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The role of hematop...
The role of hematopoietic chromosome Y loss in health and disease
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- Mattisson, Jonas, 1994- (författare)
- Uppsala universitet,Molekylära verktyg och funktionsgenomik
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- Forsberg, Lars A., Associate Professor, 1974- (preses)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Halvardson, Jonatan, 1982- (preses)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi
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- Ameur, Adam (preses)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Ganna, Andrea, Assistant Professor (opponent)
- Institute for Molecular Medicine Finland, University of Helsinki
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(creator_code:org_t)
- ISBN 9789151317885
- Uppsala : Acta Universitatis Upsaliensis, 2023
- Engelska 94 s.
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Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1939
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Abstract
Ämnesord
Stäng
- Mosaic loss of chromosome Y (mLOY) is the most common somatic mutation, and affected men have increased risk for all major causes of death, including cardiovascular diseases and cancer. As a male specific mutation, it helps explain why men live shorter lives than women. However, the causality is debated, and contrasting models have been proposed to explain how Y loss in blood could be linked with disease in other organs. In this thesis, I provide results contributing to this debate.In Paper I, we identify 156 loci associated with genetic susceptibility for mLOY. Enrichment of loci involved in processes such as cell-cycle regulation and cancer susceptibility suggest that mLOY could be viewed as a barometer of genomic instability. In Paper II, we used the mLOY-associated variants identified in Paper I to calculate a PRS for mLOY in an independent cohort. We found that men with high PRS displayed a five-fold increased risk in an age dependent manner.In Paper III, we showed that mLOY and CHIP driving SNVs often co-occur in leukocytes. Considering that they share clinical manifestations, further studies are necessary to elucidate how these mutations contributes to disease risk. In Paper IV, we studied transcriptional effects of mLOY in leukocytes and identified almost 500 dysregulated autosomal genes, varying between cell types. We also report that mLOY in specific leukocytes might be linked with different types of disease. In Paper V, regulatory T cells are shown to be affected with Y loss to a greater extent than other CD4+ T lymphocytes. We propose that mLOY might drive T lymphocytes towards the regulatory phenotype, known to exhibit immunosuppressive functions. In Paper VI, we used CITE-seq to show that expression and cell surface abundance of the immunoprotein CD99 is lower in leukocytes with Y loss. This finding provides a possible explanation how mLOY could influence normal immune response, since CD99 is essential is for the mobility and cell-to-cell interactions of leukocytes. In Paper VII, it is shown that hematological mLOY cause disease directly in other organs. Mice with mLOY was shown to have a reduced survival, increased fibrosis and cardiac dysfunction, while men in UK biobank with mLOY in blood was found to die from diseases of the circulatory system in a dose dependent manner. Treatment with TGFβ1-inhibitors could restore cardiac function in mLOY-mice. Together, the presented results show that mLOY both reflect genomic instability overall, while also causing disease directly.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Nyckelord
- loss of chromosome Y
- LOY
- mosaic loss of chromosome Y
- mLOY
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
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