Biology subjects

Andrews, C.

Publications and source records attributed to Andrews, C..

16 recordsLinked to original sources

bioRxiv2026

HPRC2: A human pangenome reference with near-complete coverage of common genetic variation

A pangenome reference overcomes the inherent limitation of any individual reference genome by integrating the variation present in a population. We present the Human Pangenome Reference Consortiums (HPRC) Release 2 (HPRC2), an openly available, second phase pangenome that is an approximately fivefold expansion in genome number over HPRC Release 1 (HPRC1) and measurable improvement in genome completeness, contiguity, and accuracy. Selecting samples with a principled algorithm prioritising common variant coverage, HPRC2 contributes 460 haplotypes that together capture over 99% of common variation observed in the All of Us Research Program v8 cohort. Combining high-coverage long and ultra-long reads with modern assemblers and polishers, we produce thousands of telomere-to-telomere (T2T) chromosomes, and relative to HPRC1 halve the number of structurally unreliable regions as well as individual base errors per haplotype. We complement the assemblies with whole genome multiple alignments and gene annotations, and derive formal pangenome coordinate systems for addressing off-reference variation, demonstrating that individual human genomes contain more than one hundred thousand variants not succinctly described with respect to existing reference genomes. We also present the first matched long-read backed pantranscriptome and panepigenome at this scale, provide continuous local-ancestry estimates spanning every genome, and outline a host of new tools and applications that leverage the pangenome resource for improved genomics analysis.

genomics↗

bioRxiv2026

Genetic Modulation of Oxycodone Self-Administration Trajectories: From Initiation to Escalating Burst Patterns

Opioid Use Disorder (OUD) remains a prominent threat to global health. Genetic background influences the susceptibility of developing OUD, although specific genetic factors remain elusive. Rodent models that differ in susceptibility to escalation and dysregulation of opioid use are valuable tools to facilitate discovery of genetic pathways. Phenotypes associated with the development of OUD were compared in seven classic inbred rat strains (M520/N, WKY/NCrl, F344/NCrl, F344/Stm, LEW/Crl, LEW/SSNHsd, LE/Stm) from the Hybrid Rat Diversity Panel (HRDP). A two-phase self-administration paradigm was utilized to assess characteristics of the acquisition of oxycodone self-administration during daily 2-h sessions, and the escalation of oxycodone use during daily 12-h sessions. Genetic background influenced the acquisition of oxycodone self-administration as indicated by differences in the initiation of responding for oxycodone during each session and different amounts of oxycodone intake. We observed that escalation of oxycodone intake between-sessions was strain dependent, and the within-session distribution of oxycodone intake was strongly influenced by strain. The M520/N strain engaged in a unique pattern of intake, characterized by rapid initiation of oxycodone responding during the acquisition phase and a significant burst-like responding during escalation. Strain-dependent sex differences were also observed in several acquisition and escalation metrics. Of interest, burst responding was more prevalent in females of the M520/N strain compared to males. Together, these data indicate that genetic background influences not only overall oxycodone intake, but specific within- and between-session metrics that capture patterns of consumption across the substance use trajectory.

animal behavior and cognition↗

bioRxiv2026

High nitrogen deposition is associated with phosphorus-efficient ectomycorrhizas in Europe's Scots pine forests

Atmospheric inorganic nitrogen (N) deposition has been linked to increased tree phosphorus (P) deficiency and shifts in ectomycorrhizal (ECM) fungal community composition across Europe, but the underlying mechanisms remain poorly understood due to the scarcity of species-level studies of fungal physiology at large spatial scales. Here, we characterized ECM communities in nine Scots pine (Pinus sylvestris L.) stands across Europes largest N deposition gradient to gain mechanistic insight into N-driven ECM community shifts, by assessing morpho-physiological traits (i.e. soil exploration types and ECM root-tip level exoenzyme activities involved in organic N and P acquisition) on individual ectomycorrhizas. Our data revealed high functional variation in foraging strategies across species and sites, including within dominant ECM genera (Cortinarius, Elaphomyces, Lactarius, Piloderma, Russula). Shifts in community-level exoenzyme activities along the N deposition gradient were consistent with increasing P limitation, with a buffering effect of phosphomonoesterase activity on host nutritional status (i.e. reduced foliar N:P). These trends were mainly driven by interspecific differences in enzymatic profiles and species turnover along the gradient, rather than intraspecific variation within widespread species. Dominant low-biomass species in high N sites (e.g. E. citrinopapillatus, L. subdulcis, R. ochroleuca) were efficient P-foragers, with some displaying high oxidative activity, potentially hampering soil carbon storage under elevated N loads. These findings highlight the role of ECM species-specific traits in mediating ecosystem processes and can help understand the future of pine forests under chronic N pollution, with potential implications for applied forestry.

