scholarly journals Beyond Mendelian Inheritance: Genetic Buffering and Phenotype Variability

Phenomics ◽  
2021 ◽  
Author(s):  
Andrea Rossi ◽  
Zacharias Kontarakis

AbstractUnderstanding the way genes work amongst individuals and across generations to shape form and function is a common theme for many genetic studies. The recent advances in genetics, genome engineering and DNA sequencing reinforced the notion that genes are not the only players that determine a phenotype. Due to physiological or pathological fluctuations in gene expression, even genetically identical cells can behave and manifest different phenotypes under the same conditions. Here, we discuss mechanisms that can influence or even disrupt the axis between genotype and phenotype; the role of modifier genes, the general concept of genetic redundancy, genetic compensation, the recently described transcriptional adaptation, environmental stressors, and phenotypic plasticity. We furthermore highlight the usage of induced pluripotent stem cells (iPSCs), the generation of isogenic lines through genome engineering, and sequencing technologies can help extract new genetic and epigenetic mechanisms from what is hitherto considered ‘noise’.

2020 ◽  
Vol 60 (1) ◽  
pp. 529-551 ◽  
Author(s):  
Tessa de Korte ◽  
Puspita A. Katili ◽  
Nurul A.N. Mohd Yusof ◽  
Berend J. van Meer ◽  
Umber Saleem ◽  
...  

In recent decades, drug development costs have increased by approximately a hundredfold, and yet about 1 in 7 licensed drugs are withdrawn from the market, often due to cardiotoxicity. This review considers whether technologies using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) could complement existing assays to improve discovery and safety while reducing socioeconomic costs and assisting with regulatory guidelines on cardiac safety assessments. We draw on lessons from our own work to suggest a panel of 12 drugs that will be useful in testing the suitability of hiPSC-CM platforms to evaluate contractility. We review issues, including maturity versus complexity, consistency, quality, and cost, while considering a potential need to incorporate auxiliary approaches to compensate for limitations in hiPSC-CM technology. We give examples on how coupling hiPSC-CM technologies with Cas9/CRISPR genome engineering is starting to be used to personalize diagnosis, stratify risk, provide mechanistic insights, and identify new pathogenic variants for cardiovascular disease.


2013 ◽  
Vol 2 (1) ◽  
pp. 2:5 ◽  
Author(s):  
Renli Ru ◽  
Yongchao Yao ◽  
Songlin Yu ◽  
Benpeng Yin ◽  
Wanwan Xu ◽  
...  

2019 ◽  
Vol 11 (489) ◽  
pp. eaax1731
Author(s):  
Giuseppe Ronzitti

Up-regulation of paralogous transcripts is a potential mechanism of genetic compensation.


2019 ◽  
Vol 25 (1) ◽  
pp. 1-3 ◽  
Author(s):  
Norman Packard ◽  
Mark A. Bedau ◽  
Alastair Channon ◽  
Takashi Ikegami ◽  
Steen Rasmussen ◽  
...  

Nature's spectacular inventiveness, reflected in the enormous diversity of form and function displayed by the biosphere, is a feature of life that distinguishes living most strongly from nonliving. It is, therefore, not surprising that this aspect of life should become a central focus of artificial life. We have known since Darwin that the diversity is produced dynamically, through the process of evolution; this has led life's creative productivity to be called Open-Ended Evolution (OEE) in the field. This article introduces the first of two special issues on current research on OEE and on the more general concept of open-endedness. Most of the papers presented in these special issues are elaborations of work presented at the Third Workshop on Open-Ended Evolution, held in Tokyo as part of the 2018 Conference on Artificial Life.


2015 ◽  
Vol 33 (3) ◽  
pp. 408-414 ◽  
Author(s):  
Anya Mezina ◽  
Saul J. Karpen

To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease presents as an aggressive form of neonatal cholestasis characterized by the destruction and obliteration of the extrahepatic bile ducts within the first few weeks of life and a rapid progression of biliary fibrosis, likely due to unremitting cholestasis and retention of biliary constituents including bile acids. In ∼5% of patients, biliary atresia is associated with laterality features, suggesting a genetic underpinning to a disease that begins soon after birth. However, biliary atresia does not occur within families and twins are discordant, indicating an absence of strict mendelian inheritance. Despite this, genes related to bile duct dysmorphogenesis/ciliopathies overlapping with features of biliary atresia in both humans and nonhuman model systems have been proposed. Taken together, strict genetic etiologies leading to a common pathway of a neonatal cholangiopathy resulting in biliary atresia remain elusive. Contributions from fibrogenesis- and inflammation-based studies suggest that early engagement of these pathways contributes to disease progression, but a recent double-blind study did not suggest any benefit from early use of corticosteroids. However, there are genetic contributions to the adaptation and response to cholangiopathies and cholestasis that may be present in certain populations that likely impact upon the response to hepatoportoenterostomy and subsequent biliary tract function. Studies utilizing next generation sequencing technologies (e.g., exome analysis) are ongoing in several laboratories around the world; they are expected to provide insights into genetic contributions to biliary atresia outcomes. Altogether, combinations of exome sequencing and large population studies are expected to reveal causative and modifying genes relevant to patients with biliary atresia as a means to provide therapeutic targets and potential opportunities for genetic screening.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elena Navarro-Guerrero ◽  
Chwen Tay ◽  
Justin P. Whalley ◽  
Sally A. Cowley ◽  
Ben Davies ◽  
...  

AbstractGenome engineering using CRISPR/Cas9 technology enables simple, efficient and precise genomic modifications in human cells. Conventional immortalized cell lines can be easily edited or screened using genome-wide libraries with lentiviral transduction. However, cell types derived from the differentiation of induced Pluripotent Stem Cells (iPSC), which often represent more relevant, patient-derived models for human pathology, are much more difficult to engineer as CRISPR/Cas9 delivery to these differentiated cells can be inefficient and toxic. Here, we present an efficient, lentiviral transduction protocol for delivery of CRISPR/Cas9 to macrophages derived from human iPSC with efficiencies close to 100%. We demonstrate CRISPR/Cas9 knockouts for three nonessential proof-of-concept genes—HPRT1, PPIB and CDK4. We then scale the protocol and validate for a genome-wide pooled CRISPR/Cas9 loss-of-function screen. This methodology enables, for the first time, systematic exploration of macrophage involvement in immune responses, chronic inflammation, neurodegenerative diseases and cancer progression, using efficient genome editing techniques.


2020 ◽  
Vol 21 (17) ◽  
pp. 6442 ◽  
Author(s):  
Akari Takai ◽  
Masamitsu Yamaguchi ◽  
Hideki Yoshida ◽  
Tomohiro Chiyonobu

Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of developmental regression or plateauing. Early infantile epileptic encephalopathy (EIEE) is one of the earliest forms of DEE, manifesting as frequent epileptic spasms and characteristic electroencephalogram findings in early infancy. In recent years, next-generation sequencing approaches have identified a number of monogenic determinants underlying DEE. In the case of EIEE, 85 genes have been registered in Online Mendelian Inheritance in Man as causative genes. Model organisms are indispensable tools for understanding the in vivo roles of the newly identified causative genes. In this review, we first present an overview of epilepsy and its genetic etiology, especially focusing on EIEE and then briefly summarize epilepsy research using animal and patient-derived induced pluripotent stem cell (iPSC) models. The Drosophila model, which is characterized by easy gene manipulation, a short generation time, low cost and fewer ethical restrictions when designing experiments, is optimal for understanding the genetics of DEE. We therefore highlight studies with Drosophila models for EIEE and discuss the future development of their practical use.


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