Immune cells lacking Y chromosome show dysregulation of autosomal gene expression

Funder: Kjell och Märta Beijers Stiftelse (SE)Funder: Hjärnfonden; doi: http://dx.doi.org/10.13039/501100003792Funder: Cancerfonden; doi: http://dx.doi.org/10.13039/501100002794Funder: Vetenskapsrådet; doi: http://dx.doi.org/10.13039/501100004359Funder: Alzheimerfonden; doi: http://dx.doi.org/10.13039/501100008599Funder: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse (SE)Funder: Science for Life Laboratory (SE)Funder: Fundacja na rzecz Nauki Polskiej (PL)Funder: Uppsala UniversityAbstract: Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease

Genetic predisposition to mosaic Y chromosome loss in blood.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.This research has been conducted using the UK Biobank Resource under application 9905 and 19808. This work was supported by the Medical Research Council [Unit Programme number MC_UU_12015/2]. Full study-specific and individual acknowledgements can be found in the supplementary information

Seksualność kobiet w trakcie leczenia raka jajnika

WSTĘP Seksualność, jako wrodzona funkcja, jest jednym z podstawowych czynników motywujących do nawiązywania relacji interpersonalnych. Zaburzenia życia seksualnego wpływają zatem negatywnie na samoocenę i kontakty społeczne. Problem ten dotyczy pacjentek po operacjach ginekologicznych, szczególnie tych w okresie leczenia onkologicznego, które oprócz choroby podstawowej, zmagają się z powikłaniami leczenia. Często aspekt ten traktują jako problem jednostkowy i w konsekwencji zostają same sobie z wieloma pytaniami. W rzeczywistości zjawisko to dotyczy znacznie większej grupy pacjentek. Podejmowanie rozmowy przez lekarza i specjalistyczna opieka seksuologa, wydają się być niezbędnym wsparciem dla pacjentek. MATERIAŁY I METODY Do badania zakwalifikowano 187 pacjentek szczecińskich poradni ginekologicznych. Kobiety odpowiadały anonimowo i dobrowolnie na pytania zawarte w specjalnie przygotowanym trzyczęściowym kwestionariuszu. Dane uzyskane w badaniu ankietowym zostały poddano analizie statystycznej. Zależności wyliczono za pomocą współczynnika V Cramera. WYNIKI U pacjentek leczonych onkologicznie zauważalny jest związek satysfakcji seksualnej ze wszystkimi obszarami jakości życia. Najsilniejszy związek występuje pomiędzy satysfakcją seksualną a sferą podmiotową pacjentek r = 0,70. Odnotowano także silny związek pomiędzy brakiem występowania objawów depresyjnych u pacjentek a satysfakcją seksualną r = 0,72. Odnotowano również znaczące pogorszenie w obszarze satysfakcji seksualnej u pacjentek w trakcie chemioterapii. DYSKUSJA W literaturze nie ma wielu badań poświęconych jakości życia i seksualności u pacjentek w trakcie leczenia raka jajnika. W niniejszej pracy wykazano, istotny wpływ depresji na pogorszenie satysfakcji z życia seksualnego. Poparty został pogląd dotyczący negatywnego wpływu objawów depresyjnych na sferę seksualną pacjentek. Nasze badania wykazały również, pogorszenie satysfakcji seksualnej u pacjentek poddanych chemioterapii. Wprowadzenie do systemu opieki medycznej psychoonkologa, może przyczynić się do szybszego powrotu pacjentek do normalnego współżycia, podnosząc jednocześnie ich jakość życia oraz satysfakcję seksualną

The Level Of Myeloid Derived-Suppressor Cells In Peripheral Blood Of Patients With Prostate Cancer After Various Types Of Therapy

