Biology subjects

Hay, A. M.

Publications and source records attributed to Hay, A. M..

3 recordsLinked to original sources

bioRxiv2026

Genetic architecture of the murine serum metabolome reveals carboxyl esterases as master regulators of circulating fatty acid metabolism

BackgroundThe systemic biochemical diversity of circulating metabolites and lipids reflects the integrated effects of genetic variation and environmental exposure. Metabolite quantitative trait locus (mQTL) studies in humans have established gene-metabolite associations, but genetic contributions can be obscured by sex, diet, age, medication use, and environmental exposures. Genetically diverse model systems offer a powerful complementary strategy to isolate genetic contributions to the biochemical diversity of the circulating metabolome. Methodology/Principal FindingsWe applied mass spectrometry profiling to serum samples in 541 mice from the Diversity Outbred (DO) population and identified 1,933 mQTL across 240 metabolites, 561 lipids, 43 oxylipins, and 4,465 MS/MS features. Co-mapping QTL, i.e., QTL hotspots, on chromosomes 8 and 17 implicated carboxyl esterase gene clusters (Ces1 and Ces2) as major regulators of circulating lipid remodeling and demonstrated genetic control of circulating protein/peptide-like features at the major histocompatibility complex and complement C3 loci. QTL hotspots on chromosomes 9 and 10 revealed previously unknown genetic drivers of lipid and amino acid metabolism. Comparisons with matched red blood cell mQTL revealed widespread compartment-specific genetic control. Conclusions/SignificanceCollectively, these findings provide a high-resolution map of the genetic regulation of the circulating metabolome, offering mechanistic insights that complement and extend human metabolic genetics.

genomics↗

bioRxiv2025

Genetic architecture of the red blood cell proteome in genetically diverse mice reveals central role of hemoglobin beta cysteine redox status in maintaining circulating glutathione pools

Red blood cells (RBCs) transport oxygen but accumulate oxidative damage over time, reducing function in vivo and during storage--critical for transfusions. To explore genetic influences on RBC resilience, we profiled proteins, metabolites, and lipids from fresh and stored RBCs obtained from 350 genetically diverse mice. Our analysis identified over 6,000 quantitative trait loci (QTL). Compared to other tissues, prevalence of trans genetic effects over cis reflects the absence of de novo protein synthesis in anucleated RBCs. QTL hotspots at Hbb, Hba, Mon1a, and storage-specific Steap3 linked ferroptosis to hemolysis. Proteasome components clustered at multiple loci, underscoring the importance of degrading oxidized proteins. Post-translational modifications (PTMs) mapped predominantly to hemoglobins, particularly cysteine residues. Loss of reactive C93 in humanized mice (HBB C93A) disrupted redox balance, affecting glutathione pools, protein glutathionylation, and redox PTMs. These findings highlight genetic regulation of RBC oxidation, with implications for transfusion biology and oxidative stress-dependent hemolytic disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/640676v1_ufig1.gif" ALT="Figure 1"> View larger version (98K): org.highwire.dtl.DTLVardef@14a3cc2org.highwire.dtl.DTLVardef@daf8b4org.highwire.dtl.DTLVardef@1fe306forg.highwire.dtl.DTLVardef@11de734_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2021

Hematologic and systemic metabolic alterations due to Mediterranean type II G6PD deficiency in a novel murine model

Deficiency of Glucose 6 phosphate dehydrogenase (G6PD) is the single most common enzymopathy, present in approximately 400 million humans (e.g. 5% of humans). Its prevalence is hypothesized to be due to conferring resistance to malaria. However, G6PD deficiency also results in hemolytic sequelae from oxidant stress. Moreover, G6PD deficiency is associated with kidney disease, diabetes, pulmonary hypertension, immunological defects, and neurodegenerative diseases. To date, the only available mouse models have decreased levels of G6PD due to promoter mutations, but with stable G6PD. However, human G6PD mutations are missense mutations that result in decreased enzymatic stability. As such, this results in very low activity in red blood cells and platelets that cannot synthesize new protein. To generate a more accurate model, the human sequence for a severe form of G6PD deficiency (Med -) was knocked into the murine G6PD locus. As predicted, G6PD levels were extremely low in RBCs and deficient mice have increased hemolytic sequalae to oxidant stress. G6PD levels were mildly decreased in non-erythroid organs, consistent with what has been observed in humans. Juxtaposition of G6PD deficient and wild-type mice revealed altered lipid metabolism in multiple organ systems. Together, these findings both establish a new mouse model of G6PD deficiency that more accurately reflects human G6PD deficiency and also advance our basic understanding of altered metabolism in this setting.

biochemistry↗