selection was the recurrence of highly pathogenic nonsynonymous mutations (m.3394T>C-m.3397A>G-m.3398T>C) at interior branches of the tree, preventing the formation of a dinucleotide STR (TATATA) in the MT-ND1 gene. At the most recent time scale in 124 mother-children transmissions, purifying selection was detectable through the loss of mtDNA variants with high predicted pathogenicity. A few haplogroup-defining sites were also heteroplasmic, agreeing with a significant propensity in 349 positions in the phylogenetic tree to revert back to the ancestral variant. This nonrandom mutation property explains the observation of heteroplasmic mutations at some haplogroup-defining sites in sequencing datasets, which may not indicate poor quality as has been claimed.
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Cavadas
authors.affiliation: Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.|Department of Biology, CBMA (Centre of Molecular and Environmental Biology), University of Minho, Braga, 4704-553, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Soares
authors.affiliation: INESC TEC, Porto, 4200-465, Portugal.|Departamento de Engenharia Informática, Faculdade de Engenharia da Universidade do Porto, Porto, 4200-465, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Camacho
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.|Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS), Porto, 4050-313, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Brandão
authors.affiliation: Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Marta D
authors.initials: MD
authors.lastname: Costa
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Verónica
authors.initials: V
authors.lastname: Fernandes
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Joana B
authors.initials: JB
authors.lastname: Pereira
authors.affiliation: Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rito
authors.affiliation: Vanderbilt Genetics Institute, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, 37232-0700.
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.|Faculdade de Medicina da Universidade do Porto, Porto, 4200-319, Portugal.
authors.forename: Luisa
authors.initials: L
authors.lastname: Pereira
mesh_terms: D000483:Alleles; D019295:Computational Biology / Q000379:methods; D004272:DNA, Mitochondrial; D019143:Evolution, Molecular; D005190:Family; D005260:Female; D005828:Genetics, Population; D006801:Humans; D008297:Male; D009154:Mutation; D010802:Phylogeny; D012641:Selection, Genetic
chemical_list: D004272:DNA, Mitochondrial
keywords: heteroplasmy; massive parallel sequencing; mother-child pairs; mtDNA; worldwide phylogenetic tree