Zebrafish: a model for the study of addiction genetics

Drug abuse and dependence are multifaceted disorders with complex genetic underpinnings. Identifying specific genetic correlates is challenging and may be more readily accomplished by defining endophenotypes specific for addictive disorders. Symptoms and syndromes, including acute drug response, consumption, preference, and withdrawal, are potential endophenotypes characterizing addiction that have been investigated using model organisms. We present a review of major genes involved in serotonergic, dopaminergic, GABAergic, and adrenoreceptor signaling that are considered to be directly involved in nicotine, opioid, cannabinoid, and ethanol use and dependence. The zebrafish genome encodes likely homologs of the vast majority of these loci. We also review the known expression patterns of these genes in zebrafish. The information presented in this review provides support for the use of zebrafish as a viable model for studying genetic factors related to drug addiction. Expansion of investigations into drug response using model organisms holds the potential to advance our understanding of drug response and addiction in humans.     

Utility of genetically modified mice for understanding the neurobiology of substance use disorders

Advances in our ability to modify the mouse genome have enhanced our understanding of the genetic and neurobiological mechanisms contributing to addiction-related behaviors underlying substance use and abuse. These experimentally induced manipulations permit greater spatial and temporal specificity for modification of gene expression within specific cellular populations and during select developmental time periods. In this review, we consider the current mouse genetic model systems that have been employed to understand aspects of addiction and highlight significant conceptual advances achieved related to substance use and abuse. The mouse models reviewed herein include conventional knock-out and knock-in, conditional knockout, transgenic, inducible transgenic, mice suitable for optogenetic control of discrete neuronal populations, and phenotype-selected mice. By establishing a reciprocal investigatory relationship between genetic findings in humans and genomic manipulations in mice, a far better understanding of the discrete neuromechanisms underlying addiction can be achieved, which is likely to provide a strong foundation for developing and validating novel therapeutics for the treatment of substance abuse disorders.     

The genetics of mammalian circadian order and disorder: implications for physiology and disease

Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.     

From phenologs to silent suppressors: Identifying potential therapeutic targets for human disease

Orthologous phenotypes, or phenologs, are seemingly unrelated phenotypes generated by mutations in a conserved set of genes. Phenologs have been widely observed and accepted by those who study model organisms, and allow one to study a set of genes in a model organism to learn more about the function of those genes in other organisms, including humans. At the cellular and molecular level, these conserved genes likely function in a very similar mode, but are doing so in different tissues or cell types and can result in different phenotypic effects. For example, the RAS‐RAF‐MEK‐MAPK pathway in animals is a highly conserved signaling pathway that animals adopted for numerous biological processes, such as vulval induction in Caenorhabditis elegans and cell proliferation in mammalian cells; but this same gene set has been co‐opted to function in a variety of cellular contexts. In this review, I give a few examples of how suppressor screens in model organisms (with a emphasis on C. elegans) can identify new genes that function in a conserved pathway in many other organisms. I also demonstrate how the identification of such genes can lead to important insights into mammalian biology. From such screens, an occasional silent suppressor that does not cause a phenotype on its own is found; such suppressors thus make for good candidates as therapeutic targets.     

Genetics of sleep and sleep disorders

Sleep remains one of the least understood phenomena in biology--even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association studies (GWAS) have uncovered ～14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep.     

Genetic analysis of nicotinic signaling in worms and flies

The nicotinic acetylcholine receptor is among the most thoroughly characterized molecules in the nervous system, and its role in mediating fast cholinergic neurotransmission has been broadly conserved in both vertebrates and invertebrates. However, the accessory molecules that facilitate or regulate nicotinic signaling remain mostly unknown. One approach to identify such molecules is to use molecular genetics in a simple, experimentally accessible organism to identify genes required for nicotinic signaling and to determine the molecular identity of the mutant genes through molecular cloning. Because cellular signaling pathways are often highly conserved between different animal phyla, the information gained from studies of simple organisms has historically provided many critical insights into more complex organisms, including humans. Genetic screens essentially make no prior assumptions about the types of molecules involved in the process being studied; thus, they are well suited for identifying previously unknown components of cell signaling pathways. The sophisticated genetic tools available in organisms such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster have also proven extremely powerful in elucidating complex biologic pathways in the absence of prior biochemical information and for assessing a molecule's in vivo function of in the context of an intact nervous system. This review describes how genetic analysis has been used to investigate nicotinic signaling mechanisms in worms and flies, and the prospects for using these studies to gain insight into nicotinic receptor function and regulation in humans.     

