Quantitative trait loci define genes and pathways underlying genetic variation in longevity

Quantitative trait locus (QTL) mapping provides a means to discover and roughly position regions of the genome that harbor genes responsible for natural variation in a complex trait. QTL mapping has been utilized extensively in the pursuit of genes contributing to longevity, chiefly in two animal models, the nematode Caenorhabditis elegans and the dipteran insect Drosophila melanogaster. Research on both species has demonstrated that a relatively small set of loci accounts for most of their genetic variance in lifespan. QTL mapping complements the discovery of longevity genes by mutagenesis screens, because the two procedures are predicted to unveil overlapping but distinct types of genes. We argue that information gained from animal models, even invertebrates, can greatly facilitate the process of gene identification and testing of homologous genes in humans.     

Comparative Genetics: Synergizing Human and NOD Mouse Studies for Identifying Genetic Causation of Type 1 Diabetes

Although once widely anticipated to unlock how human type 1 diabetes (T1D) develops, extensive study of the nonobese diabetic (NOD) mouse has failed to yield effective treatments for patients with the disease. This has led many to question the usefulness of this animal model. While criticism about the differences between NOD and human T1D is legitimate, in many cases disease in both species results from perturbations modulated by the same genes or different genes that function within the same biological pathways. Like in humans, unusual polymorphisms within an MHC class II molecule contributes the most T1D risk in NOD mice. This insight supports the validity of this model and suggests the NOD has been improperly utilized to study how to cure or prevent disease in patients. Indeed, clinical trials are far from administering T1D therapeutics to humans at the same concentration ranges and pathological states that inhibit disease in NOD mice. Until these obstacles are overcome it is premature to label the NOD mouse a poor surrogate to test agents that cure or prevent T1D. An additional criticism of the NOD mouse is the past difficulty in identifying genes underlying T1D using conventional mapping studies. However, most of the few diabetogenic alleles identified to date appear relevant to the human disorder. This suggests that rather than abandoning genetic studies in NOD mice, future efforts should focus on improving the efficiency with which diabetes susceptibility genes are detected. The current review highlights why the NOD mouse remains a relevant and valuable tool to understand the genes and their interactions that promote autoimmune diabetes and therapeutics that inhibit this disease. It also describes a new range of technologies that will likely transform how the NOD mouse is used to uncover the genetic causes of T1D for years to come.     

Does in vitro fertilisation increase type 2 diabetes and cardiovascular risk?

Since the first in-vitro fertilisation (IVF) birth in 1978, the number of children born by assisted reproductive technologies (ART) continues to increase worldwide. However, the safety issues surrounding these procedures remain controversial, and the long term impact on human health is unknown. There is emerging evidence to indicate that IVF may predispose individuals to increased incidence of obesity, elevated blood pressure, fasting glucose and triglycerides and subclinical hypothyroidism. However, few studies have been conducted to date and the underlying mechanisms are unclear. This review will summarize the existing evidence in animal models and in humans, and will discuss epigenetic alterations, which may link manipulation of the pre-implantation embryo with increased risk of the later development of obesity, insulin resistance, type 2 diabetes and cardiovascular disease in offspring. Since these diseases are the leading cause of mortality and can be delayed or prevented by lifestyle modification, prospective follow up studies in IVF born adults are now urgently required to determine the degree of risks utilizing gold standard measures in human and animal models.     

The genetic mediation of individual differences in sensitivity to pain and its inhibition

The underlying bases of the considerable interindividual variability in pain-related traits are starting to be revealed. Although the relative importance of genes versus experience in human pain perception remains unclear, rodent populations display large and heritable differences in both nociceptive and analgesic sensitivity. The identification and characterization of particularly divergent populations provides a powerful initial step in the genetic analysis of pain, because these models can be exploited to identify genes contributing to the behavior-level variability. Ultimately, DNA sequence differences representing the differential alleles at pain-relevant genes can be identified. Thus, by using a combination of "top-down" and "bottom-up" strategies, we are now able to genetically dissect even complex biological traits like pain. The present review summarizes the current progress toward these ends in both humans and rodents.     

