Leprosy as a genetic model for susceptibility to common infectious diseases

Leprosy (Hansen’s disease) is a human infectious disease that can be effectively treated with long-term administration of multi-drug therapy. In 2006, over 250,000 new cases were reported to the World Health Organization. In the nineteenth century, disagreement among leprologists regarding the hereditary or infectious nature of leprosy was resolved with the identification of the etiological agent, Mycobacterium leprae. However, epidemiological studies maintain the importance of host genetics in leprosy susceptibility. A model free genome-wide linkage scan in multi-case families from Vietnam led to the positional cloning of global genetic risk factors in the PARK2/PACRG and LTA genes. The process of identifying the susceptibility variants provided invaluable insight into the replication of genetic effects, particularly the importance of considering population-specific linkage-disequilibrium structure. As such, these studies serve to improve our understanding of leprosy pathogenesis by implicating novel biological pathways while simultaneously providing a genetic model for common infectious diseases.     

Identification of genetic loci affecting the establishment and development of Echinococcus multilocularis larvae in mice

Alveolar echinococcosis (AE) is a severe hepatic disorder caused by larval infection by the fox tapeworm Echinococcus multilocularis. The course of parasitic development and host reactions are known to vary significantly among host species, and even among different inbred strains of mice. As reported previously, after oral administration of parasite eggs, DBA/2 (D2) mice showed a higher rate of cyst establishment and more advanced protoscolex development in the liver than C57BL/6 (B6) mice. These findings strongly suggest that the outcome of AE is affected by host genetic factor(s). In the present study, the genetic basis of such strain-specific differences in susceptibility/resistance to AE in murine models was studied by whole-genome scanning for quantitative trait loci (QTLs) using a backcross of (B6 × D2)F₁ and D2 mice with varying susceptibility to E. multilocularis infection. For cyst establishment, genome linkage analysis identified one suggestive and one significant QTL on chromosomes (Chrs.) 9 and 6, respectively, whereas for protoscolex development, two suggestive and one highly significant QTLs were detected on Chrs. 6, 17 and 1, respectively. Our QTL analyses using murine AE models revealed that multiple genetic factors regulated host susceptibility/resistance to E. multilocularis infection. Moreover, our findings show that establishment of the parasite cysts in the liver is affected by QTLs that are distinct from those associated with the subsequent protoscolex development of the parasite, indicating that different host factors are involved in the host–parasite interplay at each developmental stage of the larval parasite. Further identification of responsible genes located on the identified QTLs could lead to the development of effective disease prevention and control strategies, including an intensive screening and clinical follow-up of genetically high-risk groups for AE infection.     

Phenotyping mouse chromosome substitution strains reveal multiple QTLs for febrile seizure susceptibility

Febrile seizures (FS) are the most common seizure type in children and recurrent FS are a risk factor for developing temporal lobe epilepsy. Although the mechanisms underlying FS are largely unknown, recent family, twin and animal studies indicate that genetics are important in FS susceptibility. Here, a forward genetic strategy was used employing mouse chromosome substitution strains (CSS) to identify novel FS susceptibility quantitative trait loci (QTLs). FS were induced by exposure to warm air at postnatal day 14. Video electroencephalogram monitoring identified tonic–clonic convulsion onset, defined as febrile seizure latency (FSL), as a reliable phenotypic parameter to determine FS susceptibility. FSL was determined in both sexes of the host strain (C57BL/6J), the donor strain (A/J) and CSS. C57BL/6J mice were more susceptible to FS than A/J mice. Phenotypic screening of the CSS panel identified six strains (CSS1, -2, -6 -10, -13 and -X) carrying QTLs for FS susceptibility. CSS1, -10 and -13 were less susceptible (protective QTLs), whereas CSS2, -6 and -X were more susceptible (susceptibility QTLs) to FS than the C57BL/6J strain. Our data show that mouse FS susceptibility is determined by complex genetics, which is distinct from that for chemically induced seizures. This is the first data set using CSS to screen for a seizure trait in mouse pups. It provides evidence for common FS susceptibility QTLs that serve as starting points to fine map FS susceptibility QTLs and to identify FS susceptibility genes. This will increase our understanding of human FS, working toward the identification of new therapeutic targets.     

Infectious disease — a genetic view

Genetic analysis of resistance to infectious disease reveals many important cues that have led to new insights into the interaction between pathogen and host. This knowledge might help with a better prognosis for diseases, and to the development of novel therapeutics. This review focuses on genes and loci that control susceptibility to diseases with an important epidemiologic impact, such as AIDS, hepatitis B, gastritis and peptic ulcer, tuberculosis, leprosy, malaria, schistosomiasis and leishmaniasis. New perspectives for the integration of human and mouse genetics that contribute greatly to our understanding of regulatory mechanisms in health and disease, are also discussed.     

