Biology subjects

Whitehead, C.

Publications and source records attributed to Whitehead, C..

4 recordsLinked to original sources

bioRxiv2025

Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans

Triploid and haploid conceptions are not viable and are a common occurrence in humans, where they account for 10% of all pregnancy losses. Despite the parent-of-origin being important in the etiology of the pregnancy, our knowledge of their causes is limited, especially at the point of conception. Using a dataset of 96,660 biopsies and a validation dataset of 44,324 from human blastocysts embryos generated by intra-cytoplasmic sperm injection (ICSI), we estimate that 1.1% of human conceptions (n=1,063) contain extra or missing chromosome sets in zygotes. We identify a maternal age effect, with a 1.059 per year increased risk in triploidy/haploidy (p=0.0008). In 0.03% of couples, we identified three or more triploid/haploid embryos, suggesting a personal risk effect (p=0.03). Genotype analysis of 55 triploid embryo biopsies and their parents show that one third of maternal triploid conceptions originate in meiosis I and two thirds in meiosis II. Seven of these embryos are inferred to have entirely failed to initiate meiotic recombination genome-wide, suggesting that human oocytes with pervasive meiotic recombination failure that are formed during fetal development are capable of ovulation in adult life. Finally, we identify a new type of genome-wide maternal isodiploidy (two maternal chromosome sets) in 0.05% of embryos (41 of 74,009). Collectively, our findings shed light on the biology of meiosis and the formation of human oocytes with the number of chromosome sets.

genetics↗

bioRxiv2024

Genome Report: Pseudomolecule-scale genome assemblies of Drepanocaryum sewerzowii and Marmoritis complanata

The Nepetoideae, a subfamily of Lamiaceae (mint family), is rich in aromatic plants, many of which are sought after for their use as flavours and fragrances or for their medicinal properties. Here we present genome assemblies for two species in Nepetiodeae: Drepanocaruym sewerzowii and Marmoritis complanata. Both assemblies were generated using Oxford Nanopore Q20+ reads with contigs anchored to nine pseudomolecules that resulted in 335 Mb and 305 Mb assemblies, respectively, and BUSCO scores above 95% for both the assembly and annotation. We furthermore provide a species tree for the Lamiaceae using only genome derived gene models, complementing existing transcriptome and marker-based phylogenies.

genomics↗

bioRxiv2022

Integrative metabolomics reveal the organisation of alkaloid biosynthesis in Daphniphyllum macropodum

Daphniphyllum alkaloids are structurally diverse nitrogen-containing compounds with polycyclic, stereochemically rich carbon skeletons. Understanding how plants biosynthesise these compounds may lead to greater access to allow exploration of bioactivities; however, very little is known about their biosynthetic origins. Here, we integrated metabolomics approaches to map alkaloid distribution across Daphniphyllum macropodum plants and tissues. We generated a novel untargeted metabolomics workflow to highlight trends in alkaloid distribution across tissues, using a holistic approach that does not rely on ambiguous peak annotations. Both liquid-chromatography-mass spectrometry and mass-spectrometry imaging analyses independently revealed that alkaloids have a pattern of spatial distribution based on their skeletal subtypes. The distinct alkaloid subtype localisation suggests the biosynthetic pathway is controlled spatially with intermediates transported from the phloem to the epidermis where they undergo additional derivatization. This study sets the stage for the future work on Daphniphyllum alkaloid biosynthesis and highlights how integrating different metabolomics strategies can reveal valuable insights on these compounds distribution within the plant.

plant biology↗

bioRxiv2022

Systematic analysis uncovers SYK dependency in NF1LoF melanoma cells

The loss of function (LoF) of NF1 is the third most frequent mutation that drives hyperactivated RAS and tumor growth in >10% of melanomas. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. Here, we perform a targeted kinase inhibitor screen and identify a tool compound, named MTX-216, to be highly effective in blocking NF1LoF melanoma cells. Single-cell analysis links drug-induced cytotoxicity to effective co-suppression of proliferation marker Ki-67 and the ribosomal S6 phosphorylation, an integrator of multiple RAS-mediated signaling pathways. Using a combination of kinome selectivity assay, transcriptomic analysis, and genetic experiments, we find the anti-tumor efficacy of MTX-216 to be dependent on its ability to inhibit not only PI3K (its nominal target) but also SYK, and suppression of a group of genes that regulate mitochondrial electron transport chain and whose expression is associated with poor survival in NF1LoF melanoma patients. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown show favorable effects. These studies provide a path to exploit SYK dependency to selectively block NF1LoF melanoma cells. Statement of significanceNF1LoF melanomas represent a subtype with hyperactivated RAS signaling, for which currently no targeted therapies are clinically available. Our systems pharmacology studies identify SYK as a new vulnerability in NF1LoF melanoma cells.

cancer biology↗