Genetic variability and the ecology of geographic range: a test of the central-marginal hypothesis in Australian scincid lizards

For many species, both local abundance and regional occupancy are highest near the center of their geographic distributions. One hypothesis for this pattern is that niche suitability declines with increasing distance from a species geographic center, such that populations near range margins are characterized by reduced density and increased patchiness. In these smaller edge populations, genetic drift is more powerful, leading to the loss of genetic diversity. This simple verbal model has been formalized as the central-marginal hypothesis, which predicts that core populations should have greater genetic diversity than edge populations. However, demographic shifts over time can generate a similar pattern. For example, in species with expanding ranges, populations at the range edge experience serial founder effects, creating a gradient of declining genetic diversity from the range core to edge. Testing the central-marginal hypothesis properly thus requires us to consider the confounding role of historical demography. Here, we account for the role of history in testing the central-marginal hypothesis using a genomic dataset of 25 species-level taxa of Australian skink lizards (genus: Ctenotus and Lerista). We found support for the central-marginal hypothesis in 16 of our 25 taxa, of which eight taxa recovered significant support. Unexpectedly, species with the strongest evidence for range expansion were the least likely to follow predictions of the central-marginal hypothesis. The majority of these species had range expansions that originated at the range edge, which led to lower genetic diversity at the range edge compared to the core, contrary to the central-marginal hypothesis.

Location of the t(4;14) Translocation Breakpoint Identifies a Subset of Newly-Diagnosed Multiple Myeloma Patients with Poor Prognosis

Introduction: The recombination of chromosomes 4 and 14 (t(4;14)) is a primary, predominantly clonal event in newly diagnosed multiple myeloma (ndMM) that is present in ~15% of patients. The translocation results in enhancer regions from the immunoglobulin heavy chain locus upregulating the expression of NSD2 and FGFR3 genes implicated in the disease biology of this subset of MM patients (Chesi et al. Blood. 1998, Keats et al, Leuk Lymph. 2006). The presence of t(4;14) translocation is a considered a biomarker of aggressive disease and is part of the Revised International Staging System (R-ISS) for clinical risk stratification. However, historically only ~40% of t(4;14) patients are high-risk based on the GEP70 gene expression signature. (Weinhold et al. Leukemia. 2016) Our previous analysis of a large cohort of ndMM patients described the genomic features of t(4;14) vs ndMM overall population demonstrating that only ~25% of t(4;14) patients died within 24 months of diagnosis and described biomarkers in this high-risk subset. This analysis identified both known and novel aberrations in ndMM, including some that were associated with high-risk t(4;14) (Ortiz et al Blood. 2019; 134 (Suppl_1):366). In this updated analysis, we provide a more robust analysis of the t(4;14) dataset and demonstrate the prognostic value of the NSD2 breakpoint location. Methods: We generated a large genomic dataset from t(4;14) ndMM patients with whole genome sequencing (WGS) and RNA-seq from a TOUL dataset (t(4;14) N=114) patients treated in routine practice), the IFM2009 trial (N=19), and the Myeloma Genome Project (MGP) (N=34) for discovery and validation. Gene expression, copy number aberration, single nucleotide variant and translocations were derived from RNAseq and WGS profiling of biopsies from patients aged less than 75 years who received transplant, and integrated with clinical information (including age, OS). Cytogenetic assessments from WGS were made by MANTA and used to identify translocation DNA breakpoint location. Results: In all datasets, three DNA breakpoint locations were identified, and based on their position with respect to the NSD2 gene named "no-disruption" (upstream of NSD2 gene), "early-disruption" (in the 5' UTR of NSD2 gene) and "late-disruption" (in the coding region of NSD2 gene). Using paired RNA-seq data, we identified IGH-NSD2 RNA fusion transcripts relative to the breakpoints that corresponded with previously described NSD2 isoforms. "No-disruption" and "early-disruption" breakpoints predominantly produced a fusion transcript (MB4-1) that retained the full coding sequence of the gene, while the "late-disruption" produced truncated fusion transcripts (MB4-2/3). We conducted survival analysis in our datasets based on both DNA breakpoint location and RNA fusion transcripts. This analysis demonstrated a significant difference in outcome between the patient samples with "no-disruption" and the "late-disruption" breakpoints that associated with good and poor OS, respectively (OS pval < 3e-4) in the discovery TOUL dataset. Patients with "late-disruption" had a median OS of 28.64 mo vs 59.18 mo for "early disruption" and 82.26 mo for those with "no disruption" (Figure). This association was replicated in an independent dataset (MGP N=33, replication pval<4.3e-5). The mOS difference of patients based on which fusion transcript they express is less than the difference based on breakpoint (mOS MB4-1 = 47.38 mo. vs. MB4-2/3 = 60.89 mo.). These analyses demonstrate that the breakpoint location has a stronger association with outcome than fusion transcript expression. Conclusion: From a large genomic dataset, we were able to discover and validate a clear association between the translocation breakpoints and survival outcome in t(4:14) ndMM patients. While prospective validation is needed before clinical application of our finding, molecular identification of high-risk t(4;14) patients using DNA breakpoint location may enable proper risk classification for this patient group at diagnosis, and would provide improved opportunities for risk-adjusted therapy and identification of a therapeutic target for this high-risk subpopulation. Ongoing work on mutations, copy number, and differential gene expression analyses between translocation breakpoint sub-groups and will be presented. Figure 1 Figure 1. Disclosures Stong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ortiz: Bristol Myers Squibb: Current Employment. Towfic: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pierceall: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Flynt: Bristol Myers Squibb: Current Employment. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