Host genetics and population structure effects on parasitic disease

Host genetic factors exert significant influences on differential susceptibility to many infectious diseases. In addition, population structure of both host and parasite may influence disease distribution patterns. In this study, we assess the effects of population structure on infectious disease in two populations in which host genetic factors influencing susceptibility to parasitic disease have been extensively studied. The first population is the Jirel population of eastern Nepal that has been the subject of research on the determinants of differential susceptibility to soil-transmitted helminth infections. The second group is a Brazilian population residing in an area endemic for Trypanosoma cruzi infection that has been assessed for genetic influences on differential disease progression in Chagas disease. For measures of Ascaris worm burden, within-population host genetic effects are generally more important than host population structure factors in determining patterns of infectious disease. No significant influences of population structure on measures associated with progression of cardiac disease in individuals who were seropositive for T. cruzi infection were found.     

Human genetic susceptibility to infectious disease

Recent genome-wide studies have reported novel associations between common polymorphisms and susceptibility to many major infectious diseases in humans. In parallel, an increasing number of rare mutations underlying susceptibility to specific phenotypes of infectious disease have been described. Together, these developments have highlighted a key role for host genetic variation in determining the susceptibility to infectious disease. They have also provided insights into the genetic architecture of infectious disease susceptibility and identified immune molecules and pathways that are directly relevant to the human host defence.     

Does animal behavior underlie covariation between hosts' exposure to infectious agents and susceptibility to infection? Implications for disease dynamics

Animal behavior is unique in influencing both components of the process of transmission of disease: exposure to infectious agents, and susceptibility to infection once exposed. To date, the influence of behavior on exposure versus susceptibility has largely been considered separately. Here, we ask whether these two key mechanisms act in concert in natural populations, whereby individuals who are most exposed to infectious agents or have the most contact with conspecifics are also the most susceptible or infectious. We propose three mechanisms that can generate covariation between these two key elements of the transmission of disease within and among hosts, and we provide empirical examples of each. We then use a mathematical model to examine the effect of this covariation on the dynamics of disease at the population level. First, we show that the empirical mechanisms generating covariation between behavioral and physiological components of disease transmission are widespread and include endocrine mediators of behavior, mate choice, group size, sickness behaviors, and behavioral avoidance of infectious conspecifics. The diversity of these empirical mechanisms underscores the potential importance and breadth of covariation in the disease process. Second, we show mathematically that the variability in hosts' exposure to infectious agents and susceptibility or infectiousness, and how tightly they are coupled, strongly influences the ability of a disease to invade a host population. Overall, we propose that covariation between behavioral and physiological components of transmission is likely widespread in natural populations, and can have important consequences for the dynamics of disease at the population level as well as for our understanding of sexual selection, social behavior, and animal communication.     

Use of chromosome substitution strains to identify seizure susceptibility loci in mice

Seizure susceptibility varies among inbred mouse strains. Chromosome substitution strains (CSS), in which a single chromosome from one inbred strain (donor) has been transferred onto a second strain (host) by repeated backcrossing, may be used to identify quantitative trait loci (QTLs) that contribute to seizure susceptibility. QTLs for susceptibility to pilocarpine-induced seizures, a model of temporal lobe epilepsy, have not been reported, and CSS have not previously been used to localize seizure susceptibility genes. We report QTLs identified using a B6 (host) × A/J (donor) CSS panel to localize genes involved in susceptibility to pilocarpine-induced seizures. Three hundred fifty-five adult male CSS mice, 58 B6, and 39 A/J were tested for susceptibility to pilocarpine-induced seizures. Highest stage reached and latency to each stage were recorded for all mice. B6 mice were resistant to seizures and slower to reach stages compared to A/J mice. The CSS for Chromosomes 10 and 18 progressed to the most severe stages, diverging dramatically from the B6 phenotype. Latencies to stages were also significantly shorter for CSS10 and CSS18 mice. CSS mapping suggests seizure susceptibility loci on mouse Chromosomes 10 and 18. This approach provides a framework for identifying potentially novel homologous candidate genes for human temporal lobe epilepsy.     

