Men are the weaker sex

The role of the Y chromosome in "matters of the heart"

Valeria Yunitskaya, "Biomolecule"

How is the loss of the Y chromosome associated with diseases of the cardiovascular system? Scientists from the National Institutes of Health conducted a study in which they removed the Y chromosome from red bone marrow cells in mice and revealed changes in heart tissues. And when studying this phenomenon in humans, it was found that men whose large number of white blood cells lacked a Y chromosome had an increased risk of cardiovascular diseases.

Often when the Y chromosome is mentioned, gender and sexual development come to the fore. However, not everything is so simple. As it turned out recently, a small chromosome, on which more than 70 protein-coding genes are located, can disappear from cells with age [1]. In addition, its absence may lead not only to infertility and defects in sexual development in men, but also to heart diseases [2].

The genes located on the Y chromosome are mainly associated with the manifestation and development of male sexual characteristics. At the same time, somatic cells are able to divide and function even with the loss of this chromosome [3]. Thus, the number of cells with karyotype 45,X increases in men in different organs and tissues during their lifetime. When describing a chromosome set , the following structure is used: first, the total number of chromosomes is recorded, and the sex ones are indicated after a comma, according to this, the male karyotype is normally designated as 46,XY. The phenomenon in which cells with a different set of chromosomes are present in tissues is called "mosaicism" ("Biomolecule" I have already written about mosaicism in the article "Genomic Puzzle: Discover the mosaic in yourself" [4]).

How does the loss of the Y chromosome occur?

Studies of this process are still ongoing. It is assumed that the loss of the Y chromosome occurs during the mitosis of somatic cells. In this case, individual cells will have a karyotype of 45,X. Shortening of telomeric regions and other phenomena affecting the microarchitecture of chromosomes can lead to incorrect divergence of the Y chromosome during cell division [1].

In addition, the human Y chromosome is enriched with palindromic sequences [5]. Palindromic sequences are sections of DNA in which the sequence of nucleotides when read from the 5’-end to the 3’-end coincides with the sequence in the complementary chain. The high frequency of these sequences is the reason for the formation of isodicentric chromosomes — chromosomes consisting of identical arms and containing two closely spaced centromeric regions, which leads to violations of chromosome segregation during mitosis (Fig. 1) [6].

Drawing 1. The structure of the Y chromosome. (a)
 — the normal structure of the Y chromosome. (b) is a pericentric inversion affecting the pericentromeric region of the p-shoulder and the proximal region of the q-shoulder.
As a result, there was a restructuring of the proximal region of the q-shoulder into the p-shoulder. (in)
 — sister chromatids formed during gametogenesis. (d) is the structure of the isodicentric Y chromosome.
Source: [6]

Subsequent clonal expansion of one or more stem cells with karyotype 45,X leads to clinical manifestations of mosaic loss of the Y chromosome (mosaic loss of Y, mLOY) in various organs and tissues [1].

This phenomenon is mainly characteristic of elderly people. Studies show that mosaic Y-chromosome loss (mLOY) is associated with heart disease, cancer pathology, Alzheimer's syndrome and other "age-related" diseases. Moreover, mLOY may be one of the possible reasons for shorter life expectancy in men compared to women. In young men, cases of mLOY are less common and are manifested by disorders of spermatogenesis, as well as defects in the development of the reproductive system (Fig. 2) [7-9].

Drawing 2. Consequences of mosaic Y-chromosome loss. Depending on the stage of human development, the effects of mLOY will have different phenotypic effects. Source: [9]

What does the heart have to do with it?

