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- Forsberg, Lars A., 1974-, et al.
(författare)
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Mosaic loss of chromosome Y in leukocytes matters
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:1, s. 4-7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Danielsson, Marcus, 1985-
(författare)
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Mosaic loss of chromosome Y : methods for detection and consequences for affected leukocytes and men
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It has been known for centuries that men live shorter lives than women, but until recently, the biological mechanisms driving this sex bias has been poorly understood. Mosaic loss of chromosome Y (mLOY) refers to chromosome Y aneuploidy, a male specific and the most common somatic mutation in human blood cells. Known risk factors include age, smoking and genetic predisposition. Men with mLOY carry a fraction of blood cells without the Y chromosome, due to its loss from hematopoietic progenitor cells during life. Hence, in a single cell LOY is a binary event causing the absence of almost 2% of the male haploid nuclear genome. When measured in bulk samples, it is present as a continuous mosaicism affecting a fraction of cells. A paper published in 1963 demonstrated that mLOY is frequent in cells of the hematopoietic system in aging men, but it was long viewed as a neutral event. In contrast, recent discoveries demonstrate that mLOY in blood is associated with various forms of cancer, autoimmune conditions, Alzheimer’s disease, cardiovascular events, diabetes as well as age-related macular degeneration. Studies support the hypothesis that mLOY in leukocytes may exacerbate disease processes in other organs. Thus, given the associations with several common diseases, mLOY in blood cells could help explain reduced male longevity.A main aim and a long term goal of the work presented in this thesis is the development of novel methods for improved mLOY detection. Focus here is exploration of analytes such as DNA, RNA and proteins, including studies of bulk samples as well as single cell approaches. Among the evaluated methods are SNP-arrays, ddPCR, WGS, RNA-seq and CITE-seq. Furthermore, a novel method called SPARC was developed for co-detection of the transcriptome and a panel of 92 proteins in single cells. Future methods with clinical utility for mLOY should, in addition to robust detection, be able to simultaneously discriminate mLOY in different types of immune cells. The latter builds on recent results showing cell type specificity with regard to disease associations. To meet these needs, single cell analyses using mLOY associated cell surface proteins have been pursued and proof-of-concept established. Implementation of mLOY screening in general populations has the potential to identify men with increased risk for various disease. It could be envisioned that further medical examination of men affected with mLOY would enable earlier diagnoses of ongoing disease processes as well as serving to guide targeted interventions.
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- Danielsson, Marcus, et al.
(författare)
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Reply to Veitia
- 2021
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Ingår i: European Journal of Human Genetics. - : Springer Nature. - 1018-4813 .- 1476-5438. ; 29:9, s. 1323-1324
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Mattisson, Jonas, 1994-
(författare)
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The role of hematopoietic chromosome Y loss in health and disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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