The battle of two genomes: genetics of bacterial host/pathogen interactions in mice

Genetic factors strongly determine the outcome of infectious diseases caused by various pathogens. The molecular mechanisms of resistance and susceptibility in humans, however, remains largely unknown. Complex interactions of multiple genes that control the host response to a pathogen further complicate the picture. Animal models have a tremendous potential to dissect the complex genetic system of host–pathogen interaction into single components. This is particularly true for the mouse, which will continue to develop into an invaluable tool in the identification and cloning of host resistance genes. Three main approaches have been taken to establish mouse models for human infectious diseases: 1) Production of mouse mutants by gene targeting; 2) positional cloning of host-resistance genes in mutant mice; and 3) mapping and characterization of quantitative trait loci (QTL) controlling the complex aspects of host–pathogen interactions. The contribution of all three methods to the understanding of infectious diseases in humans will be reviewed in this work, with a special emphasis on the studies of resistance/susceptibility mechanism in bacterial infections. Received: 7 September 2000 / Accepted: 23 November 2000     

Chemical mutagenesis: a new strategy against the global threat of infectious diseases

The perpetual evolution of drug-resistant microbes, the overwhelming burden of acquired immune suppression due to HIV, the emergence or re-emergence of various pathogens (West Nile virus, pandemic influenza, Creutzfeld-Jacob disease), and increased fears of bioterrorism has drawn a great deal of new attention to infectious diseases. The pathogenesis of infection is characterized by complex interactions of potentially virulent microorganisms with host genetic and acquired factors. Chemical mutagenesis of the mouse genome provides a robust method to unravel this challenging problem. To deepen our understanding of the natural host response to pathogens, our team and others are interrogating the mouse genome to define genes that are crucial to the defense against infectious diseases (pathogen recognition, viral defense, bacterial defense, prion infection). In this review we highlight the current progress of these efforts and propose a toolbox for other groups that are interested in this endeavor.     

Genetics of murine type 2 diabetes and comorbidities

Type 2 diabetes (T2D) is a polygenic and multifactorial complex disease, defined as chronic metabolic disorder. It's a major global health concern with an estimated 463 million adults aged 20–79 years with diabetes and projected to increase up to 700 million by 2045. T2D was reported to be one of the four leading causes of non-communicable disease (NCD) deaths in 2012. Environmental factors play a part in the development of polygenic forms of diabetes. Polygenic forms of diabetes often run-in families. Fortunately, T2D, which accounts for 90–95% of the entire four types of diabetes including, Type 1 diabetes (T1D), T2D, monogenic diabetes syndromes (MGDS), and Gestational diabetes mellitus, can be prevented or delayed through nutrition and lifestyle changes as well as through pharmacologic interventions. Typical symptom of the T2D is high blood glucose levels and comprehensive insulin resistance of the body, producing an impaired glucose tolerance. Impaired glucose tolerance of T2D is accompanied by extensive health complications, including cardiovascular diseases (CVD) that vary in morbidity and mortality among populations. The pathogenesis of T2D varies between populations and/or ethnic groupings and is known to be attributed extremely by genetic components and environmental factors. It is evident that genetic background plays a critical role in determining the host response toward certain environmental conditions, whether or not of developing T2D (susceptibility versus resistant). T2D is considered as a silent disease that can progress for years before its diagnosis. Once T2D is diagnosed, many metabolic malfunctions are observed whether as side effects or as independent comorbidity. Mouse models have been proven to be a powerful tool for mapping genetic factors that underline the susceptibility to T2D development as well its comorbidities. Here, we have conducted a comprehensive search throughout the published data covering the time span from early 1990s till the time of writing this review, for already reported quantitative trait locus (QTL) associated with murine T2D and comorbidities in different mouse models, which contain different genetic backgrounds. Our search has resulted in finding 54 QTLs associated with T2D in addition to 72 QTLs associated with comorbidities associated with the disease. We summarized the genomic locations of these mapped QTLs in graphical formats, so as to show the overlapping positions between of these mapped QTLs, which may suggest that some of these QTLs could be underlined by sharing gene/s. Finally, we reviewed and addressed published reports that show the success of translation of the identified mouse QTLs/genes associated with the disease in humans.

     

Molecular progress on the mapping and cloning of functional genes for blast disease in rice (Oryza sativa L.): current status and future considerations

Rice blast disease, which is caused by the fungal pathogen Magnaporthe oryzae, is a recurring problem in all rice-growing regions of the world. The use of resistance (R) genes in rice improvement breeding programmes has been considered to be one of the best options for crop protection and blast management. Alternatively, quantitative resistance conferred by quantitative trait loci (QTLs) is also a valuable resource for the improvement of rice disease resistance. In the past, intensive efforts have been made to identify major R-genes as well as QTLs for blast disease using molecular techniques. A review of bibliographic references shows over 100 blast resistance genes and a larger number of QTLs (～500) that were mapped to the rice genome. Of the blast resistance genes, identified in different genotypes of rice, ～22 have been cloned and characterized at the molecular level. In this review, we have summarized the reported rice blast resistance genes and QTLs for utilization in future molecular breeding programmes to introgress high-degree resistance or to pyramid R-genes in commercial cultivars that are susceptible to M. oryzae. The goal of this review is to provide an overview of the significant studies in order to update our understanding of the molecular progress on rice and M. oryzae. This information will assist rice breeders to improve the resistance to rice blast using marker-assisted selection which continues to be a priority for rice-breeding programmes.     

