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Current Opinion in Genetics & Development

Ralf Jauch
Cellular reprogramming using cocktails of transcription factors (TFs) affirms the epigenetic and developmental plasticity of mammalian cells. It demonstrates the ability of TFs to 'read' genetic information and to rewire regulatory networks in different cellular contexts. Silenced chromatin is not an impediment to the genome engagement by ectopically expressed TFs. Reprogramming TFs have been identified in diverse structural families that lack shared domains or sequence motifs. Interestingly, the reprogramming activity of non-redundant paralogous TFs can be switched with a few point mutations...
July 3, 2018: Current Opinion in Genetics & Development
Joaquin Sanz, Haley E Randolph, Luis B Barreiro
Humans display remarkable immune response variation when exposed to identical immune challenges. However, our understanding of the genetic, evolutionary, and environmental factors that impact this inter-individual and inter-population immune response heterogeneity is still in its early days. In this review, we discuss three fundamental questions concerning the recent evolution of the human immune system: the degree to which individuals from different populations vary in their innate immune responses, the genetic variants accounting for such differences, and the evolutionary mechanisms that led to the establishment of these variants in modern human populations...
June 28, 2018: Current Opinion in Genetics & Development
Iosif Lazaridis
I review the evolutionary history of human populations in Europe with an emphasis on what has been learned in recent years through the study of ancient DNA. Human populations in Europe ∼430-39kya (archaic Europeans) included Neandertals and their ancestors, who were genetically differentiated from other archaic Eurasians (such as the Denisovans of Siberia), as well as modern humans. Modern humans arrived to Europe by ∼45kya, and are first genetically attested by ∼39kya when they were still mixing with Neandertals...
June 27, 2018: Current Opinion in Genetics & Development
Jakob J Metzger, Mijo Simunovic, Ali H Brivanlou
Differentiation of embryonic stem cells in vitro is an important tool in dissecting and understanding the mechanisms that govern early embryologic development. In recent years, there has been considerable progress in creating organoids that model gastrulation, neurulation or organogenesis. However, one of the key challenges is reproducibility. Geometrically confining stem cell colonies considerably improves reproducibility and provides quantitative control over differentiation and tissue shape. Here, we review recent advances in controlling the two-dimensional or three-dimensional organization of cells and the effect on differentiation phenotypes...
June 26, 2018: Current Opinion in Genetics & Development
Michael Hudecek, Zoltán Ivics
Widespread treatment of human diseases with gene therapies necessitates the development of gene transfer vectors that integrate genetic information effectively, safely and economically. Indeed, significant efforts have been devoted to engineer novel tools that (i) achieve high-level stable gene transfer at low toxicity to the host cell; (ii) induce low levels of genotoxicity and possess a `safe' integration profile with a high proportion of integrations into safe genomic locations; and (iii) are associated with acceptable cost per treatment, and scalable/exportable vector production to serve large numbers of patients...
June 22, 2018: Current Opinion in Genetics & Development
Timothy M Frayling, Charli E Stoneman
Type 2 diabetes, coronary artery disease and hypertension are associated with anthropometric and biomarker traits, including waist-to-hip-ratio, body mass index and altered glucose and insulin levels. Clinical trials, for example of weight-loss interventions, show these factors are causal, but lifelong impact of subtle changes in body mass index and body fat distribution are less clear. The use of human genetics can quantify the causal effects of long-term exposure to subtle changes of modifiable risk factors...
June 20, 2018: Current Opinion in Genetics & Development
Jacob Giehm Mikkelsen
Following the successful development of virus-based gene vehicles for genetic therapies, exploitation of viruses as carriers of genetic tools for cellular reprogramming and genome editing should be right up the street. However, whereas persistent, potentially life-long gene expression is the main goal of conventional genetic therapies, tools and bits for genome engineering should ideally be short-lived and active only for a limited time. Although viral vector systems have already been adapted for potent genome editing both in vitro and in vivo, regulatable gene expression systems or self-limiting expression circuits need to be implemented limiting exposure of chromatin to genome-modifying enzymes...