Osteopetrosis: from Animal Models to Human Conditions

The term “osteopetrosis” is applied to a group of disorders characterized by an increased bone density, due to an inadequate bone resorption. A considerable part of our current knowledge on osteoclast biology is based on the study of osteopetrotic animal models. The search for mutations in these animals has unveiled many molecular mechanisms underlying osteoclast differentiation and functioning. It also supplied new candidate genes for the identification of genes involved in the human variants of this disease. All osteopetrotic genes identified so far in humans have their animal counterpart. The reverse is not true. This can partially be explained by the fact that still more than 30% of all patients suffer from osteopetrosis with an unkown molecular defect. Therefore, the studies of the osteopetrotic animal models and the correlating human osteopetrotic forms were and are still very important for our knowledge of the aetiology, prognosis and treatment of this disease. This review focuses on osteopetrotic animal models as well as human osteopetrotic conditions and their impact on osteoclast biology, pathogenesis and treatment.     

Lessons for human diabetes from experimental mouse models

A precise knowledge of the defects underlying type 1 and type 2 diabetes is essential for designing appropriate therapeutic strategies. Because experiments in humans are limited, naturally occurring, and especially genetically engineered rodent models, have revolutionized research in diabetes. We review some of the models created recently and discuss their impact on human diabetes.     

The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics

The recent rapid increase in the prevalence of obesity across the world is undoubtedly due to changes in diet and lifestyle. However, it is also indisputable that different people react differently to this change in environment and this variation in response is likely to be genetically determined. While for the majority of people this effect is presumed to be polygenic in origin, there is now strong evidence for a small number of genes having a large effect in some families with severe obesity. Studies of these families, coupled with parallel studies in murine models, have provided novel insights into the molecules involved in the regulation of appetite, energy expenditure and nutrient partitioning. We review here the lessons we have learnt from mouse models of obesity, both naturally occurring and artificially generated through targeted gene deletions, and more importantly from human monogenic syndromes of obesity. These have illuminated the critical role in which the central leptin melanocortin pathway plays in the control of mammalian food intake and body weight.     

Genetics of variation in HDL cholesterol in humans and mice

Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are genetically determined to a great extent, and quantitative trait locus (QTL) analysis has been used to identify chromosomal regions containing genes regulating HDL-C levels. We discuss new genes found to participate in HDL metabolism. We also summarize 37 mouse and 30 human QTLs for plasma HDL-C levels, finding that all but three of the mouse QTLs have been confirmed by a second cross or a homologous human QTL, that the mouse QTL map is almost saturated because 92% of recently reported QTLs are repeats of those already found, and that 28 of the 30 human QTLs are located in regions homologous to mouse QTLs. This high degree of concordance between mouse and human QTLs suggests that the underlying genes may be the same. Strategies to more rapidly identify genes underlying mouse and human QTLs for HDL-C include focusing on the mouse and using mouse-human homologies, combining crosses, and haplotyping to narrow the region. Sequence analysis and expression studies can distinguish candidate genes consistent across multiple mouse crosses, and testing the candidate genes in human association studies can provide additional evidence for the candidacy of a gene. Together these strategies can accelerate the pace of finding genes that regulate HDL.     

Experimental animal models in pancreatic carcinogenesis: lessons for human pancreatic cancer

The silent course of pancreatic cancer and its explosive fatal outcome have hindered studies of tumor histogenesis and the identification of early biochemical and genetic alterations that could help to diagnose the disease at a curable stage and develop therapeutic strategies. Experimental animal models provide important tools to assess risk factors, as well as preventive and therapeutic possibilities. Although several pancreatic cancer models presently exist, only models that closely resemble human tumors in morphological, clinical, and biological aspects present useful media for preclinical studies. Because an estimated 70% of human tumors are induced by carcinogens and because a significant association has been found between cigarette smoking and pancreatic cancer, chemically induced models are of particular value. Moreover, in such models the etiology, modifying factors, effects of diets, and naturally occurring products can be studied and early diagnostic, preventive, and therapeutic possibilities sought out. Many of the existing models are described in this review, and the advantages and shortcomings of each model and their clinical implications are discussed.     

