Biology subjects

Nystedt, B.

Publications and source records attributed to Nystedt, B..

14 recordsLinked to original sources

bioRxiv2026

A generalisable framework to inject distance information into Alphafold-like structure predictors

Structure prediction methods are now highly successful at predicting three-dimensional structures from sequence. However, it is still often desirable to supplement these methods with additional external priors on pairwise distances in the structures. We present a general method for injecting prior information into AlphaFold-like structure predictors by biasing the pair representation to produce desirable features in the distogram, which are then reflected in the structures. We demonstrate this approach to: sample alternate states by selectively pushing or pulling mobile amino acid pairs; integrate NMR NOESY data with structure prediction; and improve the success of protein-protein and protein-ligand complex prediction. We demonstrate that this approach is applicable both to AlphaFold 2 and a reproduction of AlphaFold 3 (OpenFold3). resTrain is open source, available to all users on GitHub and as a Colab notebook: github.com/clami66/resTrain

bioinformatics↗

bioRxiv2025

Mettl15-Mettl17 modulates the transition from early to late pre-mitoribosome

The assembly of the mitoribosomal small subunit involves folding and modification of rRNA, and its association with mitoribosomal proteins. This process is assisted by a dynamic network of assembly factors. Conserved methyltransferases Mettl15 and Mettl17 act on the solvent-exposed surface of rRNA. Binding of Mettl17 is associated with the early assembly stage, whereas Mettl15 is involved in the late stage, but the mechanism of transition between the two was unclear. Here, we integrate structural data from Trypanosoma brucei with mammalian homologs and molecular dynamics simulations. We reveal how the interplay of Mettl15 and Mettl17 in intermediate steps links the distinct stages of small subunit assembly. The analysis suggests a model wherein Mettl17 acts as a platform for Mettl15 recruitment. Subsequent release of Mettl17 allows a conformational change of Mettl15 for substrate recognition. Upon methylation, Mettl15 adopts a loosely bound state which ultimately leads to its replacement by initiation factors, concluding the assembly. Together, our results indicate that assembly factors Mettl15 and Mettl17 cooperate to regulate the biogenesis process, and present a structural data resource for understanding molecular adaptations of assembly factors in mitoribosome.

molecular biology↗

bioRxiv2023

The landscape of ancient human pathogens in Eurasia from the Stone Age to historical times

Infectious diseases have had devastating impacts on human populations throughout history, but important questions about their origins and past dynamics remain1. To create the first archaeogenetic-based spatiotemporal map of human pathogens, we screened shotgun sequencing data from 1,313 ancient humans covering 37,000 years of Eurasian history. We demonstrate the widespread presence of ancient bacterial, viral and parasite DNA, identifying 5,486 individual hits against 492 species from 136 genera. Among those hits, 3,384 involve known human pathogens2, many of which were detected for the first time in ancient human remains. Grouping the ancient microbial species according to their likely reservoir and type of transmission, we find that most groups are identified throughout the entire sampling period. Intriguingly, zoonotic pathogens are only detected [~]6,500 years ago, peaking [~]5,000 years ago, coinciding with the widespread domestication of livestock3. Our findings provide the first direct evidence that this lifestyle change resulted in an increased infectious disease burden. Importantly, they also suggest that the spread of these pathogens increased substantially during subsequent millenia, coinciding with the pastoralist migrations from the Eurasian Steppe4,5.

evolutionary biology↗

bioRxiv2023

Unmasking AlphaFold: integration of experiments and predictions with a smarter template mechanism

Since the release of AlphaFold, researchers have actively refined its predictions and attempted to integrate it into existing pipelines for determining protein structures. These efforts have introduced a number of functionalities and results at the latest Critical Assessment of protein Structure Prediction edition (CASP15), resulting in a marked improvement in the prediction of multimeric protein structures. However, AlphaFolds capability of predicting large protein complexes is still limited and integrating experimental data in the prediction pipeline is not straightforward. In this study, we introduce AF_unmasked to overcome these limitations. Our results demonstrate that AF_unmasked can integrate experimental information to build larger or hard to predict protein assemblies with high confidence. The resulting predictions can help interpret and augment experimental data. This new approach generates near-perfect structures even when little to no evolutionary information is available and imperfect experimental structures are used as a starting point. AF_unmasked fills incomplete structures by a procedure called"structural inpainting", which may provide insights into protein dynamics. In summary, AF_unmasked provides an easy-to-use method that efficiently integrates experiments to predict large protein complexes more confidently. Codegithub.com/clami66/AF_unmasked

bioinformatics↗

bioRxiv2022

dgram2dmap: Extraction, visualisation and formatting of distance constraints from AlphaFold distograms

