학술논문
Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
Document Type
article
Author
Asmundur Oddsson; Patrick Sulem; Gardar Sveinbjornsson; Gudny A. Arnadottir; Valgerdur Steinthorsdottir; Gisli H. Halldorsson; Bjarni A. Atlason; Gudjon R. Oskarsson; Hannes Helgason; Henriette Svarre Nielsen; David Westergaard; Juha M. Karjalainen; Hildigunnur Katrinardottir; Run Fridriksdottir; Brynjar O. Jensson; Vinicius Tragante; Egil Ferkingstad; Hakon Jonsson; Sigurjon A. Gudjonsson; Doruk Beyter; Kristjan H. S. Moore; Helga B. Thordardottir; Snaedis Kristmundsdottir; Olafur A. Stefansson; Solbritt Rantapää-Dahlqvist; Ida Elken Sonderby; Maria Didriksen; Pernilla Stridh; Jan Haavik; Laufey Tryggvadottir; Oleksandr Frei; G. Bragi Walters; Ingrid Kockum; Henrik Hjalgrim; Thorunn A. Olafsdottir; Geir Selbaek; Mette Nyegaard; Christian Erikstrup; Thorsten Brodersen; Saedis Saevarsdottir; Tomas Olsson; Kaspar Rene Nielsen; Asgeir Haraldsson; Mie Topholm Bruun; Thomas Folkmann Hansen; DBDS Genomic Consortium; Thora Steingrimsdottir; Rikke Louise Jacobsen; Rolv T. Lie; Srdjan Djurovic; Lars Alfredsson; Aitzkoa Lopez de Lapuente Portilla; Soren Brunak; Pall Melsted; Bjarni V. Halldorsson; Jona Saemundsdottir; Olafur Th. Magnusson; Leonid Padyukov; Karina Banasik; Thorunn Rafnar; Johan Askling; Lars Klareskog; Ole Birger Pedersen; Gisli Masson; Alexandra Havdahl; Bjorn Nilsson; Ole A. Andreassen; Mark Daly; Sisse Rye Ostrowski; Ingileif Jonsdottir; Hreinn Stefansson; Hilma Holm; Agnar Helgason; Unnur Thorsteinsdottir; Kari Stefansson; Daniel F. Gudbjartsson
Source
Nature Communications, Vol 14, Iss 1, Pp 1-15 (2023)
Subject
Language
English
ISSN
2041-1723
Abstract
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.