Genetic malformations often occur during early pregnancy and unraveling the genetic basis for the resulting disorder is challenging. Current technologies for the analysis and characterization of embryonic malformations are extremely labor intensive and time-consuming, and it often takes several years to study a single gene. Human embryos or cell cultures cannot be studied easily and therefore animal models are used for this purpose. Researchers often need many years to gain new insights into congenital genetic defects and the resulting malformations and disorders.
Under the lead of scientists of the Institute of Human Genetics at the University of Lübeck a joint international research team have investigated and recorded the effects of specific mutations at molecular and cellular level in a single experiment involving more than 1.5 million cells using single-cell sequencing. The resulting cell catalog, including data on mutations and their effects on development, was recently published in the journal Nature.
The aim of the new study was to establish an alternative fast method with the sensitivity required to study complex organ systems for studying embryonic malformations in mouse models using so-called single-cell RNA sequencing. As part of the study, the international research team examined the gene activity of over 100 mouse embryos with 25 different genetic changes in a single large experiment. A study of this scale would have taken years using traditional strategies. The resulting single-cell atlas of fetal gene expression enables research and identification of the different cell types responsible for embryonic malformations. On data obtained for 22 mouse mutants in a single experiment, the authors developed analytical approaches to identify deviations in cell-type composition, subtle differences in gene expression within cell types, and sharing of sub-phenotypes between mutants to gain insights into developmental pathways, and its perturbations.
Huang X, Henck J, Qiu C, Sreenivasan VKA, Balachandran S, Amarie OV, Hrabě de Angelis M, Behncke RY, Chan WL, Despang A, Dickel DE, Duran M, Feuchtinger A, Fuchs H, Gailus-Durner V, Haag N, Hägerling R, Hansmeier N, Hennig F, Marshall C, Rajderkar S, Ringel A, Robson M, Saunders LM, da Silva-Buttkus P, Spielmann N, Srivatsan SR, Ulferts S, Wittler L, Zhu Y, Kalscheuer VM, Ibrahim DM, Kurth I, Kornak U, Visel A, Pennacchio LA, Beier DR, Trapnell C, Cao J, Shendure J, Spielmann M. Single-cell, whole-embryo phenotyping of mammalian developmental disorders. Nature. 2023 Nov;623(7988):772-781. doi: 10.1038/s41586-023-06548-w. Epub 2023 Nov 15. PMID: 37968388
Zellkatalog von genetischen Entwicklungsstörungen: Universität zu Lübeck (uni-luebeck.de)