ecology↗

bioRxiv2026

A Common Pathogenic Founder Variant in Rwandan Breast Cancer Cases

Germline data from African populations remain sparse, limiting characterization of population-specific BRCA1/2 pathogenic variants. In a study of 175 Rwandan women with breast cancer, 7 unrelated carriers (4% of cases; 22% of pathogenic variant carriers) harbored the same BRCA1 frameshift variant, c.4065_4068del (p.Asn1355Lysfs*10), which is extremely rare in gnomAD yet recurrent in European, Asian, and Middle Eastern cohorts. Whole-exome sequencing and haplotype analysis of all 7 carriers revealed a shared ancestral block of approximately 581 kb surrounding the variant, and extended haplotype homozygosity and network analyses confirmed a common founder origin. Coalescent-based age estimation placed the founder event approximately 4,000--10,000 years ago. Comparison with 1000 Genomes Project data showed the founder haplotype is absent or exceedingly rare outside African and South Asian populations. These findings strongly suggest the c.4065_4068del variant as a pre-historical BRCA1 founder variant in Rwanda, with implications for targeted genetic testing, cascade screening, and cancer prevention in the region.

genetics↗

bioRxiv2026

Defining the OrrA regulon and its role in development and antibiotic production in Streptomyces venezuelae NRRL B-65442

2.Streptomyces bacteria have complex life cycles involving hyphal growth, sporulation, and the production of diverse specialised metabolites, including antibiotics. In this study, we investigated the role of the highly conserved orphan response regulator OrrA in Streptomyces venezuelae NRRL B-65442. We show that S. venezuelae {Delta}orrA mutants are defective in sporulation and, using ChIP-seq, identify five OrrA binding sites in vivo. Tandem-mass-tag proteomics revealed that OrrA directly activates two of these putative target genes, wblA and vnz_04640, a finding consistent with previous work on OrrA in the distantly related S. coelicolor. We also demonstrate that deleting wblA blocks sporulation and that overexpressing wblA restores sporulation in the {Delta}orrA mutant. Additionally, chloramphenicol biosynthesis is upregulated in both the {Delta}orrA and {Delta}wblA mutants compared with the wild type. Taken together, these results indicate that the primary function of OrrA is to regulate WblA production, and that reduced intracellular WblA levels underlie the phenotypes observed in the {Delta}orrA mutant. 3. Data summaryThe authors confirm all supporting data, code and protocols have been provided within the article, through supplementary data files and via public databases.

microbiology↗

bioRxiv2024

Exploring the impacts of human breast milk functional lipidome on infant health and growth outcomes in early life using lipid bioinformatics

Human breast milk lipidome is complex, and how changes in the functional lipid metabolism converge systematically to alter infants health outcomes is poorly understood. We used human breast milk and infant-mother dyads as a test system to demonstrate how the application of improved lipid bioinformatics can be effective in discerning systematic changes in functional lipid metabolism providing novel discoveries of how lactational programming in early life can influence infant health and growth outcomes. The study consisted of 40 mother-infant dyads where breast milk, maternal diet, infant anthropometrics [fat mass index (FMI), length z score, BMI z score, fat-free mass index (FFMI)], and infant atopic disease outcome (ear infection, cold, wheezing, diarrhea, and eczema) were collected at one and four months postpartum. Integrated Lipid Bioinformatics analyses were conducted using XLSTAT, Metaboanalyst 5.0. R software, Lipid Search, Xcalibur, and Cytoscape software. The results showed breast milk lipidome ordinated into distinct clusters based on maternal BMI status, and differences in developmental and atopic disease outcomes following redundancy analysis. Specifically, lipids from obese mothers clustered with FMI and eczema, while lipids from non-obese mothers clustered with FFM and wheezing. Receiver operating analysis was effective in identifying potential lipid biomarkers that were significantly associated with infant FMI, FFMI, and eczema during early life. Sphingolipid and glycerophospholipid pathways were significantly associated with the altered breast milk lipidome impacting infant development and atopic disease outcome during the first year of life. The findings following the advanced lipid bioinformatics suggest that the breastmilk functional lipid metabolism appears to play a key role in lipid-mediated lactational programming influencing development and atopic disease outcome, and present opportunities for potential dietary intervention in early life.

