Christensen, K. E. | Search bioRxiv

bioRxiv2023

Dissecting an ancient stress resistance trait syndrome in the compost yeast Kluyveromyces marxianus

Organisms specialized to extreme environments can be the product of millions of years of evolutionary engineering and refinement. The underlying genetics can be quite distinct from the ones operating at earlier stages of trait innovation. In this work, we have developed the multi-stress resistant yeast Kluyveromyces marxianus, which diverged from its closest relative >20 million years ago, as a model for interspecies comparative biology and genomics. In growth assays of the Kluyveromyces genus, we found that K. marxianus exhibited unique tolerance of high heat and a subset of chemical stress conditions. We then generated and analyzed omic profiles from across the genus to find molecular features associated with- and potentially causal for - K. marxianus traits. Expression profiling revealed divergent lipid processing and membrane transport programs in K. marxianus, borne out in changes in lipid utilization in experimental assays. Sequence analyses found robust evidence for expansions in gene families in the K. marxianus genome, most notably among transmembrane transporters and in metabolic enzymes. In molecular-evolution tests, we identified adaptive protein variants throughout the K. marxianus genome among which plasma membrane transporters were over-represented. These data enable a model of the molecular mechanisms and evolutionary pressures underlying K. marxianus traits, including adaptive changes to transporters, lipid processing, and membrane functions mediating stress resistance. Significance statementMany traits of basic and applied interest arose long ago and manifest in the modern day as fixed in a given species; understanding how evolution built them, potentially over millions of years, remains a key challenge in the field. In this study, we report stress-resistance phenotypes that distinguish the yeast Kluyveromyces marxianus from its relatives, and we discover unique patterns of genetic and regulatory variation in membrane-protein genes, as well as unique properties of lipid metabolism, in this species. We propose a broadly applicable model in which evolution can tune membrane lipid composition and membrane-protein function to boost cellular fitness in challenging environments.

evolutionary biology↗

bioRxiv2021

The 677C>T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice

Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimers disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677C>T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C>T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C>T allele on the C57BL/6J background (Mthfr677C>T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C>T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity as well as critical metabolites in the folate and methionine cycles are reduced in the Mthfr677C>T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data suggest critical perturbations to cerebrovascular function in Mthfr677C>T mice supporting its use as a model for preclinical studies of VCID.

genetics↗