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Nielsen, R.

Publications and source records attributed to Nielsen, R..

At least 37 records · Page 2Linked to original sources
bioRxiv2025

Diffeomorphic Independent Contrasts for Ancestral Reconstruction of Shapes

AO_SCPLOWBSTRACTC_SCPLOWAncestral reconstruction is a fundamental challenge in evolutionary biology, requiring methods that can capture complex morphological changes while accounting for phylogenetic relationships. Current approaches are based on linear assumptions that often oversimplify the spatial relationships between anatomical features and fail to account for landmark correlations within shapes. Here, we introduce a novel method that combines the ability of Large Deformation Diffeomorphic Metric Mapping (LDDMM) to model smooth, invertible transformations between shapes while preserving the relationships between landmarks with Felsensteins Independent Contrasts (IC) to iteratively reconstruct ancestral shapes along the branches of a phylogenetic tree. We call this method Diffeomorphic Independent Contrasts for Ancestral Reconstruction of Shapes (DICAROS). We validate DICAROS against two existing methods: (1) Linear predictors using Ordinary Least Squares and (2) Ancestral character estimation using maximum likelihood under Brownian Motion and apply DICAROS to a dataset of swallowtail butterfly species (Family Papilonidae, Order Lepiodetra) to reconstruct the ancestral shape and visualize evolutionary trajectories in a phylomorphospace from the contrasts. We conclude that DICAROS outperforms the existing methods in terms of accuracy and provides a more accurate reconstruction of the ancestral shape for non-symmetric phylogenetic trees. With DICAROS we show a transition between un-tailed and tailed papilinodae species while also illustrating how images of modern species would look under the DICAROS ancestral reconstruction

evolutionary biology↗
bioRxiv2025

A General Framework for Branch Length Estimation in Ancestral Recombination Graphs

Inference of Ancestral Recombination Graphs (ARGs) is of central interest in the analysis of genomic variation. ARGs can be specified in terms of topologies and coalescence times. The coalescence times are usually estimated using an informative prior derived from coalescent theory, but this may generate biased estimates and can also complicate downstream inferences based on ARGs. Here we introduce, POLEGON, a novel approach for estimating branch lengths for ARGs which uses an uninformative prior. Using extensive simulations, we show that this method provides improved estimates of coalescence times and lead to more accurate inferences of effective population sizes under a wide range of demographic assumptions (population expansion, bottleneck, split, etc). It also improves other downstream inferences including estimates of mutation rates. We apply the method to data from the 1000 Genomes Project to investigate population size histories and differential mutation signatures across populations. We also estimate coalescence times in the HLA region, and show that they exceed 30 million years in multiple segments. Significance StatementModel misspecification is a common challenge in population genetic inference, as oversimplified mathematical models often fail to capture complex evolutionary processes. Here we introduce a novel framework for branch length estimation in whole-genome genealogies, which enables accurate inference using non-informative priors and subsequent posterior calibration, rather than relying on heavily parametrized models. This flexible approach has been validated in various simulation settings. When applied to real genomic data, it enables robust inference of demography, mutation rates, and transspecies polymorphisms.

evolutionary biology↗
bioRxiv2025

Single cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss

During sustained weight gain, human white adipose tissue undergoes dramatic remodeling that may compromise adipose tissue function and lead to obesity comorbidities such as cardiometabolic disease. These comorbidities can be at least partially reversed by weight loss; however, the degree to which human adipose tissue is remodeled during weight loss is currently unclear. Here, we have used snRNA-seq combined with bulk RNA-seq and 3D light microscopy to investigate the cellular and transcriptional alterations in abdominal subcutaneous adipose tissue (ASAT) from a unique cohort of obese individuals undergoing initially modest (8-10%) lifestyle-induced weight loss followed by a more dramatic (20-45%) bariatric surgery-induced weight loss. We show that in response to this weight loss, ASAT in both males and females underwent dramatic compositional and transcriptional remodeling. Most notably, surgery-indued weight loss led to an increase in the adipose vascular compartment, a dramatic reduction in proinflammatory immune cells, and a tissue-wide reduction in inflammatory gene signatures. In response to modest weight loss, we observed an increase in specific progenitor populations and an induction of proadipogenic genes, indicating that this process is important for the early adaptation of AT to weight loss that might contribute to the early overall beneficial effects on insulin sensitivity and systemic inflammation.