Rats as models for the study of obesity

Gerontologists are concerned about obesity for two reasons. First, adiposity increases in humans with increasing age. Secondly, there is a strong possibility that the interaction between obesity and aging is deleterious. Since rats are a widely used animal model for the study of aging, it is likely that rats will be utilized in experiments designed to study the interactions between adiposity and aging. The object of this review is to provide the basic information needed for utilizing rats in such studies. To this end, changes in adipose tissue mass that occur during the life span of normal rats are described as are the types of rat models that have been used in the study of obesity. In addition, the characteristics of each of these obesity models are detailed.     

Molecular studies of identification of genes for osteoporosis: the 2002 update

We aim to give a comprehensive review, updated to 2002, of the most important and representative molecular genetic studies, performed mainly within the past decade, that aimed to identify the gene(s) involved in osteoporosis. Early reviews were largely confined to association studies in humans, but we review here, separately, the results of both association and linkage studies in humans, and quantitative trait locus (QTL) mapping in animal models. The main results of all the studies are tabulated for comparison and ease of reference, and to provide a comprehensive retrospective view of molecular genetics studies of osteoporosis. The most striking findings and the most representative studies are singled out for comment regarding the immediacy of their influence on present understanding of the genetics of osteoporosis and on the current status of genetic research in osteoporosis. This is particularly relevant for studies on the association of the vitamin D receptor (VDR) gene, for which there has been a large body of studies and reviews published. The format adopted by this review should be ideal for accommodating future new advances and studies in a fairly young field that is still developing rapidly.     

Admixture mapping as a gene discovery approach for complex human traits and diseases

Admixture mapping (AM) is a special form of conventional meiotic or recombination mapping for disease gene discovery in humans that exploits naturally occurring genetic and phenotypic differences existing in populations between which recent gene flow has occurred. Essentially, mates from two different "parental" populations with different allelic and disease-predisposing mutation profiles will produce "admixed" offspring whose genomes will be mixtures of the genomes associated with the parental populations. Strong linkage disequilibrium (LD) will exist for several generations between neighboring loci of admixed individuals and can be exploited for identifying the genomic location of trait-influencing loci. Although it may be a very clever strategy for identifying genes that influence human traits and diseases, AM can be problematic. We review the foundations, basic strategies, resources, and settings necessary for AM. We conclude that AM has potential in the identification of disease-predisposing loci, but this potential may only exist in a limited number of realistic settings.     

How obesity develops: insights from the new biology

Molecular and genetic studies of animal models have identified numerous genes that may cause or contribute to the development of obesity. They have also provided significant insight into the peripheral and central pathways that control energy intake and expenditure. Genetic studies of families and populations have generated useful information on genes and mutations associated with or linked to obesity, body fat distribution, and other relevant phenotypes. This information, combined with knowledge of the chromosomal location of genes identified from animal studies, has made it possible to identify specific mutations that contribute to the development of obesity in humans.     

