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Inter-homologue repair in fertilized human eggs?

Published on Aug 1, 2018in Nature 41.58
· DOI :10.1038/s41586-018-0379-5
Dieter Egli34
Estimated H-index: 34
(Columbia University),
Michael V. Zuccaro1
Estimated H-index: 1
(Columbia University)
+ 3 AuthorsMaria Jasin76
Estimated H-index: 76
(Memorial Sloan Kettering Cancer Center)
Many human diseases have an underlying genetic component. The development and application of methods to prevent the inheritance of damaging mutations through the human germline could have significant health benefits, and currently include preimplantation genetic diagnosis and carrier screening. Ma et al. take this a step further by attempting to remove a disease mutation from the human germline through gene editing (1). They assert the following advances: (i) the correction of a pathogenic gene mutation responsible for hypertrophic cardiomyopathy in human embryos using CRISPR-Cas9 and (ii) the avoidance of mosaicism in edited embryos. In the case of correction, the authors conclude that repair using the homologous chromosome was as or more frequent than mutagenic nonhomologous end-joining (NHEJ). Their conclusion is significant, if validated, because such a self-repair mechanism would allow gene correction without the introduction of a repair template. While the authors analyses relied on the failure to detect mutant alleles, here we suggest approaches to provide direct evidence for inter-homologue recombination and discuss other events consistent with the data. We also review the biological constraints on inter-homologue recombination in the early embryo. (1) Ma, H. et al. Correction of a pathogenic gene mutation in human embryos. Nature, doi:10.1038/nature23305 (2017).
  • References (16)
  • Citations (21)
Published on Jul 16, 2018in Nature Biotechnology 35.72
Michael Kosicki2
Estimated H-index: 2
Kärt Tomberg5
Estimated H-index: 5
Allan Bradley112
Estimated H-index: 112
Cas9-induced double stranded breaks can cause large deletions near the target site and more complex genomic rearrangements in mouse and human stem cells.
132 Citations Source Cite
Published on Jul 13, 2018in Science 41.06
Judith Reichmann10
Estimated H-index: 10
Bianca Nijmeijer9
Estimated H-index: 9
+ 7 AuthorsJan Ellenberg67
Estimated H-index: 67
At the beginning of mammalian life, the genetic material from each parent meets when the fertilized egg divides. It was previously thought that a single microtubule spindle is responsible for spatially combining the two genomes and then segregating them to create the two-cell embryo. We used light-sheet microscopy to show that two bipolar spindles form in the zygote and then independently congress the maternal and paternal genomes. These two spindles aligned their poles before anaphase but kept ...
16 Citations Source Cite
Published on Aug 1, 2017in Nature Communications 12.35
Ha Youn Shin5
Estimated H-index: 5
Chaochen Wang18
Estimated H-index: 18
+ 7 AuthorsLothar Hennighausen88
Estimated H-index: 88
CRISPR/Cas9 gene editing has been used to generate mutations in several mouse genes. Here, the authors show that targeting events using single guide RNAs cause large deletions at 17 sites in the mouse genome, suggesting that careful genotyping is needed and sequential targeting may avoid such deletions.
44 Citations Source Cite
Published on Aug 1, 2017in Nature 41.58
Hong Ma27
Estimated H-index: 27
(Oregon National Primate Research Center),
Nuria Marti-Gutierrez1
Estimated H-index: 1
(Oregon Health & Science University)
+ 28 AuthorsRiffat Ahmed10
Estimated H-index: 10
(Oregon Health & Science University)
CRISPR–Cas9 genome editing is used to induce a DNA repair response and correct a disease-causing heterozygous mutation in human embryos with reduced mosaicism and preferential repair using the wild-type copy of the gene.
