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Parental influence on human germline de novo mutations in 1,548 trios from Iceland.
Jónsson, Hákon; Sulem, Patrick; Kehr, Birte; Kristmundsdottir, Snaedis; Zink, Florian; Hjartarson, Eirikur; Hardarson, Marteinn T; Hjorleifsson, Kristjan E; Eggertsson, Hannes P; Gudjonsson, Sigurjon Axel; Ward, Lucas D; Arnadottir, Gudny A; Helgason, Einar A; Helgason, Hannes; Gylfason, Arnaldur; Jonasdottir, Adalbjorg; Jonasdottir, Aslaug; Rafnar, Thorunn; Frigge, Mike; Stacey, Simon N; Th Magnusson, Olafur; Thorsteinsdottir, Unnur; Masson, Gisli; Kong, Augustine; Halldorsson, Bjarni V; Helgason, Agnar; Gudbjartsson, Daniel F; Stefansson, Kari.
Affiliation
  • Jónsson H; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Sulem P; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Kehr B; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Kristmundsdottir S; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Zink F; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Hjartarson E; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Hardarson MT; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Hjorleifsson KE; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Eggertsson HP; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Gudjonsson SA; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Ward LD; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Arnadottir GA; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Helgason EA; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Helgason H; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Gylfason A; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Jonasdottir A; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Jonasdottir A; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Rafnar T; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Frigge M; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Stacey SN; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Th Magnusson O; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Thorsteinsdottir U; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Masson G; Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland.
  • Kong A; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Halldorsson BV; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Helgason A; School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland.
  • Gudbjartsson DF; deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland.
  • Stefansson K; School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland.
Nature ; 549(7673): 519-522, 2017 09 28.
Article de En | MEDLINE | ID: mdl-28959963
The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics and to evolutionary studies. To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35× genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32-0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45-1.57). The number of clustered mutations increases faster with the mother's age than with the father's, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19-0.33%) decrease in cytosine-phosphate-guanine to thymine-phosphate-guanine (CpG>TpG) de novo mutations and a 0.33% (95% CI 0.28-0.38%) increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C>G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.
Sujet(s)

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Parents / Vieillissement / Mutagenèse / Âge maternel / Âge paternel / Mutation germinale Limites: Adolescent / Adult / Aged / Animals / Child / Female / Humans / Male / Middle aged Pays/Région comme sujet: Europa Langue: En Journal: Nature Année: 2017 Type de document: Article Pays d'affiliation: Islande Pays de publication: Royaume-Uni

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Parents / Vieillissement / Mutagenèse / Âge maternel / Âge paternel / Mutation germinale Limites: Adolescent / Adult / Aged / Animals / Child / Female / Humans / Male / Middle aged Pays/Région comme sujet: Europa Langue: En Journal: Nature Année: 2017 Type de document: Article Pays d'affiliation: Islande Pays de publication: Royaume-Uni