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View Full Version : Y chromosome and health: new findings (2017 paper)



FGC Corp
11-06-2017, 04:16 AM
See:
citing the paper:

"Furthermore, in vitro studies show that DDX3X(the X paralogue of the Y gene DDX3Y) is a determinant of HIV-1 replication. These examples offer strong support for inherited differences in immune responses between men.."

The intuition in the past has been that the Y chr was not significant for major traits or diseases, but this recent evidence suggests that thinking may need to be revisited.


https://www.ncbi.nlm.nih.gov/pubmed/28853720
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Eur J Hum Genet. 2017 Nov;25(11):1181-1188. doi: 10.1038/ejhg.2017.128. Epub 2017 Aug 30.
The Y chromosome: a blueprint for men's health?
Maan AA1, Eales J1, Akbarov A1, Rowland J1, Xu X1, Jobling MA2, Charchar FJ3, Tomaszewski M1,4.

Abstract
The Y chromosome has long been considered a 'genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome.

FGC Corp
11-06-2017, 04:38 AM
Also of interest:
https://www.ncbi.nlm.nih.gov/pubmed/23800453/

Genome Res. 2013 Sep;23(9):1474-85. doi: 10.1101/gr.156703.113. Epub 2013 Jun 25.
The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease.

Case LK1, Wall EH, Dragon JA, Saligrama N, Krementsov DN, Moussawi M, Zachary JF, Huber SA, Blankenhorn EP, Teuscher C.
Author information
1
Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA.
Abstract
Understanding the DNA elements that constitute and control the regulatory genome is critical for the appropriate therapeutic management of complex diseases. Here, using chromosome Y (ChrY) consomic mouse strains on the C57BL/6J (B6) background, we show that susceptibility to two diverse animal models of autoimmune disease, experimental allergic encephalomyelitis (EAE) and experimental myocarditis, correlates with the natural variation in copy number of Sly and Rbmy multicopy ChrY genes. On the B6 background, ChrY possesses gene regulatory properties that impact genome-wide gene expression in pathogenic CD4(+) T cells. Using a ChrY consomic strain on the SJL background, we discovered a preference for ChrY-mediated gene regulation in macrophages, the immune cell subset underlying the EAE sexual dimorphism in SJL mice, rather than CD4(+) T cells. Importantly, in both genetic backgrounds, an inverse correlation exists between the number of Sly and Rbmy ChrY gene copies and the number of significantly up-regulated genes in immune cells, thereby supporting a link between copy number variation of Sly and Rbmy with the ChrY genetic element exerting regulatory properties. Additionally, we show that ChrY polymorphism can determine the sexual dimorphism in EAE and myocarditis. In humans, an analysis of the CD4(+) T cell transcriptome from male multiple sclerosis patients versus healthy controls provides further evidence for an evolutionarily conserved mechanism of gene regulation by ChrY. Thus, as in Drosophila, these data establish the mammalian ChrY as a member of the regulatory genome due to its ability to epigenetically regulate genome-wide gene expression in immune cells.

FGC Corp
11-06-2017, 04:59 AM
https://www.ncbi.nlm.nih.gov/pubmed/26144214

J Proteome Res. 2015 Sep 4;14(9):3474-83. doi: 10.1021/acs.jproteome.5b00512. Epub 2015 Jul 22.
DDX3Y, a Male-Specific Region of Y Chromosome Gene, May Modulate Neuronal Differentiation.
Vakilian H1, Mirzaei M2, Sharifi Tabar M1, Pooyan P1, Habibi Rezaee L1, Parker L2, Haynes PA2, Gourabi H3, Baharvand H1,4, Salekdeh GH1,5.
Author information
Abstract
Although it is apparent that chromosome complement mediates sexually dimorphic expression patterns of some proteins that lead to functional differences, there has been insufficient evidence following the manipulation of the male-specific region of the Y chromosome (MSY) gene expression during neural development. In this study, we profiled the expression of 23 MSY genes and 15 of their X-linked homologues during neural cell differentiation of NTERA-2 human embryonal carcinoma cell line (NT2) cells in three different developmental stages using qRT-PCR, Western blotting, and immunofluorescence. The expression level of 12 Y-linked genes significantly increased over neural differentiation, including RBMY1, EIF1AY, DDX3Y, HSFY1, BPY2, PCDH11Y, UTY, RPS4Y1, USP9Y, SRY, PRY, and ZFY. We showed that siRNA-mediated knockdown of DDX3Y, a DEAD box RNA helicase enzyme, in neural progenitor cells impaired cell cycle progression and increased apoptosis, consequently interrupting differentiation. Label-free quantitative shotgun proteomics based on a spectral counting approach was then used to characterize the proteomic profile of the cells after DDX3Yknockdown. Among 917 reproducibly identified proteins detected, 71 proteins were differentially expressed following DDX3Y siRNA treatment compared with mock treated cells. Functional grouping indicated that these proteins were involved in cell cycle, RNA splicing, and apoptosis, among other biological functions. Our results suggest that MSY genes may play an important role in neural differentiation and demonstrate that DDX3Y could play a multifunctional role in neural cell development, probably in a sexually dimorphic manner.

