Selective Mutation Accumulation: A Computational Model of the Paternal Age Effect

Motivation: As the mean age of parenthood grows, the effect of parental age on genetic disease and child health becomes ever more important. A number of autosomal dominant disorders show a dramatic paternal age effect due to selfish mutations: substitutions that grant spermatogonial stem cells (SSCs) a selective advantage in the testes of the father, but have a deleterious effect in offspring. In this paper we present a computational technique to model the SSC niche in order to examine the phenomenon and draw conclusions across different genes and disorders. Results: We used a Markov chain to model the probabilities of mutation and positive selection with cell divisions. The model was fitted to available data on disease incidence and also mutation assays of sperm donors. Strength of selective advantage is presented for a range of disorders including Apert\u27s syndrome and achondroplasia. Incidence of the diseases was predicted closely for most disorders and was heavily influenced by the site-specific mutation rate and the number of mutable alleles. The model also successfully predicted a stronger selective advantage for more strongly activating gain-of-function mutations within the same gene. Both positive selection and the rate of copy-error mutations are important in adequately explaining the paternal age effect. Availability and Implementation: C++/R source codes and documentation including compilation instructions are available under GNU license at https://github.com/anwala/NicheSimulation. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

WHOI Hawaii Ocean Timeseries Station (WHOTS) : WHOTS-4 2007 mooring turnaround cruise report

The Woods Hole Oceanographic Institution (WHOI) Hawaii Ocean Timeseries (HOT) Site (WHOTS), 100 km north of Oahu, Hawaii, is intended to provide long-term, high-quality air-sea fluxes as a part of the NOAA Climate Observation Program. The WHOTS mooring also serves as a coordinated part of the HOT program, contributing to the goals of observing heat, fresh water and chemical fluxes at a site representative of the oligotrophic North Pacific Ocean. The approach is to maintain a surface mooring outfitted for meteorological and oceanographic measurements at a site near 22.75°N, 158°W by successive mooring turnarounds. These observations will be used to investigate air–sea interaction processes related to climate variability. The first three WHOTS moorings (WHOTS-1 through 3) were deployed in August 2004, July 2005 and June 2006, respectively. This report documents recovery of the WHOTS-3 mooring and deployment of the fourth mooring (WHOTS-4). Both moorings used Surlyn foam buoys as the surface element and were outfitted with two Air–Sea Interaction Meteorology (ASIMET) systems. Each ASIMET system measures, records, and transmits via Argos satellite the surface meteorological variables necessary to compute air–sea fluxes of heat, moisture and momentum. The upper 155 m of the moorings were outfitted with oceanographic sensors for the measurement of temperature, conductivity and velocity in a cooperative effort with R. Lukas of the University of Hawaii. A pCO2 system was installed on the WHOT-3 buoy in a cooperative effort with Chris Sabine at the Pacific Marine Environmental Laboratory. The WHOTS mooring turnaround was done on the University of Hawaii research vessel Kilo Moana, Cruise KM-07-08, by the Upper Ocean Processes Group of the Woods Hole Oceanographic Institution. The cruise took place between 24 June and 1 July 2007. Operations began with deployment of the WHOTS-4 mooring on 25 June at approximately 22°40.2′N, 157°57.0′W in 4756 m of water. This was followed by meteorological intercomparisons and CTDs at the WHOTS-4 and WHOTS-3 sites. The WHOTS-3 mooring was recovered on June 28th followed by CTD operations at the HOT site and shipboard meteorological observations at several sites to the south of the mooring site. This report describes these cruise operations, as well as some of the in-port operations and pre-cruise buoy preparations.Funding was provided by the National Oceanic and Atmospheric Administration under Grant No. NA17RJ1223 for the Cooperative Institute for Climate and Ocean Research (CICOR)

WHOI Hawaii Ocean Timeseries Station (WHOTS) : WHOTS-5 2008 mooring turnaround cruise report

The Woods Hole Oceanographic Institution (WHOI) Hawaii Ocean Timeseries (HOT) Site (WHOTS), 100 km north of Oahu, Hawaii, is intended to provide long-term, high-quality air-sea fluxes as a part of the NOAA Climate Observation Program. The WHOTS mooring also serves as a coordinated part of the HOT program, contributing to the goals of observing heat, fresh water and chemical fluxes at a site representative of the oligotrophic North Pacific Ocean. The approach is to maintain a surface mooring outfitted for meteorological and oceanographic measurements at a site near 22.75°N, 158°W by successive mooring turnarounds. These observations will be used to investigate air–sea interaction processes related to climate variability. The first four WHOTS moorings (WHOTS-1 through 4) were deployed in August 2004, July 2005, June 2006, and June 2007, respectively. This report documents recovery of the WHOTS-4 mooring and deployment of the fifth mooring (WHOTS-5). Both moorings used Surlyn foam buoys as the surface element and were outfitted with two Air–Sea Interaction Meteorology (ASIMET) systems. Each ASIMET system measures, records, and transmits via Argos satellite the surface meteorological variables necessary to compute air–sea fluxes of heat, moisture and momentum. The upper 155 m of the moorings were outfitted with oceanographic sensors for the measurement of temperature, conductivity and velocity in a cooperative effort with R. Lukas of the University of Hawaii. A pCO2 system was installed on the WHOTS-5 buoy in a cooperative effort with Chris Sabine at the Pacific Marine Environmental Laboratory. The WHOTS mooring turnaround was done on the University of Hawaii research vessel Kilo Moana, Cruise KM-08-08, by the Upper Ocean Processes Group of the Woods Hole Oceanographic Institution. The cruise took place between 3 and 11 June 2008. Operations began with deployment of the WHOTS-5 mooring on 5 June at approximately 22°46.1'N, 157°54.1'W in 4702 m of water. This was followed by meteorological intercomparisons and CTDs at the WHOTS-4 site. A period of calmer weather was taken advantage of to recover WHOTS-4 on 6 June 2008. The Kilo Moana then returned to the WHOTS-5 mooring for CTD operations and meteorological intercomparisons. This report describes these cruise operations, as well as some of the in-port operations and pre-cruise buoy preparations.Funding was provided by the National Oceanic and Atmospheric Administration under Grant No. NA17RJ1223 for the Cooperative Institute for Climate and Ocean Research (CICOR)

Immunosuppressive niche engineering at the onset of human colorectal cancer

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune “cold” ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC

Alzheimer’s disease susceptibility gene apolipoprotein e (APOE) and blood biomarkers in UK Biobank (N=395,769)

Background: Alzheimer’s disease (AD) is a neurodegenerative condition where the underlying etiology is still unclear. Investigating the potential influence of apolipoprotein E (APOE), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. Objective: Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank. Methods:After quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential associations between APOE genotypes and biomarkers. Results: Several biomarkers significantly associated with APOE ɛ4 ‘risk’ and ɛ2 ‘protective’ genotypes (versus neutral ɛ3/ɛ3). Most associations supported previous data: for example, ɛ4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p < 0.001) and ɛ2 with lower LDL (b = –0.456 SDs, p < 0.001). There were however instances of associations found in unexpected directions: e.g., ɛ4 and increased insulin-like growth factor (IGF-1) (b = 0.017, p < 0.001) where lower levels have been previously suggested as an AD risk factor. Conclusion: These findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence herein supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways