Slightly deleterious genomic variants and transcriptome perturbations in Down syndrome embryonic selection

Popadin, Konstantin; Peischl, Stephan; Garieri, Marco; Sailani, M. Reza; Letourneau, Audrey; Santoni, Federico; Lukowski, Samuel W.; Bazykin, Georgii A.; Nikolaev, Sergey I.; Meyer, Diogo; Excoffier, Laurent; Reymond, Alexandre; Antonarakis, Stylianos E.

doi:10.1101/gr.228411.117

Cited by 18 publications

(10 citation statements)

References 70 publications

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“…We adapted existing methods in adult 9 by replacing stationary cell identities with regulons. By selecting multiple genes that co-define particular regulons as input we significantly reduced selection bias due to strongly deleterious mutations (‘survivorship bias’ 25 ). Regulons driven by pro-neurogenic genes were characterized by the lowest rate of mutated master genes ( Figure ED5b ) with the Foxo4 (#29) and Onecut3 (#18) clusters completely depleted in mutations ( Figure 3a,c ).…”

Section: Resultsmentioning

confidence: 99%

Molecular design of hypothalamus development

Romanov

Tretiakov

Kastriti

et al. 2020

Nature

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A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs 1 , 2 . Nevertheless, a developmental blueprint integrating molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development remains unresolved 3 . Here, we combine single-cell RNA-seq on 51,199 cells of ectodermal origin, gene regulatory network (GRN) screens in conjunction with GWAS-based disease phenotyping and genetic lineage reconstruction to show that 9 glial and 33 neuronal subtypes are generated by mid-gestation under the control of distinct GRNs. Combinatorial molecular codes arising from neurotransmitters, neuropeptides and transcription factors are minimally required to decode the taxonomical hierarchy of hypothalamic neurons. Differentiation of GABA and dopamine but not glutamate neurons relies on quasi-stable intermediate states with a pool of GABA progenitors giving rise to dopamine cells 4 . An unexpected abundance of chemotropic proliferation and guidance cues commonly implicated in dorsal (cortical) patterning 5 was found in the hypothalamus. Particularly, Slit / Robo loss-of-function impacted both the production and positioning of periventricular dopamine neurons. Overall, we uncover molecular principles shaping the developmental architecture of the hypothalamus and show how neuronal heterogeneity is transformed into a multimodal neural unit to endow a virtually infinite adaptive potential throughout life.

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Section: Resultsmentioning

confidence: 99%

Molecular design of hypothalamus development

Romanov

Tretiakov

Kastriti

et al. 2020

Nature

Self Cite

120

165

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“…According to Popadin et al (44), embryonic selection in DS depends on gene expression. Trisomy 21 fetuses with relatively reduced expression of HSA21 genes might be favored by embryonic selection and thus have a higher probability of being liveborn.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic behavior of genes associated with chromosome 21 aneuploidies in early embryo development

Sanchez-Ribas

Díaz-Gimeno

Sebastián-León

et al. 2019

Fertility and Sterility

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Objective: To analyze how chromosome 21 (HSA21) ploidy affects global gene expression of early human blastocysts. Design: Prospective study. Setting: University-affiliated in vitro fertilization clinic. Patient(s): A total of 26 high-quality donated embryos from in vitro fertilization (IVF) patients: trisomy 21 (n ¼ 8), monosomy 21 (n ¼ 10), and euploid (n ¼ 8) blastocysts. Intervention(s): None. Main Outcome Measure(s): Blastocyst transcriptome changes and its associated functions. Result(s): Trisomy 21, monosomy 21, and euploid blastocysts were classified by comparative genomic hybridization.The global transcriptome of whole blastocysts was analyzed with small cell number RNA sequencing, and they were compared to understand the gene expression behavior at early development and its implications for embryo implantation. We identified 1,232 differentially expressed genes (false discovery rate <0.05) in monosomy 21 compared with euploid blastocysts associated with dysregulated functions in embryo development as the Rap1 signaling pathway. Curiously, Down syndrome in early development revealed fewer transcriptomic changes than expected. In addition, Down syndrome gene expression in neonates, children, and adults revealed that the number of deregulated genes increases across life stages from blastocysts to adults, suggesting a potential dosage-compensation mechanism for human chromosome 21. Conclusion(s):At the transcriptomic level, early development in Down syndrome is mainly dosage compensated. However, monosomy 21 is strongly transcriptionally affected because early development involving main functions is associated with embryo implantation. (Fertil Steril Ò 2019;111:991-1001. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

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“…Some of these differences may be encoded on the amplified chromosome, with profound influences on DS severity. A recent study of DS patient genomes identified a dearth of deleterious alleles on sampled chromosome 21, which was inferred to reflect survivor bias in tolerated variants (POPADIN et al 2018). However, the influence of broader genetic background effects has been less clear, as there has been no systematic study exploring the aneuploidy tolerance across genotypes.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in aneuploidy prevalence and tolerance across Saccharomyces cerevisiae lineages

et al. 2021

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Individuals carrying an aberrant number of chromosomes can vary widely in their expression of aneuploidy phenotypes. A major unanswered question is the degree to which an individual’s genetic makeup influences its tolerance of karyotypic imbalance. Here we investigated within-species variation in aneuploidy prevalence and tolerance, using Saccharomyces cerevisiae as a model for eukaryotic biology. We analyzed genotypic and phenotypic variation recently published for over 1,000 S. cerevisiae strains spanning dozens of genetically defined clades and ecological associations. Our results show that the prevalence of chromosome gain and loss varies by clade and can be better explained by differences in genetic background than ecology. The relationships between lineages with high aneuploidy frequencies suggest that increased aneuploidy prevalence emerged multiple times in S. cerevisiae evolution. Separate from aneuploidy prevalence, analyzing growth phenotypes revealed that some genetic backgrounds—such as the European Wine lineage—show fitness costs in aneuploids compared to euploids, whereas other clades with high aneuploidy frequencies show little evidence of major deleterious effects. Our analysis confirms that chromosome gain can produce phenotypic benefits, which could influence evolutionary trajectories. These results have important implications for understanding genetic variation in aneuploidy prevalence in health, disease, and evolution.

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Slightly deleterious genomic variants and transcriptome perturbations in Down syndrome embryonic selection

Cited by 18 publications

References 70 publications

Molecular design of hypothalamus development

Molecular design of hypothalamus development

Transcriptomic behavior of genes associated with chromosome 21 aneuploidies in early embryo development

Genetic variation in aneuploidy prevalence and tolerance across Saccharomyces cerevisiae lineages

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