Prostate cancer is one of the most frequent cancers in men. Although several treatment options exist, their clinical effectiveness is still not satisfactory. One the possible reason of such situation might be the presence of myeloid-derived suppressor cells (MDSC) and their pro-turnorigenic activity. MDSC possess irnmunosuppressive ability and in many studies were shown to support tumor development and progression. In this study we addressed the question whether commonly used therapies of prostate cancer affect the level of MDSC populations in the patients' blood. We compared the level of granulocytic (Gr-MDSC), monocytic (Mo-MDSC) and early stage MDSC (eMDSC) in the blood of patients at different clinical stage and different tumor grading scores, who underwent either surgery or hormonal therapy alone or were given a combined treatment, including e.g. radiotherapy. The obtained results showed that the level of Gr-MDSC was significantly lower in all treated patients comparing to untreated group. On the other hand, surgery or hormonal therapy alone did not affect the level of Mo-MDSC. These results were independent of the PSA level, the tumor grading and clinical stage of the patients. In conclusion, we suggest that Mo-MDSC should be considered as a potential therapy target in the course of prostate cancer treatment to enhance its anti-tumor effectiveness

Cryptic diversity of Italian bats and the role of the Apennine refugium in the phylogeography of the western Palaearctic

The Mediterranean Basin is typified by a high degree of species rarity and endemicity that reflects its position, geomorphology, and history. Although the composition and cryptic variation of the bat faunas from the Iberian and Balkan Peninsulas are relatively well studied, data from the Apennine Peninsula are still incomplete. This is a significant shortfall, given the presumed refugial role of this region in the context of Europe's Pleistocene phylogeography. It was thus our aim to supplement the phylogeographical information from the region, generating mitochondrial sequences and reviewing published data, with a focus on the dispersal and diversification patterns characterizing taxa with different life strategies. Site-specific lineages were ascertained, especially in the genera Myotis and Plecotus and amongst the pipistrelloid bats, representing speciose radiations. It was possible to observe disjunct ranges with patches isolated south of the Alps in several species, corresponding with evolution of elevated genetic distance. The genetic subdivision within the continuous Italian range into northern and southern lineages in several taxa indicated the possible past substructure of the refugium. Several shared lineages between the Apennine and Ibero-Maghrebian regions were observed, indicating connectivity between the Adriatic and Atlantic-Mediterranean refuges, and raising questions as to which region these clades originated from and what was the direction of faunal exchange between them. In contrast to Europe's other two main refugia, the Apennine Peninsula is a smaller region with simpler phylogeographical patterns. Nevertheless, our results support the idea that the region generated novel lineages. Whereas diversification in sedentary bats may have been driven through the generation of in situ adaptations, specialization, and niche differentiation, the emergence of species with a tramp strategy could have entailed the utilization of faunal drift and the taxon cycle

Loss of chromosome Y in regulatory T cells

Abstract Background Mosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4 + T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4 + T lymphocytes are particularly affected by LOY. Publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from patients with liver, lung or colorectal cancer were used to study how LOY affects different subtypes of T lymphocyte. To validate the observations from the public data, we also generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4 + T lymphocytes enriched samples. Results Regulatory T cells had significantly more LOY than any other studied T lymphocytes subtype. Furthermore, LOY in regulatory T cells increased the ratio of regulatory T cells compared with other T lymphocyte subtypes, indicating an effect of Y loss on lymphocyte differentiation. This was supported by developmental trajectory analysis of CD4 + T lymphocytes culminating in the regulatory T cells cluster most heavily affected by LOY. Finally, we identify dysregulation of 465 genes in regulatory T cells with Y loss, many involved in the immunosuppressive functions and development of regulatory T cells. Conclusions Here, we show that regulatory T cells are particularly affected by Y loss, resulting in an increased fraction of regulatory T cells and dysregulated immune functions. Considering that regulatory T cells plays a critical role in the process of immunosuppression; this enrichment for regulatory T cells with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes

Loss of Y and clonal hematopoiesis in blood : two sides of the same coin?

These authors contributed equally: Viktor Ljungström, Jonas Mattisson, Jan P. Dumanski, Panagiotis Baliakas, Lars A. Forsberg</p

Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals

Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.These authors contributed equally: Jan P. Dumanski, Lars A. Forsberg</p

Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.

Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer's disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a "genetic wasteland", and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease