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Many of the great advances in genetics were made using species that are not especially important from a medical, economic, or even ecological perspective. Today, a small number of species are widely used as model organisms in genetics (Fig 1.17). chromosomes are present in pairs).
The most commonly used model organism are:
- The prokaryote bacterium, Escherichia coli, is the simplest genetic model organism and is often used to clone DNA sequences from other model species.
- Yeast (Saccharomyces cerevisiae) is a good general model for the basic functions of eukaryotic cells.
- The roundworm, Caenorhabditis elegans is a useful model for the development of multicellular organisms, in part because it is transparent throughout its life cycle, and its cells undergo a well-characterized series of divisions to produce the adult body.
- The fruit fly (Drosophila melanogaster) has been studied longer, and probably in more detail, than any of the other genetic model organisms still in use, and is a useful model for studying development as well as physiology and even behavior.
- The mouse (Mus musculus) is the model organism most closely related to humans, however there are some practical difficulties working with mice, such as cost, slow reproductive time, and ethical considerations.
- The zebrafish (Danio rerio) has more recently been developed by researchers as a genetic model for vertebrates.Unlike mice, zebrafish embryos develop quickly and externally to their mothers, and are transparent, making it easier to study the development of internal structures and organs.
- Finally, a small weed, Arabidopsis thaliana, is the most widely studied plant genetic model organism. This provides knowledge that can be applied to other plant species, such as wheat, rice, and corn.
1.7: Model Organisms Facilitate Genetic Advances - Biology
Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and high-precision CRISPR generated genetic editing. We will discuss how to harness these resources to understand the pathophysiological drivers of NeuP, define its relationship with comorbidities such as anxiety, depression, and sleep disorders, and explore how to apply these findings to the prediction, diagnosis, and treatment of NeuP in the clinic.
Present address: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research
Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.
Keywords: Drosophila diagnostics functional genomics genetic diseases human whole-exome sequencing zebrafish.
Copyright © 2017 by the Genetics Society of America.
Collaborations among clinicians, human geneticists…
Collaborations among clinicians, human geneticists and model organism researchers facilitate diagnosis and studies…
The workflow of the UDN and MOSC. Patients with undiagnosed conditions apply to…
Strategy to “humanize” a Drosophila…
Strategy to “humanize” a Drosophila gene to assess functional consequences of a novel…
The workflow of the Canadian…
The workflow of the Canadian RDMM Network. RDMM connects Canada’s disease gene discovery…
Model Organism Studies Can Facilitate Diagnosis and Treatment
Drosophila, TRP channels and a spectrum of Mendelian disorders
One of the earliest examples of a Drosophila mutant that informed studies of an extensive gene family implicated in numerous human disorders comes from the fly transient receptor potential (trp) gene. Studies in the 1960s identified a nonphototaxic fly mutant with a distinct electroretinogram phenotype (Cosens and Manning 1969). Subsequent studies revealed that the affected gene encodes a pore-forming cation channel that is the founding member of a large, diverse family of evolutionarily conserved proteins known as TRP channels (Montell 2005). TRP channel family members have a weak voltage-sensing transmembrane domain, a selectivity filter, and diverse N- and C-terminal domains that provide versatile activation mechanisms. TRP family members encode unique channels that respond to light, sound, chemicals, temperature, pressure, or tactile stimuli, and can integrate multiple signals. The human genome contains 28 TRP channel family members (Gray et al. 2015), 11 of which are implicated in Mendelian disorders. These disorders have diverse clinical presentations, different inheritance patterns, and affect distinct tissues (Table 1). Insights from Drosophila led to an understanding of TRP channel function, which laid the groundwork for defining the cause of these disorders as resulting from gain-of-function (GOF), loss-of-function (LOF) or modulation (alteration)-of-function mechanisms. The most extreme disease is caused by TRPV4 (Dai et al. 2010)—a gene that underlies a broad spectrum of skeletal and nervous system phenotypes. An autosomal dominant condition brachyolmias type 3 (MIM# 113500), which is characterized by short trunk, short stature, and scoliosis, as well as a series of more severe skeletal dysplasias, is due to GOF missense mutations in TRPV4 that causes the channels to be activated by stimuli to which they would not normally respond (Nishimura et al. 2012). Other variants in TRPV4 cause congenital distal spinal muscular atrophy (MIM# 600175) and Charcot-Marie-Tooth disease type 2C (MIM# 606071) (Deng et al. 2010 Landoure et al. 2010 Nilius and Owsianik 2010). Heterozygous mutations leading to these neurological phenotypes appear to have a complex impact on channel function and appear as GOF or LOF in different assays (Auer-Grumbach et al. 2010 Deng et al. 2010 Landoure et al. 2010). These functional insights would likely be identified more slowly without the mechanistic understanding of the channels provided by studies in Drosophila.