cell biology↗
bioRxiv2025

WASTER: Practical de novo phylogenomics from low-coverage short reads

The advent of affordable whole-genome sequencing has spurred numerous large-scale projects aimed at inferring the tree of life, yet achieving a complete species-level phylogeny remains a distant goal due to significant costs and computational demands. Traditional species tree inference methods, though effective, are hampered by the need for high-coverage sequencing, high-quality genomic alignments, and extensive computational resources. To address these challenges, this study introduces WASTER, a novel de novo tool for inferring shallow phylogenies directly from short-read sequences. WASTER employs a k-mer based approach for identifying variable sites, circumventing the need for genome assembly and alignment. Using simulations, we demonstrate that WASTER achieves accuracy comparable to that of traditional alignment-based methods, even for low sequencing depth, and has substantially higher accuracy than other alignment-free methods. We validate WASTERs efficacy on real data, where it accurately reconstructs phylogenies of eukaryotic species with as low depth as 1.5X. WASTER provides a fast and efficient solution for phylogeny estimation in cases where genome assembly and/or alignment may bias analyses or is challenging, for example due to low sequencing depth. It also provides a method for generating guide trees for tree-based alignment algorithms. WASTERs ability to accurately estimate shallow phylogenies from low-coverage sequencing data without relying on assembly and alignment will lead to substantially reduced sequencing and computational costs in phylogenomic projects.

bioinformatics↗
bioRxiv2024

Occurrence of Aneuploidy Across the Range of Coast Redwood (Sequoia sempervirens)

1Aneuploidy, a condition characterized by an abnormal number of chromosomes, can have significant consequences for fitness of an organism, often manifesting in reduced fertility and other developmental challenges. In plants, aneuploidy is particularly complex to study, especially in polyploid species such as coast redwood (Sequoia sempervirens), which is a hexaploid conifer (2n=6x=66). This study leverages a novel Markov Chain Monte Carlo (MCMC) method based on sequence depth to investigate the occurrence of aneuploidy across the range of coast redwood. We show that aneuploidy is prevalent in second-growth redwoods, predominantly as additional chromosomes, while tissue culture plants frequently experience chromosome loss. Although our study does not directly assess the fitness of aneuploids, the frequency of chromosomal instability observed in tissue culture plants compared to second-growth and old-growth trees raises questions about their long-term developmental viability and potential to become established trees. These findings have significant implications for redwood conservation and restoration strategies, especially as tissue culture becomes the primary mode of producing nursery stock plants used in reforestation.

plant biology↗
bioRxiv2024

Challenges in detecting ecological interactions using sedimentary ancient DNA data

With increasing availability of ancient and modern environmental DNA technology, whole-community species occurrence and abundance data over time and space is becoming more available. Sedimentary ancient DNA data can be used to infer associations between species, which can generate hypotheses about biotic interactions, a key part of ecosystem function and biodiversity science. Here, we have developed a realistic simulation to evaluate five common methods from different fields for this type of inference. We find that across all methods tested, false discovery rates of inter-species associations are high under simulation conditions where the assumptions of the methods are violated in a variety of ecologically realistic ways. Additionally, we find that for more realistic simulation scenarios, with sample sizes that are currently realistic for this type of data models are typically unable to detect interactions better than random assignment of associations. Different methods perform differentially well depending on the number of taxa in the dataset. Some methods (SPIEC-EASI, SparCC) assume that there are large numbers of taxa in the dataset, and we find that SPIEC-EASI is highly sensitive to this assumption while SparCC is not. Additionally, we find that for many methods, default calibration can result in high false discovery rates. We find that for small numbers of species, no method consistently outperforms logistic and linear regression, indicating a need for further testing and methods development.

ecology↗
bioRxiv2024

Evolution and Diversification of the Aposematic Poison Frog, Oophaga pumilio, in Bocas del Toro

The aposematic strawberry poison frog, Oophaga pumilio, is an iconic model system for studying the evolution and maintenance of color variation. Through most of its range, this frog is red with blue limbs. However, frogs from the Bocas del Toro Province, Panama, show striking variance in color and pattern, both sympatrically and allopatrically. This observation contradicts standard models of the evolution of aposematism and has led to substantial speculation about its evolutionary and molecular causes. Since the enigma of O. pumilio phenotypic variation is partly unresolved because of its large, [~] 6.7 Gb genome, we here sequence exomes from 347 individuals from ten populations and map a number of genetic factors responsible for the color and pattern variation. The kit gene is the primary candidate underlying the blue-red polymorphism in Dolphin Bay, where an increase in melanosomes is correlated with blue coloration. Additionally, the ttc39b gene, a known enhancer of yellow-to-red carotenoid conversion in birds, is the primary factor behind the yellow-red polymorphism in the Bastimentos West area. The causal genetic regions show evidence of selective sweeps acting locally to spread the rare phenotype. Our analyses suggest an evolutionary model in which selection is driving the formation of new morphs in a dynamic system resulting from a trade-off between predation avoidance, intraspecific competition, and mate choice.

