Biology subjects

Arbeithuber, B.

Publications and source records attributed to Arbeithuber, B..

7 recordsLinked to original sources

bioRxiv2025

ImplantoMetrics - Multidimensional trophoblast invasion assessment by combining 3D-in-vitro modeling and deep learning analysis

Infertility affects millions of couples worldwide, and in vitro fertilization is a key therapeutic strategy for achieving parenthood. Despite advances, the first IVF attempt fails in [~]60% of patients, highlighting the need for innovative solutions to improve clinical outcomes. Challenges include the limited ability to study embryo implantation, inadequate methods to test therapeutic drugs, and lack of metrics to evaluate implantation images. To address these issues, we developed ImplantoMetrics, a Fiji plugin for quantitative assessment of trophoblast invasion in combination with a 3D-in-vitro model. ImplantoMetrics uses Convolutional Neural Network and XGBoosting to accurately measure multidimensional expansion patterns. It allows quantitative evaluation of therapeutic interventions, and enables a complex study of trophoblast invasion. Compared to manual methods, ImplantoMetrics is [~]13-times faster and reduces errors through automation. Beyond implantation research, ImplantoMetrics offers a comprehensive tool to study spheroid invasion in different biological contexts, as e.g. demonstrated here for cancer research.

developmental biology↗

bioRxiv2024

Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age

Mitochondria, cellular powerhouses, harbor DNA (mtDNA) inherited from the mothers. MtDNA mutations can cause diseases, yet whether they increase with age in human germline cells--oocytes--remains understudied. Here, using highly accurate duplex sequencing of full-length mtDNA, we detected de novo mutations in single oocytes, blood, and saliva in women between 20 and 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies ([≥]1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/627454v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@18242f6org.highwire.dtl.DTLVardef@fa5a97org.highwire.dtl.DTLVardef@51a452org.highwire.dtl.DTLVardef@1fb2374_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2021

Discovery of an unusual high number of de novo mutations in sperm of older men using duplex sequencing

De novo mutations (DNMs) are an important player in heritable diseases and evolution. Of particular interest are highly recurrent DNMs associated with congenital disorders that have been described as selfish mutations expanding in the male germline, thus becoming more frequent with age. Here, we have adapted duplex sequencing (DS), an ultra-deep sequencing method that renders sequence information on both DNA strands; thus, one mutation can be reliably called in millions of sequenced bases. With DS, we examined [~]4.5 kb of the FGFR3 coding region in sperm DNA from older and younger donors. We identified sites with variant frequencies of 10-4 to 10-5, with an overall mutation frequency of the region of [~]6x10-7. Some of the substitutions were re-current and were found at a higher variant frequency in older donors than in younger ones, or exclusively, in older donors. Also, older donors harbored more mutations associated with congenital disorders. Other mutations were present in both age groups suggesting that these might result from a different mechanism (e.g., post-zygotic mosaicism). We also observed that independent of age, the frequency and deleteriousness of the mutational spectra was more similar to COSMIC than to gnomAD variants. Our approach is an important strategy to identify mutations that could be associated with a gain-of-function of the receptor tyrosine kinase activity, with unexplored consequences in a society with delayed fatherhood.