Distograms are data structures output by AlphaFold, along with the predicted 3D coordinates of the target protein, that encode predictions about Euclidean distances between pairs of amino acids. Although distograms are often overlooked, they do provide information that is to some extent complementary to that of the final 3D model. Here, we introduce dgram2dmap, a simple tool to convert distograms into distance maps that can be visualised and used in external tools for further downstream analyses. dgram2dmap runs within seconds to minutes, is open source and available on GitHub: https://github.com/clami66/dgram2dmap.

bioinformatics↗

bioRxiv2022

Evolution of ipsilateral breast cancer decoded by proteogenomics

Ipsilateral breast tumor recurrence (IBTR) is a clinically important event, where an isolated in-breast recurrence is a potentially curable event but also associated with an increased risk of distant metastases and breast cancer death. It currently remains unclear if IBTRs are associated with molecular changes that can be explored as a resource for precision medicine strategies targeting locally recurring breast cancer. Here, we employed a recently developed proteogenomics workflow to analyze a cohort of 27 primary breast cancers and their matched IBTRs by whole genome sequencing, RNA sequencing, and mass spectrometry-based proteomics to define proteogenomic features of tumor evolution. Analysis of mutational signatures, copy number changes, and cancer specific mutations revealed a relationship with estrogen and progesterone receptor statuses and increased levels of genetic change. This in turn altered the re-programming of the transcriptome and proteome towards a recurring molecular disease phenotype with high replicating capacity and a higher degree of genomic instability possibly enhanced by high expression of APOBEC3B. In conclusion, this study defines how primary breast tumors differentially evolve into different ipsilateral recurrent malignancies depending on their key biomarker status, suggesting that further enhancing the genomic instability in some tumors could serve as an alternative treatment option.

cancer biology↗

bioRxiv2022

Genomic analyses of the Linum distyly supergene reveal convergent evolution at the molecular level

Supergenes govern balanced polymorphisms in a wide range of systems. The reciprocal placement of stigmas and anthers in pin and thrum floral morphs of distylous species constitutes an iconic example of a balanced polymorphism governed by a supergene, the distyly S-locus. Recent studies have shown that the Primula and Turnera distyly supergenes are both hemizygous in thrums, but it remains unknown if hemizygosity is pervasive among distyly S-loci. Here we have characterized the genetic architecture and evolution of the distyly supergene in Linum by generating a chromosome-level genome assembly of Linum tenue, followed by the identification of the S-locus using population genomic data. We show that hemizygosity and thrum-specific expression of S-linked genes, including a pistil-expressed candidate gene for style length, are major features of the Linum S-locus. Structural variation is likely instrumental for recombination suppression, and although the non-recombining dominant haplotype has accumulated transposable elements, S-linked genes are not under relaxed purifying selection. Our findings reveal remarkable convergence in the genetic architecture and evolution of independently derived distyly supergenes. The chromosome-level genome assembly and detailed characterization of the distyly S-locus in L. tenue will facilitate elucidation of molecular mechanisms underlying the different forms of flowers described by Darwin.

evolutionary biology↗

bioRxiv2022

GenErode: a bioinformatics pipeline to investigate genome erosion in endangered and extinct species

BackgroundMany wild species have suffered drastic population size declines over the past centuries, which have led to genomic erosion processes characterized by reduced genetic diversity, increased inbreeding, and accumulation of harmful mutations. Yet, genomic erosion estimates of modern-day populations often lack concordance with dwindling population sizes and conservation status of threatened species. One way to directly quantify the genomic consequences of population declines is to compare genome-wide data from pre-decline museum samples and modern samples. However, doing so requires computational data processing and analysis tools specifically adapted to comparative analyses of degraded, ancient or historical, DNA data with modern DNA data as well as personnel trained to perform such analyses. ResultsHere, we present a highly flexible, scalable, and modular pipeline to compare patterns of genomic erosion using samples from disparate time periods. The GenErode pipeline uses state-of-the-art bioinformatics tools to simultaneously process whole-genome re-sequencing data from ancient/historical and modern samples, and to produce comparable estimates of several genomic erosion indices. No programming knowledge is required to run the pipeline and all bioinformatic steps are well-documented, making the pipeline accessible to users with different backgrounds. GenErode is written in Snakemake and Python3 and uses Conda and Singularity containers to achieve reproducibility on high-performance compute clusters. The source code is freely available on GitHub (https://github.com/NBISweden/GenErode). ConclusionsGenErode is a user-friendly and reproducible pipeline that enables the standardization of genomic erosion indices from temporally sampled whole genome re-sequencing data.