bioinformatics↗

bioRxiv2024

High fat low carbohydrate diet is linked to protection against CNS autoimmunity

Multiple sclerosis (MS) is a common central nervous system (CNS) autoimmune disease, and diets and nutrients are emerging as critical contributing factors. However, a comprehensive understanding of their impacts and the underlying mechanisms involved is lacking. Harnessing state-of-the-art nutritional geometry analytical methods, we first revealed that globally, increased carbohydrate supply was associated with increased MS disease burden, while fat supply had an opposite effect. Furthermore, in a preclinical MS mouse model, experimental autoimmune encephalomyelitis (EAE), we found that an isocaloric diet high in carbohydrate aggravated EAE, while a diet enriched in fat was fully protective. This was reflected by reduced neuroinflammation and skewing towards anti-inflammatory phenotypes, which involved transcriptomic, epigenetic and immunometabolic changes. We showcased that manipulating diets is a potentially efficient and cost-effective approach to prevent and/or ameliorate EAE. This exhibits translational potentials for intervention/prevention of MS and possibly other autoimmune diseases.

immunology↗

bioRxiv2024

High-throughput discovery of regulatory effector domains in human RNA-binding proteins

RNA regulation plays an integral role in tuning gene expression and is controlled by thousands of RNA-binding proteins (RBPs). We develop and use a high-throughput recruitment assay (HT-RNA-Recruit) to identify regulatory domains within human RBPs by recruiting over 30,000 protein tiles from 367 RBPs to a reporter mRNA. We discover over 100 unique RNA-regulatory effectors in 86 distinct RBPs, presenting evidence that RBPs contain functionally separable domains that dictate their post-transcriptional control of gene expression, and identify some with unique activity at 5 or 3UTRs. We identify some domains that downregulate gene expression both when recruited to DNA and RNA, and dissect their mechanisms of regulation. Finally, we build a synthetic RNA regulator that can stably maintain gene expression at desired levels that are predictable by a mathematical model. This work serves as a resource for human RNA-regulatory effectors and expands the synthetic repertoire of RNA-based genetic control tools. Highlights- HT-RNA-Recruit identifies hundreds of RNA-regulatory effectors in human proteins. - Recruitment to 5 and 3 UTRs identifies regulatory domains unique to each position. - Some protein domains have both transcriptional and post-transcriptional regulatory activity. - We develop a synthetic RNA regulator and a mathematical model to describe its behavior.

synthetic biology↗

bioRxiv2024

Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men

Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a novel dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using a custom array. We first tested how genetic predictions of baldness generalize from Europe to Africa, finding that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness in African populations performed notably worse than in European populations. Subsequently, we conducted the first African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for present age, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10-5, r2 < 0.2). Most baldness associations were autosomal, and the X chromosomes does not appear to have a large impact on baldness in African men. Finally, we examined the evolutionary causes of continental differences in genetic architecture. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, we did not find evidence that European-ascertained baldness hits were enriched for signatures of ancient introgression. Most loci that are associated with androgenetic alopecia are evolving neutrally. However, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how evolutionary history contributes to the limited portability of genetic predictions across ancestries.

genomics↗

bioRxiv2023

Primate origins of human event cognition

Human language relies on a rich cognitive machinery, partially shared with other animals. One key mechanism, decomposing events into causally-linked agent-patient roles, however, has remained elusive with no known animal equivalent. In humans, agent-patient relations in event cognition drive how languages are processed neurally and expressions structured syntactically. We compared visual event tracking between humans and great apes, using stimuli that would elicit causal processing in humans. After accounting for attention to background information, we found similar gaze patterns to agent-patient relations in all species, mostly alternating attention to agents and patients, presumably in order to learn the nature of the event, and occasionally privileging agents under specific conditions. Six-month-old infants, in contrast, did not follow agent-patient relations and attended mostly to background information. We conclude that event role tracking, a cognitive foundation of syntax, evolved long before language but requires time and experience to become ontogenetically available. Significance statementHuman adults and great apes, but not human infants, track natural events as agent-patient relations, a cognitive foundation for syntax.