New roles for model genetic organisms in understanding and treating human disease: report from the 2006 Genetics Society of America meeting

Fundamental biological knowledge and the technology to acquire it have been immeasurably advanced by past efforts to understand and manipulate the genomes of model organisms. Has the utility of bacteria, yeast, worms, flies, mice, plants, and other models now peaked and are humans poised to become the model organism of the future? The Genetics Society of America recently convened its 2006 meeting entitled "Genetic Analysis: Model Organisms to Human Biology" to examine the future role of genetic research. (Because of time limitations, the meeting was unable to cover the substantial contributions and future potential of research on model prokaryotic organisms.) In fact, the potential of model-organism-based studies has grown substantially in recent years. The genomics revolution has revealed an underlying unity between the cells and tissues of eukaryotic organisms from yeast to humans. No uniquely human biological mechanisms have yet come to light. This common evolutionary heritage makes it possible to use genetically tractable organisms to model important aspects of human medical disorders such as cancer, birth defects, neurological dysfunction, reproductive failure, malnutrition, and aging in systems amenable to rapid and powerful experimentation. Applying model systems in this way will allow us to identify common genes, proteins, and processes that underlie human medical conditions. It will allow us to systematically decipher the gene-gene and gene-environment interactions that influence complex multigenic disorders. Above all, disease models have the potential to address a growing gap between our ability to collect human genetic data and to productively interpret and apply it. If model organism research is supported with these goals in mind, we can look forward to diagnosing and treating human disease using information from multiple systems and to a medical science built on the unified history of life on earth.     

Conservation and co-option in developmental programmes: the importance of homology relationships

One of the surprising insights gained from research in evolutionary developmental biology (evo-devo) is that increasing diversity in body plans and morphology in organisms across animal phyla are not reflected in similarly dramatic changes at the level of gene composition of their genomes. For instance, simplicity at the tissue level of organization often contrasts with a high degree of genetic complexity. Also intriguing is the observation that the coding regions of several genes of invertebrates show high sequence similarity to those in humans. This lack of change (conservation) indicates that evolutionary novelties may arise more frequently through combinatorial processes, such as changes in gene regulation and the recruitment of novel genes into existing regulatory gene networks (co-option), and less often through adaptive evolutionary processes in the coding portions of a gene. As a consequence, it is of great interest to examine whether the widespread conservation of the genetic machinery implies the same developmental function in a last common ancestor, or whether homologous genes acquired new developmental roles in structures of independent phylogenetic origin. To distinguish between these two possibilities one must refer to current concepts of phylogeny reconstruction and carefully investigate homology relationships. Particularly problematic in terms of homology decisions is the use of gene expression patterns of a given structure. In the future, research on more organisms other than the typical model systems will be required since these can provide insights that are not easily obtained from comparisons among only a few distantly related model species.     

Ultrasonic vocalizations in mouse models for speech and socio‐cognitive disorders: insights into the evolution of vocal communication

Comparative analyses used to reconstruct the evolution of traits associated with the human language faculty, including its socio‐cognitive underpinnings, highlight the importance of evolutionary constraints limiting vocal learning in non‐human primates. After a brief overview of this field of research and the neural basis of primate vocalizations, we review studies that have addressed the genetic basis of usage and structure of ultrasonic communication in mice, with a focus on the gene FOXP2 involved in specific language impairments and neuroligin genes (NL‐3 and NL‐4) involved in autism spectrum disorders. Knockout of FoxP2 leads to reduced vocal behavior and eventually premature death. Introducing the human variant of FoxP2 protein into mice, in contrast, results in shifts in frequency and modulation of pup ultrasonic vocalizations. Knockout of NL‐3 and NL‐4 in mice diminishes social behavior and vocalizations. Although such studies may provide insights into the molecular and neural basis of social and communicative behavior, the structure of mouse vocalizations is largely innate, limiting the suitability of the mouse model to study human speech, a learned mode of production. Although knockout or replacement of single genes has perceptible effects on behavior, these genes are part of larger networks whose functions remain poorly understood. In humans, for instance, deficiencies in NL‐4 can lead to a broad spectrum of disorders, suggesting that further factors (experiential and/or genetic) contribute to the variation in clinical symptoms. The precise nature as well as the interaction of these factors is yet to be determined.     