genetics↗

bioRxiv2018

High inter- and intraspecific turnover of satellite repeats in great apes

BackgroundSatellite repeats are a structural component of centromeres and telomeres, and in some instances their divergence is known to drive speciation. Due to their highly repetitive nature, satellite sequences have been understudied and underrepresented in genome assemblies. To investigate their turnover in great apes, we studied satellite repeats in human, chimpanzee, bonobo, gorilla, and Sumatran and Bornean orangutans, using unassembled short and long sequencing reads.\n\nResultsThe density of satellite repeats, as identified from accurate short reads (Illumina), varied greatly among great ape genomes. These were dominated by a handful of abundant repeated motifs, frequently shared among species, which formed two groups: (1) the (AATGG)n repeat (critical for heat shock response) and its derivatives; and (2) subtelomeric 32-mers. Using the densities of abundant repeats, individuals could be classified into species. However clustering did not reproduce the accepted species phylogeny, suggesting rapid repeat evolution. Several abundant repeats were enriched in males vs. females; using existing Y chromosome assemblies or FIuorescent In Situ Hybridization, we validated location for some of them on the Y. Finally, applying a novel computational tool, we identified many satellite repeats completely embedded within long Oxford Nanopore and Pacific Biosciences reads. Such repeats were up to 59 kb in length and consisted of perfect repeats interspersed with other similar sequences.\n\nConclusionsOur results based on sequencing reads generated with three different technologies provide the first detailed characterization of great ape satellite repeats, and open new avenues for exploring their functions.

evolutionary biology↗

bioRxiv2018

Family reunion via error correction: An efficient analysis of duplex sequencing data

Duplex sequencing is the most accurate approach for identification of sequence variants present at very low frequencies. Its power comes from pooling together multiple descendants of both strands of original DNA molecules, which allows distinguishing true nucleotide substitutions from PCR amplification and sequencing artifacts. This strategy comes at a cost--sequencing the same molecule multiple times increases dynamic range but significantly diminishes coverage, making whole genome duplex sequencing prohibitively expensive. Furthermore, every duplex experiment produces a substantial proportion of singleton reads that cannot be used in the analysis and are, technically, thrown away. In this paper we demonstrate that a significant fraction of these reads contains PCR or sequencing errors within duplex tags. Correction of such errors allows \"reuniting\" these reads with their respective families increasing the output of the method and making it more cost effective. Additionally, we combine error correction strategy with a number of algorithmic improvements in a new version of the duplex analysis software, Du Novo 2.0, readily available through Galaxy, Bioconda, and as the source code.

bioinformatics↗

bioRxiv2018

Length asymmetry and heterozygosity strongly influences the evolution of poly-A microsatellites at meiotic recombination hotspots

Meiotic recombination has strong, but poorly understood, effects on short tandem repeat (STR) instability. Here, we screened thousands of single recombinant products to characterize the transmission and evolution of polymorphic poly-A repeats at a human recombination hotspot. We show that length asymmetry between heterozygous poly-As plays a key role in the recombination outcome and their transmission. A difference of 10 As (9A/19A) elevates the frequency of non-crossovers, complex recombination products, and long conversion tracts. Moreover, asymmetry also influences STR transmission: the shorter allele is transmitted more frequently (deletion bias) at the asymmetric STR (9A/19A), while the longer allele is favored (insertion bias) at the site with a small STR length difference (6A/7A). Finally, potentially due to this opposing insertion/deletion driven evolution, we find that poly-As are enriched at human recombination hotspots predominantly with short poly-As, possibly influencing open chromatin regions that in turn can activate hotspots.

evolutionary biology↗

bioRxiv2018

A high resolution view of adaptive events

Coadaptation between bacterial hosts and plasmids often involves a small number of highly reproducible mutations. Yet little is known about the underlying complex dynamics that leads to such a single \"correct\" solution. Observing mutations in fine detail along the adaptation trajectory is necessary for understanding this phenomenon. We studied coadaptation between E. coli and a common artificial plasmid, pBR322, in a continuous turbidostat culture. To obtain a high resolution picture of early adaptive events, we used a highly sensitive duplex sequencing strategy to directly observe and track mutations with frequencies undetectable with conventional methods. The observed highly reproducible trajectories are governed by clonal interference and show rapid increases in the frequencies of beneficial mutations controlling plasmid replication followed by a profound diversity crash corresponding to the emergence of chromosomal variants. To the best of our knowledge our study represents the first comprehensive assessment of adaptive processes at a very fine level of resolution. Our work highlights the hidden complexity of coadaptation, and provides an experimental and theoretical foundation for future studies.

evolutionary biology↗