Biology subjects

Li, X. C.

Publications and source records attributed to Li, X. C..

4 recordsLinked to original sources

bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗

bioRxiv2018

Mitochondria-encoded genes contribute to the evolution of heat and cold tolerance among Saccharomyces species

Over time, species evolve substantial phenotype differences. Yet, genetic analysis of these traits is limited by reproductive barriers to those phenotypes that distinguish closely related species. Here, we conduct a genome-wide non-complementation screen to identify genes that contribute to a major difference in thermal growth profile between two Saccharomyces species. S. cerevisiae is capable of growing at temperatures exceeding 40{degrees}C, whereas S. uvarum cannot grow above 33{degrees}C but outperforms S. cerevisiae at 4{degrees}C. The screen revealed only a single nuclear-encoded gene with a modest contribution to heat tolerance, but a large effect of the species mitochondrial DNA (mitotype). Furthermore, we found that, while the S. cerevisiae mitotype confers heat tolerance, the S. uvarum mitotype confers cold tolerance. Recombinant mitotypes indicate multiple genes contribute to thermal divergence. Mitochondrial allele replacements showed that divergence in the coding sequence of COX1 has a moderate effect on both heat and cold tolerance, but it does not explain the entire difference between the two mitochondrial genomes. Our results highlight a polygenic architecture for interspecific phenotypic divergence and point to the mitochondrial genome as an evolutionary hotspot for not only reproductive incompatibilities, but also thermal divergence in yeast.

evolutionary biology↗

bioRxiv2018

Mitochondrial DNA and temperature tolerance in lager yeasts

A growing body of research suggests that the mitochondrial genome (mtDNA) is important for temperature adaptation. In the yeast genus Saccharomyces, species have diverged in temperature tolerance, driving their use in high or low temperature fermentations. Here we experimentally test the role of mtDNA in temperature tolerance in synthetic and industrial hybrids (Saccharomyces cerevisiae x Saccharomyces eubayanus, or Saccharomyces pastorianus), which cold-brew lager beer. We find that the relative temperature tolerances of hybrids correspond to the parent donating mtDNA, allowing us to modulate lager strain temperature preferences. The strong influence of mitotype on the temperature tolerance of otherwise identical hybrid strains provides support for the mitochondrial climactic adaptation hypothesis in yeasts and demonstrates how mitotype has influenced the world's most commonly fermented beverage.\n\nOne Sentence SummaryMitochondrial genome origin affects the temperature tolerance of synthetic and industrial lager-brewing yeast hybrids.

genetics↗

bioRxiv2016

Directional evolution in temperature-responsive gene expression in yeast

Gene regulation is a ubiquitous mechanism by which organisms respond to their environment. While organisms are often found to be adapted to the environments they experience, the role of gene regulation in environmental adaptation is not often known. In this study, we examine divergence in cis-regulatory effects between two Saccharomyces species, S. cerevisiae and S. uvarum, that have substantially diverged in their thermal growth profile. We measured allele specific expression (ASE) in the species hybrid at three temperatures, the highest of which is lethal to S. uvarum but not the hybrid or S. cerevisiae. We find that S. uvarum alleles can be expressed at the same level as S. cerevisiae alleles at high temperature and most cis-acting differences in gene expression are not dependent on temperature. While a small set of 136 genes show temperature-dependent ASE, we find no indication that signatures of directional cis-regulatory evolution are associated with temperature. Within promoter regions we find binding sites enriched upstream of temperature responsive genes, but only weak correlations between binding site and expression divergence. Our results indicate that temperature divergence between S. cerevisiae and S. uvarum has not caused widespread divergence in cis-regulatory activity, but point to a small subset of genes where the species alleles show differences in magnitude or opposite responses to temperature. The difficulty of explaining divergence in cis-regulatory sequences with models of transcription factor binding sites and nucleosome positioning highlights the importance of identifying mutations that underlie cis-regulatory divergence between species.

genomics↗