Cargando…

Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis

Children show a higher incidence of leukemia compared to young adolescents, yet their cells have less age-related (oncogenic) somatic mutations. Newborns with Down syndrome have an even higher risk of developing leukemia, which is thought to be driven by mutations that accumulate during fetal develo...

Descripción completa

Detalles Bibliográficos
Autores principales: Hasaart, Karlijn A. L., Manders, Freek, van der Hoorn, Marie-Louise, Verheul, Mark, Poplonski, Tomasz, Kuijk, Ewart, de Sousa Lopes, Susana M. Chuva, van Boxtel, Ruben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395765/
https://www.ncbi.nlm.nih.gov/pubmed/32737409
http://dx.doi.org/10.1038/s41598-020-69822-1
_version_ 1783565462133538816
author Hasaart, Karlijn A. L.
Manders, Freek
van der Hoorn, Marie-Louise
Verheul, Mark
Poplonski, Tomasz
Kuijk, Ewart
de Sousa Lopes, Susana M. Chuva
van Boxtel, Ruben
author_facet Hasaart, Karlijn A. L.
Manders, Freek
van der Hoorn, Marie-Louise
Verheul, Mark
Poplonski, Tomasz
Kuijk, Ewart
de Sousa Lopes, Susana M. Chuva
van Boxtel, Ruben
author_sort Hasaart, Karlijn A. L.
collection PubMed
description Children show a higher incidence of leukemia compared to young adolescents, yet their cells have less age-related (oncogenic) somatic mutations. Newborns with Down syndrome have an even higher risk of developing leukemia, which is thought to be driven by mutations that accumulate during fetal development. To characterize mutation accumulation in individual stem and progenitor cells of Down syndrome and karyotypically normal fetuses, we clonally expanded single cells and performed whole-genome sequencing. We found a higher mutation rate in haematopoietic stem and progenitor cells during fetal development compared to the post-infant rate. In fetal trisomy 21 cells the number of somatic mutations is even further increased, which was already apparent during the first cell divisions of embryogenesis before gastrulation. The number and types of mutations in fetal trisomy 21 haematopoietic stem and progenitor cells were similar to those in Down syndrome-associated myeloid preleukemia and could be attributed to mutational processes that were active during normal fetal haematopoiesis. Finally, we found that the contribution of early embryonic cells to human fetal tissues can vary considerably between individuals. The increased mutation rates found in this study, may contribute to the increased risk of leukemia early during life and the higher incidence of leukemia in Down syndrome.
format Online
Article
Text
id pubmed-7395765
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-73957652020-08-04 Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis Hasaart, Karlijn A. L. Manders, Freek van der Hoorn, Marie-Louise Verheul, Mark Poplonski, Tomasz Kuijk, Ewart de Sousa Lopes, Susana M. Chuva van Boxtel, Ruben Sci Rep Article Children show a higher incidence of leukemia compared to young adolescents, yet their cells have less age-related (oncogenic) somatic mutations. Newborns with Down syndrome have an even higher risk of developing leukemia, which is thought to be driven by mutations that accumulate during fetal development. To characterize mutation accumulation in individual stem and progenitor cells of Down syndrome and karyotypically normal fetuses, we clonally expanded single cells and performed whole-genome sequencing. We found a higher mutation rate in haematopoietic stem and progenitor cells during fetal development compared to the post-infant rate. In fetal trisomy 21 cells the number of somatic mutations is even further increased, which was already apparent during the first cell divisions of embryogenesis before gastrulation. The number and types of mutations in fetal trisomy 21 haematopoietic stem and progenitor cells were similar to those in Down syndrome-associated myeloid preleukemia and could be attributed to mutational processes that were active during normal fetal haematopoiesis. Finally, we found that the contribution of early embryonic cells to human fetal tissues can vary considerably between individuals. The increased mutation rates found in this study, may contribute to the increased risk of leukemia early during life and the higher incidence of leukemia in Down syndrome. Nature Publishing Group UK 2020-07-31 /pmc/articles/PMC7395765/ /pubmed/32737409 http://dx.doi.org/10.1038/s41598-020-69822-1 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hasaart, Karlijn A. L.
Manders, Freek
van der Hoorn, Marie-Louise
Verheul, Mark
Poplonski, Tomasz
Kuijk, Ewart
de Sousa Lopes, Susana M. Chuva
van Boxtel, Ruben
Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis
title Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis
title_full Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis
title_fullStr Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis
title_full_unstemmed Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis
title_short Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis
title_sort mutation accumulation and developmental lineages in normal and down syndrome human fetal haematopoiesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395765/
https://www.ncbi.nlm.nih.gov/pubmed/32737409
http://dx.doi.org/10.1038/s41598-020-69822-1
work_keys_str_mv AT hasaartkarlijnal mutationaccumulationanddevelopmentallineagesinnormalanddownsyndromehumanfetalhaematopoiesis
AT mandersfreek mutationaccumulationanddevelopmentallineagesinnormalanddownsyndromehumanfetalhaematopoiesis
AT vanderhoornmarielouise mutationaccumulationanddevelopmentallineagesinnormalanddownsyndromehumanfetalhaematopoiesis
AT verheulmark mutationaccumulationanddevelopmentallineagesinnormalanddownsyndromehumanfetalhaematopoiesis
AT poplonskitomasz mutationaccumulationanddevelopmentallineagesinnormalanddownsyndromehumanfetalhaematopoiesis
AT kuijkewart mutationaccumulationanddevelopmentallineagesinnormalanddownsyndromehumanfetalhaematopoiesis
AT desousalopessusanamchuva mutationaccumulationanddevelopmentallineagesinnormalanddownsyndromehumanfetalhaematopoiesis
AT vanboxtelruben mutationaccumulationanddevelopmentallineagesinnormalanddownsyndromehumanfetalhaematopoiesis