Y-chromosome not going extinct, but losing it may be risk factor for Alzheimer disease

y chromosome loss alzheimers

I have spent the entirety of my career at MIT’s Whitehead Institute defending the honor of the Y chromosome in the face of innumerable insults to its character and its future prospects.

So says Massachusetts Institute of Technology biology professor David Page—just about every time that he gives a public talk dealing with the male sex chromosome. It’s not only because the Y chromosome is the focus of his research, but also because the Y chromosome has been under-appreciated. Until a couple of years ago, evolutionary geneticists were predicting that this smallest of human chromosomes would vanish within 10 million years, leaving us with all female descendants.

But in 2014 researchers at the University of California at Berkeley demonstrated that prediction to be completely wrong (published in PLOS Genetics). Furthermore, over the years, Page and his MIT team have been finding Y chromosome genes to be engaged more broadly in cellular processes than had been previously thought at the onset of the human genome project when it was decided that Y chromosome sequences were not worthy of inclusion in the first human genomes to be sequenced.

But there’s also a quote that goes: “Be careful what you wish for, because you might get it.” Throughout the history of medicine, physicians have known all too well that that the incidence and severity of different diseases often vary dramatically between males and females. This applies not just to conditions affecting male and female organs, but to a plethora of conditions, from systemic lupus erythematosus (favors women 9 to 1) to autism spectrum disorder (1.33-15.7:1, depending on the study, in favor of males). While this phenomenon has always been central to assessing a patient’s risk for a disease, very little research has gone into answering why.

Data are coming in now, however, and they’re putting the often forgotten sex chromosome at center stage—this month as a major risk factor for one of the most common and notorious degenerative brain conditions: Alzheimer disease, a condition for which gender has never been observed to be a risk factor. To be sure, incidence is higher in women, but only in accordance with increased lifespan, so aging has always been considered to be a more important determinant.

That’s according to a watershed study from Uppsala University in Sweden published May 23 in the American Journal of Human Genetics. The discovery elevates the status of the Y chromosome, but maybe not in a way that should make it so proud.

Men are from Mars, women are from Venus

That bestselling book title of 1992 alludes to the obvious fact that males and females are different in many ways and it applies fairly to the genome. In his final State of the Union address in 2000,  President Bill Clinton highlighted that all humans share 99.9 percent of their genetic sequences a result from the then new Human Genome Project, but that’s only kind of true.

Today, we know that’s more like 99.7 percent, but more importantly it’s correct only if you compare two humans of the same gender. Another widely publicized finding was that we share 99.0 percent of our genome with our closes living ancestor, the chimpanzee, but that also is not accounting for gender. It may surprise people that the genetic similarity between males and females is only 98.5 percent; thus, genetically, you are more like a chimpanzee of your own gender than like a human of the opposite gender, but those those differences are due to sequences that males carry on the Y chromosome. Since the sex chromosomes (Y and X) are present not only in your reproductive cells, but all of your cells that retain a nucleus, it should make sense that the presence or absence of a Y chromosome affects cell function.

The strange and eventful history of the Y chromosome

Sans teeth, sans eyes, sans taste, sans everything—these are the losses of old age that Shakespeare noted in his famous “All the Word’s a Stage” soliloquy (As You Like It Act II, Scene vii). But as humanity progresses through new ages, will it be sans Y chromosome? Until recently, geneticists thought the answer was yes for a simple reason: the Y chromosome has lost a lot of genes.

It’s a story that began about 300 million years ago, when the ancestors of mammals diverged from reptiles; that’s roughly the same time period when comparative genome analysis shows that X and Y chromosomes emerged. With reptiles, determination of gender depends on environmental factors that effect an egg, particularly temperature. In the case of birds (which are neither mammal nor reptile) they have sex chromosomes, but opposite the mammalian scenario. The large bird sex chromosome is called Z and the gender with two copies (ZZ) is male, while the female bird has ZW. It’s different from the XX and XY system of mammals, because it evolved independently in birds, either after or before they diverged from dinosaurs, but long after they diverged evolutionarily from mammals.

Related article:  Behold the octopus: Problem solver, tool user and now, gene editor

The X and Y chromosomes of early mammals emerged 300 million years ago from ordinary chromosomes that gradually took on gender-specific roles. The early Y chromosome was much larger than the Y of today. It started off the size of an X (which is the eighth largest human chromosome by total base pair number), then shrunk as genes were lost. When researchers first realized this had happened, based on the amount of genetic sequences remaining on the Y today versus what had been there 300 million years ago, they extrapolated and found that the Y has just 10 million years to live. But that extrapolation was proven wrong when the Berkeley study of 2014 demonstrated that most of the Y genes had been lost early on. Afterward, some new genes actually had migrated to the Y from non-sex chromosomes, and for at least the last 100 million years, the Y has been small, but stable in size, so it should continue long after 10 million years into the future.

Mosaic of Y losses

The usual thing to do in research on genetics of Alzheimer disease is look for correlations between presence of the disease and presence of genetic variants that are inherited. If you have certain genes that are present commonly in Alzheimer patients, then you’re at increased risk of developing the disease. But a newer focus, one that occupies the researchers in Uppsala, is to look at genetic changes that are not inherited, but that occur subsequent to fertilization of an embryo and through life all the way through old age. If this puts you in mind of cancer, you have the concept. While the risk of many cancers is linked to inherited sequences, cancer is notorious for developing from genetic mistakes in one particular cell type. While many known cell-type specific changes that can lead to cancer occur in non-sex chromosomes, several studies have linked certain cancers to loss of the Y chromosome.

In their new paper in the American Journal of Genetics, the Uppsala researchers have expanded the Y chromosome disease findings to include Alzheimer disease. Specifically, they identified an association between Alzheimer disease and loss of the Y chromosome in some blood cells. It’s called a mosaic loss, because it’s not a universal Y chromosome loss affecting all all body cells, nor even all blood cells. Rather, some cells lose the chromosome while others do not, and if it’s showing up in blood cells it’s plausible that brain cells also could be losing Y chromosomes.

Importantly, the loss of the Y chromosome is associated not only with Alzheimer disease; it also is associated independently with old age and with smoking. This may account for why aging and smoking are both independent risk factors for Alzheimer disease, but what does the study mean with respect to the influence of male gender? Didn’t we say at the beginning that gender was not an Alzheimer risk factor, that due to living longer women actually have a higher incidence?

The answer probably has to do with fact that in medicine often there are multiple pathways to a common outcome. The Uppsala study results mean that in men a pathway to Alzheimer disease involves mosaic Y chromosome loss. In women, it obviously must be something else, but if that’s the case is Alzheimer disease really the same condition in women versus men? At this point it’s too early to know, just as it’s too early to know about whether other conditions whose symptoms and pathology look the same in males and females really are the same. Various cancers, SLE, autism, and other afflictions could turn out to be different conditions too. While the jury is still out, just realizing the possibility broadens our perspective on disease, and this may be just one more reason for men—and women—to pay tribute to the X chromosome’s tiny partner.

David Warmflash is an astrobiologist, physician and science writer. Follow@CosmicEvolution to read what he is saying on Twitter. 

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