학술논문
Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
Document Type
Original Paper
Author
Oddsson, Asmundur; Sulem, Patrick; Sveinbjornsson, Gardar; Arnadottir, Gudny A.; Steinthorsdottir, Valgerdur; Halldorsson, Gisli H.; Atlason, Bjarni A.; Oskarsson, Gudjon R.; Helgason, Hannes; Nielsen, Henriette Svarre; Westergaard, David; Karjalainen, Juha M.; Katrinardottir, Hildigunnur; Fridriksdottir, Run; Jensson, Brynjar O.; Tragante, Vinicius; Ferkingstad, Egil; Jonsson, Hakon; Gudjonsson, Sigurjon A.; Beyter, Doruk; Moore, Kristjan H. S.; Thordardottir, Helga B.; Kristmundsdottir, Snaedis; Stefansson, Olafur A.; Rantapää-Dahlqvist, Solbritt; Sonderby, Ida Elken; Didriksen, Maria; Stridh, Pernilla; Haavik, Jan; Tryggvadottir, Laufey; Frei, Oleksandr; Walters, G. Bragi; Kockum, Ingrid; Hjalgrim, Henrik; Olafsdottir, Thorunn A.; Selbaek, Geir; Nyegaard, Mette; Erikstrup, Christian; Brodersen, Thorsten; Saevarsdottir, Saedis; Olsson, Tomas; Nielsen, Kaspar Rene; Haraldsson, Asgeir; Bruun, Mie Topholm; Hansen, Thomas Folkmann; Steingrimsdottir, Thora; Jacobsen, Rikke Louise; Lie, Rolv T.; Djurovic, Srdjan; Alfredsson, Lars; Lopez de Lapuente Portilla, Aitzkoa; Brunak, Soren; Melsted, Pall; Halldorsson, Bjarni V.; Saemundsdottir, Jona; Magnusson, Olafur Th.; Padyukov, Leonid; Banasik, Karina; Rafnar, Thorunn; Askling, Johan; Klareskog, Lars; Pedersen, Ole Birger; Masson, Gisli; Havdahl, Alexandra; Nilsson, Bjorn; Andreassen, Ole A.; Daly, Mark; Ostrowski, Sisse Rye; Jonsdottir, Ingileif; Stefansson, Hreinn; Holm, Hilma; Helgason, Agnar; Thorsteinsdottir, Unnur; Stefansson, Kari; Gudbjartsson, Daniel F.
Source
Nature Communications. 14(1)
Subject
Language
English
ISSN
2041-1723
Abstract
Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.
Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.