June 18, 2018: Current Opinion in Genetics & Development
Effie Apostolou, Matthias Stadtfeld
The discovery of induced pluripotent stem cells (iPSCs) has solidified the concept of transcription factors as major players in controlling cell identity and provided a tractable tool to study how somatic cell identity can be dismantled and pluripotency established. A number of landmark studies have established hallmarks and roadmaps of iPSC formation by describing relative kinetics of transcriptional, protein and epigenetic changes, including alterations in DNA methylation and histone modifications. Recently, technological advancements such as single-cell analyses, high-resolution genome-wide chromatin assays and more efficient reprogramming systems have been used to challenge and refine our understanding of the reprogramming process...
June 16, 2018: Current Opinion in Genetics & Development
Jing Guo, Jian Yang, Peter M Visscher
Natural selection can shape the genetic architecture of complex traits. In human populations, signals of positive selection at genetic loci have been detected through a variety of genome-wide scanning approaches without the knowledge of how genes affect traits or fitness. In the past decade, genome-wide association studies (GWAS) have provided unprecedented insights into the genetic basis of quantitative variation in complex traits. Summary statistics generated from these GWAS have been shown to be an extraordinary data source that can be utilized to detect and quantify natural selection in the genetic architecture of complex traits...
June 15, 2018: Current Opinion in Genetics & Development
Leslea J Hlusko
The past few years of genetic research on primate quantitative trait variation have been notable in the diversity of phenotypes explored, ranging from classic skeletal measurements to behavior, through to levels of gene expression, and with observations from both captive and wild populations. These studies demonstrate the importance of captive pedigreed breeding colonies, populations that can be matched to their wild counterparts to enable comparison of genetic architectures. Non-human primate genotype:phenotype maps are essential for placing human variation within an evolutionary framework as well as for gaining insight to human biology...
June 15, 2018: Current Opinion in Genetics & Development
Abhijit Shukla, Danwei Huangfu
Large portions of the human genome harbor functional noncoding elements, which can regulate a variety of biological processes and have important implications for disease risk and therapeutic outcomes. However, assigning specific functions to noncoding sequences remains a major challenge. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein (Cas) systems have emerged as a powerful approach for targeted genome and epigenome perturbation. CRISPR systems are now harnessed for high-throughput screening of the noncoding genome to uncover functional regulatory elements and to define their precise functions with superior speed...
June 15, 2018: Current Opinion in Genetics & Development
Jovica Ninkovic, Magdalena Götz
Cell replacement therapies aim at reestablishment of neuronal circuits after brain injury, stroke or neurodegeneration. Recently, direct reprogramming of resident glial cells into the affected neuronal subtypes has become a feasible and promising option for central nervous system regeneration. Direct reprogramming relies on the implementation of a new transcriptional program defining the desired neuronal identity in fully differentiated glial cells implying the more or less complete down-regulation of the program for the former identity of the glial cell...
June 14, 2018: Current Opinion in Genetics & Development
Kazuki Kurimoto, Mitinori Saitou
Germ cells undergo epigenome reprogramming for proper development of the next generation. The realization of germ cell derivation from human and mouse pluripotent stem cells offers unprecedented opportunity for investigation of germline development. Primordial germ cells reconstituted in vitro (PGC-like cells [PGCLCs]) show progressive dilution of genomic DNA methylation, tightly linked with chromatin remodeling, during their specification. PGCLCs can be further expanded by plane culture, allowing maintenance of the gene-expression profiles of early PGCs and continuance of the DNA methylation erasure, thereby establishing an epigenetic `blank slate'...
