In the Garden of Branching Processes

The current paper surveys and develops numerical methods for Markovian multitype branching processes in continuous time. Particular attention is paid to the calculation of means, variances, extinction probabilities, and marginal distributions in the presence of a Poisson stream of immigrant particles. The Poisson process assumption allows for temporally complex patterns of immigration and facilitates application of marked Poisson processes and Campbell’s formulas. The methods and formulas derived are applied to four models: two population genetics models, a model for vaccination against an infectious disease in a community of households, and a model for the growth of resistant HIV virus in patients undergoing drug therap

Activity of Genes with Functions in Human Williams-Beuren Syndrome Is Impacted by Mobile Element Insertions in the Gray Wolf Genome.

In canines, transposon dynamics have been associated with a hyper-social behavioral syndrome, although the functional mechanism has yet to be described. We investigate the epigenetic and transcriptional consequences of these behavior-associated mobile element insertions (MEIs) in dogs and Yellowstone gray wolves. We posit that the transposons themselves may not be the causative feature; rather, their transcriptional regulation may exert the functional impact. We survey four outlier transposons associated with hyper-sociability, with the expectation that they are targeted for epigenetic silencing. We predict hyper-methylation of MEIs, suggestive that the epigenetic silencing of and not the MEIs themselves may be driving dysregulation of nearby genes. We found that transposon-derived sequences are significantly hyper-methylated, regardless of their copy number or species. Further, we have assessed transcriptome sequence data and found evidence that MEIs impact the expression levels of six genes (WBSCR17, LIMK1, GTF2I, WBSCR27, BAZ1B, and BCL7B), all of which have known roles in human Williams-Beuren syndrome due to changes in copy number, typically hemizygosity. Although further evidence is needed, our results suggest that a few insertions alter local expression at multiple genes, likely through a cis-regulatory mechanism that excludes proximal methylation

BioSimulator.jl: Stochastic simulation in Julia

Biological systems with intertwined feedback loops pose a challenge to mathematical modeling efforts. Moreover, rare events, such as mutation and extinction, complicate system dynamics. Stochastic simulation algorithms are useful in generating time-evolution trajectories for these systems because they can adequately capture the influence of random fluctuations and quantify rare events. We present a simple and flexible package, BioSimulator.jl, for implementing the Gillespie algorithm, $\tau$-leaping, and related stochastic simulation algorithms. The objective of this work is to provide scientists across domains with fast, user-friendly simulation tools. We used the high-performance programming language Julia because of its emphasis on scientific computing. Our software package implements a suite of stochastic simulation algorithms based on Markov chain theory. We provide the ability to (a) diagram Petri Nets describing interactions, (b) plot average trajectories and attached standard deviations of each participating species over time, and (c) generate frequency distributions of each species at a specified time. BioSimulator.jl's interface allows users to build models programmatically within Julia. A model is then passed to the simulate routine to generate simulation data. The built-in tools allow one to visualize results and compute summary statistics. Our examples highlight the broad applicability of our software to systems of varying complexity from ecology, systems biology, chemistry, and genetics. The user-friendly nature of BioSimulator.jl encourages the use of stochastic simulation, minimizes tedious programming efforts, and reduces errors during model specification.Comment: 27 pages, 5 figures, 3 table

Impact of genetic counseling and Connexin-26 and Connexin-30 testing on deaf identity and comprehension of genetic test results in a sample of deaf adults: A prospective, longitudinal study

Using a prospective, longitudinal study design, this paper addresses the impact of genetic counseling and testing for deafness on deaf adults and the Deaf community. This study specifically evaluated the effect of genetic counseling and Connexin-26 and Connexin-30 genetic test results on participants' deaf identity and understanding of their genetic test results. Connexin-26 and Connexin-30 genetic testing was offered to participants in the context of linguistically and culturally appropriate genetic counseling. Questionnaire data collected from 209 deaf adults at four time points (baseline, immediately following pre-test genetic counseling, 1-month following genetic test result disclosure, and 6-months after result disclosure) were analyzed. Four deaf identity orientations (hearing, marginal, immersion, bicultural) were evaluated using subscales of the Deaf Identity Development Scale-Revised. We found evidence that participants understood their specific genetic test results following genetic counseling, but found no evidence of change in deaf identity based on genetic counseling or their genetic test results. This study demonstrated that culturally and linguistically appropriate genetic counseling can improve deaf clients' understanding of genetic test results, and the formation of deaf identity was not directly related to genetic counseling or Connexin-26 and Connexin-30 genetic test results.CGSP received funding from the National Human Genome Research Institute (Ethical, Legal, and Social Issues Branch) (R01 HG003871, http://projectreporter.nih.gov); and from the Brocher Foundation (http://www.brocher.ch/en/brocher-fundati???on-in-brief/) in support of this research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Effect of Pre-test Genetic Counseling for Deaf Adults on Knowledge of Genetic Testing

Empirical data on genetic counseling outcomes in the deaf population are needed to better serve this population. This study was an examination of genetics knowledge before and after culturally and linguistically appropriate pre-test genetic counseling in a diverse deaf adult sample. Individuals ≥18 years old with early-onset sensorineural deafness were offered connexin-26/30 testing and genetic counseling. Participants completed questionnaires containing 10 genetics knowledge items at baseline and following pre-test genetic counseling. The effects of genetic counseling, prior beliefs about etiology, and participant’s preferred language on genetics knowledge scores were assessed (n = 244). Pre-test genetic counseling (p = .0007), language (p < .0001), prior beliefs (p < .0001), and the interaction between counseling and beliefs (p = .035) were predictors of genetics knowledge. American Sign Language (ASL)-users and participants with “non-genetic/unknown” prior beliefs had lower knowledge scores than English-users and participants with “genetic” prior beliefs, respectively. Genetics knowledge improved after genetic counseling regardless of participants’ language; knowledge change was greater for the “non-genetic/unknown” beliefs group than the “genetic” beliefs group. ASL-users’ lower knowledge scores are consistent with evidence that ethnic and cultural minority groups have less genetics knowledge, perhaps from exposure and access disparities. Culturally and linguistically appropriate pre-test genetic counseling significantly improved deaf individuals’ genetics knowledge. Assessing deaf individuals’ prior beliefs is important for enhancing genetics knowledge

Effect of Rhesus D incompatibility on schizophrenia depends on offspring sex.

