Biology subjects

Mace, E.

Publications and source records attributed to Mace, E..

25 records · Page 2Linked to original sources

bioRxiv2022

Genetic diversity analysis and characterization of Ugandan sorghum

The National Genebank of Uganda houses diverse and rich Sorghum bicolor germplasm collection. This genetic diversity resource is untapped, under-utilized and has not been systematically incorporated into sorghum breeding programs. In this study, we characterized the germplasm collection using whole genome SNP markers. Discriminant analysis of principal components (DAPC) was implemented to study racial ancestry of the accessions in comparison to a global sorghum diversity set and characterize sub-groups and admixture in the Ugandan germplasm. Genetic structure and phylogenetic analysis was conducted to identify distinct genotypes in the Ugandan collection and relationships among groups. Furthermore, in a case study for identification of potentially useful adaptive trait variation for breeding, we performed genome-wide association studies for juvenile cold tolerance. Genomic regions potentially involved in adaptation of Ugandan sorghum varieties to cooler climatic conditions were identified that could be of interest for expansion of sorghum production into temperate latitudes. The study demonstrates how genebank genomics can potentially facilitate effective and efficient usage of valuable, untapped germplasm collections for agronomic trait evaluation and subsequent allele mining.

plant biology↗

bioRxiv2020

CD56 regulates human NK cell cytotoxicity through Pyk2

Natural killer (NK) cells are innate immune cells that control viral infection and tumorigenic cell growth through targeted cell lysis and cytokine secretion. Human NK cells are classically defined as CD56+CD3- in peripheral blood. CD56 is neural cell adhesion molecule (NCAM1), and despite its ubiquitous expression on human NK cells, the role of CD56 in human NK cell cytotoxic function has not been fully explored. In non-immune cells, NCAM can induce signaling, mediate adhesion, and promote exocytosis, in part through interactions with focal adhesion kinase (FAK). Here we describe the generation and use of CD56-deficient human NK cell lines to define a novel requirement for CD56 in target cell lysis. Namely, we demonstrate that deletion of CD56 on the NK92 cell line led to impaired cytotoxic function against multiple susceptible target cell lines. Deletion of CD56 in a second NK cell line, YTS cells, led to a less severe cytotoxicity defect but impairment in cytokine secretion. Confocal microscopy of wild-type and CD56-KO NK92 cells conjugated to susceptible targets revealed that CD56-KO cells failed to polarize during immunological synapse (IS) formation and had severely impaired exocytosis of lytic granules at the IS. Phosphorylation of the FAK family member Pyk2 at tyrosine 402 was decreased in NK92 CD56-KO cells, demonstrating a functional link between CD56 and IS formation and signaling in human NK cells. Cytotoxicity, lytic granule exocytosis, and the phosphorylation of Pyk2 were rescued by the reintroduction of NCAM140 (CD56), into NK92 CD56-KO cells. These data highlight a novel functional role for CD56 in stimulating exocytosis and promoting cytotoxicity in human NK cells.

immunology↗

bioRxiv2019

Human NK cell deficiency as a result of biallelic mutations in MCM10

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here we report a novel cause of NKD resulting from compound heterozygous mutations in MCM10 that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. By modeling MCM10 deficiency in human NK cell lines and primary NK cell precursors, we demonstrate that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function.

immunology↗

bioRxiv2019

Persistent DNA Hyper-methylation Dampens Host Anti-Mycobacterial Immunity

Mycobacterium tuberculosis (Mtb) has co-evolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to shorten existing therapy and improve outcomes will require identifying the full complement by which host immunity is inhibited. Perturbing host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, LCMV and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of TB patients and their asymptomatic household contacts demonstrating that TB patients have DNA hyper-methylation of the IL-2-STAT5, TNF-NF-{varkappa}B and IFN-{gamma} signaling pathways. By MSRE-qPCR, multiple genes of the IL-12-IFN-{gamma} signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1 and JAK2) were hyper-methylated in TB patients. The DNA hyper-methylation of these pathways is associated with decreased immune responsiveness with decreased mitogen induced upregulation of IFN-{gamma}, TNF, IL-6 and IL-1{beta} production. The DNA hyper-methylation of the IL-12-IFN-{gamma} pathway was associated with decreased IFN-{gamma} induced gene expression and decreased IL-12 inducible up-regulation of IFN-{gamma}. This work demonstrates that immune cells from TB patients are characterized by DNA hyper-methylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and non-specific immune responsiveness.

