Genetic variants that disrupt protein-coding DNA are ubiquitous in the human population, with ~100 such loss-of-function variants per individual. While most loss-of-function variants are rare, a subset have risen to high frequency and occur in a homozygous state in healthy individuals. It is unknown why these common variants are well-tolerated, even though some affect essential genes implicated in Mendelian disease. Here, we combine genomic, proteomic, and biochemical data to demonstrate that many common nonsense variants do not ablate protein production from their host genes. We provide direct evidence for previously proposed mechanisms of gene rescue such as alternative splicing and C-terminal truncation. Furthermore, we identify novel mechanisms of rescue, including alternative translation initiation at non-canonical start codons and stop codon readthrough. Our results suggest a molecular explanation for the mild fitness costs of common nonsense variants, and indicate that translational plasticity plays a prominent role in shaping human genetic diversity.

The origin and evolution of species ranges remains a central focus of historical biogeography and the advent of likelihood methods based on phylogenies has revolutionized the way in which range evolution has been studied. A decade ago, the first elements of what turned out to be a popular inference approach of ancestral ranges based on the processes of Dispersal, local Extinction and Cladogenesis (DEC) was proposed. The success of the DEC model lies in its use of a flexible statistical framework known as a Continuous Time Markov Chain and since, several conceptual and computational improvements have been proposed using this as a baseline approach. In the spirit of the original version of DEC, we introduce DEC eXtended (DECX) by accounting for rapid expansion and local extinction as possible anagenetic events on the phylogeny but without increasing model complexity (i.e. in the number of free parameters). Classical vicariance as a cladogenetic event is also incorporated by making use of temporally flexible constraints on the connectivity between any two given areas in accordance with the movement of landmasses and dispersal opportunity over time. DECX is built upon a previous implementation in C/C++ and can analyze phylogenies on the order of several thousand tips in a few minutes. We test our model extensively on Pseudo Observed Datasets and on well-curated and recently published data from various island clades and a worldwide phylogeny of Amphibians (3309 species). We also propose the very first implementation of the DEC model that can specifically account for trees with fossil tips (i.e. non-ultrametric) using the phylogeny of palpimanoid spiders as a case study. In this paper, we argue in favour of the proposed improvements, which have the advantage of being computationally efficient while toeing the line of increased biological realism.

The evolutionary dynamics of transposable elements (TEs) are still poorly understood. One reason is that TE abundance needs to be studied at the population level, and despite recent advances in sequencing technologies, characterizing TE abundance in multiple populations by sequencing individuals separately is still too expensive. While sequencing pools of individuals (Pool-Seq) dramatically reduces sequencing costs, a comparison of TE abundance between pooled samples has been difficult, if not impossible, due to various biases. Here, we introduce a novel bioinformatic tool, PoPoolationTE2, which is specifically tailored for the comparison of TE abundance among pooled population samples or different tissues. Using computer simulations we demonstrate that PoPoolationTE2 not only faithfully recovers TE insertion frequencies and positions but, by homogenizing the power to identify TEs acrosss samples, it provides an unbiased comparison of TE abundance between pooled population samples. We anticipate that PoPoolationTE2 will greatly facilitate the analysis of TE insertion patterns in a broad range of applications.

Recent genetic studies have established that the KhoeSan populations of southern Africa are distinct from all other African populations and have remained largely isolated during human prehistory until about 2,000 years ago. Dozens of different KhoeSan groups exist, belonging to three different language families, but very little is known about population history within southern Africa. We examine new genome-wide polymorphism data and whole mitochondrial genomes for more than one hundred South Africans from the ≠Khomani San and Nama populations of the Northern Cape, analyzed in conjunction with 19 additional southern African populations. Our analyses reveal fine-scale population structure in and around the Kalahari Desert. Surprisingly, this structure does not always correspond to linguistic or subsistence categories as previously suggested, but rather reflects the role of geographic barriers and the ecology of the greater Kalahari Basin. Regardless of subsistence strategy, the indigenous Khoe-speaking Nama pastoralists and the N|u-speaking ≠Khomani (formerly hunter-gatherers) share recent ancestry with other Khoe-speaking forager populations that forms a rim around the Kalahari Desert. We reconstruct earlier migration patterns and estimate that the southern Kalahari populations were among the last to experience gene flow from Bantu-speakers, approximately 14 generations ago. We conclude that local adoption of pastoralism, at least by the Nama, appears to have been primarily a cultural process with limited impact from eastern African genetic diffusion.

Despite being heritable and under selection, traits often do not appear to evolve as predicted by evolutionary theory. Indeed, conclusive evidence for contemporary adaptive evolution remains elusive in wild vertebrate populations, and stasis seems to be the norm. Here we show that a wild rodent population has evolved to become lighter, but that both this evolutionary change and the selective pressure that drives it are not apparent on the phenotypic level. Thereby we demonstrate that understanding and predicting the response of wild populations to environmental change requires an explicitly (quantitative) genetic approach, and that natural populations can show a rapid and adaptive, but easily missed, evolutionary response.

Divergence-time estimation based on molecular phylogenies and the fossil record has provided insights into fundamental questions of evolutionary biology. In Bayesian node dating, phylogenies are commonly time calibrated through the specification of calibration densities on nodes representing clades with known fossil occurrences. Unfortunately, the optimal shape of these calibration densities is usually unknown and they are therefore often chosen arbitrarily, which directly impacts the reliability of the resulting age estimates. As possible solutions to this problem, two non-exclusive alternative approaches have recently been developed, the “fossilized birth-death” model and “total-evidence dating”. While these approaches have been shown to perform well under certain conditions, they require including all (or a random subset) of the fossils of each clade in the analysis, rather than just relying on the oldest fossils of clades. In addition, both approaches assume that fossil records of different clades in the phylogeny are all the product of the same underlying fossil sampling rate, even though this rate has been shown to differ strongly between higher-level taxa. We here develop a flexible new approach to Bayesian node dating that combines advantages of traditional node dating and the fossilized birth-death model. In our new approach, calibration densities are defined on the basis of first fossil occurrences and sampling rate estimates that can be specified separately for all clades. We verify our approach with a large number of simulated datasets, and compare its performance to that of the fossilized birth death model. We find that our approach produces reliable age estimates that are robust to model violation, on par with the fossilized birth-death model. By applying our approach to a large dataset including sequence data from over 1000 species of teleost fishes as well as 147 carefully selected fossil constraints, we recover a timeline of teleost diversification that is incompatible with previously assumed vicariant divergences of freshwater fishes. Our results instead provide strong evidence for trans-oceanic dispersal of cichlids and other groups of teleost fishes.