Chromosomal instability in human trophoblast stem cells and placentas DOI Creative Commons
Danyang Wang,

Andrew Cearlock,

Katherine Lane

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 25, 2025

The human placenta, a unique tumor-like organ, is thought to exhibit rare aneuploidy associated with adverse pregnancy outcomes. Discrepancies in reported prevalence placentas stem from limitations modeling and detection methods. Here, we use isogenic trophoblast cells (TSCs) derived both naïve primed pluripotent (hPSCs) reveal the spontaneous occurrence of aneuploidy, suggesting chromosomal instability (CIN) as an inherent feature lineage. We identify potential pathways contributing tolerance CIN, such autophagy, which may support survival aneuploid cells. Despite extensive abnormalities, TSCs maintain their proliferative differentiation capacities. These findings are further validated placentas, where observe high heterogeneous across trophoblasts, particularly invasive extravillous trophoblasts. Our study challenges traditional view placenta provides insights into implications CIN placental function.

Language: Английский

Aneuploidy and complex genomic rearrangements in cancer evolution DOI
Toby M. Baker, Sara Waise, Maxime Tarabichi

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(2), P. 228 - 239

Published: Jan. 29, 2024

Language: Английский

Citations

22
Clonal dynamics and somatic evolution of haematopoiesis in mouse DOI Creative Commons
Chiraag Kapadia, Nicholas Williams,

Kevin J. Dawson

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of haematopoietic cell pool during murine ageing. We isolated progenitors from young old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse accrue approximately 45 per year, a rate only threefold greater than human despite vastly different organismal sizes lifespans. Phylogenetic patterns show that multipotent progenitor pools are established embryogenesis, after which they independently self-renew parallel over life, evenly contributing to differentiated peripheral blood. The grows steadily mouse lifespan 70,000 cells, self-renewing every 6 weeks. Aged mice did not display profound loss diversity characteristic However, targeted sequencing showed small, expanded clones context ageing, were larger more numerous following haematological perturbations, exhibiting landscape similar humans. Our data illustrate both conserved features distinct age-associated evolution short-lived mouse.

Language: Английский

Citations

2
Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia DOI Creative Commons
Eleonora Khabirova, Laura Jardine, Tim H. H. Coorens

et al.

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(4), P. 743 - 751

Published: March 14, 2022

Abstract KMT2A- rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A -rearranged B-cell acute lymphoblastic (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination single lymphoblast transcriptomes against a developing bone marrow reference. B-ALL was uniquely dominated by early lymphocyte precursor (ELP) state, whereas less adverse NUTM1 demonstrated signals later B cells, in line most other B-ALLs. We compared lymphoblasts ELP cells revealed that cancer harbored hybrid myeloid–lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve specificity. validated surface coexpression exemplar flow cytometry. Through analysis shared mutations separate leukemias from child relapsing as AML, established rearrangement occurred very development, before hematopoietic specification, emphasizing cell origin cannot be inferred transcriptional state.

Language: Английский

Citations

63
Genetic mosaicism in the human brain: from lineage tracing to neuropsychiatric disorders DOI
Sara Bizzotto, Christopher A. Walsh

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 23(5), P. 275 - 286

Published: March 23, 2022

Language: Английский

Citations

56
On the reproductive capabilities of aneuploid human preimplantation embryos DOI Creative Commons
Antonio Capalbo, Maurizio Poli, Chaim Jalas

et al.

The American Journal of Human Genetics, Journal Year: 2022, Volume and Issue: 109(9), P. 1572 - 1581

Published: Sept. 1, 2022

Language: Английский

Citations

48
IVF outcomes of embryos with abnormal PGT-A biopsy previously refused transfer: a prospective cohort study DOI Open Access
David H. Barad, David F. Albertini, Emanuela Molinari

et al.