Candidate gene analysis of quantitative disease resistance in wheat

 Knowledge of the biological significance underlying quantitative trait loci (QTLs) for disease resistance is generally limited. In recent years, advances in plant-microbe interactions and genome mapping have lead to an increased understanding of the genes involved in plant defense and quantitative disease resistance. Here, we report on the application of the candidate-gene approach to the mapping of QTLs for disease resistance in a population of wheat recombinant inbreds. Over 50 loci, representing several classes of defense response (DR) genes, were placed on an existing linkage map and the genome was surveyed for QTLs associated with resistance to several diseases including tan spot, leaf rust, Karnal bunt, and stem rust. Analysis revealed QTLs with large effects in regions of putative resistance (R) genes, as previously reported. Several candidate genes, including oxalate oxidase, peroxidase, superoxide dismutase, chitinase and thaumatin, mapped within previously identified resistance QTLs and explained a greater amount of the phenotypic variation. A cluster of closely linked DR genes on the long arm of chromosome 7B, which included genes for catalase, chitinase, thaumatins and an ion channel regulator, had major effects for resistance to leaf rust of adult plants under conditions of natural infestation. The results of this study indicate that many minor resistance QTLs may be from the action of DR genes, and that the candidate-gene approach can be an efficient method of QTL identification. Received: 12 June 1998 / Accepted: 24 July 1998     

Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes

Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000–13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change—containing variation acquired from archaic hominins or adaptive variants in specific populations—improving our understanding of the relative biological importance of innate immunity pathways in natural conditions.     

Reconstruction of a functional human gene network, with an application for prioritizing positional candidate genes

Most common genetic disorders have a complex inheritance and may result from variants in many genes, each contributing only weak effects to the disease. Pinpointing these disease genes within the myriad of susceptibility loci identified in linkage studies is difficult because these loci may contain hundreds of genes. However, in any disorder, most of the disease genes will be involved in only a few different molecular pathways. If we know something about the relationships between the genes, we can assess whether some genes (which may reside in different loci) functionally interact with each other, indicating a joint basis for the disease etiology. There are various repositories of information on pathway relationships. To consolidate this information, we developed a functional human gene network that integrates information on genes and the functional relationships between genes, based on data from the Kyoto Encyclopedia of Genes and Genomes, the Biomolecular Interaction Network Database, Reactome, the Human Protein Reference Database, the Gene Ontology database, predicted protein-protein interactions, human yeast two-hybrid interactions, and microarray co-expressions. We applied this network to interrelate positional candidate genes from different disease loci and then tested 96 heritable disorders for which the Online Mendelian Inheritance in Man database reported at least three disease genes. Artificial susceptibility loci, each containing 100 genes, were constructed around each disease gene, and we used the network to rank these genes on the basis of their functional interactions. By following up the top five genes per artificial locus, we were able to detect at least one known disease gene in 54% of the loci studied, representing a 2.8-fold increase over random selection. This suggests that our method can significantly reduce the cost and effort of pinpointing true disease genes in analyses of disorders for which numerous loci have been reported but for which most of the genes are unknown.     

Norovirus disease: changing epidemiology and host susceptibility factors

Noroviruses cause the majority of acute viral gastroenteritis cases that occur worldwide. The increased recognition of noroviruses as the cause of outbreaks and sporadic disease is due to the recent availability of improved norovirus-specific diagnostics. Transmission of these viruses is facilitated by their high prevalence in the community, shedding of infectious virus particles from asymptomatic individuals and the high stability of the virus in the environment. Currently, the spectrum of clinical disease and the understanding of host susceptibility factors are changing. Cases of chronic norovirus gastroenteritis have been observed in transplant recipients and unusual clinical presentations have been recognized in otherwise healthy adults that are under physical stress. Recently, noroviruses were found to bind to gut-expressed carbohydrates, leading to a correlation between a person's genetically determined carbohydrate expression and their susceptibility to Norwalk virus infection. Greater community surveillance and further investigation of carbohydrate receptor-binding properties could provide further insights into norovirus transmission, susceptibility and pathogenesis, and should aid in developing vaccines and antiviral therapies for this common viral disease.     

Enteric pathogen exploitation of the microbiota-generated nutrient environment of the gut

Residing within the intestine is a large community of commensal organisms collectively termed the microbiota. This community generates a complex nutrient environment by breaking down indigestible food products into metabolites that are used by both the host and the microbiota. Both the invading intestinal pathogen and the microbiota compete for these metabolites, which can shape both the composition of the flora, as well as susceptibility to infection. After infection is established, pathogen mediated inflammation alters the composition of the microbiota, which further shifts the makeup of metabolites in the gastrointestinal tract. A greater understanding of the interplay between the microbiota, the metabolites they generate, and susceptibility to enteric disease will enable the discovery of novel therapies against infectious disease.