Although central to many studies of phenotypic variation and disease susceptibility, characterizing the genetic architecture of complex traits has been unexpectedly difficult. For example, most of the susceptibility genes that contribute to highly heritable conditions such as obesity and type 2 diabetes (T2D) remain to be identified despite intensive study. We took advantage of mouse models of diet-induced metabolic disease in chromosome substitution strains (CSSs) both to characterize the genetic architecture of diet-induced obesity and glucose homeostasis and to test the feasibility of gene discovery. Beginning with a survey of CSSs, followed with genetic and phenotypic analysis of congenic, subcongenic, and subsubcongenic strains, we identified a remarkable number of closely linked, phenotypically heterogeneous quantitative trait loci (QTLs) on mouse chromosome 6 that have unexpectedly large phenotypic effects. Although fine-mapping reduced the genomic intervals and gene content of these QTLs over 3000-fold, the average phenotypic effect on body weight was reduced less than threefold, highlighting the “fractal” nature of genetic architecture in mice. Despite this genetic complexity, we found evidence for 14 QTLs in only 32 recombination events in less than 3000 mice, and with an average of four genes located within the three body weight QTLs in the subsubcongenic strains. For Obrq2a1, genetic and functional studies collectively identified the solute receptor Slc35b4 as a regulator of obesity, insulin resistance, and gluconeogenesis. This work demonstrated the unique power of CSSs as a platform for studying complex genetic traits and identifying QTLs.

Current treatments have largely failed to slow the rapidly increasing world-wide prevalence of obesity and its co-morbidities. Despite a strong genetic contribution to obesity (40-70%), only a small percentage of heritability is explained with current knowledge of monogenic abnormalities, common sequence variants and conventional modes of inheritance. Epigenetic effects are rarely tested in humans because of difficulties arranging studies that distinguish conventional and transgenerational inheritance while simultaneously controlling environmental factors and learned behaviors. However, growing evidence from model organisms implicates genetic and environmental factors in one generation that affect phenotypes in subsequent generations. In this report, we provide the first evidence for paternal transgenerational genetic effects on body weight and food intake. This test focused on the obesity-resistant 6C2d congenic strain, which carries the Obrq2a(A/J) allele on an otherwise C57BL/6J background. Various crosses between 6C2d and the control C57BL/6J strain showed that the Obrq2a(A/J) allele in the paternal or grandpaternal generation was sufficient to inhibit diet-induced obesity and reduce food intake in the normally obesity-susceptible, high food intake C57BL/6J strain. These obesity-resistant and reduced food intake phenotypes were transmitted through the paternal lineage but not the maternal lineage with equal strength for at least two generations. Eliminating social interaction between the father and both his offspring and the pregnant dam did not significantly affect food intake levels, demonstrating that the phenotype is transmitted through the male germline rather than through social interactions. Persistence of these phenotypes across multiple generations raises the possibility that transgenerational genetic effects contribute to current metabolic conditions.

Buchner DA, Burrage LC, Hill AE, Yazbek SN, O'Brien WE, Croniger CM, Nadeau JH. Resistance to diet-induced obesity in mice with a single substituted chromosome. Physiol Genomics 35: 116 -122, 2008. First published July 15, 2008 doi:10.1152/physiolgenomics.00033.2008.-Obesity and its comorbidities are taking an increasing toll on human health. Key pathways that were identified with single gene variants in humans and model organisms have led to improved understanding and treatment of rare cases of human obesity. However, similar progress remains elusive for the more common multifactorial cases of metabolic dysfunction and disease. A survey of mouse chromosome substitution strains (CSSs) provided insight into the complex genetic control of dietinduced obesity and related conditions. We now report a survey of 60 traits related to obesity and metabolic syndrome in mice with a single substituted chromosome as well as selected traits measured in congenic strains derived from the substituted strain. We found that each strain that was resistant to diet-induced obesity had a distinct phenotype that uniquely modeled different combinations of traits related to metabolic disease. For example, the chromosome 6 CSS remained insulin resistant in the absence of obesity, demonstrating an atypical relationship between body weight and insulin resistance. These results provide insights into the genetic control of constant components of this mouse model of diet-induced metabolic disease as well as phenotypes that vary depending on genetic background. A better understanding of these genotype-phenotype relationships may enable a more individualized diagnosis and treatment of obesity and the metabolic syndrome. C57BL/6J; A/J; metabolic syndrome; quantitative trait locus; congenic strain THE IMPACT OF OBESITY on human health is considerable given the comorbidities such as cardiovascular disease and type 2 diabetes. Heritable factors account for 45-75% of variation in body mass index (BMI), the most common measure of obesity (8). Genetic studies have revealed a great deal about the molecular basis of obesity, with substantial progress coming from studies of mouse models (4). Genes such as leptin and its receptor are mutated in rare cases of human obesity and mouse models of monogenic obesity (7). However, most cases of human obesity are thought to be polygenic, and the identity of the genes and pathways involved has largely eluded discovery in both humans and mice (2).The metabolic basis of human obesity is similarly complex. Various findings support important contributions of feeding behavior, nonexercise activity thermogenesis, in utero environment, microbial content in the gut, and resting energy expenditure, among others (10, 15-17, 21, 25, 29). At the individual level, the metabolic basis of obesity is probably attributable to variable combinations of these and other factors. To study the many genetic and metabolic factors at work within an individual, a complete panel of mouse chromosome substitution strains (CSSs) was analyzed for...

