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Article
| Open AccessSelfish conflict underlies RNA-mediated parent-of-origin effects
In Caenorhabditis tropicalis, selective expression of genetic alleles from one parent but not the other can arise from maternally inherited small transcripts acting via the PIWI-interacting RNA host defence pathway.
- Pinelopi Pliota
- , Hana Marvanova
- & Alejandro Burga
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Article
| Open AccessEmbryo-scale reverse genetics at single-cell resolution
We present the ‘zebrafish single-cell atlas of perturbed embryos’, single-cell trancriptomic data of developing zebrafish embryos across various timepoints and with genetic perturbations.
- Lauren M. Saunders
- , Sanjay R. Srivatsan
- & Cole Trapnell
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Article |
OBOX regulates mouse zygotic genome activation and early development
OBOX, PRD-like homeobox domain transcription factors (OBOX1–OBOX8), are key regulators of mouse zygotic genome activation and early embryogenesis.
- Shuyan Ji
- , Fengling Chen
- & Wei Xie
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Article
| Open AccessSpatial multiomics map of trophoblast development in early pregnancy
A multiomics single-cell atlas of the human maternal–fetal interface including the myometrium, combining spatial transcriptomics data with chromatin accessibility, provides a comprehensive analysis of cell states as placental cells infiltrate the uterus during early pregnancy.
- Anna Arutyunyan
- , Kenny Roberts
- & Roser Vento-Tormo
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Article |
Somatic mosaicism reveals clonal distributions of neocortical development
A comprehensive analysis of brain somatic mosaicism across the neocortex demonstrates the origins and distribution patterns of cells within the human brain.
- Martin W. Breuss
- , Xiaoxu Yang
- & Joseph G. Gleeson
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Article |
Extensive phylogenies of human development inferred from somatic mutations
Somatic mutations obtained from laser microdissected biopsies of human tissues are used to reconstruct the developmental phylogenies of these tissues back to the zygote.
- Tim H. H. Coorens
- , Luiza Moore
- & Michael R. Stratton
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Article |
Clonal dynamics in early human embryogenesis inferred from somatic mutation
Adult human tissues from diverse sites around the body are used to reconstruct cellular phylogenies from early development, using somatic mutations as an internal barcode.
- Seongyeol Park
- , Nanda Maya Mali
- & Young Seok Ju
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Article |
An aged immune system drives senescence and ageing of solid organs
An aged, senescent immune system has a causal role in driving systemic ageing, and the targeting of senescent immune cells with senolytic drugs has the potential to suppress morbidities associated with old age.
- Matthew J. Yousefzadeh
- , Rafael R. Flores
- & Laura J. Niedernhofer
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Article |
Inherent mosaicism and extensive mutation of human placentas
Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.
- Tim H. H. Coorens
- , Thomas R. W. Oliver
- & Sam Behjati
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Article
| Open AccessRegulatory genomic circuitry of human disease loci by integrative epigenomics
The authors present EpiMap, a compendium that comprises 10,000 epigenomic maps across more than 800 biosamples for the annotation of genome-wide association study circuitry.
- Carles A. Boix
- , Benjamin T. James
- & Manolis Kellis
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Article |
PCNA activates the MutLγ endonuclease to promote meiotic crossing over
A new mechanism explaining how double Holliday junctions are specifically resolved into crossovers during meiosis is shown that resembles the initiation of DNA mismatch repair.
- Dhananjaya S. Kulkarni
- , Shannon N. Owens
- & Neil Hunter
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Letter |
The RIPK4–IRF6 signalling axis safeguards epidermal differentiation and barrier function
Signalling between the transcription factor IRF6 and the kinase RIPK4, in particular the phosphorylation of IRF6 by RIPK4, regulates epidermal differentiation and lipid metabolism, thereby maintaining the function of the epidermal barrier.
- Nina Oberbeck
- , Victoria C. Pham
- & Vishva M. Dixit
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Article |
Genetic compensation triggered by mutant mRNA degradation
Transcriptional adaptation, a genetic compensation process by which organisms respond to mutations by upregulating related genes, is triggered by mRNA decay and involves a sequence-dependent mechanism.