FGC Corp
11-06-2017, 05:02 AM
Note:
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FGC Corp
11-06-2017, 07:36 PM
Also:

https://www.ncbi.nlm.nih.gov/pubmed/27118832

Proc Natl Acad Sci U S A. 2016 May 10;113(19):5388-93. doi: 10.1073/pnas.1522987113. Epub 2016 Apr 26.
Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents.
Brai A1, Fazi R1, Tintori C1, Zamperini C1, Bugli F2, Sanguinetti M2, Stigliano E3, Esté J4, Badia R4, Franco S4, Martinez MA4, Martinez JP5, Meyerhans A6, Saladini F7, Zazzi M7, Garbelli A8, Maga G9, Botta M10.
Author information
Abstract
Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEAD-box polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target

FGC Corp
11-08-2017, 08:34 PM
Another paper:
https://link.springer.com/content/pdf/10.1186/s13293-015-0024-z.pdf

Y genetic variation and phenotypic diversity in

health and disease

Laure K Case1 and Cory Teuscher1,2,3*


Excerpt:

" A role for the Y chromosome (ChrY) in mediating sex differences outside of
development and reproduction has historically been overlooked due to its unusual genetic composition andthe predominant testes-specific expression of ChrY-encoded genes. However, ample evidence now existssupporting ChrY as a mediator of other physiological traits in males, and genetic variation in ChrY has been linked to several diseases, including heart disease, cancer, and autoimmune diseases in experimental animal models, as well as humans. The genetic and molecular mechanisms by which ChrY modulates phenotypic variation in males remain unknown but may be a function of copy number variation between homologous X-Y multicopy genes driving differential gene expression."

FGC Corp
11-09-2017, 11:46 PM
Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):3491-3496. doi: 10.1073/pnas.1620889114. Epub 2017 Feb 27.
Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection.

Krementsov DN1, Case LK1, Dienz O2, Raza A1, Fang Q1, Ather JL1, Poynter ME1, Boyson JE2, Bunn JY3, Teuscher C4,5.
Author information
Abstract
Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden. Using a murine model of influenza A virus (IAV) infection and a panel of chromosome Y (ChrY) consomic strains on the C57BL/6J background, we present data showing that genetic variation in ChrY influences IAV pathogenesis in males. Specific ChrY variants increase susceptibility to IAV in males and augment pathogenic immune responses in the lung, including activation of proinflammatory IL-17-producing γδ T cells, without affecting viral replication. In addition, susceptibility to IAV segregates independent of copy number variation in multicopy ChrY gene families that influence susceptibility to other immunopathological phenotypes, including survival after infection with coxsackievirus B3. These results demonstrate a critical role for genetic variation in ChrY in regulating susceptibility to infectious disease.

https://www.ncbi.nlm.nih.gov/pubmed/28242695

FGC Corp
11-11-2017, 12:34 AM
See:
citing the paper:

"Furthermore, in vitro studies show that DDX3X(the X paralogue of the Y gene DDX3Y) is a determinant of HIV-1 replication. These examples offer strong support for inherited differences in immune responses between men.."

The intuition in the past has been that the Y chr was not significant for major traits or diseases, but this recent evidence suggests that thinking may need to be revisited.


https://www.ncbi.nlm.nih.gov/pubmed/28853720
Send to

Eur J Hum Genet. 2017 Nov;25(11):1181-1188. doi: 10.1038/ejhg.2017.128. Epub 2017 Aug 30.
The Y chromosome: a blueprint for men's health?
Maan AA1, Eales J1, Akbarov A1, Rowland J1, Xu X1, Jobling MA2, Charchar FJ3, Tomaszewski M1,4.

Abstract
The Y chromosome has long been considered a 'genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome.

Human DDX3 protein:

Computer graphic credit: By Emw - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8767100



19689

pauleug
04-19-2019, 03:01 AM
I have to read more on UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene. Any recommendations?