A new subspecies in the Turdus nudigenis complex (Aves: Turdidae) from the Cauca River valley of Colombia

The taxonomy of the T. nudigenis complex has historically been challenging due to the uniformity in plumage among taxa, poorly known vocal variation, and allopatric distributions. Recent phylogenetic analyses have contributed to understanding relationships within the genus; however, much remains to be learned about the extent of phenotypic and genetic differentiation within taxa and its implications in species limits. Here, we analyze the taxonomic status of an enigmatic member of the T. nudigenis complex restricted to the Cauca River valley of Colombia. Our phylogenetic analyses suggest that the Cauca valley population is genetically distinctive from other members of the complex, although its sister relationships with respect to T. grayi and T. nudigenis could not be fully resolved due to paraphyly in the group. Based on similarity of plumage, calls, and biogeographic proximity we tentatively treat this taxon as a new subspecies of T. grayi. Populations from the northern Caribbean T. grayi casius/incomptus and the new taxon inhabit similar environmental conditions, being apparently isolated by the humid Nechí lowlands. A formal analysis of vocalizations coupled with a more robust genomic dataset are needed to resolve the systematic affinities and taxonomic status of several members of the T. nudigenis complex.

Population genomics of Drosophila suzukii reveal longitudinal population structure and signals of migrations in and out of the continental United States

Drosophila suzukii, or spotted-wing drosophila, is now an established pest in many parts of the world, causing significant damage to numerous fruit crop industries. Native to East Asia, D. suzukii infestations started in the United States (U.S.) a decade ago, occupying a wide range of climates. To better understand invasion ecology of this pest, knowledge of past migration events, population structure, and genetic diversity is needed. In this study, we sequenced whole genomes of 237 individual flies collected across the continental U.S., as well as several sites in Europe, Brazil, and Asia, to identify and analyze hundreds of thousands of genetic markers. We observed strong population structure between Western and Eastern U.S. populations, but no evidence of any population structure between different latitudes within the continental U.S., suggesting there is no broad-scale adaptations occurring in response to differences in winter climates. We detect admixture from Hawaii to the Western U.S. and from the Eastern U.S. to Europe, in agreement with previously identified introduction routes inferred from microsatellite analysis. We also detect potential signals of admixture from the Western U.S. back to Asia, which could have important implications for shipping and quarantine policies for exported agriculture. We anticipate this large genomic dataset will spur future research into the genomic adaptations underlying D. suzukii pest activity and development of novel control methods for this agricultural pest.