- Mohamed A. El-Brolosy
- , Zacharias Kontarakis
- & Didier Y. R. Stainier
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Brief Communications Arising |
Inter-homologue repair in fertilized human eggs?
- Dieter Egli
- , Michael V. Zuccaro
- & Maria Jasin
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Letter |
Subepithelial telocytes are an important source of Wnts that supports intestinal crypts
Subepithelial telocytes are identified as a source of Wnt signals that enable proliferation and differentiation of intestinal stem cells, an essential function for maintenance of the intestinal epithelium.
- Michal Shoshkes-Carmel
- , Yue J. Wang
- & Klaus H. Kaestner
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Letter |
Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size
In a ferret model, the microcephaly-associated gene Aspm regulates cortical expansion by controlling the transition of ventricular radial glial cells to more differentiated cell types.
- Matthew B. Johnson
- , Xingshen Sun
- & Byoung-Il Bae
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Article |
Placentation defects are highly prevalent in embryonic lethal mouse mutants
Analysis of embryonic lethal and sub-viable mouse knockout lines reveals that ablation of many genes affects placental development, and that the occurrence of placental defects is co-associated with abnormal brain, heart and vascular system development.
- Vicente Perez-Garcia
- , Elena Fineberg
- & Myriam Hemberger
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Letter |
Somatic mutations reveal asymmetric cellular dynamics in the early human embryo
Whole-genome sequencing of normal blood cells sampled from 241 adults is used to infer mosaic point mutations that are likely to have arisen during early embryogenesis, providing insight into how early cellular dynamics may affect adult tissues.
- Young Seok Ju
- , Inigo Martincorena
- & Michael R. Stratton
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Article |
Rare and low-frequency coding variants alter human adult height
Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.
- Eirini Marouli
- , Mariaelisa Graff
- & Guillaume Lettre
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Letter |
RIPK1 inhibits ZBP1-driven necroptosis during development
In the absence of RIPK1, ZBP1 engages RIPK3 in a RHIM-dependent manner and acts as a critical activator of RIPK3/MLKL-dependent necroptosis.
- Kim Newton
- , Katherine E. Wickliffe
- & Vishva M. Dixit
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Article |
Developmental mechanisms of stripe patterns in rodents
Alx3-induced modulation of Mitf expression alters melanocyte differentiation and gives rise to the hair colour differences underlying the repeated evolution of dorsal stripes in rodents.
- Ricardo Mallarino
- , Corneliu Henegar
- & Hopi E. Hoekstra
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Article |
High-throughput discovery of novel developmental phenotypes
Identification and characterization, using a comprehensive embryonic phenotyping pipeline, of 410 lethal alleles during the generation of the first 1,751 of 5,000 unique gene knockouts produced by the International Mouse Phenotyping Consortium.
- Mary E. Dickinson
- , Ann M. Flenniken
- & Stephen A. Murray
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Letter |
Cloche is a bHLH-PAS transcription factor that drives haemato-vascular specification
The zebrafish cloche gene is required for the formation of most endothelial and haematopoietic cells, however, it has been difficult to isolate; this study reveals that cloche encodes a PAS-domain-containing bHLH transcription factor, and a mammalian orthologue can partially rescue cloche mutants, indicating a possible conserved role in mammals.
- Sven Reischauer
- , Oliver A. Stone
- & Didier Y. R. Stainier
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Letter |
Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease
Preclinical evaluation and optimization of mitochondrial replacement therapy reveals that a modified form of pronuclear transfer is likely to give rise to normal pregnancies with a reduced risk of mitochondrial DNA disease, but may need further modification to eradicate the disease in all cases.
- Louise A. Hyslop
- , Paul Blakeley
- & Mary Herbert
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Letter |
The gene cortex controls mimicry and crypsis in butterflies and moths
Wing colour patterning of multiple species in the butterfly genus Heliconius is controlled by differential expression of the gene cortex, a member of a conserved family of cell cycle regulators.