Genes involved in animal models of obesity and anorexia

Pathological deviations in bodyweight is a major increasing health problem in industrialized societies. It is currently unclear what genetic mechanisms are involved in the long-term control of human body-weight and to what extent these genes are involved in pathological deviations of bodyweight control such as anorexia and obesity. Major support for the concept of genetic control of bodyweight has recently emerged from different animal models. A number of new genes have been found during recent years that, when mutated, have a negative effect on bodyweight in animals and sometimes also in man. Although available evidence points toward a multifactorial nature of weight disorders in most human subjects, the single genes isolated in animal models may become powerful tools to elucidate the genetics also in man. In addition, these genes may serve to promote the development of targeted small-drug pharmaceuticals aimed at novel biochemical pathways. Finally, the uncovering of several quantitative trait loci (QTL) influencing body mass, body fat or fat topography in the mouse and rat has now also made it possible to perform studies of polygenically caused obesity in rodents. The role of the Genome Project in developing a complete gene map will greatly facilitate transforming these OTLs to actual molecules involved in the biology of bodyweight.     

Lessons in obesity from transgenic animals

Many genetic manipulations have created models of obesity, leanness or resistance to dietary obesity in mice, often providing insights into molecular mechanisms that affect energy balance, and new targets for anti-obesity drugs. Since many genes can affect energy balance in mice, polymorphisms in many genes may also contribute to obesity in humans, and there may be many causes of primary leptin resistance. Secondary leptin resistance (due to high leptin levels) can be investigated by combining the ob mutation with other obesity genes. Some transgenic mice have failed to display the expected phenotype, or have even been obese when leanness was expected. Compensatory changes in the expression of other genes during development, or opposing influences of the gene on energy balance, especially in global knockout mice, may offer explanations for such findings. Obesity has been separated from insulin resistance in some transgenic strains, providing new insights into the mechanisms that usually link these phenotypes. It has also been shown that in some transgenic mice, obesity develops without hyperphagia, or leanness without hypophagia, demonstrating that generalised physiological explanations for obesity in individual humans may be inappropriate. Possibly the most important transgenic model of obesity so far created is the Type 1 11beta-hydroxysteroid dehydrogenase over-expressing mouse, since this models the metabolic syndrome in humans. The perspectives into obesity offered by transgenic mouse models should assist clinical researchers in the design and interpretation of their studies in human obesity.     

Genome-wide expression studies of atherosclerosis: critical issues in methodology, analysis, interpretation of transcriptomics data

During the past 6 years, gene expression profiling of atherosclerosis has been used to identify genes and pathways relevant in vascular (patho)physiology. This review discusses some critical issues in the methodology, analysis, and interpretation of the data of gene expression studies that have made use of vascular specimens from animal models and humans. Analysis of gene expression studies has evolved toward the genome-wide expression profiling of large series of individual samples of well-characterized donors. Despite the advances in statistical and bioinformatical analysis of expression data sets, studies have not yet fully exploited the potential of gene expression data sets to obtain novel insights into the molecular mechanisms underlying atherosclerosis. To assess the potential of published expression data, we compared the data of a CC chemokine gene cluster between 18 murine and human gene expression profiling articles. Our analysis revealed that an adequate comparison is mainly hindered by the incompleteness of available data sets. The challenge for future vascular genomic profiling studies will be to further improve the experimental design, statistical, and bioinformatical analysis and to make data sets freely accessible.     

What have rare genetic syndromes taught us about the pathophysiology of the common forms of obesity?

Obesity is a central feature for several congenital syndromes, including Prader-Willi, Angelman, Bardet-Biedl, Cohen, Alström andBörjeson-Forssman-Lehmann syndromes, and Albright's hereditary osteodystrophy. Although a role for the central nervous system, including the hypothalamus-pituitary axis, has been suggested for the etiology of obesity in these syndromes, the pathophysiologic pathways are as yet not well defined, and in many cases may identify currently unknown mechanisms. Nevertheless, many of the causative genes and unusual mechanisms, including parental imprinting of genes and complex patterns of inheritance, have been identified. We review the latest advances in understanding congenital syndromes in which obesity is purely genetic, drawing on comparisons to genetic studies of obesity in the human population as well as to those in experimental and agricultural animal models. An understanding of the genetic basis for these syndromes will provide a more comprehensive picture of the mechanisms that control food intake and energy balance in humans.