A study was conducted on 38 mice, during which the Y chromosome was removed from red bone marrow cells using CRISPR-Cas9 technology [2]. As is known, in the process of mitosis, the threads of the division spindle are attached to the centromeric regions of the chromosomes, due to which the segregation of chromosomes to the poles of the cell occurs. After exposure to CRISPR-Cas9 on centromeric regions, their fragmentation occurs, and subsequently the divergence of chromosomes during division is disrupted, which is why partial loss of chromosomes is possible [10]. For the targeted effect of CRISPR-Cas9 on the desired parts of the genome, the participation of guide RNAs (gRNAs) is necessary. As part of the experiment, gRNAs were used that target repetitive sequences in the centromeric regions of the Y chromosome. Delivery of the gRNA and Cas9 complex was carried out using lentiviral vectors (for more information, see the article "Lentiviral vectors: how they became the best vectors for ex vivo therapy" [11]). After that, cells modified in a similar way were planted in young male mice whose bone marrow was removed. As a result of this procedure, it was found that 49-81% of white blood cells in the recipients' blood do not have the Y chromosome. In the control group, 37 mice also underwent bone marrow transplantation, but they did not lose the Y chromosome [2].

The observation period for rodents was 2 years. It turned out that 40% of mice with the removed Y chromosome survived for 600 days after transplantation. While in the control group, this indicator was 60% [2].

Heart diseases were also noted in mice with a missing Y chromosome. Approximately 15 months after the start of the study, the strength of heart contraction decreased by 20% in mice in the experimental group. In addition, fibrosis of the heart muscle began [2].

In addition to experiments with mice, the researchers analyzed samples from more than 15,000 men obtained at the UK Biobank. It was found that men, at least 40% of whose leukocytes were deprived of the Y chromosome, were 30% more likely to die from diseases of the circulatory system than those whose number of cells with a normal karyotype was greater [2].

Conclusion

Analyzing the data obtained, it is too early to draw unambiguous conclusions about the relationship between cardiac pathologies and mLOY. However, this phenomenon should be taken into account in clinical practice and continue to study not only the mechanisms of Y-chromosome loss by cells, but also the effect of mLOY on other organs and systems of the body.

Literature

1.   Maki Fukami, Mami Miyado. (2022). Mosaic loss of the Y chromosome and men's health. Reprod Medicine & Biology. 21;

2.   Soichi Sano, Keita Horitani, Hayato Ogawa, Jonatan Halvardson, Nicholas W. Chavkin, et. al.. (2022). Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality. Science. 377, 292-297;

3.   Xihan Guo, Xueqin Dai, Tao Zhou, Han Wang, Juan Ni, et. al.. (2020). Mosaic loss of human Y chromosome: what, how and why. Hum Genet. 139, 421-446;

4.   Genomic Puzzle: Discover the mosaic in yourself;
Patricia Balaresque, Turi E. King, Emma J. Parkin, Evelyne Heyer, Denise Carvalho‐Silva, et. al.. (2014). Gene Conversion Violates the Stepwise Mutation Model for Microsatellites inY‐Chromosomal Palindromic Repeats. Human Mutation. 35, 609-617;

5.   Lauren E. Hipp, Lauren H. Mohnach, Sainan Wei, Inas H. Thomas, Maha E. Elhassan, et. al.. (2016). Isodicentric Y mosaicism involving a 46, XX cell line: Implications for management. Am. J. Med. Genet.. 170, 233-238;

6.   Mark A. Jobling, Chris Tyler-Smith. (2017). Human Y-chromosome variation in the genome-sequencing era. Nat Rev Genet. 18, 485-497;

7.   Lars A Forsberg, Chiara Rasi, Niklas Malmqvist, Hanna Davies, Saichand Pasupulati, et. al.. (2014). Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat Genet. 46, 624-628;

8.   Mami Miyado, Maki Fukami. (2019). Losing maleness: Somatic Y chromosome loss at every stage of a man's life. FASEB BioAdvances;

9.   Fatwa Adikusuma, Nicole Williams, Frank Grutzner, James Hughes, Paul Thomas. (2017). Targeted Deletion of an Entire Chromosome Using CRISPR/Cas9. Molecular Therapy. 25, 1736-1738;

10. Lentiviral vectors: how they became the best vectors for ex vivo therapy.

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