解码遗传学/安进公司Kari Stefansson研究小组取得一项新突破。他们报道了妊娠早期序列多样性丧失。该项研究成果发表在2025年5月21日出版的《自然》上。

在这里，该课题组研究人员通过对来自467个受妊娠丢失影响的三胞胎（胎儿、母亲和父亲）的1007个胎儿样本和934个亲本样本的全基因组测序，表征了早期妊娠丢失的序列多样性。亲代基因组测序使他们能够确定染色体异常的亲代和减数分裂起源，在他们的一半中检测到。这进一步使他们能够评估来自传递额外染色体的父母的两条同源染色体的新生突变，并确定它们的时间，揭示了6.6%的母亲突变发生在胎儿卵母细胞中姐妹染色单体形成之前。该课题组研究人员发现，受妊娠流产影响的三人组中新生突变的数量与9,651名成人三人组相似，但在妊娠流产病例中致病性小（< 50bp）序列变异基因型的数量是成人的三倍。总的来说，他们的研究结果表明，由于胎儿中的致病性小序列变异基因型，136例妊娠中约有1例流产。他们的研究结果强调了在怀孕早期失去的大量基因序列多样性。

研究人员表示，每一代，人类的基因组在减数分裂期间都会被洗刷，一个受精卵就会产生人体的所有细胞。减数分裂错误导致染色体异常是已知的妊娠丢失的主要原因，但整倍体妊娠丢失的遗传病因在很大程度上仍未得到解释。

附：英文原文

Title: Sequence diversity lost in early pregnancy

Author: Arnadottir, Gudny A., Jonsson, Hakon, Hartwig, Tanja Schlaikjr, Gruhn, Jennifer R., Mller, Peter Loof, Gylfason, Arnaldur, Westergaard, David, Chan, Andrew Chi-Ho, Oddsson, Asmundur, Stefansdottir, Lilja, Roux, Louise le, Steinthorsdottir, Valgerdur, Swerford Moore, Kristjan H., Olafsson, Sigurgeir, Olason, Pall I., Eggertsson, Hannes P., Halldrsson, Gsli 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

Issue&Volume: 2025-05-21

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.

DOI: 10.1038/s41586-025-09031-w

Source: https://www.nature.com/articles/s41586-025-09031-w