title: Global human frequencies of predicted nuclear pathogenic variants and the role played by protein hydrophobicity in pathogenicity potential.
abstract: Mitochondrial proteins are coded by nuclear (nDNA) and mitochondrial (mtDNA) genes, implying a complex cross-talk between the two genomes. Here we investigated the diversity displayed in 104 nuclear-coded mitochondrial proteins from 1,092 individuals from the 1000 Genomes dataset, in order to evaluate if these genes are under the effects of purifying selection and how that selection compares with their mitochondrial encoded counterparts. Only the very rare variants (frequency < 0.1%) in these nDNA genes are indistinguishable from a random set from all possible variants in terms of predicted pathogenicity score, but more frequent variants display distinct signs of purifying selection. Comparisons of selection strength indicate stronger selection in the mtDNA genes compared to this set of nDNA genes, accounted for by the high hydrophobicity of the proteins coded by the mtDNA. Most of the predicted pathogenic variants in the nDNA genes were restricted to a single continental population. The proportion of individuals having at least one potential pathogenic mutation in this gene set was significantly lower in Europeans than in Africans and Asians. This difference may reflect demographic asymmetries, since African and Asian populations experienced main expansions in middle Holocene, while in Europeans the main expansions occurred earlier in the post-glacial period.
authors.affiliation: 1] Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto 4200-465, Portugal [2] Faculdade de Medicina da Universidade do Porto, Porto 4200-319, Portugal.
authors.forename: Luísa
authors.initials: L
authors.lastname: Pereira
authors.affiliation: Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto 4200-465, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Soares
authors.affiliation: 1] Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto 4200-465, Portugal [2] Instituto de Ciências Biomédicas da Universidade do Porto (ICBAS), Porto 4050-313, Portugal.
authors.forename: Petr
authors.initials: P
authors.lastname: Triska
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: Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto 4200-465, Portugal.
authors.forename: Agnes
authors.initials: A
authors.lastname: van der Waerden
authors.affiliation: School of Informatics and Computing, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Li
authors.affiliation: School of Informatics and Computing, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Predrag
authors.initials: P
authors.lastname: Radivojac
authors.affiliation: Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232-0700, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
mesh_terms: D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D014644:Genetic Variation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D004247:DNA