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Using genetically engineered animal models in the postgenomic era to understand gene function in alcoholism.

Reilly MT, Harris RA, Noronha A - Alcohol Res (2012)

Bottom Line: Even newer genetic-engineering technologies have given researchers the ability to control when and where a specific gene or mutation is activated or deleted, allowing investigators to narrow the role of the gene's function to circumscribed neural pathways and across development.These technologies are important for all areas of neuroscience, and several public and private initiatives are making a new generation of genetic-engineering tools available to the scientific community at large.Finally, high-throughput "next-generation sequencing" technologies are set to rapidly increase knowledge of the genome, epigenome, and transcriptome, which, combined with genetically engineered mouse mutants, will enhance insight into biological function.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.

ABSTRACT
Over the last 50 years, researchers have made substantial progress in identifying genetic variations that underlie the complex phenotype of alcoholism. Not much is known, however, about how this genetic variation translates into altered biological function. Genetic animal models recapitulating specific characteristics of the human condition have helped elucidate gene function and the genetic basis of disease. In particular, major advances have come from the ability to manipulate genes through a variety of genetic technologies that provide an unprecedented capacity to determine gene function in the living organism and in alcohol-related behaviors. Even newer genetic-engineering technologies have given researchers the ability to control when and where a specific gene or mutation is activated or deleted, allowing investigators to narrow the role of the gene's function to circumscribed neural pathways and across development. These technologies are important for all areas of neuroscience, and several public and private initiatives are making a new generation of genetic-engineering tools available to the scientific community at large. Finally, high-throughput "next-generation sequencing" technologies are set to rapidly increase knowledge of the genome, epigenome, and transcriptome, which, combined with genetically engineered mouse mutants, will enhance insight into biological function. All of these resources will provide deeper insight into the genetic basis of alcoholism.

No MeSH data available.


Related in: MedlinePlus

Exploring the relationship between genotype and phenotype by using high-throughput sequencing and genetically engineered animal models. Novel high-throughput “next-generation sequencing” technology can be used together with new genetic engineering technology to understand gene function in alcoholism. Compared with traditional sequencing, “next-generation sequencing” allows researchers to efficiently and cost-effectively obtain large amounts of genomic data (e.g., from large cohorts of humans with and without disease) to detect all the genomic, epigenomic, and transcriptomic variation associated with the disease, creating comprehensive “disease maps.” In a next step, functional information can be attached to these disease maps that defines how the various components of the map (i.e., individual genes) act and interact, for example, using genetically engineered animal models. Genomic variations associated with human diseases can be engineered into rodent models (or other experimental organisms) and detailed phenotypic analyses can be performed, further refining disease maps with functional annotation.
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f1-arcr-34-3-282: Exploring the relationship between genotype and phenotype by using high-throughput sequencing and genetically engineered animal models. Novel high-throughput “next-generation sequencing” technology can be used together with new genetic engineering technology to understand gene function in alcoholism. Compared with traditional sequencing, “next-generation sequencing” allows researchers to efficiently and cost-effectively obtain large amounts of genomic data (e.g., from large cohorts of humans with and without disease) to detect all the genomic, epigenomic, and transcriptomic variation associated with the disease, creating comprehensive “disease maps.” In a next step, functional information can be attached to these disease maps that defines how the various components of the map (i.e., individual genes) act and interact, for example, using genetically engineered animal models. Genomic variations associated with human diseases can be engineered into rodent models (or other experimental organisms) and detailed phenotypic analyses can be performed, further refining disease maps with functional annotation.

Mentions: Another exciting possibility is the use of new animal genetic-engineering techniques to reproduce specific genetic changes seen in human alcoholics. For example, as described above, detailed genetic sequencing of both DNA and RNA (i.e., the genome and transcriptome) from many humans now is feasible, owing to the rapidly decreasing cost of next-generation DNA sequencing. This will lead to the discovery of changes in gene sequence or gene expression that are candidates for differences in the development of alcohol dependence. These same genomic changes then can be introduced into mice or other animal models by knockin, transgenic, or other approaches (see figure). This approach already has shown promise in the alcohol field. For example, one of several variants (i.e., polymorphism) of the gene encoding the μ-opioid receptor is associated with enhanced subjective responses to alcohol in humans and differentially affects treatment response to naltrexone (Ray and Hutchinson 2007). To directly deter-subjective responses to alcohol in humans and differentially affects treatment response to naltrexone (Ray and Hutchinson 2007). To directly determine the functional consequences of this polymorphism, a knockin mouse was generated that harbors the human allele. The results indicate that the knockin mouse shows a greater brain dopamine response after alcohol challenge, possibly providing a mechanism by which the human variant of the μ-opioid receptor affects drinking (Ramchandani et al. 2010). Additional characterization of this “humanized” mouse model surely will provide important information about the functional consequences of this polymorphism on alcohol behaviors.