Zebrafish and melanoma
Research on zebrafish complements research on flies because zebrafish share vertebrate-specific features with human, such as similar organ structures. Zebrafish offer a number of experimental advantages for investigation of human disease mechanisms and therapeutic strategies (Phillips and Westerfield 2014). Chief among these are the ease of genetic manipulation, the ability to replace zebrafish genes with human genes, sensitive phenotypic analyses, and the capacity to conduct high-throughput screens of small molecules for potential therapeutics.
Examples discussed here involve human melanomas, which are genetically diverse cancers. This genetic heterogeneity makes it difficult to discover which gene mutations are primary drivers of oncogenesis, and which are critical modifiers that promote metastatic disease. A valine-to-glutamic acid mutation at position 600 in the human BRAF gene is the most frequent mutation driving human melanomas, but mutations in other genes are required for metastasis (Pollock et al. 2003). In searches for “second hit” loci in BRAF V600E melanomas, a region of chromosome 1q21 was identified as a key driver of metastasis, but the presence of >50 genes in the identified interval made it difficult to determine the primary driver (Lin et al. 2008). Testing genes in the corresponding zebrafish chromosomal interval revealed a single gene, SET domain, bifurcated 1 (SETDB1) that cooperates with BRAF V600E to drive melanoma formation and growth (Ceol et al. 2011). The 1q21 interval was subsequently linked to familial melanoma in human (Macgregor et al. 2011), establishing SETDB1 as a major human melanoma oncogene. A high-throughput chemical screen of these zebrafish with ∼2000 substances identified inhibitors of dihydroorotate dehydrogenase (DHODH), such as the anti-inflammatory drug leflunomide, as suppressors of neural crest development and melanoma formation (White et al. 2011). This work in zebrafish led to Phase I/II clinical trials of leflunomide in combination with a previously studied BRAF-inhibitor for treatment of melanoma. The ability to create sensitized zebrafish lines with human genes, coupled with the ability to screen thousands of compounds for their capacity to rescue disease phenotypes, illustrates the power of zebrafish studies for illuminating human disease pathogenesis and revealing novel drug targets.
[The mouse model and human disease]
The mouse is an ideal model organism for studies of human disease, because mouse is physiologically very similar to human. Also, there is a large genetic reservoir of potential models of human diseases that has been generated. In addition, high-resolution genetic and physical linkage maps are now available and the sequence of mouse genome will be completed in the near future. Furthermore, the techniques necessary for the modification of mouse genome, such as transgenic and knockout techniques, and chromosome engineering methods have been established. These techniques enable us to introduce any mutations anywhere in the mouse genome. The methods for analyzing complex genetic diseases also have been developed. These advances facilitate the identification and cloning of mouse disease loci and the establishment of new models. It makes mouse the model organism of choice by academic and industrial researchers to study human diseases. In Part I of this review, we summarize the classical and modern approaches that provide the basis of establishing mouse model of human diseases. In the following parts, we will list more than 100 mouse models of human diseases. In most of these models, the mouse mutant phenotype closely resembles the human disease phenotype. These mouse models are valuable sources for the understanding of the human diseases and they can be used to develop strategies for prevention and treatment of the diseases.
1.7: Model Organisms Facilitate Genetic Advances - Biology
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Zebrafish as a Model Organism for the Development of Drugs for Skin Cancer
Skin cancer, which includes melanoma and squamous cell carcinoma, represents the most common type of cutaneous malignancy worldwide, and its incidence is expected to rise in the near future. This condition derives from acquired genetic dysregulation of signaling pathways involved in the proliferation and apoptosis of skin cells. The development of animal models has allowed a better understanding of these pathomechanisms, with the possibility of carrying out toxicological screening and drug development. In particular, the zebrafish (Danio rerio) has been established as one of the most important model organisms for cancer research. This model is particularly suitable for live cell imaging and high-throughput drug screening in a large-scale fashion. Thanks to the recent advances in genome editing, such as the clustered regularly-interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) methodologies, the mechanisms associated with cancer development and progression, as well as drug resistance can be investigated and comprehended. With these unique tools, the zebrafish represents a powerful platform for skin cancer research in the development of target therapies. Here, we will review the advantages of using the zebrafish model for drug discovery and toxicological and phenotypical screening. We will focus in detail on the most recent progress in the field of zebrafish model generation for the study of melanoma and squamous cell carcinoma (SCC), including cancer cell injection and transgenic animal development. Moreover, we will report the latest compounds and small molecules under investigation in melanoma zebrafish models.
Keywords: drug development inhibitor screening melanoma skin cancer squamous cell carcinoma transgenic zebrafish.
Conflict of interest statement
The authors declare no conflict of interest.