animal behavior and cognition↗

bioRxiv2023

Diversity and community structure of anaerobic gut fungi in the rumen of wild and domesticated herbivores

The rumen houses a diverse community that plays a major role in the digestion process in ruminants. Anaerobic gut fungi (AGF) are key contributors to plant digestion in the rumen. Here, we present a global amplicon-based survey of the rumen mycobiome by examining 206 samples from 15 animal species, 15 countries and six continents. The rumen mycobiome was highly diverse, with 81 out of 88 currently recognized AGF genera or candidate genera identified. However, only six genera (Neocallimastix, Orpinomyces, Caecomyces, Cyllamyces, NY9, and Piromyces) were present at > 4% relative abundance. AGF diversity was higher in members of the families Antilocapridae and Cervidae compared to Bovidae. Community structure analysis identified a pattern of phylosymbiosis, where host family (10% of total variance) and species (13.5%) partially explained the rumen mycobiome composition. Domestication (11.14%) and biogeography (14.1%) also partially explained AGF community structure, although sampling limitation, geographic range restrictions, and direct association between domestication status and host species hindered accurate elucidation of the relative contribution of each factor. Pairwise comparison of rumen versus fecal samples obtained from the same subject (n=13) demonstrated greater diversity and inter-sample variability in rumen over fecal samples. The genera Neocallimastix and Orpinomyces were present in higher abundance in rumen samples, while Cyllamyces and Caecomyces were enriched in fecal samples. Comparative analysis of global rumen and feces datasets revealed a similar pattern. Our results provide a global view of AGF community in the rumen and identify patterns of AGF variability between rumen and feces in herbivores tract. ImportanceRuminants are highly successful and economically important mammalian suborder. Ruminants are herbivores that digest plant material with the aid of microorganisms residing in their GI tract. The rumen compartment represents the most important location where microbially-mediated plant digestion occurs in ruminants, and is known to house a bewildering array of microbial diversity. An important component of the rumen microbiome is the anaerobic gut fungi, members of the phylum Neocallimastigomycota. So far, studies examining AGF diversity have mostly employed fecal samples, and little is currently known regarding the identity of AGF residing in the rumen compartment, factors that impact the observed patterns of diversity and community structure of AGF in the rumen, and how AGF communities in the rumen compare to AGF communities in feces. Here, we examined the rumen AGF diversity using amplicon-based surveys targeting a wide range of wild and domesticated ruminants (n=206, 15 different animal species) obtained from 15 different countries. Our results demonstrate that while highly diverse, no new AGF genera were identified in the rumen mycobiome samples examined. Our analysis also indicate that animal host phylogeny plays a more important role in shaping AGF diversity in the rumen, compared to biogeography and domestication status. Finally, we demonstrate that a greater level of diversity and higher inter-sample variability was observed in rumen compared to fecal samples, with two genera (Neocallimastix and Orpinomyces) present in higher abundance in rumen samples, and two others (Cyllamyces and Caecomyces) enriched in fecal samples. Our results provide a global view of the identity, diversity, and community structure of AGF in ruminants, elucidate factors impacting diversity and community structure of the rumen mycobiome, and identify patterns of AGF community variability between the rumen and feces in the herbivorous GIT tract.

microbiology↗

bioRxiv2022

High-throughput functional characterization of combinations of transcriptional activators and repressors

Despite growing knowledge of the functions of individual human transcriptional effector domains, much less is understood about how multiple effector domains within the same protein combine to regulate gene expression. Here, we measure transcriptional activity for 8,400 effector domain combinations by recruiting them to reporter genes in human cells. In our assay, weak and moderate activation domains synergize to drive strong gene expression, while combining strong activators often results in weaker activation. In contrast, repressors combine linearly and produce full gene silencing, and repressor domains often overpower activation domains. We use this information to build a synthetic transcription factor whose function can be tuned between repression and activation independent of recruitment to target genes by using a small molecule drug. Altogether, we outline the basic principles of how effector domains combine to regulate gene expression and demonstrate their value in building precise and flexible synthetic biology tools.

synthetic biology↗

bioRxiv2022

Large-scale mapping and systematic mutagenesis of human transcriptional effector domains

