Biology subjects

Williams, M.

Publications and source records attributed to Williams, M..

4 recordsLinked to original sources

bioRxiv2017

Unbiased association and expression studies identify novel genes for tooth development

Previously reported co-occurrence of colorectal cancer (CRC) and tooth agenesis (TA) and the overlap in disease-associated gene variants suggest involvement of similar molecular pathways. In this study, we took an unbiased approach and tested genome-wide significant CRC-associated variants for association with isolated TA. Thirty single nucleotide variants (SNVs) in CRC-predisposing genes/loci were genotyped in a discovery dataset composed of 440 individuals with and without isolated TA. Genome-wide significant associations were found between TA and DUSP10 rs6687758 (P=1.25 x 10-9) and ATF1 rs11169552 (P=4.36 x 10-10), with strong association found with CASC8 rs10505477 (P=8.2 x 10-5). Additional CRC marker haplotypes were also significantly associated with TA (P<0.0002). Genotyping an independent dataset consisting of 52 cases with TA and 427 controls confirmed the association with CASC8.\n\nAtf1 and Dusp10 expression was detected in the mouse developing teeth from early bud stages to the formation of the complete tooth, suggesting a potential role for these genes and their encoded proteins in tooth development. Our findings suggest Atf1 and Dusp10 as new tooth development genes, while having a role in colorectal cancer. While their individual contributions in tooth development remain to be elucidated, these genes may be considered additional candidates to be tested in future human genetic studies.

genetics↗

bioRxiv2017

Speed breeding: a powerful tool to accelerate crop research and breeding

The growing human population and a changing environment have raised significant concern for global food security, with the current improvement rate of several important crops inadequate to meet future demand [1]. This slow improvement rate is attributed partly to the long generation times of crop plants. Here we present a method called speed breeding, which greatly shortens generation time and accelerates breeding and research programs. Speed breeding can be used to achieve up to 6 generations per year for spring wheat (Triticum aestivum), durum wheat (T. durum), barley (Hordeum vulgare), chickpea (Cicer arietinum), and pea (Pisum sativum) and 4 generations for canola (Brassica napus), instead of 2-3 under normal glasshouse conditions. We demonstrate that speed breeding in fully-enclosed controlled-environment growth chambers can accelerate plant development for research purposes, including phenotyping of adult plant traits, mutant studies, and transformation. The use of supplemental lighting in a glasshouse environment allows rapid generation cycling through single seed descent and potential for adaptation to larger-scale crop improvement programs. Cost-saving through LED supplemental lighting is also outlined. We envisage great potential for integrating speed breeding with other modern crop breeding technologies, including high-throughput genotyping, genome editing, and genomic selection, accelerating the rate of crop improvement.

plant biology↗

bioRxiv2017

Prediction of fluoroquinolone susceptibility directly from whole genome sequence data using liquid chromatography-tandem mass spectrometry to identify mutant genotypes.

Fluoroquinolone resistance in bacteria is multifactorial, involving target site mutations, reductions in fluoroquinolone entry due to reduced porin production, increased fluoroquinolone efflux, enzymes that modify fluoroquinolones, and Qnr, a DNA mimic that protects the drug target from fluoroquinolone binding. Here we report a comprehensive analysis using transformation and in vitro mutant selection, of the relative importance of each of these mechanisms in fluoroquinolone resistance and non-susceptibility, using Klebsiella pneumoniae, one of the most clinically important multi-drug resistant bacterial species known, as a model system. Our improved biological understanding was then used to generate rules that could be predict fluoroquinolone susceptibility in K. pneumoniae clinical isolates. Key to the success of this predictive process was the use of liquid chromatography tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria, identifying which sequence variants seen in the whole genome sequence data were functionally important in the context of fluoroquinolone susceptibility.

microbiology↗

bioRxiv2017

Prediction Of Cephalosporin And Carbapenem Susceptibility In Multi-Drug Resistant Gram-Negative Bacteria Using Liquid Chromatography-Tandem Mass Spectrometry

In vitro antibacterial susceptibility testing informs clinical decision making concerning antibacterial therapeutics. Predicting, in a timely manner, which bacterial infection will respond to treatment by a given antibacterial drug reduces morbidity, mortality, and healthcare costs. It also allows prudent antibacterial use, because clinicians can focus on the least broad-spectrum agent suitable for each patient. Existing susceptibly testing methodologies rely on growth of bacteria in the presence of an antibacterial drug. There is significant interest in the possibility of predicting antibacterial drug susceptibility directly though the analysis of bacterial DNA or protein, because this may lead to more rapid susceptibility testing directly from clinical samples. Here we report a robust and tractable methodology that allows measurement of the abundance of key proteins responsible for antibacterial drug resistance within samples of 1 {micro}g of total bacterial protein. The method allowed correct prediction of {beta}-lactam susceptibility in clinical isolates from four key bacterial species and added considerable value over and above the information generated by whole genome sequencing, allowing for gene expression, not just gene presence to be considered, which is key when considering the complex interplays of multiple mechanisms of resistance.

microbiology↗