259 Citations Source Cite
Published on May 1, 2015in Scientific Reports 4.12
Toru Suzuki6
Estimated H-index: 6
Maki Asami3
Estimated H-index: 3
Anthony C.F. Perry33
Estimated H-index: 33
Mammalian genomes can be edited by injecting pronuclear embryos with Cas9 cRNA and guide RNA (gRNA) but it is unknown whether editing can also occur during the onset of embryonic development, prior to pronuclear embryogenesis. We here report Cas9-mediated editing during sperm-induced meiotic exit and the initiation of development. Injection of unfertilized, mouse metaphase II (mII) oocytes with Cas9 cRNA, gRNA and sperm enabled efficient editing of transgenic and native alleles. Pre-loading oocy...
24 Citations Source Cite
Published on Jan 14, 2015in PLOS ONE 2.77
Bijal A. Parikh4
Estimated H-index: 4
(Washington University in St. Louis),
Diana L. Beckman8
Estimated H-index: 8
(Washington University in St. Louis)
+ 2 AuthorsWayne M. Yokoyama65
Estimated H-index: 65
(Washington University in St. Louis)
The bacterial CRISPR-Cas9 system has been adapted for use as a genome editing tool. While several recent reports have indicated that successful genome editing of mice can be achieved, detailed phenotypic and molecular analyses of the mutant animals are limited. Following pronuclear micro-injection of fertilized eggs with either wild-type Cas9 or the nickase mutant (D10A) and single or paired guide RNA (sgRNA) for targeting of the tyrosinase (Tyr) gene, we assessed genome editing in mice using ra...
30 Citations Source Cite
Published on Oct 1, 2014in Nature Genetics 27.13
Francesca Cole17
Estimated H-index: 17
Frédéric Baudat22
Estimated H-index: 22
+ 3 AuthorsMaria Jasin11
Estimated H-index: 11
(Memorial Sloan Kettering Cancer Center)
Scott Keeney, Bernard de Massy, Maria Jasin and colleagues report a method to perform tetrad analysis (analysis of all four chromatids from a single meiosis) in mouse and analyzed two recombination hotspots in mouse oocytes and spermatocytes. They show that gene conversion frequently spares the binding site of the hotspot-specifying protein PRDM9.
47 Citations Source Cite
Published on Sep 1, 2014in Biology of Reproduction 3.18
Kristin M. Whitworth22
Estimated H-index: 22
(University of Missouri),
Kiho Lee11
Estimated H-index: 11
(University of Missouri)
+ 13 AuthorsEric M. Walters20
Estimated H-index: 20
(University of Missouri)
Targeted modification of the pig genome can be challenging. Recent applications of the CRISPR/Cas9 system hold promise for improving the efficacy of genome editing. When a designed CRISPR/Cas9 system targeting CD163 or CD1D was introduced into somatic cells, it was highly efficient in inducing mutations. When these mutated cells were used with somatic cell nuclear transfer, offspring with these modifications were created. When the CRISPR/Cas9 system was delivered into in vitro produced presumpti...
155 Citations Source Cite
Published on Apr 15, 2013in Genes & Development 9.46
Liisa Kauppi12
Estimated H-index: 12
(University of Helsinki),
Marco Barchi15
Estimated H-index: 15
(University of Rome Tor Vergata)
+ 3 AuthorsScott Keeney47
Estimated H-index: 47
(Memorial Sloan Kettering Cancer Center)
Different organisms display widely different numbers of the programmed double-strand breaks (DSBs) that initiate meiotic recombination (e.g., hundreds per meiocyte in mice and humans vs. dozens in nematodes), but little is known about what drives these species-specific DSB set points or the regulatory pathways that control them. Here we examine male mice with a lowered dosage of SPO11, the meiotic DSB catalyst, to gain insight into the effect of reduced DSB numbers on mammalian chromosome dynami...