bioinformatics↗

bioRxiv2021

Environmentally-induced DNA methylation is inherited across generations in an aquatic keystone species (Daphnia magna)

Environmental stress can result in epigenetic modifications that are passed down several generations. Such epigenetic inheritance can have significant impact on eco-evolutionary dynamics, but the phenomenon remains controversial in ecological model systems. Here, we used whole-genome bisulfite sequencing on individual water fleas (Daphnia magna) to assess whether environmentally-induced DNA methylation can persist for up to four generations. Genetically identical females were exposed to a control treatment, one of three natural stressors (high temperature, zinc, microcystin), or the methylation-inhibitor 5-azacytidine. After exposure, lines were propagated clonally for four generations under control conditions. We identified between 70 and 225 differentially methylated CpG positions (DMPs) between controls and F1 individuals whose mothers (and therefore they themselves as germ cells) were exposed to one of the three natural stressors. Between 46% and 58% of these environmentally-induced DMPs persisted until generation F4 without attenuation in their magnitude of differential methylation. DMPs were enriched in exons and largely stressor-specific, suggesting a possible role in environment-dependent gene regulation. In contrast, treatment with the compound 5-azacytidine demonstrated that pervasive hypo-methylation upon exposure is reset almost completely after a single generation. These results suggest that environmentally-induced DNA methylation is non-random and stably inherited across generations in Daphnia, making epigenetic inheritance a putative factor in the eco-evolutionary dynamics of fresh-water communities. Author summaryWater fleas are important keystone species mediating eco-evolutionary dynamics in lakes and ponds. It is currently an open question in how far epigenetic inheritance contributes to the ability of Daphnia populations to adapt to environmental stress. Using a range of naturally occurring stressors and a multi-generational design, we show that environmentally-induced DNA methylation variants are stably inherited for at least four generations in Daphnia magna. The induced variation in DNA methylation are stressor-specific and almost exclusively found in exons, bearing the signatures of functional adaptations. Our findings imply that ecological adaptations of Daphnia to seasonal fluctuations can be underpinned by epigenetic inheritance of DNA methylation without changes in gene frequencies.

evolutionary biology↗

bioRxiv2020

Genomics of an avian neo-sex chromosome reveals the evolutionary dynamics of recombination suppression and sex-linked genes

How the avian sex chromosomes first evolved from autosomes remains elusive as 100 million years (Myr) of divergence and degeneration obscure their evolutionary history. Sylvioidea songbirds is an emerging model for understanding avian sex chromosome evolution because a unique chromosome fusion event [~]24 Myr ago has formed enlarged "neo-sex chromosomes" consisting of an added (new) and an ancestral (old) part. Here, we report the female genome (ZW) of one Sylvioidea species, the great reed warbler (Acrocephalus arundinaceus). We confirm that the added region has been translocated to both Z and W, and show that the added-W part has been heavily reorganised within itself and with the ancestral-W. Next, we show that recombination between Z and W continued after the fusion event, and that recombination suppression took [~]10 Myr to be completed and arose locally and non-linearly along the sex chromosomes. This pattern is inconsistent with that of large inversions and instead suggests gradual and mosaic recombination suppression. We find that the added-W mirrors the ancestral-W in terms of repeat accumulation, loss of genetic variation, and gene degeneration. Lastly, we show that genes being maintained on W are slowly evolving and dosage sensitive, and that highly conserved genes across broad taxonomic groups, regardless of sex-linkage, evolve slower on both Z and W. This study reveals complex expansion of recombination suppression along avian sex chromosomes, and that the evolutionary trajectory of sex-linked genes is highly predictable and governed partly by sex-linkage per se, partly by their functional properties.

evolutionary biology↗

bioRxiv2019

Single-molecule genome assembly of the Basket Willow, Salix viminalis, reveals earliest stages of sex chromosome expansion

