Extinction in a branching process: Why some of the fittest strategies cannot guarantee survival

The fitness of a biological strategy is typically measured by its expected reproductive rate, the first moment of its offspring distribution. However, strategies with high expected rates can also have high probabilities of extinction. A similar situation is found in gambling and investment, where strategies with a high expected payoff can also have a high risk of ruin. We take inspiration from the gambler's ruin problem to examine how extinction is related to population growth. Using moment theory we demonstrate how higher moments can impact the probability of extinction. We discuss how moments can be used to find bounds on the extinction probability, focusing on s-convex ordering of random variables, a method developed in actuarial science. This approach generates "best case" and "worst case" scenarios to provide upper and lower bounds on the probability of extinction. Our results demonstrate that even the most fit strategies can have high probabilities of extinction.Comment: Best case extrema adde

Measuring microsatellite conservation in mammalian evolution with a phylogenetic birth-death model.

Microsatellites make up ∼3% of the human genome, and there is increasing evidence that some microsatellites can have important functions and can be conserved by selection. To investigate this conservation, we performed a genome-wide analysis of human microsatellites and measured their conservation using a binary character birth--death model on a mammalian phylogeny. Using a maximum likelihood method to estimate birth and death rates for different types of microsatellites, we show that the rates at which microsatellites are gained and lost in mammals depend on their sequence composition, length, and position in the genome. Additionally, we use a mixture model to account for unequal death rates among microsatellites across the human genome. We use this model to assign a probability-based conservation score to each microsatellite. We found that microsatellites near the transcription start sites of genes are often highly conserved, and that distance from a microsatellite to the nearest transcription start site is a good predictor of the microsatellite conservation score. An analysis of gene ontology terms for genes that contain microsatellites near their transcription start site reveals that regulatory genes involved in growth and development are highly enriched with conserved microsatellites

The genetics of adaptive shape shift in stickleback: pleiotropy and effect size.

The distribution of effect sizes of genes underlying adaptation is unknown (Orr 2005

Tandem repeats as sources of variation

Tandem repeats make up a small fraction of the human genome, but due to their high rates of expansion and contraction, they are predicted to be highly polymorphic. When tandem repeats are found within functional regions of the genome, these polymorphisms can modulate phenotypes, which can result in disease. This thesis investigates tandem repeats composed of short subunits, called microsatellites, short tandem repeats, or simple sequence repeats. Part of this thesis investigates how these tandem repeats can be conserved in mammals, and explains how the most conserved of these repeats are found in regions of the genome that regulate gene expression and mRNA translation. Many of these highly conserved microsatellites are found in genes that regulate development, highlighting the exciting possibility that mammalian development can be modulated by these hypermutable elements. Some regulatory microsatellites have the potential to form unusual DNA structures, and these structures are known to regulate RNA production and DNA replication. To further investigate how tandem repeats can form alternative DNA structures, this thesis examines how DNA polymerase interacts with repeats known to form various structures. A relatively new method of DNA sequencing, from Pacific Biosciences, records polymerase activity in real-time and at single-molecule resolution. The sequencer kinetics are used to study the interaction between polymerase and two structures: G-quadruplex DNA, known for its ability to pause polymerase and its prevalence in regulatory regions; and Z-DNA, a left-handed double helix that is also prevalent in regulatory regions. In total, this thesis examines how human microsatellites can be sources of phenotypic variation, and discusses methods for genotyping and interpreting the genetic variation prevalent in these repeats

Potential use of RNA-dependent RNA polymerase (RdRp) inhibitor against SARS-CoV2 infection

Favipiravir, an inhibitor of RNA-dependent RNA polymerase used against the Japanese flu, was recently suggested as a potential COVID-19 inhibitor. Since Favipiravir targets a critical and a viral specific process, using it as a treatment could be beneficial in slowing the outbreak. Though there have been many suggested antivirals to treat SARS-CoV-2 infection, most treatments target host-associated pathways that may cause adverse effects, Favipiravir or similar combination may be the best remedy against COVID-19 pandemic

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals

Microsatellite Tandem Repeats Are Abundant in Human Promoters and Are Associated with Regulatory Elements

<div><p>Tandem repeats are genomic elements that are prone to changes in repeat number and are thus often polymorphic. These sequences are found at a high density at the start of human genes, in the gene’s promoter. Increasing empirical evidence suggests that length variation in these tandem repeats can affect gene regulation. One class of tandem repeats, known as microsatellites, rapidly alter in repeat number. Some of the genetic variation induced by microsatellites is known to result in phenotypic variation. Recently, our group developed a novel method for measuring the evolutionary conservation of microsatellites, and with it we discovered that human microsatellites near transcription start sites are often highly conserved. In this study, we examined the properties of microsatellites found in promoters. We found a high density of microsatellites at the start of genes. We showed that microsatellites are statistically associated with promoters using a wavelet analysis, which allowed us to test for associations on multiple scales and to control for other promoter related elements. Because promoter microsatellites tend to be G/C rich, we hypothesized that G/C rich regulatory elements may drive the association between microsatellites and promoters. Our results indicate that CpG islands, G-quadruplexes (G4) and untranslated regulatory regions have highly significant associations with microsatellites, but controlling for these elements in the analysis does not remove the association between microsatellites and promoters. Due to their intrinsic lability and their overlap with predicted functional elements, these results suggest that many promoter microsatellites have the potential to affect human phenotypes by generating mutations in regulatory elements, which may ultimately result in disease. We discuss the potential functions of human promoter microsatellites in this context.</p> </div