Sequence diversity lost in early pregnancy
成果类型：
Article
署名作者：
Arnadottir, Gudny A.; Jonsson, Hakon; Hartwig, Tanja Schlaikjaer; Gruhn, Jennifer R.; Moller, Peter Loof; Gylfason, Arnaldur; Westergaard, David; Chan, Andrew Chi-Ho; Oddsson, Asmundur; Stefansdottir, Lilja; le Roux, Louise; Steinthorsdottir, Valgerdur; Moore, Kristjan H. Swerford; Olafsson, Sigurgeir; Olason, Pall I.; Eggertsson, Hannes P.; Halldorsson, Gisli H.; Walters, G. Bragi; Stefansson, Hreinn; Gudjonsson, Sigurjon A.; Palsson, Gunnar; Jensson, Brynjar O.; Fridriksdottir, Run; Petersen, Jesper Friis; Helgason, Agnar; Norddahl, Gudmundur L.; Rohde, Palle Duun; Saemundsdottir, Jona; Magnusson, Olafur Th.; Halldorsson, Bjarni V.; Bliddal, Sofie; Banasik, Karina; Gudbjartsson, Daniel F.; Nyegaard, Mette; Sulem, Patrick; Thorsteinsdottir, Unnur; Hoffmann, Eva R.; Nielsen, Henriette Svarre; Stefansson, Kari
署名单位：
Decode Genetics; University of Copenhagen; University of Copenhagen; Aalborg University; University of Copenhagen; Copenhagen University Hospital; Reykjavik University; University of Iceland; Statens Serum Institut; University of Iceland; University of Copenhagen
刊物名称：
Nature
ISSN/ISSBN：
0028-2738
DOI：
10.1038/s41586-025-09031-w
发表日期：
2025-06-19
关键词：
joint consensus recommendation
medical genetics
american-college
maternal age
germline
association
variants
STANDARDS
genomics
rates
摘要：
Every generation, the human genome is shuffled during meiosis and a single fertilized egg gives rise to all of the cells of the body(1). Meiotic errors leading to chromosomal abnormalities are known causes of pregnancy loss(2,3), but genetic aetiologies of euploid pregnancy loss remain largely unexplained(4). Here we characterize sequence diversity in early pregnancy loss through whole-genome sequencing of 1,007 fetal samples and 934 parental samples from 467 trios affected by pregnancy loss (fetus, mother and father). Sequenced parental genomes enabled us to determine both the parental and meiotic origins of chromosomal abnormalities, detected in half of our set. It further enabled us to assess de novo mutations on both homologous chromosomes from parents transmitting extra chromosomes, and date them, revealing that 6.6% of maternal mutations occurred before sister chromatid formation in fetal oocytes. We find a similar number of de novo mutations in the trios affected by pregnancy loss as in 9,651 adult trios, but three times the number of pathogenic small (<50 bp) sequence variant genotypes in the loss cases compared with adults. Overall, our findings indicate that around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus. Our results highlight the vast sequence diversity that is lost in early pregnancy.