Human gene expression is regulated by over two thousand transcription factors and chromatin regulators1,2. Effector domains within these proteins can activate or repress transcription. However, for many of these regulators we do not know what type of transcriptional effector domains they contain, their location in the protein, their activation and repression strengths, and the amino acids that are necessary for their functions. Here, we systematically measure the transcriptional effector activity of >100,000 protein fragments (each 80 amino acids long) tiling across most chromatin regulators and transcription factors in human cells (2,047 proteins). By testing the effect they have when recruited at reporter genes, we annotate 307 new activation domains and 592 new repression domains, a [~]5-fold increase over the number of previously annotated effectors3,4. Complementary rational mutagenesis and deletion scans across all the effector domains reveal aromatic and/or leucine residues interspersed with acidic, proline, serine, and/or glutamine residues are necessary for activation domain activity. Additionally, the majority of repression domain sequences contain either sites for SUMOylation, short interaction motifs for recruiting co-repressors, or are structured binding domains for recruiting other repressive proteins. Surprisingly, we discover bifunctional domains that can both activate and repress and can dynamically split a cell population into high- and low-expression subpopulations. Our systematic annotation and characterization of transcriptional effector domains provides a rich resource for understanding the function of human transcription factors and chromatin regulators, engineering compact tools for controlling gene expression, and refining predictive computational models of effector domain function.

systems biology↗

bioRxiv2021

Validation of non-invasive body-surface gastric mapping for detecting electrophysiological biomarkers by simultaneous high-resolution serosal mapping in a porcine model

Gastric disorders are increasingly prevalent, but reliable clinical tools to objectively assess gastric function are lacking. Body-surface gastric mapping (BSGM) is a non-invasive method for the detection of gastric electrophysiological biomarkers including slow wave direction, which have correlated with symptoms in patients with gastroparesis and functional dyspepsia. However, no studies have validated the relationship between gastric slow waves and body surface activation profiles. This study aimed to comprehensively evaluate the relationship between gastric slow waves and body-surface recordings. High-resolution electrode arrays were placed to simultaneously capture slow waves from the gastric serosa (32x6 electrodes at 4 mm resolution) and abdominal surface (8x8 at 20 mm inter-electrode spacing) in a porcine model. BSGM signals were extracted based on a combination of wavelet and phase information analyses. A total of 1185 individual cycles of slow waves assessed, out of which 897 (76%) were normal antegrade waves, occurring in 10/14 (71%) subjects studied. BSGM accurately detected the underlying slow wave in terms of frequency (r = 0.99, p = 0.43) as well as the direction of propagation (p = 0.41, F-measure: 0.92). In addition, the cycle-by-cycle match between BSGM and transitions of gastric slow waves in terms either or both temporal and spatial abnormalities was demonstrated. These results validate BSGM as a suitable method for non-invasively and accurately detecting gastric slow wave activation profiles from the body surface. Single sentence summarySimultaneous recordings of the stomach using serosal and body-surface electrode arrays demonstrated reliable detection of frequency and classification of propagation.

physiology↗

bioRxiv2020

A Novel CD206 Targeting Peptide Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice

Activated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. RP-832c selectively binds to CD206 on M2 polarized bone marrow derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression, and a transient increase in M1 marker TNF, which resolves over a 24hr period. To elucidate the antifibrotic effect of RP-832c, we used a murine model of bleomycin (BLM) -induced early-stage pulmonary fibrosis. RP-832c significantly reduced bleomycin-induced fibrosis in a dosage dependent manner, as well as decreased CD206, TGF-{beta}1 and -SMA expression in mouse lungs. Interestingly we did not observe any changes in the resident alveolar macrophage marker CD170 expression. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased fibrosis in the lung, as well as significantly decreased inflammatory cytokines TNF, IL-6, IL-10, INF-{gamma}, CXCL1/2, and fibrosis markers TGF-{beta}1 and MMP-13. In comparison with FDA approved drugs, Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed on body weight or blood chemistry. In summary, RP-832c is a potential agent to mitigate the overactivity of M2 macrophages in pathogenesis several pulmonary fibrotic diseases, including SARS-CoV-2 induced lung fibrosis.

pathology↗

bioRxiv2019

A custom genotyping array reveals population-level heterogeneity for the genetic risks of prostate cancer and other cancers in Africa

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. We find that samples from Ghana and Nigeria cluster together, while samples from Senegal and South Africa yield distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores were also generated for each genome in the MADCaP pilot dataset, and we found that predicted risks of CaP are lower in Senegal and higher in Nigeria.\n\nSignificanceWe have developed an Africa-specific genotyping array which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.

genomics↗