Sex chromosomes have evolved independently multiple times in eukaryotes and are therefore considered a prime example of convergent genome evolution. Sex chromosomes are known to emerge after recombination is halted between a homologous pair of chromosomes and this leads to a range of non-adaptive modifications causing the gradual degeneration and gene loss on the sex-limited chromosome. However, because studies on sex chromosomes have primarily focused on old and highly differentiated sex chromosomes, the causes of recombination suppression and the pace at which degeneration subsequently occurs remain unclear. Here, we use long- and short-read single molecule sequencing approaches to assemble and annotate a draft genome of the basket willow, Salix viminalis, a species with a female heterogametic system at the earliest stages of sex chromosome emergence. Our single-molecule approach allowed us to phase the emerging Z and W haplotypes in a female, and we detected very low levels of Z/W divergence, largely the result of the accumulation of single nucleotide polymorphisms in the non-recombining region. Linked-read sequencing of the same female and an additional male (ZZ) revealed the presence of two evolutionary strata supported by both divergence between the Z and W haplotypes and by haplotype phylogenetic trees. Gene order is still largely conserved between the Z and W homologs, although a few genes present on the Z have already been lost from the W. Furthermore, we use multiple lines of evidence to test for inversions, which have long been assumed to halt recombination between the sex chromosomes. Our data suggest that selection against recombination is a more gradual process at the earliest stages of sex chromosome formation than would be expected from an inversion. Our results present a cohesive understanding of the earliest genomic consequences of recombination suppression as well as valuable insights into the initial stages of sex chromosome formation.

evolutionary biology↗

bioRxiv2018

Sarek: A portable workflow for whole-genome sequencing analysis of germline and somatic variants

SummaryWhole-genome sequencing (WGS) is a cornerstone of precision medicine, but portable and reproducible open-source workflows for WGS analyses of germline and somatic variants are lacking. We present Sarek, a modular, comprehensive, and easy-to-install workflow, combining a range of software for the identification and annotation of single-nucleotide variants (SNVs), insertion and deletion variants (indels), structural variants, tumor sample heterogeneity, and karyotyping from germline or paired tumor/normal samples. Sarek is implemented in a bioinformatics workflow language (Nextflow) with Docker and Singularity compatible containers, ensuring easy deployment and full reproducibility at any Linux based compute cluster or cloud computing environment. Sarek supports the human reference genomes GRCh37 and GRCh38, and can readily be used both as a core production workflow at sequencing facilities and as a powerful stand-alone tool for individual research groups.\n\nAvailabilitySource code and instructions for local installation are available at GitHub (https://github.com/SciLifeLab/Sarek) under the MIT open-source license, and we invite the research community to contribute additional functionality as a collaborative open-source development project.

bioinformatics↗

bioRxiv2017

Natural variation at FLOWERING LOCUS T2 mediates local adaptation in a key life history trait in European aspen

BackgroundThe initiation of growth cessation and dormancy represent critical life-history tradeoffs between survival and growth, and have important fitness effects in perennial plants. Such adaptive life history traits often show strong local adaptation along environmental gradients but despite their importance, the genetic architecture of these traits remains poorly understood.\n\nResultsWe integrate whole genome re-sequencing with environmental and phenotypic data from common garden experiments to investigate the genomic basis of local adaptation across a latitudinal gradient in European aspen (Populus tremula). We discover a single genomic region containing the PtFT2 gene that mediates local adaptation in the timing of bud set and that explains 65% of the observed genetic variation in bud set. This locus is the likely target of a recent selective sweep that originated right before or during colonization of northern Scandinavia following the last glaciation. Field and greenhouse experiments confirm that variation in PtFT2 gene expression affect the phenotypic variation in bud set that we observe in wild natural populations.\n\nConclusionsOur results reveal a major effect locus that determine the timing of bud set and that have facilitated rapid adaptation to shorter growing seasons and colder climates in European aspen. The discovery of a single locus explaining a substantial fraction of the variation in a key life history trait is remarkable given that such traits are generally considered to be highly polygenic. These findings provide a dramatic illustration of how loci of large-effect for adaptive traits can arise and be maintained over large geographical scales in natural populations.

evolutionary biology↗

bioRxiv2016

SweGen: A whole-genome map of genetic variability in a cross-section of the Swedish population

Here we describe the SweGen dataset, a high-quality map of genetic variation in the Swedish population. This data represents a basic resource for clinical genetics laboratories as well as for sequencing-based association studies, by providing information on the frequencies of genetic variants in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide population based cohort of over 10,000 individuals. From this sample collection, 1,000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole genome sequencing (WGS). Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a whole-genome map of aggregated variant frequencies in the Swedish population that we hereby release to the scientific community.

genetics↗