evolutionary biology↗
bioRxiv2024

Evolutionary new centromeres in the snowy owl genome putatively seeded from a transposable element

Comparative genomic studies in birds have revealed that bird genomes are relatively repeat-poor and stable in terms of karyotype, size, and gene synteny/collinearity compared to other vertebrates. One notable exception is the owls, with cytogenetic studies demonstrating large variations in karyotypes and the evolution of unusual centromeric satellite repeats in some species. However, there has so far not been an investigation into genome architecture and repeat landscape of owls. Here, we present a chromosome-level genome assembly for the snowy owl (Bubo scandiacus). We find that the repeat DNA content in the relatively large snowy owl genome (1.6 Gb) is among the highest reported for any bird genome to date (28.34% compared to an average of [~]10% in other birds). The bulk of the snowy owl genomic repeat landscape consists of centromeric satellite DNA, which appears to have originated from an endogenous retrovirus (ERV1). Using gene collinearity analyses we show that the position of these evolutionary new centromeres (ECNs) are not homologous with chicken centromeres, and are located in regions with collinearity breaks to other bird genomes due to chromosomal rearrangements. Our results support rapid transposable element-driven evolution of lineage-specific centromeres, which could have played a role in reproductive isolation and speciation of the snowy owl.

genomics↗
bioRxiv2024

vcfgl: A flexible genotype likelihood simulator for VCF/BCF files

MotivationAccurate quantification of genotype uncertainty is pivotal in ensuring the reliability of genetic inferences drawn from NGS data. Genotype uncertainty is typically modeled using Genotype Likelihoods (GLs), which can help propagate measures of statistical uncertainty in base calls to downstream analyses. However, the effects of errors and biases in the estimation of GLs, introduced by biases in the original base call quality scores or the discretization of quality scores, as well as the choice of the GL model, remain under-explored. ResultsWe present vcfgl, a versatile tool for simulating genotype likelihoods associated with simulated read data. It offers a framework for researchers to simulate and investigate the uncertainties and biases associated with the quantification of uncertainty, thereby facilitating a deeper understanding of their impacts on downstream analytical methods. Through simulations, we demonstrate the utility of vcfgl in benchmarking GL-based methods. The program can calculate GLs using various widely used genotype likelihood models and can simulate the errors in quality scores using a Beta distribution. It is compatible with modern simulators such as msprime and SLiM, and can output data in pileup, VCF/BCF and gVCF file formats. The vcfgl program is freely available as an efficient and user-friendly software written in C/C++. Availabilityvcfgl is freely available at https://github.com/isinaltinkaya/vcfgl. Contactisin.altinkaya@sund.ku.dk Supplementary informationSupplementary information is available online.

bioinformatics↗
bioRxiv2024

Robust and Accurate Bayesian Inference of Genome-Wide Genealogies for Large Samples

The Ancestral Recombination Graph (ARG), which describes the full genealogical history of a sample of genomes, is a vital tool in population genomics and biomedical research. Recent advancements have increased ARG reconstruction scalability to tens or hundreds of thousands of genomes, but these methods rely on heuristics, which can reduce accuracy, particularly in the presence of model misspecification. Moreover, they reconstruct only a single ARG topology and cannot quantify the considerable uncertainty associated with ARG inferences. To address these challenges, we here introduce SINGER, a novel method that accelerates ARG sampling from the posterior distribution by two orders of magnitude, enabling accurate inference and uncertainty quantification for large samples. Through extensive simulations, we demonstrate SINGERs enhanced accuracy and robustness to model misspecification compared to existing methods. We illustrate the utility of SINGER by applying it to African populations within the 1000 Genomes Project, identifying signals of local adaptation and archaic introgression, as well as strong support of trans-species polymorphism and balancing selection in HLA regions.

genetics↗
bioRxiv2023

Fast and accurate estimation of selection coefficients and allele histories from ancient and modern DNA