95 Citations Source Cite
Published on Sep 1, 2011in Nature Communications 12.35
Dieter Egli34
Estimated H-index: 34
(New York Stem Cell Foundation),
Alice E. Chen11
Estimated H-index: 11
(Harvard University)
+ 11 AuthorsWilliam G. Kearns1
Estimated H-index: 1
The generation of human cell lines using somatic cell nuclear transfer has been difficult to achieve. In this study, Egli et al. show that while mouse eggs reprogram somatic cells within hours, human eggs arrest after nuclear transfer which may be due to a lack of genome transcription.
54 Citations Source Cite
Cited By21
Published on Jun 3, 2019in Nature Medicine 32.62
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Published on Jun 1, 2019in Pharmaceutical medicine
François Hirsch23
Estimated H-index: 23
(French Institute of Health and Medical Research),
Christine Lemaitre (French Institute of Health and Medical Research)+ 1 AuthorsLluís Montoliu33
Estimated H-index: 33
(Spanish National Research Council)
For more than 40 years, scientists have been developing tools and technologies for genome modification; however, initial progress was slow and few outside of the molecular biology community took an interest in the field. Everything has dramatically changed with the recent appearance of the so-called precision approaches, and especially with the ‘CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) revolution’. With great powers come great responsibilities. CRISPR-derived technologie...
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Published on Apr 30, 2019in PLOS Biology 9.16
Haoyi Wang (Chinese Academy of Sciences), Hui Yang (Chinese Academy of Sciences)
During the second World Summit of Human Gene Editing, Jiankui He presented the gene-editing project that led to the birth of two baby girls with man-made C-C chemokine receptor type 5 (CCR5) mutations. This extremely irresponsible behavior violated the ethical consensus of scientists all over the world. His presentation revealed a troubling lack not only of basic medical ethics but also of the requisite understanding of genetics and gene editing. Here, we review the rationale and design of his e...
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Published on Mar 1, 2019
Yuyan Yang (Peking Union Medical College), Yue Huang (Peking Union Medical College)
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Published on Feb 1, 2019in Mammalian Genome 2.69
Andy Greenfield28
Estimated H-index: 28
Genome editing is revolutionising our ability to modify genomes with exquisite precision for medical and agricultural applications, and in basic research. The first International Summit on Human Genome Editing, organised jointly by the US National Academies of Sciences and Medicine, the Chinese Academy of Sciences and the UK Royal Society, was held in Washington DC at the end of 2015. Its aim was to explore scientific, legal and ethical perspectives on the prospective use of human genome editing...
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Published on Feb 1, 2019in Nature Methods 26.92
Vivien Marx16
Estimated H-index: 16
Editing the genome of human embryos is ethically fraught. But some projects show how diligent, ethical work can grow the gene-editing field.
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Published on Jan 2, 2019in Human Genetics 3.93
Cheryl Y. Gregory-Evans24
Estimated H-index: 24
(University of British Columbia),
Xia Wang6
Estimated H-index: 6
(University of British Columbia),
Kevin Gregory-Evans25
Estimated H-index: 25
(University of British Columbia)
Over the last three decades, genetic studies have made great strides toward the identification of genes and genetic mechanisms underlying congenital disorders of the eye. However, despite the vast knowledge available this has not translated into treatments to prevent or repair the damage in the clinical setting. Recently, new research in technologies, such as tissue regeneration, next generation designer drugs, and genome editing, have become available for some genetic disorders that might be ap...
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Published on Dec 1, 2018in Synthetic and Systems Biotechnology
Huayi Liu1
Estimated H-index: 1
(Sichuan University),
Lian Wang1
Estimated H-index: 1
(Sichuan University),
Yunzi Luo12
Estimated H-index: 12
(Sichuan University)
Abstract Since 2013, the CRISPR-based bacterial antiviral defense systems have revolutionized the genome editing field. In addition to genome editing, CRISPR has been developed as a variety of tools for gene expression regulations, live cell chromatin imaging, base editing, epigenome editing, and nucleic acid detection. Moreover, in the context of further boosting the usability and feasibility of CRISPR systems, novel CRISPR systems and engineered CRISPR protein mutants have been explored and st...
1 Citations Source Cite