Multiple paths toward repeated phenotypic evolution in the spiny-leg adaptive radiation (Tetragnatha; Hawai'i)

The repeated evolution of phenotypes provides clear evidence for the role of natural selection in driving evolutionary change. However, the evolutionary origin of repeated phenotypes can be difficult to disentangle as it can arise from a combination of factors such as gene flow, shared ancestral polymorphisms or mutation. Here, we investigate the presence of these evolutionary processes in the Hawaiian spiny-leg Tetragnatha adaptive radiation, which includes four microhabitat-specialists or ecomorphs, with different body pigmentation and size (Green, Large Brown, Maroon, and Small Brown). We investigated the evolutionary history of this radiation using 76 newly generated low-coverage, whole-genome resequenced samples, along with phylogenetic and population genomic tools. Considering the Green ecomorph as the ancestral state, our results suggest that the Green ecomorph likely re-evolved once, the Large Brown and Maroon ecomorphs evolved twice and the Small Brown evolved three times. We found that the evolution of the Maroon and Small Brown ecomorphs likely involved ancestral hybridization events, while the Green and Large Brown ecomorphs likely evolved through novel mutations, despite a high rate of incomplete lineage sorting in the dataset. Our findings demonstrate that the repeated evolution of ecomorphs in the Hawaiian spiny-leg Tetragnatha is influenced by multiple evolutionary processes.publishedVersio

A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland

Background: The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population. Methods: Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact. Findings: We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = −232 pmol/L, βSD = −0.695, P = 4.43 × 10−4) and higher 30-min glucose (β = 1.20 mmol/L, βSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10−6) and HbA1c (β = 0.113 HbA1c%, βSD = 0.205, P = 7.84 × 10−3). The variant explained 2.5% of diabetes variance in Greenland. Interpretation: The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1–3% in large populations.publishedVersio

STEAK: A specific tool for transposable elements and retrovirus detection in high-throughput sequencing data

The advancements of high-throughput genomics have unveiled much about the human genome highlighting the importance of variations between individuals and their contribution to disease. Even though numerous software have been developed to make sense of large genomics datasets, a major short falling of these has been the inability to cope with repetitive regions, specifically to validate structural variants and accordingly assess their role in disease. Here we describe our program STEAK, a massively parallel software designed to detect chimeric reads in high-throughput sequencing data for a broad number of applications such as identifying presence/absence, as well as discovery of transposable elements (TEs), and retroviral integrations. We highlight the capabilities of STEAK by comparing its efficacy in locating HERV-K HML-2 in clinical whole genome projects, target enrichment sequences, and in the 1000 Genomes CEU Trio to the performance of other TE and virus detecting tools. We show that STEAK outperforms other software in terms of computational efficiency, sensitivity, and specificity. We demonstrate that STEAK is a robust tool, which allows analysts to flexibly detect and evaluate TE and retroviral integrations in a diverse range of sequencing projects for both research and clinical purposes

Multiple paths toward repeated phenotypic evolution in the spiny-leg adaptive radiation (Tetragnatha; Hawai'i).

Funder: Peder Sather Center for Advanced Study; doi: http://dx.doi.org/10.13039/100012388Funder: Fulbright/CONICYT Doctoral FellowshipFunder: Integrative Biology Department and the Graduate Division of UC BerkeleyFunder: Margaret C. Walker FundFunder: Alexander von Humboldt Postdoctoral FellowshipFunder: Sigma Xi; doi: http://dx.doi.org/10.13039/100011084The repeated evolution of phenotypes provides clear evidence for the role of natural selection in driving evolutionary change. However, the evolutionary origin of repeated phenotypes can be difficult to disentangle as it can arise from a combination of factors such as gene flow, shared ancestral polymorphisms or mutation. Here, we investigate the presence of these evolutionary processes in the Hawaiian spiny-leg Tetragnatha adaptive radiation, which includes four microhabitat-specialists or ecomorphs, with different body pigmentation and size (Green, Large Brown, Maroon, and Small Brown). We investigated the evolutionary history of this radiation using 76 newly generated low-coverage, whole-genome resequenced samples, along with phylogenetic and population genomic tools. Considering the Green ecomorph as the ancestral state, our results suggest that the Green ecomorph likely re-evolved once, the Large Brown and Maroon ecomorphs evolved twice and the Small Brown evolved three times. We found that the evolution of the Maroon and Small Brown ecomorphs likely involved ancestral hybridization events, while the Green and Large Brown ecomorphs likely evolved through novel mutations, despite a high rate of incomplete lineage sorting in the dataset. Our findings demonstrate that the repeated evolution of ecomorphs in the Hawaiian spiny-leg Tetragnatha is influenced by multiple evolutionary processes

GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal

Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (β SD(SE) = −0.22 (0.03), p = 6.5 × 10 −12) and total cholesterol (−0.17 (0.03), p = 1.1 × 10 −8) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance. [Figure not available: see fulltext.].</p