Biology subjects

Sivertsson, A.

Publications and source records attributed to Sivertsson, A..

5 recordsLinked to original sources

bioRxiv2026

The genetic architecture of dementia risk: how Alzheimer's disease vulnerability converges on lipid metabolism and immune cell networks

Although genome-wide association studies (GWAS) have identified numerous dementia risk loci, their cell-type and tissue-specific contexts remain largely unresolved. We introduced HPA GeneSet Explorer, a statistical pipeline designed to systemically map Genome wide association study (GWAS) disease risk genes across the Human Protein Atlas (HPA). This approach generates a multiscale transcriptomic map of genetic risk, spanning systemic organs, brain regions, and cell types. Applying this framework to Alzheimers disease (AD), Lewy body dementia (DLB), and Frontotemporal dementia (FTD) revealed convergent neuronal enrichment in all three diseases. In addition, we identified AD-specific enrichment in immune system and liver associated gene modules, along with DLB-specific enrichment in ciliary modules. By mapping these vulnerabilities in non-demented samples, we provide a blueprint of the baseline vulnerability hotspots that can precede clinical neurodegeneration, offering new targets for disease-specific therapies and biomarker discovery.

neuroscience↗

bioRxiv2022

Deciphering the determinants of recombinant protein yield across the human secretome

Mammalian cells are critical hosts for the production of most therapeutic proteins and many proteins for biomedical research. While cell line engineering and bioprocess optimization have yielded high protein titers of some recombinant proteins, many proteins remain difficult to express. Here, we decipher the factors influencing yields in Chinese hamster ovary (CHO) cells as they produce 2165 different proteins from the human secretome. We demonstrate that variation within our panel of proteins cannot be explained by transgene mRNA abundance. Analyzing the expression of the 2165 human proteins with machine learning, we find that protein features account for only 15% of the variability in recombinant protein yield. Meanwhile, transcriptomic signatures account for 75% of the variability across 95 representative samples. In particular, we observe divergent signatures regarding ER stress and metabolism among the panel of cultures expressing different recombinant proteins. Thus, our study unravels the factors underlying the variation on recombinant protein production in CHO and highlights transcriptomics signatures that could guide the rational design of CHO cell systems tailored to specific proteins.

systems biology↗

bioRxiv2022

Genome-wide single cell annotation of the human protein-coding genes

An important quest for the life science community is to deliver a complete annotation of the human building-blocks of life, the genes and the proteins. Here, we report on a genome-wide effort to annotate all protein-coding genes based on single cell transcriptomics data representing all major tissues and organs in the human body, integrated with data from bulk transcriptomics and antibody-based tissue profiling. Altogether, 25 tissues have been analyzed with single cell transcriptomics resulting in genome-wide expression in 444 single cell types using a strategy involving pooling data from individual cells to obtain genome-wide expression profiles of individual cell type. We introduce a new genome-wide classification tool based on clustering of similar expression profiles across single cell types, which can be visualized using dimensional reduction maps (UMAP). The clustering classification is integrated with a new "tau" score classification for all protein-coding genes, resulting in a measure of single cell specificity across all cell types for all individual genes. The analysis has allowed us to annotate all human protein-coding genes with regards to function and spatial distribution across individual cell types across all major tissues and organs in the human body. A new version of the open access Human Protein Atlas (www.proteinatlas.org) has been launched to enable researchers to explore the new genome-wide annotation on an individual gene level.

systems biology↗

bioRxiv2019

Discovery of functional alternatively spliced PKM transcripts in human cancers

The association of pyruvate kinase muscle type (PKM) with survival of cancer patients is controversial. Here, we focus on different transcripts of PKM and investigate the association between their mRNA expression and the clinical survival of the patients in 25 different cancers. We find that the transcript encoding PKM2, and three other functional transcripts are prognostic in multiple cancers. Our integrative analysis shows that the functions of these four transcripts are highly conservative in different cancers. Next, we validate the prognostic effect of these transcripts in an independent kidney renal clear-cell carcinoma (KIRC) cohort and identify a prognostic signature which could distinguish high- and low-risk KIRC patients. Finally, we reveal the functional role of alternatively spliced PKM transcripts in KIRC, and discover the protein products of different transcripts of PKM. Our analysis demonstrated that alternatively spliced transcripts of not only PKM but also other genes should be considered in cancer studies, since it may enable the discovery and targeting of the right protein product for development of the efficient treatment strategies.

systems biology↗

bioRxiv2018

The human secretome - the proteins secreted from human cells

The proteins secreted by human tissues (the secretome) are important for the basic understanding of human biology, but also for identification of potential targets for future diagnosis and therapy. Here, we present an annotation of all predicted secreted proteins (n=2,623) with information about their spatial distribution in the human body. A high-throughput mammalian cell factory was established to create a resource of recombinant full-length proteins. This resource was used for phenotypic assays involving {beta}-cell dedifferentiation and for development of targeted proteomics assays. A comparison between host cells, including omics analysis, shows that many of the proteins that failed to be generated in CHO cells could be rescued in human HEK293 cells. In conclusion, the human secretome has been mapped and characterized to facilitate further exploration of the human secretome.

molecular biology↗