We here present CLUES2, a full-likelihood method to infer natural selection from sequence data that is an extension of the method CLUES. We make several substantial improvements to the CLUES method that greatly increases both its applicability and its speed. We add the ability to use ARGs on ancient data as emissions to the underlying HMM, which enables CLUES2 to use both temporal and linkage information to make estimates of selection coefficients. We also fully implement the ability to estimate distinct selection coefficients in different epochs, which allows for the analysis of changes in selective pressures through time. In addition, we greatly increase the computational efficiency of CLUES2 over CLUES using several approximations to the forward-backward algorithms and develop a new way to reconstruct historic allele frequencies by integrating over the uncertainty in the estimation of the selection coefficients. We illustrate the accuracy of CLUES2 through extensive simulations and validate the importance sampling framework for integrating over the uncertainty in the inference of gene trees. We also show that CLUES2 is well-calibrated by showing that under the null hypothesis, the distribution of log-likelihood ratios follows a chi-squared distribution with the appropriate degrees of freedom. We run CLUES2 on a set of recently published ancient human data from Western Eurasia and test for evidence of changing selection coefficients through time. We find significant evidence of changing selective pressures in several genes correlated with the introduction of agriculture to Europe and the ensuing dietary and demographic shifts of that time. In particular, our analysis supports previous hypotheses of strong selection on lactase persistence during periods of ancient famines and attenuated selection in more modern periods.

evolutionary biology↗
bioRxiv2023

Utilizing Non-Invasive Prenatal Test Sequencing Data Resource for Human Genetic Investigation

Non-invasive prenatal testing (NIPT) employs ultra-low-pass sequencing of maternal plasma cell-free DNA to detect fetal trisomy. With exceptional sensitivity, specificity, and safety, NIPT has gained global adoption, exceeding ten million tests, establishing it as one of the largest human genetic resources. This resource holds immense potential for exploring population genetic variations and their correlations with phenotypes. Here, we present comprehensive methods tailored for analyzing large, low-depth NIPT genetic datasets, involving customized algorithms and software for genetic variation detection, genotype imputation, and genome-wide association analysis. Through evaluations, we demonstrate that, when integrated with appropriate probabilistic models and population-specific haplotype reference panels, accurate allele frequency estimation and high genotype imputation accuracy (0.8 to 0.9) are achievable for genetic variants with alternative allele frequencies between 0.01 and 0.05, at sequencing depths of 0.1x to 0.25x. Additionally, we attained an R-square exceeding 0.9 for estimating genetic effect sizes across various sequencing platforms. These findings establish a robust theoretical and practical foundation for leveraging NIPT data in advancing medical genetic studies, not only in realms of maternal and child health, but also for long-term health outcomes. HighlightsO_LIIntroduction of probabilistic model integration for analyzing large-scale, low-pass non-invasive prenatal test (NIPT) sequencing data C_LIO_LIEvaluation of protocols for variant detection, genotype imputation, and genome-wide association analyses with NIPT data C_LI

bioinformatics↗
bioRxiv2023

Revisiting the Briggs ancient DNA damage model: a fast regression method to estimate postmortem damage

MotivationOne essential initial step in the analysis of ancient DNA is to authenticate its ancientness to ensure reliable conclusions. That is, meticulously assessing whether next-generation sequencing reads exhibit ancient characteristics, with a particular focus on the postmortem damage (PMD) signal induced by cytosine deamination in the fragments termini. We present a novel statistical method implementation in a fast multithreaded program ngsBriggs that enables the rapid quantification of PMD by calculation of the Briggs ancient damage model parameters (Briggs parameters). ResultsUsing a fast multinomial regression approach, ngsBriggs accurately models the Briggs parameters, quantifying the PMD signal from single and double-stranded DNA regions. We revisit and extend the original Briggs model, with ngsBriggs modeling PMD signals for contemporary sequencing platforms. Furthermore, ngsBriggs asserts itself as a reliable and consistent tool, by accurately estimating the Briggs parameters across a variety of contamination levels. The classification accuracy of ngsBriggs significantly exceeds the current tool available when discerning ancient-from modern sequencing reads to decontaminate samples. Our novel method and implementation ngsBriggs outperforms existing tools regarding computational speed and accuracy, establishing its practicality and usability. Our tool, ngsBriggs offers a practical and accurate toolset for researchers seeking to authenticate ancient DNA and improve the quality of their data. Availabilityhttps://github.com/lz398/metadamage_briggs

bioinformatics↗
bioRxiv2023

CASTER: Direct species tree inference from whole-genome alignments

Genomes contain mosaics of discordant evolutionary histories, challenging the accurate inference of the tree of life. While genome-wide data are routinely used for discordance-aware phylogenomic analyses, due to modeling and scalability limitations, the current practice leaves out large chunks of the genomes. As more high-quality genomes become available, we urgently need discordance-aware methods to infer the tree directly from a multiple genome alignment. Here, we introduce CASTER, a site-based method that eliminates the need to predefine recombination-free loci. CASTER is statistically consistent under incomplete lineage sorting and is scalable to hundreds of mammalian whole genomes. We show both in simulations and on real data that CASTER is scalable and accurate and that its per-site scores can reveal interesting patterns of evolution across the genome.

