Biomedical subjects

Chad A Shaw

Publications and source records attributed to Chad A Shaw.

6 recordsLinked to original sources

PubMed2026

Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease.

The molecular pathways linking genetic variants to Parkinson's disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analysed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer's disease metabolome. A PD acylcarnitine signature was further replicated in human post-mortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.

Humans↗

PubMed2003

Development of a comparative genomic hybridization microarray and demonstration of its utility with 25 well-characterized 1p36 deletions.

Chromosomal abnormalities, such as deletions and duplications, are characterized by specific and often complex phenotypes resulting from an imbalance in normal gene dosage. However, routine chromosome banding is not sensitive enough to detect subtle chromosome aberrations (<5-10 Mb). Array-based comparative genomic hybridization (array CGH) is a powerful new technology capable of identifying chromosomal imbalance at a high resolution by co-hybridizing differentially labeled test and control DNAs to a microarray of genomic clones. We used a previously assembled contig of large-insert clones that span 10.5 Mb of the most distal region of 1p36 to design a microarray. The array includes 97 clones from 1p36, 41 clones from the subtelomeric regions of all human chromosomes, and three clones from each of the X and Y chromosomes. We used this microarray to study 25 subjects with well-characterized deletions of 1p36. All array CGH results agree with the deletion sizes and locations of the breakpoints in these subjects as determined previously by FISH and microsatellite analyses. Terminal deletions, interstitial deletions, derivative chromosomes and complex rearrangements were also identified. We anticipate that array CGH will change the diagnostic approach to many congenital and acquired genetic diseases such as mental retardation, birth defects and cancer.

Chromosome Aberrations↗

PubMed2003

Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions.

Terminal deletions of 1p36 result in a mental retardation syndrome that is presumably caused by haploinsufficiency of a number of genes. Although monosomy 1p36 is the most commonly observed terminal deletion syndrome in humans, the molecular mechanism(s) that generates and stabilizes terminal deletions of 1p36 is not completely understood. Our previous molecular analysis of a large cohort of monosomy 1p36 subjects demonstrated that deletion sizes vary widely from approximately 1 Mb to >10.5 Mb in the most distal portion of 1p36 with no single common breakpoint. In this report, we have identified the precise breakpoint junctions in three subjects with apparently pure terminal deletions of 1p36 ranging from 2.5 to 4.25 Mb. These junctions revealed one deletion to be stabilized by telomeric repeat sequences and two to have terminal deletions associated with cryptic interrupted inverted duplications at the ends of the chromosomes. These interrupted inverted duplication/deletion breakpoints are reminiscent of those seen in tumor cell lines that have undergone breakage-fusion-bridge (BFB) cycles leading to gene amplification. We propose a pre-meiotic model for the formation of these deletions in which a terminally deleted chromosome is generated in the germ line and passes through at least one BFB cycle to produce gametes with terminal deletions associated with interrupted inverted duplications. These data suggest that, on a molecular level, seemingly pure terminal deletions visualized cytogenetically may be more complex, and BFB cycles may play an important role in generating terminal deletions associated with genetic disease in humans.

Animals↗

PubMed2003

TagA, a putative serine protease/ABC transporter of Dictyostelium that is required for cell fate determination at the onset of development.

The tag genes of Dictyostelium are predicted to encode multi-domain proteins consisting of serine protease and ATP-binding cassette transporter domains. We have identified a novel tag gene, tagA, which is involved in cell type differentiation. The tagA mRNA accumulates during the first four hours of development, whereas TagA protein accumulates between two and ten hours of development and decreases thereafter. Wild-type cells express tagA in prespore cells and mature spores, defining tagA expression as prespore specific. However, tagA mutant cells that activate the tagA promoter do not sporulate, but instead form part of the outer basal disc and lower cup of the fruiting body. tagA mutant aggregates elaborate multiple prestalk cell regions during development and produce spores asynchronously and with low viability. tagA mutants produce about twice as many prestalk cells as the wild type as judged by a prestalk cell reporter construct. When mixed with wild-type cells, tagA(-) cells become overrepresented in the prestalk cell population, suggesting that this phenotype is cell-autonomous. These results suggest that TagA is required for the specification of an initial population of prespore cells in which tagA is expressed. Expression profiling uncovered a delay in the transcriptional program between 2 and 6 hours, coincident with TagA expression, revealing an early function for TagA. TagA also appears to play a general role in cell fate determination since tagA mutants express a spore coat protein gene (cotB) within vacuolated cells that form part of the stalk and they express a prestalk/stalk-specific gene (ecmB) within cells that become spores. The expression of TagA at two hours of development, the observed coincident delay in the transcriptional program and the subsequent mis-expression of cell-type specific genes provide evidence for cell fate determination beginning in some cells much earlier than previously believed.

ATP-Binding Cassette Transporters↗

PubMed2002

Exact sampling formulas for multi-type Galton-Watson processes.

Exact formulas for the mean and variance of the proportion of different types in a fixed generation of a multi-type Galton-Watson process are derived. The formulas are given in terms of iterates of the probability generating function of the offspring distribution. It is also shown that the sequence of types backwards from a randomly sampled particle in a fixed generation is a non-homogeneous Markov chain where the transition probabilities can be given explicitly, again in terms of probability generating functions. Two biological applications are considered: mutations in mitochondrial DNA and the polymerase chain reaction.

Computer Simulation↗

PubMed2002

Theoretical consideration of amplification strategies.

Experimentalists would like to perform large-scale expression analysis on samples drawn from small cell populations and even single cells. Amplification of the source material is required to assay such small samples under all existing array technologies. In this report we consider the very different theoretical properties of linear and PCR-based amplification. A suggestion is made concerning a hybrid amplification strategy incorporating the advantages offered by both approaches.

Gene Amplification↗