Biology subjects

Weber, A. M.

Publications and source records attributed to Weber, A. M..

5 recordsLinked to original sources

bioRxiv2023

Temporal Complexity of the BOLD-Signal In Preterm Versus Term Infants

Preterm birth causes alterations in cerebral development. We calculated the Hurst exponent (H) - a measure of temporal complexity - from resting state functional magnetic resonance signal in preterm and term born infants. Anatomical, fMRI, and diffusion weighted imaging data from 716 neonates born between 23-43 weeks gestational age were obtained from the Developing Human Connectome Project. H was assessed in brain tissues and 13 resting state networks. H significantly increased with age, and earlier birth age contributed to lower H values. In most brain regions, H begins below 0.5 at preterm age and crosses 0.5 at term age. Motor and sensory networks demonstrated the greatest increase in H. Correlations between indirect measures of myelination and H were moderate. Overall, H appears to reflect developmental processes in the neonatal brain, as BOLD signal in the preterm infant transforms from anticorrelated to correlated but is reduced compared to term born infants.

neuroscience↗

bioRxiv2022

Human commensal Candida albicans strains demonstrate substantial within-host diversity and retained pathogenic potential

Candida albicans is a frequent colonizer of human mucosal surfaces as well as an opportunistic pathogen. C. albicans is remarkably versatile in its ability to colonize diverse host sites with differences in oxygen and nutrient availability, pH, immune responses, and resident microbes, among other cues. It is unclear how the genetic background of a commensal colonizing population can influence the shift to pathogenicity. Therefore, we undertook an examination of commensal isolates from healthy donors with a goal of identifying site-specific phenotypic adaptation and genetic variation associated with these phenotypes. We demonstrate that healthy people are reservoirs for genotypically and phenotypically diverse C. albicans strains, and that this genetic diversity includes both SNVs and structural rearrangements. Using limited diversity exploitation, we identified a single nucleotide change in the uncharacterized ZMS1 transcription factor that was sufficient to drive hyper invasion into agar. However, our commensal strains retained the capacity to cause disease in systemic models of infection, including outcompeting the SC5314 reference strain during systemic competition assays. This study provides a global view of commensal strain variation and within-host strain diversity of C. albicans and suggests that selection for commensalism in humans does not result in a fitness cost for invasive disease.

microbiology↗

bioRxiv2020

Expectations and blind spots for structural variation detection from short-read alignment and long-read assembly

Virtually all genome sequencing efforts in national biobanks, complex and Mendelian disease programs, and emerging clinical diagnostic approaches utilize short-reads (srWGS), which present constraints for genome-wide discovery of structural variants (SVs). Alternative long-read single molecule technologies (lrWGS) offer significant advantages for genome assembly and SV detection, while these technologies are currently cost prohibitive for large-scale disease studies and clinical diagnostics (∼5-12X higher cost than comparable coverage srWGS). Moreover, only dozens of such genomes are currently publicly accessible by comparison to millions of srWGS genomes that have been commissioned for international initiatives. Given this ubiquitous reliance on srWGS in human genetics and genomics, we sought to characterize and quantify the properties of SVs accessible to both srWGS and lrWGS to establish benchmarks and expectations in ongoing medical and population genetic studies, and to project the added value of SVs uniquely accessible to each technology. In analyses of three trios with matched srWGS and lrWGS from the Human Genome Structural Variation Consortium (HGSVC), srWGS captured ∼11,000 SVs per genome using reference-based algorithms, while haplotype-resolved assembly from lrWGS identified ∼25,000 SVs per genome. Detection power and precision for SV discovery varied dramatically by genomic context and variant class: 9.7% of the current GRCh38 reference is defined by segmental duplications (SD) and simple repeats (SR), yet 91.4% of deletions that were specifically discovered by lrWGS localized to these regions. Across the remaining 90.3% of the human reference, we observed extremely high concordance (93.8%) for deletions discovered by srWGS and lrWGS after error correction using the raw lrWGS reads. Conversely, lrWGS was superior for detection of insertions across all genomic contexts. Given that the non-SD/SR sequences span 90.3% of the GRCh38 reference, and encompass 95.9% of coding exons in currently annotated disease associated genes, improved sensitivity from lrWGS to discover novel and interpretable pathogenic deletions not already accessible to srWGS is likely to be incremental. However, these analyses highlight the added value of assembly-based lrWGS to create new catalogues of functional insertions and transposable elements, as well as disease associated repeat expansions in genomic regions previously recalcitrant to routine assessment.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

bioRxiv2017

Signatures of selection at drug resistance loci in Mycobacterium tuberculosis

Tuberculosis (TB) is the leading cause of death by an infectious disease, and global TB control efforts are increasingly threatened by drug resistance in Mycobacterium tuberculosis (M. tb). Unlike most bacteria, where lateral gene transfer is an important mechanism of resistance acquisition, resistant M. tb arises solely by de novo chromosomal mutation. Using whole genome sequencing data from two natural populations of M. tb, we characterized the population genetics of known drug resistance loci using measures of diversity, population differentiation, and convergent evolution. We found resistant sub-populations to be less diverse than susceptible sub-populations, consistent with ongoing transmission of resistant M. tb. A subset of resistance genes (\"sloppy targets\") were characterized by high diversity and multiple rare variants; we posit that a large genetic target for resistance and relaxation of purifying selection contribute to high diversity at these loci. For \"tight targets\" of selection, the path to resistance appeared narrower, evidenced by single favored mutations that arose numerous times on the phylogeny and segregated at markedly different frequencies in resistant and susceptible sub-populations. These results suggest that diverse genetic architectures underlie drug resistance in M. tb, and combined approaches are needed to identify causal mutations. Extrapolating from patterns observed in well-characterized genes, we identified novel candidate variants involved in resistance. The approach outlined here can be extended to identify resistance variants for new drugs, to investigate the genetic architecture of resistance, and, when phenotypic data are available, to find candidate genetic loci underlying other positively selected traits in clonal bacteria.\n\nImportanceMycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), is a significant burden on global health. Antibiotic treatment imposes strong selective pressure on M. tb populations. Identifying the mutations that cause drug resistance in M. tb is important for guiding TB treatment and halting the spread of drug resistance. Whole genome sequencing (WGS) of M. tb isolates can be used to identify novel mutations mediating drug resistance and to predict resistance patterns faster than traditional methods of drug susceptibility testing. We have used WGS from natural populations of drug resistant M. tb to characterize effects of selection for advantageous mutations on patterns of diversity at genes involved in drug resistance. The methods developed here can be used to identify novel advantageous mutations, including new resistance loci, in M. tb and other clonal pathogens.

microbiology↗

bioRxiv2017

VaPoR: a high-speed validation approach for structural variation using long-read sequencing technology.

AbstractSummaryAlthough there are numerous algorithms that have been developed to identify structural variation (SVs) in genomic sequences, there is a dearth of approaches that can be used to evaluate their results. The emergence of new sequencing technologies that generate longer sequence reads can, in theory, provide direct evidence for all types of SVs regardless of the length of region through which it spans. However, current efforts to use these data in this manner require the use of large computational resources to assemble these sequences as well as manual inspection of each region. Here, we present VaPoR, a highly efficient algorithm that autonomously validates large SV sets using long read sequencing data. We assess of the performance of VaPoR on both simulated and real SVs with regards to various features including accuracy and sensitivity of breakpoint evaluation and report a high fidelity rate.\n\nAvailabilityhttps://github.com/mills-lab/VaPoR\n\nContactremills@umich.edu\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