Rhesus D incompatibility increases risk for schizophrenia, with some evidence that risk is limited to male offspring. The purpose of this study is to determine whether risk for schizophrenia due to Rhesus D incompatibility differs by offspring sex using a nuclear family-based candidate gene approach and a meta-analysis approach. The genetic study is based on a sample of 277 nuclear families with RHD genotype data on at least one parent and at least one child diagnosed with schizophrenia or related disorder. Meta-analysis inclusion criteria were (1) well-defined sample of schizophrenia patients with majority born before 1970, (2) Rhesus D incompatibility phenotype or genotype data available on mother and offspring, and by offspring sex. Two of ten studies, plus the current genetic study sample, fulfilled these criteria, for a total of 358 affected males and 226 affected females. The genetic study found that schizophrenia risk for incompatible males was significantly greater than for compatible offspring (p=0.03), while risk for incompatible and compatible females was not significantly different (p=.32). Relative risks for incompatible males and females were not significantly different from each other. Meta-analysis using a larger number of affected males and females supports their difference. Taken together, these results provide further support that risk of schizophrenia due to Rhesus D incompatibility is limited to incompatible males, although a weak female incompatibility effect cannot be excluded. Sex differences during fetal neurodevelopment should be investigated to fully elucidate the etiology of schizophrenia

Rings Reconcile Genotypic and Phenotypic Evolution within the Proteobacteria.

Although prokaryotes are usually classified using molecular phylogenies instead of phenotypes after the advent of gene sequencing, neither of these methods is satisfactory because the phenotypes cannot explain the molecular trees and the trees do not fit the phenotypes. This scientific crisis still exists and the profound disconnection between these two pillars of evolutionary biology--genotypes and phenotypes--grows larger. We use rings and a genomic form of goods thinking to resolve this conundrum (McInerney JO, Cummins C, Haggerty L. 2011. Goods thinking vs. tree thinking. Mobile Genet Elements. 1:304-308; Nelson-Sathi S, et al. 2015. Origins of major archaeal clades correspond to gene acquisitions from bacteria. Nature 517:77-80). The Proteobacteria is the most speciose prokaryotic phylum known. It is an ideal phylogenetic model for reconstructing Earth's evolutionary history. It contains diverse free living, pathogenic, photosynthetic, sulfur metabolizing, and symbiotic species. Due to its large number of species (Whitman WB, Coleman DC, Wiebe WJ. 1998. Prokaryotes: the unseen majority. Proc Nat Acad Sci U S A. 95:6578-6583) it was initially expected to provide strong phylogenetic support for a proteobacterial tree of life. But despite its many species, sequence-based tree analyses are unable to resolve its topology. Here we develop new rooted ring analyses and study proteobacterial evolution. Using protein family data and new genome-based outgroup rooting procedures, we reconstruct the complex evolutionary history of the proteobacterial rings (combinations of tree-like divergences and endosymbiotic-like convergences). We identify and map the origins of major gene flows within the rooted proteobacterial rings (P &lt; 3.6 × 10(-6)) and find that the evolution of the "Alpha-," "Beta-," and "Gammaproteobacteria" is represented by a unique set of rings. Using new techniques presented here we also root these rings using outgroups. We also map the independent flows of genes involved in DNA-, RNA-, ATP-, and membrane- related processes within the Proteobacteria and thereby demonstrate that these large gene flows are consistent with endosymbioses (P &lt; 3.6 × 10(-9)). Our analyses illustrate what it means to find that a gene is present, or absent, within a gene flow, and thereby clarify the origin of the apparent conflicts between genotypes and phenotypes. Here we identify the gene flows that introduced photosynthesis into the Alpha-, Beta-, and Gammaproteobacteria from the common ancestor of the Actinobacteria and the Firmicutes. Our results also explain why rooted rings, unlike trees, are consistent with the observed genotypic and phenotypic relationships observed among the various proteobacterial classes. We find that ring phylogenies can explain the genotypes and the phenotypes of biological processes within large and complex groups like the Proteobacteria

The Quantitative-MFG Test: A linear mixed effect model to detect maternal-offspring gene interactions

Maternal-offspring gene interactions, aka maternal-fetal genotype (MFG) incompatibilities, are neglected in complex diseases and quantitative trait studies. They are implicated in birth to adult onset diseases but there are limited ways to investigate their influence on quantitative traits. We present the Quantitative-MFG (QMFG) test, a linear mixed model where maternal and offspring genotypes are fixed effects and residual correlations between family members are random effects. The QMFG handles families of any size, common or general scenarios of MFG incompatibility, and additional covariates. We develop likelihood ratio tests (LRTs) and rapid score tests and show they provide correct inference. In addition, the LRT’s alternative model provides unbiased parameter estimates. We show that testing the association of SNPs by fitting a standard model, which only considers the offspring genotypes, has very low power or can lead to incorrect conclusions. We also show that offspring genetic effects are missed if the MFG modeling assumptions are too restrictive. With GWAS data from the San Antonio Family Heart Study, we demonstrate that the QMFG score test is an effective and rapid screening tool. The QMFG test therefore has important potential to identify pathways of complex diseases for which the genetic etiology remains to be discovered