- Nicola J. Nadeau
- , Carolina Pardo-Diaz
- & Chris D. Jiggins
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Letter |
Genetic compensation induced by deleterious mutations but not gene knockdowns
Zebrafish embryos injected with egfl7 morpholino exhibit severe vascular defects but egfl7 mutants do not show any obvious phenotypes, illustrating the power of comparing mutants and morphants to identify modifier genes.
- Andrea Rossi
- , Zacharias Kontarakis
- & Didier Y. R. Stainier
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Letter |
The maternal-age-associated risk of congenital heart disease is modifiable
Increased maternal age is known to increase the risk of congenital heart disease in offspring; here, this link is investigated by transplanting ovaries between young and old mice, revealing that the maternal-age-associated risk is independent of the age of the ovaries but depends on the age of the mother, and that this risk can be mitigated by maternal genetic background or exercise.
- Claire E. Schulkey
- , Suk D. Regmi
- & Patrick Y. Jay
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Letter |
Genome sequencing of normal cells reveals developmental lineages and mutational processes
On the basis of whole-genome sequences of clonal lines derived from normal mouse tissues, variation in mutational patterns and load across different tissues are described and early embryonic cell divisions are reconstructed.
- Sam Behjati
- , Meritxell Huch
- & Michael R. Stratton
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Letter |
Genome-scale functional characterization of Drosophila developmental enhancers in vivo
Systematically assaying the activity of 7,705 candidate enhancers during Drosophila embryogenesis shows that nearly half are active in the embryo and display dynamic spatial patterns during development; enhancer activity is matched to expression patterns of putative target genes and predictive cis-regulatory motifs are identified.
- Evgeny Z. Kvon
- , Tomas Kazmar
- & Alexander Stark
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Article
| Open AccessElephant shark genome provides unique insights into gnathostome evolution
Whole-genome analysis of the elephant shark, a cartilaginous fish, shows that it is the slowest evolving of all known vertebrates, lacks critical bone formation genes and has an unusual adaptive immune system.
- Byrappa Venkatesh
- , Alison P. Lee
- & Wesley C. Warren
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Letter |
DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance
In Caenorhabditis elegans, genome instability in the form of exogenous and endogenous DNA damage in germ cells evokes elevated heat- and oxidative-stress resistance in somatic tissues; this is mediated by MPK-1, which triggers the induction of putative secreted peptides associated with innate immunity, leading to activation of the ubiquitin–proteasome system.
- Maria A. Ermolaeva
- , Alexandra Segref
- & Björn Schumacher
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Article |
The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis
This study identifies a deubiquitinase (DUB) that specifically recognises and cleaves linear ubiquitin chains, implicating linear (de)ubiquitination in Wnt signalling and angiogenesis; mutations in gumby cause defects in angiogenesis in mice, and structural and biochemical analysis shows that gumby encodes a linear-ubiquitin-specific DUB.
- Elena Rivkin
- , Stephanie M. Almeida
- & Sabine P. Cordes
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Letter |
De novo mutations in histone-modifying genes in congenital heart disease
Exome sequencing of patients with congenital heart disease (CHD) and their unaffected parents reveals an excess of strong-effect, protein-altering de novo mutations in genes expressed in the developing heart, many of which regulate chromatin modification in key developmental genes; collectively, these mutations are predicted to account for approximately 10% of severe CHD cases.
- Samir Zaidi
- , Murim Choi
- & Richard P. Lifton
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Letter |
A systematic genome-wide analysis of zebrafish protein-coding gene function
A project to identify the phenotypes of disruptive mutations in every zebrafish protein-coding gene has so far revealed potentially disruptive mutations in more than 38% of the protein-coding genes, and the phenotypic consequences of each allele can be assessed using a novel multi-allelic phenotyping scheme.
