Biology subjects

Hewett, A.

Publications and source records attributed to Hewett, A..

6 recordsLinked to original sources

bioRxiv2025

Benchmarking imputation accuracy in the presence or absence of a reference panel

Whole genome sequencing (WGS) of a large number of samples is costly. Solutions to reduce this cost include targeting a proportion of the genome (e.g. SNP arrays) or lowering the sequencing depth (low-coverage WGS, lcWGS) but both solutions suffer from either genotype missingness or uncertainty. Genomic imputation addresses this problem by inferring missing or uncertain genotypes using a collection of high quality genomic data (a reference panel). However, certain methods can impute a lcWGS dataset without a reference panel. Because the investment into generating a reference panel can be prohibitively expensive in non-model species, a benchmarking of the accuracy of these alternative methods of imputation can help inform study design. Here, we imputed a dataset of 2800 lcWGS in the presence and absence of a reference panel of 502 samples. We used 32 individuals sequenced at both high and low coverage to estimate the accuracy of each method and explored the limitations of lcWGS sample size and reference panel size. Although the best results were achieved with a large reference panel, using only a lcWGS dataset showed accurate imputation, when over 500 samples were used and we account for missing data and low frequency alleles. In addition, imputing with or without a reference panel gave similar results in a GWAS for a polygenic trait but required some quality control in the identification of homozygous-by-descent segments. Thus, while using a reference panel remains the ideal approach, imputation in suitably large lcWGS datasets can provide sufficient accuracy given proper quality control.

genomics↗

bioRxiv2025

Genomic bases of short-term evolution in the wild revealed by long-term monitoring and population-scale sequencing

Understanding how wild populations adapt to rapid environmental change requires linking phenotypic evolution to its genomic basis over contemporary timescales. This remains challenging because genetic and environmental effects are often intertwined. Here, we leverage a 30-year study of Swiss barn owls (Tyto alba) to explore this process. During this period, owls have evolved darker plumage and increased spottiness, two melanin-based traits associated with fitness. Whole-genome sequencing of 3,102 individuals reveals that these traits are largely controlled by few loci of major effect with partially overlapping architectures. Temporal allele frequency analyses show subtle but consistent shifts at these loci. Simulations indicate that genetic drift alone cannot explain these changes, whereas models incorporating selection do. Our findings demonstrate that selection on a small number of loci can drive rapid phenotypic evolution in the wild. This work underscores the adaptive potential of natural populations and the value of long-term genomic monitoring under accelerating climate change.

evolutionary biology↗

bioRxiv2025

SCD1 and SCD5 Modulate PARP-Dependent DNA Repair via Fatty Acid Desaturation in Glioblastoma

Glioblastoma (GBM) relies on fatty acid metabolism to sustain its aggressive growth. While the role of stearoyl-CoA desaturase-1 (SCD1) in GBM is established, the function of its brain-enriched isoform, SCD5, remains unexplored. Here, we demonstrate that SCD5 is essential for glioblastoma stem cell (GSC) maintenance and genomic stability, with elevated expression in GSCs that declines upon differentiation, underscoring its role in tumor initiation. Through shotgun lipidomics, 13C metabolic flux analysis, and functional genomics, we reveal that SCD1 and SCD5 play non-redundant roles in fatty acid desaturation, with SCD5 preferentially desaturating C18:0 and uniquely contributing to sphingolipid remodeling. Genetic silencing of either isoform disrupts cell cycle progression, impairs DNA damage repair, and reduces GSC viability, while SCD5 knockdown significantly extends survival in orthotopic GBM models. Mechanistically, loss of SCD activity or saturated fatty acid accumulation triggers PARP1 hyperactivation and subsequent degradation, depleting RAD51 to compromise homologous recombination and induce parthanatos. These findings uncover a lipid-mediated vulnerability in GBM, linking fatty acid desaturation to PARP1-dependent genome integrity. Targeting SCD5 may offer a novel therapeutic strategy to eliminate therapy-resistant GSCs and enhance the efficacy of genotoxic or immunotherapeutic interventions.

cancer biology↗

bioRxiv2025

Parasite-mediated inbreeding depression in wild red deer

Inbreeding depression is the reduction in fitness of inbred individuals relative to their more outbred counterparts. Parasitism also reduces fitness and is a route by which inbreeding depression may operate, yet the complete pathway from inbreeding to parasitism to fitness has almost never been documented in the wild. Using high-quality, individual-level data on fitness in juveniles and adult females, longitudinal infection data for three gastrointestinal helminth parasites, and genomic inbreeding coefficients we test for parasite-mediated inbreeding depression in a wild ungulate population (red deer, Cervus elaphus). We found evidence for parasite-mediated inbreeding depression via strongyle nematodes in juvenile survival, independent of direct adverse effects of inbreeding on survival and indirect effects of inbreeding on survival via birth weight. Inbreeding also reduced fitness in reproductive adults by reducing overwinter survival. Our study reveals three independent pathways by which inbreeding depresses fitness and highlights the rarely-studied route of parasitism.

ecology↗

bioRxiv2023

Genetic architecture of inbreeding depression may explain its persistence in a population of wild red deer

Inbreeding depression is of major concern in declining populations, but relatively little is known about its genetic architecture in wild populations, such as the degree to which it is composed of large or small effect loci and their distribution throughout the genome. We combine fitness and genomic data from a wild population of red deer to investigate the genomic distribution of inbreeding effects. Inspired by the runs of homozygosity (ROH)-based inbreeding coefficient, FROH, we use chromosome-specific inbreeding coefficients (FROHChr) to explore whether the effect of inbreeding varies between chromosomes. Under the assumption that within an individual the probability of being identical-by-descent is equal across all chromosomes, we used a multi-membership model to estimate the deviation of FROHChr from the average inbreeding effect. This novel approach ensures effect sizes are not overestimated whilst maximising the power of our available dataset containing >35,000 autosomal SNPs. We find that most chromosomes confer a minor reduction in fitness-related traits, which when these effects are summed, results in the observed inbreeding depression in birth weight, survival and lifetime breeding success. However, no chromosomes had a significantly detrimental effect compared to the overall effect of inbreeding. We conclude that in this population, inbreeding depression is the result of multiple mild or moderately deleterious mutations spread across all chromosomes. As predicted by genetic theory these mutations will be inefficiently purged, explaining the persistence of inbreeding depression in this population.

evolutionary biology↗

bioRxiv2021

Stimulating music supports attention in listeners with attentional difficulties

Background music is widely used to sustain attention, but little is known about what musical properties aid attention. This may be due to inter-individual variability in neural responses to music. We test the hypothesis that music can sustain attention by affecting oscillations via acoustic amplitude modulation, differentially for those with varying levels of attentional difficulty. We first show that heavily-modulated music improves sustained attention for participants with more ADHD symptoms. FMRI showed this music elicited greater activity in attentional networks in this group only, and EEG showed greater stimulus-brain coupling for this group in response to the heavily-modulated music. Finally, we parametrically manipulated the depth and rate of amplitude modulations inserted in otherwise-identical music, and found that beta-range modulations helped more than other frequency ranges for participants with more ADHD symptoms. Results suggest the possibility of an oscillation-based neural mechanism for targeted music to support improved cognitive performance.

neuroscience↗