The impact of fast radiation on the phylogeny of Bactrocera fruit flies

True fruit flies (Tephritidae) include several species that cause extensive damage to agriculture worldwide. Among them, species of the genus Bactrocera are widely studied to understand the traits associated to their invasiveness and ecology. Comparative approaches based on a reliable phylogenetic framework are particularly effective, but, to date, molecular phylogenies of Bactrocera are still controversial. Here, we employed a comprehensive genomic dataset to infer a robust backbone phylogeny of eleven representative Bactrocera species and two outgroups. We further provide the first genome scaled inference of their divergence using calibrated relaxed clock. The results of our analyses support a closer relationship of B. dorsalis to B. latifrons than to B. tryoni, in contrast to all mitochondrial-based phylogenies. By comparing different evolutionary models, we show that this incongruence likely derives from the fast and recent radiation of these species that occurred around 2 million years ago, which may be associated with incomplete lineage sorting and possibly (ongoing) hybridization. These results can serve as basis for future comparative analyses and highlight the utility of using large datasets and efficient phylogenetic approaches to study the evolutionary history of species of economic importance.

Privacy-aware character pattern matching over outsourced encrypted data

Providing a method to efficiently search into outsourced encrypted data, without forsaking strong privacy guarantees, is a pressing concern rising from the separation of data ownership and data management typical of cloud-based applications. While several existing solutions allow a client to look-up the occurrences of a substring in an outsourced document collection, the practical application requirements in terms of privacy and efficiency call for the improvement of such solutions. In this work, we present a privacy-preserving substring search protocol with a polylogarithmic communication cost and a limited computational effort on the server side. The proposed protocol provides search pattern and access pattern privacy, for both exact string search, and character-pattern search with wildcards. Its extension to a multi-user setting shows significant savings in terms of outsourced storage w.r.t. a baseline solution where the whole dataset is replicated. The performance figures of an optimized implementation of our protocol, searching into a remotely stored genomic dataset, validate the practicality of the approach exhibiting a data transfer of less than 50 kiB to execute a query over a document of 40 MiB, with execution times on client and server in the range of a few seconds and a few minutes, respectively.

Ghost lineages deceive introgression tests and call for a new null hypothesis

The data that is known and sampled in any evolutionary study is always a small part of what exists, known or not, or what has existed in the past and is extinct. Therefore it is likely that all detected past horizontal gene fluxes, hybridization, introgressions, admixtures or transfers, involve "ghosts", that is, extinct or unsampled lineages. The presence of these ghosts is acknowledged by all scientists, but almost all wish that and make as if their blurring influence would be low, like a background noise that, with a reasonable approximation, can be ignored. We assess this undervalued hypothesis by qualifying and quantifying the effect of ghost lineages on introgression detection by the popular D-statistics method. We use a genomic dataset of bears to illustrate and circumscribe the possibility of misinterpretation and show on simulated data that under certain conditions, far from unrealistic, most results interpreted from D-statistics, concerning the existence of introgression and the identity of donors and recipients of horizontal gene flows, are erroneous. In particular, the use of a distant outgroup, usually given as a solid ground for these tests, leads in fact to an increase in the error probability, and to false interpretations in a vast majority of the cases. We argue for a switch of the null hypothesis: the results of detection methods for gene fluxes should be interpreted with the full and visible participation of the unknown ghosts.

Population genomic analyses confirm male-biased mutation rates in snakes

Male-biased mutation rates occur in a diverse array of organisms. The ratio of male-to-female mutation rate may have major ramifications for evolution across the genome, and for sex-linked genes in particular. In ZW species, the Z chromosome is carried by males two-thirds of the time, leading to the prediction that male-biased mutation rates will have a disproportionate effect on the evolution of Z-linked genes relative to autosomes and the W chromosome. Colubroid snakes (including colubrids, elapids, and viperids) have ZW sex determination, yet male-biased mutation rates have not been well studied in this group. Here we analyze a population genomic dataset from rattlesnakes to quantify genetic variation within and genetic divergence between species. We use a new method for unbiased estimation of population genetic summary statistics to compare variation between the Z chromosome and autosomes and to calculate net nucleotide differentiation between species. We find evidence for a 2.03-fold greater mutation rate in male rattlesnakes relative to females, corresponding to an average μZ/μA ratio of 1.1. Our results from snakes are quantitatively similar to birds, suggesting that male-biased mutation rates may be a common feature across vertebrate lineages with ZW sex determination.