- Ross N. W. Kettleborough
- , Elisabeth M. Busch-Nentwich
- & Derek L. Stemple
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Letter |
RNAi triggered by specialized machinery silences developmental genes and retrotransposons
In the fission yeast Schizosaccharomyces pombe RNA interference (RNAi) machinery promotes heterochromatin assembly and silencing of centromeric repeats; here it is shown that RNAi participates in silencing other genomic regions, such as sexual differentiation genes and retrotransposons, and this process is regulated by developmental and environmental signals.
- Soichiro Yamanaka
- , Sameet Mehta
- & Shiv I. S. Grewal
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Letter |
Feedback from rhodopsin controls rhodopsin exclusion in Drosophila photoreceptors
- Daniel Vasiliauskas
- , Esteban O. Mazzoni
- & Claude Desplan
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Article |
Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice
- Frédéric Langevin
- , Gerry P. Crossan
- & Ketan J. Patel
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News |
Young mammal hearts heal themselves
Organs in baby mice can recover from damage that occurs in the first week of life.
- Janelle Weaver
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Letter |
Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells
A common stem cell is known to produce both neural plate and mesoderm, but the factors regulating this choice are unknown. This study determines that Tbx6-dependent modulation of the developmental transcription factor Sox2 drives the fate of axial stem cells. In the absence of Tbx6, cells aberrantly upregulated Sox2 activity, with the result that cells originally destined to be mesoderm turned into ectopic neural tubes. In the absence of the N1 enhancer, this aberrant regulation is corrected and cells follow the appropriate fate, even in the absence of Tbx6. Therefore, active repression of the neural fate program is essential for mesoderm tissue to develop from axial stem cells.
- Tatsuya Takemoto
- , Masanori Uchikawa
- & Hisato Kondoh
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Article |
Asymmetric cell divisions promote Notch-dependent epidermal differentiation
This study focuses on developing mouse skin where mitotic basal progenitor cells switch from symmetric divisions to asymmetric division concomitant with stratification. Using a novel technical approach, the genetic pathway regulating spindle orientation is dissected, providing the first direct evidence that the proteins governing spindle orientation (LGN, NuMA and Dctn1) promote asymmetric cell divisions regulated by Notch signalling in mammalian cells in vivo.
- Scott E. Williams
- , Slobodan Beronja
- & Elaine Fuchs
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Article |
Variability in gene expression underlies incomplete penetrance
Even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may generate phenotypic diversity. Intestinal specification in the nematode Caenorhabditis elegans, in which wild-type cell fate is invariant and controlled by a small transcriptional network, is now studied. The results demonstrate that mutations in developmental networks can expose stochastic variability in gene expression, leading to phenotypic variation.
- Arjun Raj
- , Scott A. Rifkin
- & Alexander van Oudenaarden
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Letter |
Transcriptional role of cyclin D1 in development revealed by a genetic–proteomic screen
Although cyclin D1 is frequently overexpressed in human cancers, the full range of its functions in normal development and oncogenesis is unclear. Here, tagged cyclin D1 knock-in mouse strains are developed to allow a search for cyclin D1-binding proteins in different mouse organs using high-throughput mass spectrometry. The results show that, in addition to its established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development.
- Frédéric Bienvenu
- , Siwanon Jirawatnotai
- & Piotr Sicinski
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Letter |
KAP1 controls endogenous retroviruses in embryonic stem cells
Much of the mammalian genome is derived from retroelements, a significant proportion of which are endogenous retroviruses (ERVs). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation, but the initiators of this process are largely unknown. Here, deletion of KAP1 is shown to lead to a marked upregulation of a range of ERVs in mouse embryonic stem cells and in early embryos.
- Helen M. Rowe
- , Johan Jakobsson
- & Didier Trono
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Letter |
A role for the elongator complex in zygotic paternal genome demethylation
After fertilization in mammals, the maternal and paternal genomes undergo epigenetic reprogramming to prepare for the transition from germ cell to somatic cell transcription programs. One of the events that takes place is the demethylation of the paternal genome. To identify the factors involved in this process, a live cell imaging system is now used to monitor the paternal DNA methylation state in zygotes; Elp3, a component of the elongator complex, is found to have an important role.
- Yuki Okada
- , Kazuo Yamagata
- & Yi Zhang