Biology subjects

Seefried, F.

Publications and source records attributed to Seefried, F..

4 recordsLinked to original sources

bioRxiv2025

Learning the Unseen: Data-Augmented Deep Learning for PTM Discovery with Prosit-PTM

Post-translational modifications (PTMs) are critical regulators of protein function, yet confidently identifying and localizing PTM sites across proteomes remains a challenging task. Integrating peptide property predictions into spectrum interpretation improves identification performance, but training data enabling zero-shot prediction across diverse PTMs are scarce. Here, we present a major expansion of the ProteomeTools dataset, comprising over 977,000 synthetic peptides, covering 22 PTM-residue combinations. Furthermore we developed Prosit-PTM, a model with chemically-informed encoding and amino acid substitution-based augmentation trained with our novel ground-truth dataset, that achieves accurate zero-shot predictions. Applied to modified peptides, Prosit-PTM enhances PTM-site localization in phosphoproteomics, increases identification of multiply modified peptides in histones, and enables data-driven rescoring for unseen modifications such as HLA peptides. Furthermore, the learned embeddings of amino acids and modifications capture physicochemical relationships underlying PTM-driven HLA presentation. Prosit-PTM is integrated into multiple open-source tools enabling PTM-aware rescoring, site localization, spectral library generation, and beyond.

bioinformatics↗

bioRxiv2025

Evidence of inbreeding depression on stature in Brown Swiss cattle

BackgroundSmall effective population size and the disproportionately large use of few genetically superior bulls in artificial insemination lead to extensive runs of homozygosity and an increased risk of homozygosity for deleterious alleles in domestic cattle, which may cause inbreeding depression. The adverse effects of inbreeding on phenotypic performance are well established, but the genetic variants contributing to inbreeding depression remain largely unknown. This study aimed to analyse the impacts of inbreeding on stature (measured as height at the sacral bone) in a cohort of 15,306 Brown Swiss (BS) cows that have imputed genotypes at 20 million sequence variants and stature measurements as height at the sacral bone. ResultsThe average genomic inbreeding coefficient of the 15,306 BS cows estimated from runs of homozygosity (ROH) was 0.369 ({+/-} 0.022). We found a loss in stature, decreasing from a height of 0.076 cm at the sacral bone per 1% increase in inbreeding (p = 1.94e-09). Contributions to inbreeding depression were significant for long (> 2 Mb), medium (0.1 - 2 Mb), and short (50 kb - 0.1 Mb) ROH (p = 1.29e-12, p = 3.20e-04 and p = 1.77e-06, respectively), suggesting that both ancient and recent inbreeding have negative effects on stature. Non-additive association testing identified a novel recessive quantitative trait locus (QTL) for stature on chromosome 25 with the most significantly (p = 2.35e-21) associated SNP residing at 14,535,327 bp. Cows homozygous for the alternate allele of the top associated SNP were 2 cm shorter than heterozygous and reference allele homozygotes. Fine mapping of the QTL identified a splice donor variant (rs447836030 at 25:14,515,474) of the gene ABCC6 encoding ATP binding cassette subfamily C member 6 which causes exon skipping as both a positional and functional candidate causal variant. ConclusionsOur study reveals evidence for inbreeding depression on stature in a large cohort of BS cattle. We also uncover a recessive QTL that decreases stature through non-additive association testing. This QTL harbors a high-impact variant affecting a splice donor site of ABCC6 which leads to exon skipping, thereby possibly contributing to inbreeding depression. Accumulating non-lethal deleterious alleles in ROH may reduce the overall fitness of the BS cattle population.

genomics↗

bioRxiv2024

Unifying the analysis of bottom-up proteomics data with CHIMERYS

Proteomic workflows generate vastly complex peptide mixtures that are analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), creating thousands of spectra, most of which are chimeric and contain fragment ions from more than one peptide. Because of differences in data acquisition strategies such as data-dependent (DDA), data-independent (DIA) or parallel reaction monitoring (PRM), separate software packages employing different analysis concepts are used for peptide identification and quantification, even though the underlying information is principally the same. Here, we introduce CHIMERYS, a novel, spectrum-centric search algorithm designed for the deconvolution of chimeric spectra that unifies proteomic data analysis. Using accurate predictions of peptide retention time, fragment ion intensities and applying regularized linear regression, it explains as much fragment ion intensity as possible with as few peptides as possible. Together with rigorous false discovery rate control, CHIMERYS accurately identifies and quantifies multiple peptides per tandem mass spectrum in DDA, DIA and PRM experiments.

biochemistry↗

bioRxiv2021

A 1-bp deletion in bovine QRICH2 causes low sperm count and immotile sperm with multiple morphological abnormalities

BackgroundSemen quality and male fertility are monitored in artificial insemination bulls to ensure high insemination success rates. Only ejaculates that fulfill minimum quality requirements are processed and eventually used for artificial inseminations. We examined 70,990 ejaculates from 1343 Brown Swiss bulls to identify bulls from which all ejaculates were rejected due to low semen quality. This procedure identified a bull that produced twelve ejaculates with an aberrantly low number of sperm (0.2{+/-}0.2 x 109 sperm per ml) which were mostly immotile due to multiple morphological abnormalities. ResultsThe genome of the bull was sequenced at 12-fold coverage to investigate a suspected genetic cause. Comparing the sequence variant genotypes of the bull with those from 397 fertile bulls revealed a 1-bp deletion in the coding sequence of QRICH2 encoding glutamine rich 2 as a compelling candidate causal variant. The 1-bp deletion causes a frameshift in translation and induces a premature termination codon (ENSBTAP00000018337.1:p.Cys1644AlafsTer52). The analysis of testis transcriptomes from 76 bulls showed that the transcript with the premature termination codon is subjected to nonsense-mediated mRNA decay. The 1-bp deletion resides on a 675 kb haplotype spanning 181 SNPs from the Illumina BovineHD Bead chip. The haplotype segregates at a frequency of 5% in the Brown Swiss cattle population. This analysis also identified another bull that carried the 1-bp deletion in the homozygous state. Semen analyses from the second bull confirmed low sperm concentration and immotile sperm with multiple morphological abnormalities primarily affecting the sperm flagellum and, to a lesser extent, the sperm head. ConclusionsA recessive loss-of-function allele of bovine QRICH2 likely causes low sperm concentration and immotile sperm with multiple morphological abnormalities. Routine sperm analyses unambiguously identify homozygous bulls. A direct gene test can be implemented to monitor the frequency of the undesired allele in cattle populations.

genetics↗