Genomic and transcriptomic insights into the regulation of snake venom production

Genomic and transcriptomic insights into the regulation of snake venom production

Adam D Hargreaves, Martin T Swain, Matthew J Hegarty, Darren W Logan, John F Mulley

The gene regulatory mechanisms underlying the rapid replenishment of snake venom following expenditure are currently unknown. Using a comparative transcriptomic approach we find that venomous and non-venomous species produce similar numbers of secreted products in their venom or salivary glands and that only one transcription factor (Tbx3) is expressed in venom glands but not salivary glands. We also find evidence for temporal variation in venom production. We have generated a draft genome sequence for the painted saw-scaled viper, Echis coloratus, and identified conserved transcription factor binding sites in the upstream regions of venom genes. We find binding sites to be conserved across members of the same gene family, but not between gene families, indicating that multiple gene regulatory networks are involved in venom production. Finally, we suggest that negative regulation may be important for rapid activation of the venom replenishment cycle.

Fixation in large populations: a continuous view of a discrete problem

Fixation in large populations: a continuous view of a discrete problem

Fabio A. C. C. Chalub, Max O. Souza
(Submitted on 27 Aug 2014)

We study fixation in large, but finite populations with two types, and dynamics governed by birth-death processes. By considering a restricted class of such processes, which includes most classical evolutionary processes, we derive a continuous approximation for the probability of fixation that is valid beyond the weak-selection (WS) limit. Indeed, in the derivation three regimes naturally appear: selection-driven, balanced, and quasi-neutral — the latter two require WS, while the former can appear with or without WS. From the continuous approximations, we then obtain asymptotic approximations for evolutions with at most one equilibrium, in the selection-driven regime, that does not preclude a weak-selection regime. As an application, we show that the fixation pattern for the Hawk and Dove game satisfies what we term the one-half law: if the Evolutionary Stable Strategy (ESS) is outside a small interval around $\sfrac{1}{2}$, the fixation is of dominance type. We also show that outside of the weak-selection regime the dynamics of large populations can have very little resemblance to the infinite population case. In addition, we also show results for the case of two equilibria. Finally, we present a continuous restatement of the definition of an ESSN strategy, that is valid for large populations. We then present two applications of this restatement: we obtain a definition valid in the quasi-neutral regime that recovers the one-third law under linear fitness and, as a generalisation, we introduce the concept of critical-frequency.

Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth

Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth

Fabien Delahaye, Neil Ari Wijetunga, Hye J Heo, Jessica N Tozour, Yong Mei Zhao, John M Greally, Francine H Einstein

Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34+ hematopoietic stem/progenitor cells (HSPCs) showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. A sexually dimorphic response was found, intrauterine growth restriction (IUGR) associated with substantially greater epigenetic dysregulation in males but large for gestational age (LGA) growth affecting females predominantly. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular aging and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life.

DISEASES: Text mining and data integration of disease–gene associations

DISEASES: Text mining and data integration of disease–gene associations

Sune Pletscher-Frankild, Albert Pallejà, Kalliopi Tsafou, Janos X Binder, Lars Juhl Jensen

Text mining is a flexible technology that can be applied to numerous different tasks in biology and medicine. We present a system for extracting disease–gene associations from biomedical abstracts. The system consists of a highly efficient dictionary-based tagger for named entity recognition of human genes and diseases, which we combine with a scoring scheme that takes into account co-occurrences both within and between sentences. We show that this approach is able to extract half of all manually curated associations with a false positive rate of only 0.16%. Nonetheless, text mining should not stand alone, but be combined with other types of evidence. For this reason, we have developed the DISEASES resource, which integrates the results from text mining with manually curated disease–gene associations, cancer mutation data, and genome-wide association studies from existing databases. The DISEASES resource is accessible through a user-friendly web interface at, where the text-mining software and all associations are also freely available for download.

A genomic map of the effects of linked selection in Drosophila

A genomic map of the effects of linked selection in Drosophila

Eyal Elyashiv, Shmuel Sattath, Tina T. Hu, Alon Strustovsky, Graham McVicker, Peter Andolfatto, Graham Coop, Guy Sella
(Submitted on 23 Aug 2014)

Natural selection at one site shapes patterns of genetic variation at linked sites. Quantifying the effects of ‘linked selection’ on levels of genetic diversity is key to making reliable inference about demography, building a null model in scans for targets of adaptation, and learning about the dynamics of natural selection. Here, we introduce the first method that jointly infers parameters of distinct modes of linked selection, notably background selection and selective sweeps, from genome-wide diversity data, functional annotations and genetic maps. The central idea is to calculate the probability that a neutral site is polymorphic given local annotations, substitution patterns, and recombination rates. Information is then combined across sites and samples using composite likelihood in order to estimate genome-wide parameters of distinct modes of selection. In addition to parameter estimation, this approach yields a map of the expected neutral diversity levels along the genome. To illustrate the utility of our approach, we apply it to genome-wide resequencing data from 125 lines in Drosophila melanogaster and reliably predict diversity levels at the 1Mb scale. Our results corroborate estimates of a high fraction of beneficial substitutions in proteins and untranslated regions (UTR). They allow us to distinguish between the contribution of sweeps and other modes of selection around amino acid substitutions and to uncover evidence for pervasive sweeps in untranslated regions (UTRs). Our inference further suggests a substantial effect of linked selection from non-classic sweeps. More generally, we demonstrate that linked selection has had a larger effect in reducing diversity levels and increasing their variance in D. melanogaster than previously appreciated.

Escape from crossover interference increases with maternal age

Escape from crossover interference increases with maternal age

Christopher L. Campbell, Nicholas A. Furlotte, Nick Eriksson, David Hinds, Adam Auton
(Submitted on 23 Aug 2014)

Recombination plays a fundamental role in meiosis, ensuring the proper segregation of chromosomes and contributing to genetic diversity by generating novel combinations of alleles. Using data derived from directUtoUconsumer genetic testing, we investigated patterns of recombination in over 4,200 families. Our analysis revealed a number of sex differences in the distribution of recombination. We find the fraction of male events occurring within hotspots to be 4.6% higher than for females. We confirm that the recombination rate increases with maternal age, while hotspot usage decreases, with no such effects observed in males. Finally, we show that the placement of female recombination events becomes increasingly deregulated with maternal age, with an increasing fraction of events appearing to escape crossover interference.

IPED2: Inheritance Path based Pedigree Reconstruction Algorithm for Complicated Pedigrees

IPED2: Inheritance Path based Pedigree Reconstruction Algorithm for Complicated Pedigrees

Dan He, Zhanyong Wang, Laxmi Parida, Eleazar Eskin
(Submitted on 23 Aug 2014)

Reconstruction of family trees, or pedigree reconstruction, for a group of individuals is a fundamental problem in genetics. The problem is known to be NP-hard even for datasets known to only contain siblings. Some recent methods have been developed to accurately and efficiently reconstruct pedigrees. These methods, however, still consider relatively simple pedigrees, for example, they are not able to handle half-sibling situations where a pair of individuals only share one parent. In this work, we propose an efficient method, IPED2, based on our previous work, which specifically targets reconstruction of complicated pedigrees that include half-siblings. We note that the presence of half-siblings makes the reconstruction problem significantly more challenging which is why previous methods exclude the possibility of half-siblings. We proposed a novel model as well as an efficient graph algorithm and experiments show that our algorithm achieves relatively accurate reconstruction. To our knowledge, this is the first method that is able to handle pedigree reconstruction based on genotype data only when half-sibling exists in any generation of the pedigree.