The genetic architecture of complex traits underlying physiology and disease in most organisms remains elusive. We still know little about the number of genes that underlie these traits, the magnitude of their effects, or the extent to which they interact. Chromosome substitution strains (CSSs) enable statistically powerful studies based on testing engineered inbred strains that have single, unique, and nonoverlapping genetic differences, thereby providing measures of phenotypic effects that are attributable to individual chromosomes. Here, we report a study of phenotypic effects and gene interactions for 90 blood, bone, and metabolic traits in a mouse CSS panel and 54 traits in a rat CSS panel. Two key observations emerge about the genetic architecture of these traits. First, the traits tend to be highly polygenic: across the genome, many individual chromosome substitutions each had significant phenotypic effects and, within each of the chromosomes studied, multiple distinct loci were found. Second, strong epistasis was found among the individual chromosomes. Specifically, individual chromosome substitutions often conferred surprisingly large effects (often a substantial fraction of the entire phenotypic difference between the parental strains), with the result that the sum of these individual effects often dramatically exceeded the difference between the parental strains. We suggest that strong, pervasive epistasis may reflect the presence of several phenotypically-buffered physiological states. These results have implications for identification of complex trait genes, developmental and physiological studies of phenotypic variation, and opportunities to engineer phenotypic outcomes in complex biological systems. chromosome substitution ͉ genetic variation ͉ quantitative trait loci

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, with approximately 70% of cases resulting from hepatitis B and C viral infections, aflatoxin exposure, chronic alcohol use or genetic liver diseases. The remaining approximately 30% of cases are associated with obesity, type 2 diabetes and related metabolic diseases, although a direct link between these pathologies and HCCs has not been established. We tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that C57BL/6J but not A/J males were susceptible to non-alcoholic steatohepatitis (NASH) and HCC on a high-fat but not low-fat diet. This strain-diet interaction represents an important model for genetically controlled, diet-induced HCC. Susceptible mice showed morphological characteristics of NASH (steatosis, hepatitis, fibrosis and cirrhosis), dysplasia and HCC. mRNA profiles of HCCs versus tumor-free liver showed involvement of two signaling networks, one centered on Myc and the other on NFkappaB, similar to signaling described for the two major classes of HCC in humans. miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment. A switch from high-fat to low-fat diet reversed these outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. A similar diet modification may have important implications for prevention of HCCs in humans.

We conducted active, laboratory-based surveillance for isolates from patients with invasive infections across China from August 2009 to July 2010. DNA sequencing methods were used to define species, and susceptibility to fluconazole and voriconazole was determined by the Clinical and Laboratory Standards Institute M44-A2 disk diffusion method but using up-to-date clinical breakpoints or epidemiological cutoff values. Candida spp. made up 90.5% of the 814 yeast strains isolated, followed by Cryptococcus neoformans (7.7%) and other non-Candida yeast strains (1.7%). Bloodstream isolates made up 42.9% of the strains, isolates from ascitic fluid made up 22.1%, but pus/tissue specimens yielded yeast strains in <5% of the cases. Among the Candida isolates, Candida albicans was the most common species from specimens other than blood (50.1%) but made up only 23% of the bloodstream isolates (P < 0.001). C. parapsilosis complex species were the most common Candida isolates from blood (33.2%). Uncommon bloodstream yeast strains included Trichosporon spp., C. pelliculosa, and the novel species C. quercitrusa, reported for the first time as a cause of candidemia. Most (>94%) of the isolates of C. albicans, C. tropicalis, and the C. parapsilosis complex were susceptible to fluconazole and voriconazole, as were all of the Trichosporon strains; however, 12.2% of the C. glabrata sensu stricto isolates were fluconazole resistant and 17.8% had non-wild-type susceptibility to voriconazole. Seven C. tropicalis strains were cross-resistant to fluconazole and voriconazole; six were from patients in the same institution. Resistance to fluconazole and voriconazole was seen in 31.9% and 13.3% of the uncommon Candida and non-Candida yeast strains, respectively. Causative species and azole susceptibility varied with the geographic region. This study provided clinically useful data on yeast strains and their antifungal susceptibilities in China.

The epidemiology of candidaemia varies between hospitals and geographic regions. Although there are many studies from Asia, a large-scale cross-sectional study across Asia has not been performed. We conducted a 12-month, laboratory-based surveillance of candidaemia at 25 hospitals from China, Hong Kong, India, Singapore, Taiwan and Thailand. The incidence and species distribution of candidaemia were determined. There were 1601 episodes of candidaemia among 1.2 million discharges. The overall incidence was 1.22 episodes per 1000 discharges and varied among the hospitals (range 0.16-4.53 per 1000 discharges) and countries (range 0.25-2.93 per 1000 discharges). The number of Candida blood isolates and the total number of fungal isolates were highly correlated among the six countries (R² = 0.87) and 25 hospitals (R² = 0.77). There was a moderate correlation between incidence of candidaemia and the intensive care unit (ICU)/total bed ratio (R² = 0.47), although ICUs contributed to only 23% of candidaemia cases. Of 1910 blood isolates evaluated, Candida albicans was most frequently isolated (41.3%), followed by Candida tropicalis (25.4%), Candida glabrata (13.9%) and Candida parapsilosis (12.1%). The proportion of C. tropicalis among blood isolates was higher in haemato-oncology wards than others wards (33.7% versus 24.5%, p 0.0058) and was more likely to be isolated from tropical countries than other Asian countries (46.2% versus 18.9%, p 0.04). In conclusion, the ICU settings contribute, at least in part, to the incidence variation among hospitals. The species distribution is different from Western countries. Both geographic and healthcare factors contribute to the variation of species distribution.