Y: A Chromosome Gives Up

26. July 2016
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With old age, the loss of the Y chromosome occurs in many leukocytes in men. This phenomenon is a risk factor for getting tumours – and as new evidence indicates for getting Alzheimer's dementia as well. Is the Y to blame for the fact that men die earlier than women?

The loss of the Y chromosome in leukocytes in men of increasing age is referred to as “lifetime-acquired loss of chromosome Y” (LOY). According to the new analysis, which appeared in American Journal of Human Genetics, LOY increases the likelihood of acquiring Alzheimer’s disease. The researchers examined this relationship in three independent studies.

One case-control study showed that men with an existing Alzheimer’s diagnosis exhibit a higher level of LOY than do control subjects. This was consistent with the results of two prospectively designed studies: men whom were ascertained via blood-test to have LOY were more frequently found during the follow-up to have dementia. The Y chromosome, with its “sex determining region of Y” (SRY), is a significant determinant of masculinity in humans. Is there, hand in hand with the gradual degeneration of ‘man force’ over the course of life, a similar thing happening to the cells upstairs?

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© National Human Genome Research Institute, Wikimedia Commons

The Y chromosome: nothing much going on?

For a long time it was assumed that genetically speaking there is not much going on in the Y chromosome. A withered wasteland made up of many highly repetitive, noncoding pseudogenes whose role on the genetic diversity stage is reduced to being the lineage carrier in the transfer of one singular piece of crucial information: the expression of the male gender.

The Y chromosome can be subdivided into different areas. In the male specific region (MSY) one finds the genes excluded from meiotic recombination. There exist genes here such as SRY, transcription encoding factors which are involved in the formation of the testis and consequently in sexual differentiation. In addition, the pseudoautosomal regions (PAR), which participate in recombination, are represented on the Y chromosome, and their genetic information is also able to be found on X- chromosomes. The remaining portion of the Y chromosome is present as a “heterochromatine region” and is thus genetically inactive.

Many diseases are primarily a male problem

In many diseases a gender specific epidemiology with clear bias toward the male sex is evident. This applies particularly to tumour diseases: according to one epidemiological study, in the United States in the years 1977-2006 at least 32 of the detected 36 tumour types were associated with increased mortality rates in men.

Moreover, there are other diseases with a high impact on overall mortality, such as atherosclerosis and myocardial infarction, which make themselves more at home with members of the male gender. Asthma and psychiatric diseases such as schizophrenia are further examples.

Factors such as lifestyle occupy a substantial position as connecting elements between male phenotype and the emergence of certain diseases. Nonetheless genetic foundations, which are insufficiently examined in this context, also appear to be relevant.

The Y chromosome and cancers

In order to more precisely explore genetic causes of high cancer mortality in men, researchers at Uppsala University two years ago studied the role of LOY in tumorigenesis. A study involving 1,153 elderly men showed that an increased extent of LOY correlated to incidence of tumours and an increased overall mortality rate. The association mainly existed between non-haematological cancers and LOY.

The fact that LOY apparently represents a risk factor for two fully disparate disease entities such Alzheimer’s disease and solid tumours raises the question of why this is so. The researchers suggest that LOY is associated with limited immunological capabilities of the blood cells.

Alongside LOY the MSY genes of the Y chromosome also seem to play a role in tumorigenesis. The Y-encoded testis-specific protein (TSPY) is a member of the group of proteins that are encoded by genes MSY. As the name enables us to immediately assume, its usual occurrence is almost exclusively limited to the testis. In studies, however, it was able to be observed that in certain neoplastic diseases the ectopic expression of various MSY genes was elevated. What is striking is that we are dealing with tumours here, such as hepatocellular carcinoma (HCC) which occur significantly more frequently in men.

One possible explanation of this relationship: It seems likely that some MSY genes are regulatory genes which modulate the gene expression in tumorigenesis events. Thus there could among the MSY genes be proto-oncogenes concealed that promote tumour growth. Interestingly, if we turn to look at the homologous counterpart of TSPY, which is located on the “female” X chromosome, we are dealing with a tumour suppressor gene, ie. a regulatory gene which inhibits tumour growth.

The Y chromosome and cardiovascular diseases

It’s not only tumour diseases, but also cardiovascular diseases, such as coronary heart disease (CHD) involving myocardial infarction, which afflict men more often. Here as well, an explanation could be hiding in the Y chromosome. At least in animal models it has been noted that the SRY locus regulates tyrosine hydroxylase, an important enzyme in the synthesis of noradrenaline and thus the ‘screwing point’ in the regulation of blood pressure. Hypertension in turn is a classic risk factor for the development of arteriosclerosis and thus also of CHD – and it also relates primarily to the male.

Inflammation events are also crucially involved in the development of atherosclerosis. And here the Y chromosome apparently also has a say in matters: MSY genes potentially bring about macrophage activation, the basis of an inflammatory response in the body.

A basis for PanYk?

The findings indicated should not lead members of the relevant gender to rush off in sudden despair. Rather, it is hoped that science can come to find the basic reason underlying the unfair state of affairs whereby men constantly reach the end of life sooner. The discovery of possible regulatory genes in tumour progression also holds out the prospect for using these in targeted and individualised therapy, in order to stop tumour growth – and to reduce elevated mortality rates among men. The same also applies to other diseases such as atherosclerosis, for which there currently are no gender specific therapeutical approaches.

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