Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients' phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.

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Zielske, S., Glaubrecht, M. & Haase, M. (2010). Origin and radiation of rissooidean gastropods (Caenogastropoda) in ancient lakes of Sulawesi. —Zoologica Scripta, 40, 221–237. We investigated diversity and origin of as well as relationships among rissooidean gastropods from the ancient lakes of Sulawesi. Analyses of morphological, anatomical and genetic data (16S rRNA, COI and 18S rRNA) revealed ten new species: Sulawesidrobia perempuan sp. n., which is probably parthenogenetic, Sulawesidrobia soedjatmokoi sp. n., Sulawesidrobia mahalonaensis sp. n., Sulawesidrobia anceps sp. n., Sulawesidrobia bicolor sp. n., Sulawesidrobia megalodon sp. n., Sulawesidrobia abreui sp. n., Sulawesidrobia datar sp. n., Sulawesidrobia yunusi sp. n. and Sulawesidrobia towutiensis sp. n. In two cases morphological and anatomical differentiation between pairs of species were not paralleled by genetic differentiation suggesting young speciation events and incomplete lineage sorting as a likely explanation. A Bayesian phylogenetic analysis including representatives of most rissooidean families placed SulawesidrobiaPonder & Haase 2005 among Tateidae and thus indicated an Australasian origin of the genus. Relationships among the Sulawesian species suggested that isolated Lake Poso was colonised only once whereas the lakes of the Malili system experienced repeated colonizations.

The South Pacific archipelago Vanuatu has a very complex geological history including three major phases of volcanism creating island belts and phases of repeated submergence and re‐emergence. An important issue for the evolution of the biota of Vanuatu ambiguously discussed in the geological literature is the question whether the entire archipelago has been submerged until the early Pleistocene or if at least parts of the island of Espiritu Santo have remained subaerial throughout the Pliocene. We used a time‐calibrated phylogenetic analysis of freshwater gastropods of the family Tateidae based on COI, 16S rRNA and ITS2 to infer the colonization history of Vanuatu. Our analyses suggested that Espiritu Santo was colonized c. 3 Mya. Espiritu Santo was probably the place of origin for the subsequent colonization of the island of Erromango (2 Mya) and the Pleistocene radiation across the remaining archipelago. We describe 10 new species largely based on morphological and anatomical data. The genetic data in particular of the species from the young islands are taxonomically incongruent probably due to incomplete lineage sorting typical for young radiations. In contrast, the paraphyly of Fluviopupa espiritusantoana appearing in three distant clades indicates either the existence of cryptic species or the long survival of the stem species of almost the entire radiation.

Aim Tateid freshwater gastropods have an enigmatic distribution in the South Pacific (SP) region. We reconstructed their diversification and dispersal pathways and estimated a timeframe for their radiations. Location New Caledonia, Vanuatu, Fiji, the Austral Islands, further species from Sulawesi, Australia, New Zealand and Lord Howe Island. Methods Bayesian and maximum likelihood methods were used to calculate dated phylogenies based on two mitochondrial and three nuclear gene fragments, test hypotheses and perform ancestral range reconstructions. We compared two calibration strategies based on the COI substitution rate and two sets of island ages selected (1) independent of the ancestral range reconstruction and (2) using information from the latter. Results The common ancestor of the SP Tateidae occurred in Australia. Its descendents colonized Sulawesi and Lord Howe Island and gave rise to the radiations on New Caledonia and New Zealand. The more remote archipelagos harbouring the genus Fluviopupa Pilsbry, 1911 were colonized out of New Zealand. Fluviopupa evolved on the Austral Islands and colonized the archipelago against the progression rule from east to west. Vanuatu was colonized twice independently from the Austral Islands and served as hub for dispersal events to Fiji and Lord Howe Island. The second strategy for calibrating the time trees resulted in considerable younger colonization estimates, was generally well in accordance with the geological record and required fewer ad hoc hypotheses to explain the diversification and dispersal pattern. Main conclusions Our analyses of the evolutionary history of Tateidae across the SP revealed several enigmatic aspects not in accordance with the dominant pattern published for other taxa. In particular, the complex westward dispersal pathways of Fluviopupa, which originated on the Austral Islands but had an ancestor in New Zealand, are unique. Geographical distance was not an appropriate predictor of relationships.