The role of mutation rate variation and genetic diversity in the architecture of human disease

Background We have investigated the role that the mutation rate and the structure of genetic variation at a locus play in determining whether a gene is involved in disease. We predict that the mutation rate and its genetic diversity should be higher in genes associated with disease, unless all genes that could cause disease have already been identified. Results Consistent with our predictions we find that genes associated with Mendelian and complex disease are substantially longer than non-disease genes. However, we find that both Mendelian and complex disease genes are found in regions of the genome with relatively low mutation rates, as inferred from intron divergence between humans and chimpanzees, and they are predicted to have similar rates of non-synonymous mutation as other genes. Finally, we find that disease genes are in regions of significantly elevated genetic diversity, even when variation in the rate of mutation is controlled for. The effect is small nevertheless. Conclusions Our results suggest that gene length contributes to whether a gene is associated with disease. However, the mutation rate and the genetic architecture of the locus appear to play only a minor role in determining whether a gene is associated with disease

Climate Change and American Bullfrog Invasion: What Could We Expect in South America?

BACKGROUND: Biological invasion and climate change pose challenges to biodiversity conservation in the 21(st) century. Invasive species modify ecosystem structure and functioning and climatic changes are likely to produce invasive species' range shifts pushing some populations into protected areas. The American Bullfrog (Lithobates catesbeianus) is one of the hundred worst invasive species in the world. Native from the southeast of USA, it has colonized more than 75% of South America where it has been reported as a highly effective predator, competitor and vector of amphibian diseases. METHODOLOGY/PRINCIPAL FINDINGS: We modeled the potential distribution of the bullfrog in its native range based on different climate models and green-house gases emission scenarios, and projected the results onto South America for the years of 2050 and 2080. We also overlaid projected models onto the South American network of protected areas. Our results indicate a slight decrease in potential suitable area for bullfrog invasion, although protected areas will become more climatically suitable. Therefore, invasion of these sites is forecasted. CONCLUSION/SIGNIFICANCE: We provide new evidence supporting the vulnerability of the Atlantic Forest Biodiversity Hotspot to bullfrog invasion and call attention to optimal future climatic conditions of the Andean-Patagonian forest, eastern Paraguay, and northwestern Bolivia, where invasive populations have not been found yet. We recommend several management and policy strategies to control bullfrog invasion and argue that these would be possible if based on appropriate articulation among government agencies, NGOs, research institutions and civil society

Large scale variation in the rate of germ-line de novo mutation, base composition, divergence and diversity in humans

It has long been suspected that the rate of mutation varies across the human genome at a large scale based on the divergence between humans and other species. However, it is now possible to directly investigate this question using the large number of de novo mutations (DNMs) that have been discovered in humans through the sequencing of trios. We investi- gate a number of questions pertaining to the distribution of mutations using more than 130,000 DNMs from three large datasets. We demonstrate that the amount and pattern of variation differs between datasets at the 1MB and 100KB scales probably as a consequence of differences in sequencing technology and processing. In particular, datasets show differ- ent patterns of correlation to genomic variables such as replication time. Never-the-less there are many commonalities between datasets, which likely represent true patterns. We show that there is variation in the mutation rate at the 100KB, 1MB and 10MB scale that can- not be explained by variation at smaller scales, however the level of this variation is modest at large scales–at the 1MB scale we infer that ~90% of regions have a mutation rate within 50% of the mean. Different types of mutation show similar levels of variation and appear to vary in concert which suggests the pattern of mutation is relatively constant across the genome. We demonstrate that variation in the mutation rate does not generate large-scale variation in GC-content, and hence that mutation bias does not maintain the isochore struc- ture of the human genome. We find that genomic features explain less than 40% of the explainable variance in the rate of DNM. As expected the rate of divergence between spe- cies is correlated to the rate of DNM. However, the correlations are weaker than expected if all the variation in divergence was due to variation in the mutation rate. We provide evidence that this is due the effect of biased gene conversion on the probability that a mutation will become fixed. In contrast to divergence, we find that most of the variation in diversity can be explained by variation in the mutation rate. Finally, we show that the correlation between divergence and DNM density declines as increasingly divergent species are considered

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Darwinian and demographic forces affecting human protein coding genes

Past demographic changes can produce distortions in patterns of genetic variation that can mimic the appearance of natural selection unless the demographic effects are explicitly removed. Here we fit a detailed model of human demography that incorporates divergence, migration, admixture, and changes in population size to directly sequenced data from 13,400 protein coding genes from 20 European-American and 19 African-American individuals. Based on this demographic model, we use several new and established statistical methods for identifying genes with extreme patterns of polymorphism likely to be caused by Darwinian selection, providing the first genome-wide analysis of allele frequency distributions in humans based on directly sequenced data. The tests are based on observations of excesses of high frequency–derived alleles, excesses of low frequency–derived alleles, and excesses of differences in allele frequencies between populations. We detect numerous new genes with strong evidence of selection, including a number of genes related to psychiatric and other diseases. We also show that microRNA controlled genes evolve under extremely high constraints and are more likely to undergo negative selection than other genes. Furthermore, we show that genes involved in muscle development have been subject to positive selection during recent human history. In accordance with previous studies, we find evidence for negative selection against mutations in genes associated with Mendelian disease and positive selection acting on genes associated with several complex diseases