June 13, 2018: Current Opinion in Genetics & Development
Michael Dannemann, Fernando Racimo
The sequencing of ancient DNA from archaic humans-Neanderthals and Denisovans-has revealed that modern and archaic humans interbred at least twice during the Pleistocene. The field of human paleogenomics has now turned its attention towards understanding the nature of this genetic legacy in the gene pool of present-day humans. What exactly did modern humans obtain from interbreeding with Neanderthals and Denisovans? Was the introgressed genetic material beneficial, neutral or maladaptive? Can differences in phenotypes among present-day human populations be explained by archaic human introgression? These questions are of prime importance for our understanding of recent human evolution, but will require careful computational modeling and extensive functional assays before they can be answered in full...
June 9, 2018: Current Opinion in Genetics & Development
Natsuko Rivera-Yoshida, Juan A Arias Del Angel, Mariana Benítez
Multicellular development occurs in diverse microbial lineages and involves the complex interaction among biochemical, physical and ecological factors. We focus on the mechanical forces that appear to be relevant for the scale and material qualities of individual cells and small cellular conglomerates. We review the effects of such forces on the development of some paradigmatic microorganisms, as well as their overall consequences in multicellular structures. Microbes exhibiting multicellular development have been considered models for the evolutionary transition to multicellularity...
June 6, 2018: Current Opinion in Genetics & Development
Makoto Takeo, Takashi Tsuji
In this decade, great progress has been made in the field of organ regeneration by incorporating emerging concepts from the fields of stem cell biology and developmental biology, and this progress has pioneered a new frontier in regenerative medicine. The generation of bioengineered organ germ-utilizing, fate-determined, organ-inductive epithelial and mesenchymal cells has provided evidence for the concept of functional organ regeneration in vivo. Organoid studies have verified that nearly all organs can be generated in the form of a mini-organ by recapitulating embryonic body patterning and establishing an organ-forming field among self-organizing pluripotent stem cells by utilizing cytokines that mimic the patterning and positional signals of organogenesis...
June 5, 2018: Current Opinion in Genetics & Development
Fyodor D Urnov
Genome editing with engineered nucleases (zinc finger, TAL effector, or CRISPR/Cas9-based) enables `write' access to regulatory programs executed by primary human cells. A decade of its clinical development, along with a reduction of conventional gene therapy to medical and commercial practice, has made cell reprogramming via editing a viable clinical modality. Reviewed here are the first examples of this to enter the clinic: ex vivo edited T cells for infectious disease and cancer, and hematopoietic stem/progenitor cells for the hemoglobinopathies...
June 4, 2018: Current Opinion in Genetics & Development
Fabian Suchy, Hiromitsu Nakauchi
By probing early embryogenesis and regeneration, interspecies chimeras provide a unique platform for discovery and clinical use. Although efficient generation of human:animal chimeric embryos remains elusive, recent advancements attempt to overcome incompatibilities in xenogeneic development and transplantation.
May 30, 2018: Current Opinion in Genetics & Development
Xiang Li, Jun Xu, Hongkui Deng
Cellular fate reprogramming holds great promise to generate functional cell types for replenishing new cells and restoring functional loss. Inspired by transcription factor-induced reprogramming, the field of cellular reprogramming has greatly advanced and developed into divergent streams of reprogramming approaches. Remarkably, increasing studies have shown the power and advantages of small molecule-based approaches for cellular fate reprogramming, which could overcome the limitations of conventional transgenic-based reprogramming...
May 29, 2018: Current Opinion in Genetics & Development
Fabio Marsoner, Philipp Koch, Julia Ladewig
The development of organoids derived from human pluripotent stem cells heralded a new area in studying human organ development and pathology outside of the human body. Triggered by the seminal work of pioneers in the field such as Yoshiki Sasai or Hans Clevers, organoid research has become one of the most rapidly developing fields in cell biology. The potential applications are manifold reaching from developmental studies to tissue regeneration and drug screening. In this review, we will concentrate on brain organoids of cortical identity...
May 25, 2018: Current Opinion in Genetics & Development
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