immunology↗

bioRxiv2019

Large-scale GWAS in sorghum reveals common genetic control of grain size among cereals

O_LIGrain size is a key yield component of cereal crops and a major quality attribute. It is determined by a genotypes genetic potential and its capacity to fill the grains.\nC_LIO_LIThis study aims to dissect the genetic architecture of grain size in sorghum via an integrated genome wide association study (GWAS) using a diversity panel of 837 individuals and a BC-NAM population of 1,421 individuals.\nC_LIO_LIIn order to isolate genetic effects associated with grain size, rather than the genotypes capacity to fill grain, a field treatment of removing half of the panicle during flowering was imposed. Extensive variation in grain size with high heritability was observed in both populations across 5 field trials. Subsequent GWAS analyses uncovered 92 grain size QTL, which were significantly enriched for orthologues of known grain size genes in rice and maize. Significant overlap between the 92 QTL and grain size QTL in rice and maize was also found, supporting common genetic control of this trait among cereals. Further analysis found grain size genes with opposite effect on grain number were less likely to overlap with the grain size QTL from this study, indicating the treatment facilitated identification of genetic regions related to the genetic potential of grain size rather than the capacity to fill the grain.\nC_LIO_LIThese results enhance understanding of the genetic architecture of grain size in cereal, and pave the way for exploration of underlying molecular mechanisms in cereal crops and manipulation of this trait in breeding practices.\nC_LI

genetics↗

bioRxiv2019

Demultiplexing overlapping signaling scaffold functions to probe lipid messenger coupling to cytoskeletal dynamics.

The coordination of lipid messenger signaling with cytoskeletal regulation is central to many organelle-specific signaling and regulatory processes. While central to many aspects of cell physiology, this coupling often depends on the function of multi-domain scaffolds that orchestrate transient interactions and dynamic feedback among a spectrum of signaling intermediates and regulatory proteins on organelles. Understanding scaffold protein functions has remained challenging given this complexity. This work employs live-cell imaging and statistical analyses to deconvolve (demultiplex) how the multi-domain scaffold IQGAP1 coordinates phosphoinositide signaling with organelle-specific actin regulation and membrane processing events. Using actin-ensconced endosomes that localize to the basal cortex of polarized epithelial cells as a model system, we demonstrate abilities to dissect how IQGAP1 transitions between different actin and endosomal-membrane tethered states. We provide evidence IQGAP1 functions as a transient inhibitor of actin growth around the endosomes in at least one of these states. While not easily distilled via standard (static) colocalization analyses or traditional pathway perturbations methods, this negative regulation was revealed via a series of dynamic correlation and multiple regression analyses. These methods also uncovered that the negative actin regulation is linked to GTPase-dependent tethering to the endosomal membrane. Moreover, the scaffold transitions underlying this control are shown to depend on the production of PIP3 lipid messengers by the lipid kinase PI3K. Overall, these methods and results provide new insights in to how IQGAP1 act as a signaling hub by orchestrating time-dependent membrane and cytoskeletal protein interactions and provide new routes to dissect scaffold-mediated pathway regulation in a variety of settings.

biophysics↗

bioRxiv2018

A domestication history of dynamic adaptation and genomic deterioration in sorghum

The evolution of domesticated cereals was a complex interaction of shifting selection pressures and repeated introgressions. Genomes of archaeological crops have the potential to reveal these dynamics without being obscured by recent breeding or introgression. We report a temporal series of archaeogenomes of the crop sorghum (Sorghum bicolor) from a single locality in Egyptian Nubia. These data indicate no evidence for the effects of a domestication bottleneck but instead suggest a steady decline in genetic diversity over time coupled with an accumulating mutation load. Dynamic selection pressures acted sequentially on architectural and nutritional domestication traits, and adaptation to the local environment. Later introgression between sorghum races allowed exchange of adaptive traits and achieved mutual genomic rescue through an ameliorated mutation load. These results reveal a model of domestication in which genomic adaptation and deterioration was not focused on the initial stages of domestication but occurred throughout the history of cultivation.

evolutionary biology↗