Using genetically engineered animal models in the postgenomic era to understand gene function in alcoholism.

Reilly MT, Harris RA, Noronha A - Alcohol Res (2012)

Exploring the relationship between genotype and phenotype by using high-throughput sequencing and genetically engineered animal models. Novel high-throughput “next-generation sequencing” technology can be used together with new genetic engineering technology to understand gene function in alcoholism. Compared with traditional sequencing, “next-generation sequencing” allows researchers to efficiently and cost-effectively obtain large amounts of genomic data (e.g., from large cohorts of humans with and without disease) to detect all the genomic, epigenomic, and transcriptomic variation associated with the disease, creating comprehensive “disease maps.” In a next step, functional information can be attached to these disease maps that defines how the various components of the map (i.e., individual genes) act and interact, for example, using genetically engineered animal models. Genomic variations associated with human diseases can be engineered into rodent models (or other experimental organisms) and detailed phenotypic analyses can be performed, further refining disease maps with functional annotation.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860404&req=5

f1-arcr-34-3-282: Exploring the relationship between genotype and phenotype by using high-throughput sequencing and genetically engineered animal models. Novel high-throughput “next-generation sequencing” technology can be used together with new genetic engineering technology to understand gene function in alcoholism. Compared with traditional sequencing, “next-generation sequencing” allows researchers to efficiently and cost-effectively obtain large amounts of genomic data (e.g., from large cohorts of humans with and without disease) to detect all the genomic, epigenomic, and transcriptomic variation associated with the disease, creating comprehensive “disease maps.” In a next step, functional information can be attached to these disease maps that defines how the various components of the map (i.e., individual genes) act and interact, for example, using genetically engineered animal models. Genomic variations associated with human diseases can be engineered into rodent models (or other experimental organisms) and detailed phenotypic analyses can be performed, further refining disease maps with functional annotation.
Mentions: Another exciting possibility is the use of new animal genetic-engineering techniques to reproduce specific genetic changes seen in human alcoholics. For example, as described above, detailed genetic sequencing of both DNA and RNA (i.e., the genome and transcriptome) from many humans now is feasible, owing to the rapidly decreasing cost of next-generation DNA sequencing. This will lead to the discovery of changes in gene sequence or gene expression that are candidates for differences in the development of alcohol dependence. These same genomic changes then can be introduced into mice or other animal models by knockin, transgenic, or other approaches (see figure). This approach already has shown promise in the alcohol field. For example, one of several variants (i.e., polymorphism) of the gene encoding the μ-opioid receptor is associated with enhanced subjective responses to alcohol in humans and differentially affects treatment response to naltrexone (Ray and Hutchinson 2007). To directly deter-subjective responses to alcohol in humans and differentially affects treatment response to naltrexone (Ray and Hutchinson 2007). To directly determine the functional consequences of this polymorphism, a knockin mouse was generated that harbors the human allele. The results indicate that the knockin mouse shows a greater brain dopamine response after alcohol challenge, possibly providing a mechanism by which the human variant of the μ-opioid receptor affects drinking (Ramchandani et al. 2010). Additional characterization of this “humanized” mouse model surely will provide important information about the functional consequences of this polymorphism on alcohol behaviors.

Bottom Line: Even newer genetic-engineering technologies have given researchers the ability to control when and where a specific gene or mutation is activated or deleted, allowing investigators to narrow the role of the gene's function to circumscribed neural pathways and across development.These technologies are important for all areas of neuroscience, and several public and private initiatives are making a new generation of genetic-engineering tools available to the scientific community at large.Finally, high-throughput "next-generation sequencing" technologies are set to rapidly increase knowledge of the genome, epigenome, and transcriptome, which, combined with genetically engineered mouse mutants, will enhance insight into biological function.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.

ABSTRACT
Over the last 50 years, researchers have made substantial progress in identifying genetic variations that underlie the complex phenotype of alcoholism. Not much is known, however, about how this genetic variation translates into altered biological function. Genetic animal models recapitulating specific characteristics of the human condition have helped elucidate gene function and the genetic basis of disease. In particular, major advances have come from the ability to manipulate genes through a variety of genetic technologies that provide an unprecedented capacity to determine gene function in the living organism and in alcohol-related behaviors. Even newer genetic-engineering technologies have given researchers the ability to control when and where a specific gene or mutation is activated or deleted, allowing investigators to narrow the role of the gene's function to circumscribed neural pathways and across development. These technologies are important for all areas of neuroscience, and several public and private initiatives are making a new generation of genetic-engineering tools available to the scientific community at large. Finally, high-throughput "next-generation sequencing" technologies are set to rapidly increase knowledge of the genome, epigenome, and transcriptome, which, combined with genetically engineered mouse mutants, will enhance insight into biological function. All of these resources will provide deeper insight into the genetic basis of alcoholism.

No MeSH data available.


Related in: MedlinePlus