The rise in the number of genotyped ancient individuals provides an opportunity to estimate population admixture models for many populations. However, in models describing modern populations as mixtures of ancient ones, it is typically difficult to estimate the model mixing coefficients and to evaluate its fit to the data.

We present LINADMIX, designed to tackle this problem by solving a constrained linear model when both the ancient and the modern genotypes are represented in a low-dimensional space. LINADMIX estimates the mixing coefficients and their standard errors, and computes a p-value for testing the model fit to the data. We quantified the performance of LINADMIX using an extensive set of simulated studies. We show that LINADMIX can accurately estimate admixture coefficients, and is robust to factors such as population size, genetic drift, proportion of missing data, and various types of model misspecification.

LINADMIX is available as a python code at https//github.com/swidler/linadmix.

Supplementary data are available at Bioinformatics online.

Supplementary data are available at Bioinformatics online.Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known cerebral small vessel disease genes, including HTRA1, in 3,853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 messenger RNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases (gnomAD v3.1.1 (p = 3.12 x 10-17, OR = 21.9), TOPMed freeze 5 (p = 7.6 x 10-18, OR = 27.1) and 1000 Genomes (p = 1.5 x 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counseling.Bisphenol A (BPA) is one of the most investigated compound as a suspected endocrine disrupting chemical. It has been found at nM concentrations in the maternal serum, cord serum, and amniotic fluid and also permeates placental tissues. Attempts are being made to replace BPA with the analog Bisphenol S (BPS). Also BPS was found in maternal and umbilical cord serum, and urine samples from a large population of pregnant women. A few studies investigated BPA impact on the placentation process, and even less are available for BPS. This work aimed to elucidate and compare the effects of BPA and BPS on physiological functions of HTR-8/SVneo cells, derived from extravillous trophoblast of first-trimester pregnancy. Proliferation and migration ability of trophoblast cells were assessed in vitro after exposure to BPA or BPS (10-13 – 10-3 M). Further, induction of the inflammatory response by the bisphenols was studied. To provide insight into the molecular pathways implicated in the responses, experiments were carried out in the presence or absence of tamoxifen as estrogen receptors (ERs) blocker, and U0126 as ERK1/2 phosphorylation inhibitor. Data indicate that BPA significantly affects both proliferation and migration of HTR-8/SVneo cells, through ER and ERK1/2 mediated processes. Differently, BPS only acts on proliferation, again through ER and ERK1/2 mediated processes. BPS, but not BPA, induces secretion of interleukins 6 and 8. Such effect is inhibited by blocking ERK1/2 phosphorylation. To the best of our knowledge, these are the first data showing that BPS affects trophoblast functions through ER/MAPK modulation.

Clinical decision making is increasingly guided by accurate and recurrent determination of presence and frequency of (somatic) variants and their haplotype through panel sequencing of disease-relevant genomic regions. Haplotype calling (phasing), however, is difficult and error prone unless variants are located on the same read which limits the ability of short-read sequencing to detect, e.g., co-occurrence of drug-resistance variants. Long-read panel sequencing enables direct phasing of amplicon variants besides having multiple other benefits, however, high error rates of current technologies prevented their applicability in the past.

We have developed Nanopanel2, a variant caller for Nanopore panel sequencing data. Nanopanel2 works directly on base-called FAST5 files and uses allele probability distributions and several other filters to robustly separate true from false positive (FP) calls. It effectively calls SNVs and INDELs with variant allele frequencies as low as 1% and 5% respectively and produces only few low-frequency false-positive calls (∼1 FP call with VAF¡5% per kb amplicon). Haplotype compositions are then determined by direct phasing. Nanopanel2 is the first somatic variant caller for Nanopore data, enabling accurate, fast (turnaround <48h) and cheap (sequencing costs ∼10$/sample) diagnostic workflows.

The data for this study have been deposited at zenodo.org under DOIs accession numbers 4110691 and 4110698. selleck products Nanopanel2 is open source and available at https//github.com/popitsch/nanopanel2.

Supplementary data are available at Bioinformatics online.

Supplementary data are available at Bioinformatics online.

Improvements in next-generation sequencing have enabled genome-based diagnosis for patients with genetic diseases. However, accurate interpretation of human variants requires knowledge from a number of clinical cases. Additionally, manual analysis of each variant detected in a patient’s genome requires enormous time and effort. To reduce the cost of diagnosis, various computational tools have been developed to predict the pathogenicity of human variants, but the shortage and bias of available clinical data can lead to overfitting of algorithms.

We developed a pathogenicity predictor, 3Cnet, that uses recurrent neural networks to analyse the amino acid context of human variants. As 3Cnet is trained on simulated variants reflecting evolutionary conservation and clinical data, it can find disease-causing variants in patient genomes with 2.2 times greater sensitivity than currently available tools, more effectively discovering pathogenic variants and thereby improving diagnosis rates.

Codes (https//github.com/KyoungYeulLee/3Cnet/) and data (https//zenodo.