Using Functional Genetics to Understand Breast Cancer Biology

Genetic screens were for long the prerogative of those that studied model organisms. The discovery in 2001 that gene silencing through RNA interference (RNAi) can also be brought about in mammalian cells paved the way for large scale loss-of-function genetic screens in higher organisms. In this article, we describe how functional genetic studies can help us understand the biology of breast cancer, how it can be used to identify novel targets for breast cancer therapy, and how it can help in the identification of those patients that are most likely to respond to a given therapy.Much remains to be learned regarding the function of mammalian genes. Only some quarter of all human genes have well-described functions. It is likely that quite a few of these currently unannotated genes will turn out to play key parts in cancer biology. For example, a 70-gene gene signature that can discriminate breast tumors of good and poor prognosis contained some 20 genes of currently unknown function (van ‘t Veer et al. 2002). The fact that these genes of unknown function foretell breast cancer prognosis hints at a role for at least some of these genes in breast cancer biology. The unbiased search for genes that contribute to breast cancer development is therefore likely to yield a rich harvest of new insights. RNA interference allows us to suppress genes systematically on a large scale and study the effects of gene suppression on specific cellular processes or signaling pathways. Consequently, RNA interference-based genetic screens have the potential to deepen our understanding of the molecular events that cause breast cancer, to find novel targets for therapy and to find biomarkers of drug responsiveness. In this article, we will describe the technologies available to perform both gain-of-function and loss-of-function genetic screens and will illustrate how such functional genetic screens have been used in the recent past to study a variety of outstanding questions in the biology of breast cancer.     

Entering the second century of maize quantitative genetics

Maize is the most widely grown cereal in the world. In addition to its role in global agriculture, it has also long served as a model organism for genetic research. Maize stands at a genetic crossroads, as it has access to all the tools available for plant genetics but exhibits a genetic architecture more similar to other outcrossing organisms than to self-pollinating crops and model plants. In this review, we summarize recent advances in maize genetics, including the development of powerful populations for genetic mapping and genome-wide association studies (GWAS), and the insights these studies yield on the mechanisms underlying complex maize traits. Most maize traits are controlled by a large number of genes, and linkage analysis of several traits implicates a ‘common gene, rare allele'' model of genetic variation where some genes have many individually rare alleles contributing. Most natural alleles exhibit small effect sizes with little-to-no detectable pleiotropy or epistasis. Additionally, many of these genes are locked away in low-recombination regions that encourage the formation of multi-gene blocks that may underlie maize''s strong heterotic effect. Domestication left strong marks on the maize genome, and some of the differences in trait architectures may be due to different selective pressures over time. Overall, maize''s advantages as a model system make it highly desirable for studying the genetics of outcrossing species, and results from it can provide insight into other such species, including humans.     

Mice without telomerase: what can they teach us about human cancer?

Unicellular organisms, human cells and mice have provided insights into the processes of senescence, crisis, genomic instability and cancer in humans. Here, Artandi and DePinho discuss how studies in mice have uncovered a complex interplay between the ARF-p53 pathway, genomic instability due to telomere dysfunction, and the suppression or promotion of cancer.     

Lifespan Modulation in Mice and the Confounding Effects of Genetic Background

We are currently in the midst of a revolution in ageing research,with several dietary,genetic and pharmacological interventions now known to modulate ageing in model organisms.Excitingly,these interventions also appear to have beneficial effects on late-life health.For example,dietary restriction(DR) has been shown to slow the incidence of age-associated cardiovascular disease,metabolic disease,cancer and brain ageing in non-human primates and has been shown to improve a range of health indices in humans.While the idea that DR's ability to extend lifespan is often thought of as being universal,studies in a range of organisms,including yeast,mice and monkeys,suggest that this may not actually be the case.The precise reasons underlying these differential effects of DR on lifespan are currently unclear,but genetic background may be an important factor in how an individual responds to DR.Similarly,recent findings also suggest that the responsiveness of mice to specific genetic or pharmacological interventions that modulate ageing may again be influenced by genetic background.Consequently,while there is a clear driver to develop interventions to improve late-life health and vitality,understanding precisely how these act in response to particular genotypes is critical if we are to translate these findings to humans.We will consider of the role of genetic background in the efficacy of various lifespan interventions and discuss potential routes of utilising genetic heterogeneity to further understand how particular interventions modulate lifespan and healthspan.