Zebrafish as a relevant model…
Zebrafish as a relevant model for human disease and cancer therapy. The zebrafish…
Zebrafish model for high-throughput drug…
Zebrafish model for high-throughput drug screening. Zebrafish is a valuable tool for high-throughput…
The tumor suppressor hexamethylene bisacetamide…
The tumor suppressor hexamethylene bisacetamide inducible 1 ( HEXIM1) gene inhibits melanoma in…
Drug development and inhibitor screening…
Drug development and inhibitor screening using selected MEKi and PI3K/mTOR inhibitors. Zebrafish plays…
Recent advances in systems and synthetic biology approaches for developing novel cell-factories in non-conventional yeasts
Microbial bioproduction of chemicals, proteins, and primary metabolites from cheap carbon sources is currently an advancing area in industrial research. The model yeast, Saccharomyces cerevisiae, is a well-established biorefinery host that has been used extensively for commercial manufacturing of bioethanol from myriad carbon sources. However, its Crabtree-positive nature often limits the use of this organism for the biosynthesis of commercial molecules that do not belong in the fermentative pathway. To avoid extensive strain engineering of S. cerevisiae for the production of metabolites other than ethanol, non-conventional yeasts can be selected as hosts based on their natural capacity to produce desired commodity chemicals. Non-conventional yeasts like Kluyveromyces marxianus, K. lactis, Yarrowia lipolytica, Pichia pastoris, Scheffersomyces stipitis, Hansenula polymorpha, and Rhodotorula toruloides have been considered as potential industrial eukaryotic hosts owing to their desirable phenotypes such as thermotolerance, assimilation of a wide range of carbon sources, as well as ability to secrete high titers of protein and lipid. However, the advanced metabolic engineering efforts in these organisms are still lacking due to the limited availability of systems and synthetic biology methods like in silico models, well-characterised genetic parts, and optimized genome engineering tools. This review provides an insight into the recent advances and challenges of systems and synthetic biology as well as metabolic engineering endeavours towards the commercial usage of non-conventional yeasts. Particularly, the approaches in emerging non-conventional yeasts for the production of enzymes, therapeutic proteins, lipids, and metabolites for commercial applications are extensively discussed here. Various attempts to address current limitations in designing novel cell factories have been highlighted that include the advances in the fields of genome-scale metabolic model reconstruction, flux balance analysis, 'omics'-data integration into models, genome-editing toolkit development, and rewiring of cellular metabolisms for desired chemical production. Additionally, the understanding of metabolic networks using 13 C-labelling experiments as well as the utilization of metabolomics in deciphering intracellular fluxes and reactions have also been discussed here. Application of cutting-edge nuclease-based genome editing platforms like CRISPR/Cas9, and its optimization towards efficient strain engineering in non-conventional yeasts have also been described. Additionally, the impact of the advances in promising non-conventional yeasts for efficient commercial molecule synthesis has been meticulously reviewed. In the future, a cohesive approach involving systems and synthetic biology will help in widening the horizon of the use of unexplored non-conventional yeast species towards industrial biotechnology.
Keywords: (13)C-metabolic flux analysis CRISPR/Cas9 Carbon rewiring Cre-loxP Flux balance analysis Genome-scale metabolic model Homologous recombination Metabolic engineering.
Advances in genetic engineering of the avian genome: “Realising the promise”
This review provides an historic perspective of the key steps from those reported at the 1st Transgenic Animal Research Conference in 1997 through to the very latest developments in avian transgenesis. Eighteen years later, on the occasion of the 10th conference in this series, we have seen breakthrough advances in the use of viral vectors and transposons to transform the germline via the direct manipulation of the chicken embryo, through to the establishment of PGC cultures allowing in vitro modification, expansion into populations to analyse the genetic modifications and then injection of these cells into embryos to create germline chimeras. We have now reached an unprecedented time in the history of chicken transgenic research where we have the technology to introduce precise, targeted modifications into the chicken genome, ranging from new transgenes that provide improved phenotypes such as increased resilience to economically important diseases the targeted disruption of immunoglobulin genes and replacement with human sequences to generate transgenic chickens that express “humanised” antibodies for biopharming and the deletion of specific nucleotides to generate targeted gene knockout chickens for functional genomics. The impact of these advances is set to be realised through applications in chickens, and other bird species as models in scientific research, for novel biotechnology and to protect and improve agricultural productivity.
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The mouse has been a powerful force in elucidating the genetic basis of human physiology and pathophysiology. From its beginnings as the model organism for cancer research and transplantation biology to the present, when dissection of the genetic basis of complex disease is at the forefront of genomics research, an enormous and remarkable mouse resource infrastructure has accumulated. This review summarizes those resources and provides practical guidelines for their use, particularly in the analysis of quantitative traits.
Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), formerly the Baylor Miraca Genetics Laboratories (BMGL), which performs clinical exome sequencing and chromosomal microarray analysis for genome-wide detection of CNV. J.R.L. serves on the Scientific Advisory Board of BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The other authors declare no conflicts of interest.