Obesity is the result of excess energy intake relative to expenditure, however little is known about why some individuals are more prone to weight gain than others. Inbred strains of mice also vary in their susceptibility to obesity and therefore represent a valuable model to study the genetics and physiology of weight gain and its comorbidities such as type 2 diabetes. C57BL/6J mice are susceptible to obesity and insulin resistance when fed an obesogenic diet, whereas A/J mice are resistant despite increased caloric intake. Analysis of B6- and A/J-derived chromosome substitution strains and congenic strains revealed a complex genetic and physiological basis for this phenotype. To improve our understanding of the molecular mechanisms underlying susceptibility to metabolic disease we analyzed global gene expression patterns in 6C1 and 6C2 congenic strains. 6C1 is susceptible whereas 6C2 is resistant to diet-induced obesity. In addition, we demonstrate that 6C1 is glucose intolerant and insulin resistant relative to 6C2. Pathway analysis of global gene expression patterns in muscle, adipose, and liver identified expression level differences between 6C1 and 6C2 in pathways related to basal transcription factors, endocytosis, and mitochondrial oxidative phosphorylation (OxPhos). The OxPhos expression differences were subtle but evident in each complex of the electron transport chain and were associated with a marked increase in mitochondrial oxidative capacity in the livers of the obese strain 6C1 relative to the obesity-resistant strain 6C2. These data suggests the importance of hepatic mitochondrial function in the development of obesity and insulin resistance.

In the MENA region, the role of HEV as an infectious threat to blood safety is under-investigated. More data are needed to quantify the risk of transmission and to assess clinical outcomes. This requires, at least, surveillance screening of donors and recipients for HEV markers using sensitive and specific serological tests. At the present time, serious consideration should be given to selective screening for certain groups of patients (e.g., immunocompromised, pregnant women and others) who commonly require blood transfusion and are at high risk of hepatic failure or chronicity from HEV infection.

ObjectivesTo review trends in non-communicable (NCD) research output in the Arab region, in terms of quantity and quality, study design, setting and focus. We also examined differences by time and place, and assessed gaps between research output and NCD burden.MethodsA scoping review of a total of 3,776 NCD-related reports published between 2000 and 2013 was conducted for seven Arab countries. Countries were selected to represent diverse socio-economic development levels in the region: Regression analyses were used to assess trends in publications over time and by country. Research gaps were assessed by examining the degree of match between proportionate literature coverage of the four main NCDs (CVD, cancer, DM, and COPD) and cause-specific proportional mortality rates (PMR).ResultsThe annual number of NCD publications rose nearly 5-fold during the study period, with higher income countries having the higher publication rates (per million populations) and the most rapid increases. The increase in the publication rate was particularly prominent for descriptive observational studies, while interventional studies and systematic reviews remained infrequent (slope coefficients = 13.484 and 0.883, respectively). Gap analysis showed a mismatch between cause-specific PMR burden and NCD research output, with a relative surplus of reports on cancer (pooled estimate +38.3%) and a relative deficit of reports on CVDs (pooled estimate -30.3%).ConclusionThe widening disparity between higher and lower-income countries and the discordance between research output and disease burden call for the need for ongoing collaboration among Arab academic institutions, funding agencies and researchers to guide country-specific and regional research agendas, support and conduct.

The review lists the genetic diseases reported in Lebanese individuals, surveys genetic programs and services, and highlights the absence of basic genetic health services at the individual and community level. The incidence of individual diseases is not determined, yet the variety of genetic diseases reported is tremendous, most of which follow autosomal recessive inheritance reflecting the social norms in the population, including high rates of consanguinity, which favor the increase in incidence of these diseases. Genetic services including all activities for the diagnosis, care, and prevention of genetic diseases at community level are extremely inadequate. Services are limited to some clinical and laboratory diagnostic services with no genetic counseling. These services are localized within the capital thus preventing their accessibility to high-risk communities. Screening programs, which are at the core of public health prevention services, are minimal and not nationally mandated. The absence of adequate genetic services is attributed to many factors undermining the importance of genetic diseases and their burden on society, the most important of which is genetic illiteracy at all levels of the population, including high-risk families, the general public, and most importantly health care providers and public health officials. Thus, a country like Lebanon, where genetic diseases are expected to be highly prevalent, is in utmost need for community genetics services. Strategies need to be developed to familiarize public health officials and medical professionals with medical genetics leading to a public health infrastructure that delivers community genetics services for the prevention and care of genetic disorders at community level.

BackgroundIn the Arab world, intervention and policy response to non-communicable diseases (NCD) has been weak despite extensive epidemiological evidence highlighting the alarmingly increased prevalence of chronic diseases. Generating genetic information is one key component to promote efficient disease management strategies. This study undertook a scoping review to generate the profile of the undertaken research on genetics of NCD publications in selected Arab countries. An analysis of the research produced examined the extent, range, nature, topic and methods of published research. The study aimed at identifying the gaps in genetic NCD research to inform policy action for NCD prevention and control.MethodsThe scoping review was conducted based on the five-stage methodological framework and included countries in Arab region selected to represent various economies and epidemiological transitions.ResultsThe search identified 555 articles that focus on genetics-NCD research in the selected Arab countries over the duration of this study (January 2000 to December 2013). The most commonly conducted research was descriptive and clinically focused, rather than etiologically focused. Country-specific carrier and risk screening studies were not among the top research designs. The genetic component of certain highly heritable diseases, as well as diabetes, obesity, hypertension, chronic lung dysfunction and metabolic syndrome were all under investigated.ConclusionsThis scoping review identified gaps for further research in the context of bioinformatics and genome-wide association studies. Genetic research in the Arab region has to be redirected towards NCDs with the highest morbidity, heritability and health burden within each country. A focused research plan to include community genetics is required for its proper integration in the Arab community.