evolutionary biology↗
bioRxiv2023

Genetic basis of aposematic coloration in a mimetic radiation of poison frogs

The evolution of mimicry in a single species or population has rippling inter and intraspecific effects across ecological communities, providing a fascinating mechanism of phenotypic diversification. In this study we present the first identification of genes underlying Mullerian mimicry in a vertebrate, the Peruvian mimic poison frog, Ranitomeya imitator. We sequenced 124 R. imitator exomes and discovered loci with both strong divergence between different mimetic morphs and phenotypic associations within an intraspecific admixture zone, implicating mc1r, asip, bsn, retsat, and krt8.2 in the evolution of mimetic color phenotypes. We confirmed these associations for most candidate genes through linkage mapping in a lab-reared pedigree. We also sequenced transcriptomes from the model species, allowing tests for introgression and revealing that the mimetic resemblance between R. imitator and the models evolved independently. Selection analyses of the candidate genes show that the mimicry phenotypes likely have evolved through selective sweeps acting on polygenic variation. Our results suggest that the evolutionary origins and molecular mechanisms underlying mimicry phenotypes in vertebrates may be radically different from those previously documented in invertebrates such as the iconic Heliconius butterfly mimicry complex. One Sentence SummaryMullerian mimicry evolved through independent selective sweeps on color and pattern loci in the mimic poison frog.

evolutionary biology↗
bioRxiv2023

Symbiotic acacia ants drive nesting behavior by birds in an African savanna

Mutualisms between plants and ants are common features of tropical ecosystems around the globe and can have cascading effects on interactions with the ecological communities in which they occur. In an African savanna, we assessed whether acacia ants influence nest site selection by tree-nesting birds. Birds selected nest sites in trees inhabited by ant species that vigorously defend against browsing mammals. Future research could address the extent to which hatching and fledging rates depend on the species of ant symbiont, and why ants tolerate nesting birds but not other tree associates (especially insects).

ecology↗
bioRxiv2023

Transcriptomic responses of sponge holobionts to in situ, seasonal anoxia and hypoxia

Deoxygenation can be fatal for many marine animals; however, some sponge species are tolerant of hypoxia and anoxia. Indeed, two sponge species, Eurypon sp. 2 and Hymeraphia stellifera, survive seasonal anoxia for months at a time. To understand their tolerance mechanisms, we performed differential gene expression analyses on the sponges, their mitochondria and their microbial symbionts under in situ conditions of normoxia, hypoxia and anoxia. Each species possessed a unique microbiome, but the microbiomes of each species were dominated by a species-specific Thaumarchaeon and a Gammaproteobacterium. Holobiont gene expression was species-and oxygen-level dependent, though there were some shared interspecific responses to deoxygenation. In general, few changes occurred in the expression of sponge metabolic genes as a function of oxygenation level, indicating that they may remain metabolically active under anoxia. However, ATP synthesis genes were significantly upregulated under hypoxia when compared to normoxia, and genes for DNA replication were downregulated. Mitochondrial gene expression was effectively unchanged under both hypoxia and anoxia. Nevertheless, both anoxia and hypoxia caused upregulation of heat shock proteins (HSPs), indicating cellular level adaptations to deoxygenation stress. A meta-analysis demonstrated that sponge transcriptional responses to anoxia were distinct from those displayed by other invertebrates while dormant, and the hypothesis of sponge dormancy under anoxia was not supported. Thaumarchaeota symbionts also upregulated stress response genes in hypoxia, while maintaining expression of oxygen-dependent metabolic pathways under hypoxia and anoxia. Gammaproteobacteria symbionts showed relatively few noteworthy changes in gene expression in response to anoxia but decreased metabolic gene expression in hypoxia. There was no clear evidence of upregulated anaerobic respiration in the transcriptomes of the sponge holobionts under anoxia or hypoxia. The tolerance of some sponges to prolonged anoxia warrants further investigation and could give them an advantage in future oceans following climate change as well as in ancient oceans when oxygen concentrations were lower than at present.

ecology↗