Sequence diversity lost in early pregnancy
Gudny A. Arnadottir, Hákon Jónsson, Tanja Schlaikjær Hartwig, Jennifer R. Gruhn, Peter Möller, Arnaldur Gylfason, David Westergaard, Andrew C. Chan, Ásmundur Oddsson, Lilja Stefánsdóttir, Louise le Roux, Valgerður Steinthórsdóttir, Kristjan H. S. Moore, Sigurgeir Ólafsson, Pall I. Olason, Hannes P. Eggertsson, Gísli H. Halldórsson, G. Bragi Walters, Hreinn Stefánsson, Sigurjón A. Guðjónsson, Gunnar Pálsson, Brynjar Ö. Jensson, Rún Friðriksdóttir, Jesper Friis Petersen, Henriette Svarre Nielsen, Tanja Schlaikjær Hartwig, Sofie Bliddal, David Westergaard, Karina Banasik, Karina Banasik, Maria Christine Krog, Astrid Marie Kolte, Nina la Cour Freiesleben, Sisse Rye Ostrowski, Erik Sørensen, Mille Løhr, Eva R. Hoffmann, Eva Hoffmann, Jenny Gruhn, Andy Chi Ho Chan, Kāri Stefánsson, Hákon Jónsson, Kári Stefánsson, Valgerður Steinthórsdóttir, Hákon Jónsson, Ólafur Þ. Magnússon, Valgerdur Steinthorsdottir, Louise Ambye, Lone Schmidt, Pia Rørbæk Kamstrup, Mette Nyegaard, Agnar Helgason, Gudmundur L. Norddahl, Palle Duun Rohde, Jona Saemundsdottir, Gudmundur L. Norddahl, Bjarni V. Halldórsson, Sofie Bliddal, Karina Banasik, Daníel F. Guðbjartsson, Sofie Bliddal, Patrick Sulem, Unnur Thorsteinsdottir, Eva R. Hoffmann, Henriette Svarre Nielsen, Kāri Stefánsson, Eva R. Hoffmann, Henriette Svarre Nielsen, Kāri Stefánsson, Kāri Stefánsson
Abstract
Every generation, the human genome is shuffled during meiosis and a single fertilized egg gives rise to all of the cells of the body1. Meiotic errors leading to chromosomal abnormalities are known causes of pregnancy loss2,3, but genetic aetiologies of euploid pregnancy loss remain largely unexplained4. 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. Around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus.