Identification of Medically Actionable Secondary Findings in the 1000 Genomes

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.     

Embryos of common thresher shark Alopias vulpinus in southern Brazil, South Atlantic Ocean

Eight embryonic thresher sharks Alopias vulpinus (53·9–124 cm total length) were collected from two females caught by commercial longline off southern Brazil in September and November 2004. Morphometric measurements are provided.     

Linkage analyses of human peptidase C (PEPC), human factor H (HF), and coagulation factor XIIIB (F13B)

Summary Linkage data on human peptidase C (PEPC), human factor H (HF), and coagulation factor XIIIB (F13B) are presented. The results confirm linkage between HF and F13B (lod=5.32 at =0.10 in males), and give strong evidence for linkage between PEPC and HF (lod=5.14 at =0.10 in males) and between PEPC and F13B (lod=3.55 at =0.10 in males). The claim that PEPA is linked with HF must be withdrawn.     

Defining null expectations for animal site fidelity

Site fidelity—the tendency to return to previously visited locations—is widespread across taxa. Returns may be driven by several mechanisms, including memory, habitat selection, or chance; however, pattern-based definitions group different generating mechanisms under the same label of ‘site fidelity’, often assuming memory as the main driver. We propose an operational definition of site fidelity as patterns of return that deviate from a null expectation derived from a memory-free movement model. First, using agent-based simulations, we show that without memory, intrinsic movement characteristics and extrinsic landscape characteristics are key determinants of return patterns and that even random movements may generate substantial probabilities of return. Second, we illustrate how to implement our framework empirically to establish ecologically meaningful, system-specific null expectations for site fidelity. Our approach provides a conceptual and operational framework to test hypotheses on site fidelity across systems and scales.     

Surveying nonvisual arrestins reveals allosteric interactions between functional sites

Arrestins are important scaffolding proteins that are expressed in all vertebrate animals. They regulate cell-signaling events upon binding to active G-protein coupled receptors (GPCR) and trigger endocytosis of active GPCRs. While many of the functional sites on arrestins have been characterized, the question of how these sites interact is unanswered. We used anisotropic network modeling (ANM) together with our covariance compliment techniques to survey all the available structures of the nonvisual arrestins to map how structural changes and protein-binding affect their structural dynamics. We found that activation and clathrin binding have a marked effect on arrestin dynamics, and that these dynamics changes are localized to a small number of distant functional sites. These sites include α-helix 1, the lariat loop, nuclear localization domain, and the C-domain β-sheets on the C-loop side. Our techniques suggest that clathrin binding and/or GPCR activation of arrestin perturb the dynamics of these sites independent of structural changes.     

Evidence of biotic resistance to exotic plant invasion in degraded Bornean forests

Intact tropical forests are generally considered to be resistant to invasions by exotic species, although the shrub Clidemia hirta (Melastomataceae) is highly invasive in tropical forests outside its native range. Release from natural enemies (e.g., herbivores and pathogens) contributes to C. hirta invasion success where native melastomes are absent, and here we examine the role of enemies when C. hirta co-occurs with native Melastomataceae species and associated herbivores and pathogens. We study 21 forest sites within agricultural landscapes in Sabah, Malaysian Borneo, recording herbivory rates in C. hirta and related native Melastoma spp. plants along two 100-m transects per site that varied in canopy cover. Overall, we found evidence of enemy release; C. hirta had significantly lower herbivory (median occurrence of herbivory per plant = 79% of leaves per plant; median intensity of herbivory per leaf = 6% of leaf area) than native melastomes (93% and 20%, respectively). Herbivory on C. hirta increased when closer to native Melastoma plants with high herbivory damage, and in more shaded locations, and was associated with fewer reproductive organs on C. hirta. This suggests host-sharing by specialist Melastomataceae herbivores is occurring and may explain why invasion success of C. hirta is lower on Borneo than at locations without related native species present. Thus, natural enemy populations may provide a “biological control service” to suppress invasions of exotic species (i.e., biotic resistance). However, lower herbivory pressures in more open canopy locations may make highly degraded forests within these landscapes more susceptible to invasion.