Human Reproduction, Journal Year: 2022, Volume and Issue: 37(6), P. 1194 - 1206

Published: March 28, 2022

What are the outcomes for patients who choose to move embryos diagnosed as abnormal by preimplantation genetic testing aneuploidy (PGT-A) a new institution transfer after diagnosing refused them?Many seek have selected with PGT-A trophectoderm biopsies transferred recognizing that these can still offer chance of pregnancy and live birth.: is widely practiced method selecting based on biopsy few cells. Many clinical practices refuse even when there no other 'normal' available.This prospective cohort 69 couples who, since 2014, moved total 444 previously at their parent institutions our practice. Among these, 50 have, thus far, undergone 57 cycles 141 embryos.Embryos (mostly using next generation sequencing) were academically affiliated private fertility research center in New York City. Female age retrieval was 41.35 ± 3.98 years, 74% Caucasian, 12% Asian 10% African descent. All identified among prospectively recorded center's registry.Among 144 102 (72.3%) had only 1 or 2 chromosomal abnormalities, 30 (21.3%) 3 more 9 (6.4%) 'undiagnosed' because degraded DNA, yet been transfer. Transfer resulted 8 births, 11 miscarriages voluntary terminations. One child born segmental duplication required repair coarctation aorta newborn. willing such transfers result establishment ongoing euploid pregnancies births.Findings this case series represent chose having elsewhere may not be representative wider population undergoing IVF general. Not all phenotypes present immediate postnatal period so it will important continue follow development children.PGT-A clinics refusal biopsies, those mosaic findings, consequently large numbers infertile women prematurely advised motherhood through third-party egg-donation.This work supported intramural funds from Center Human Reproduction not-for-profit Foundation Reproductive Medicine, both York, NY, USA. N.G. D.H.B. listed co-inventors several U.S. patents. patents (US Patent# 7,615,544) relates pre-supplementation hypo-androgenic androgens, DHEA testosterone and, therefore, least peripherally related subject manuscript. D.F.A. also received travel speaker honoraria pharmaceutical medical device companies, though none here presented shareholder Fertility Nutraceuticals he receive royalty payments LLC.N/A.

Language: Английский

Citations

47
Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death DOI Creative Commons
Alicia B. Byrne, Peer Arts, Thuong Ha

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(1), P. 180 - 189

Published: Jan. 1, 2023

Abstract Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy 200 families who had experienced fetal or newborn death, providing a definitive candidate genetic diagnosis in 105 Our cohort provides evidence of severe atypical utero presentations known disorders identifies novel phenotypes disease genes. Inheritance 42% diagnoses were either autosomal recessive (30.8%), X-linked (3.8%) dominant (excluding de novos, 7.7%), with risk recurrence future pregnancies. report that at least ten (5%) used their preimplantation (5) prenatal 12 emphasize the clinical importance genomic investigations pregnancy short turnaround times diagnostic reporting followed by systematic research follow-up investigations. This approach has potential enable accurate counseling

Language: Английский

Citations

34
Clonal evolution during metastatic spread in high-risk neuroblastoma DOI
Gunes Gundem, Max F. Levine, Stephen S. Roberts

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(6), P. 1022 - 1033

Published: May 11, 2023

Language: Английский

Citations

28
Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth DOI Creative Commons
Robin N. Beaumont, Christopher Flatley, Marc Vaudel

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(11), P. 1807 - 1819

Published: Oct. 5, 2023

Abstract A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy growth, we report genome-wide association analyses in the ( n = 65,405), 61,228) paternal 52,392) genomes, yielding 40 independent signals. Twenty-six signals are classified fetal, four three maternal. parent-of-origin effect seen near KCNQ1 . Genetic correlation colocalization reveal overlap with birth genetics, but 12 loci predominantly or only affecting weight, connections to development morphology, transport of antibodies amino acids. Mendelian randomization indicate that genetically mediated higher causally associated preeclampsia risk shorter gestational duration. Moreover, these support role insulin regulating providing key link between growth.

Language: Английский

Citations

28
Genomic alterations driving precancerous to cancerous lesions in esophageal cancer development DOI
Jiang Chang, Xuan Zhao, Yichen Wang

et al.

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(12), P. 2038 - 2050.e5

Published: Nov. 30, 2023

Language: Английский

Citations

28