Unraveling the secrets of the human Y chromosome

For the first time ever, scientists have fully decoded the Y chromosome.

It’s one of the tiniest human chromosomes – the stubby counterpart to the X chromosome. But it's also a definitive part of the genome for all males everywhere.

"We looked at the results on the screen and it was putting everything together in a way that we had never seen before. We saw that visualization and thought, 'Wow, we can actually do this.'"

There may be more to the Y than meets the eye when it comes to understanding cancer risk, fertility, and biology in general.

Today, On Point: Unraveling the secrets of the Y chromosome – and maybe of men, too.

Pille Hallast, research scientist at the Jackson Laboratory for Genomic Medicine. First author of the study that completely sequenced 43 Y chromosomes from men across the world.

Richard Reeves, president of the American Institute for Boys and Men. Author of the book “Of Boys and Men: Why the Modern Male Is Struggling, Why It Matters, and What to Do About It."

Dr. Stephen Leslie, associate professor of urology at the Creighton University School of Medicine.

Adam Philippy, senior investigator at the Center for Genomics and Data Science Research, part of the National Human Genome Research Institute.

Part I

MEGHNA CHAKRABARTI: Ok, guys. And I literally mean guys. For all the men listening right now – what is the one thing that dwells in each and every one of the 30 trillion cells in your body, that defines you as the male of the species?

I’ll give you a second or two here to think about it. Okay, maybe you didn't even need that long, because it's an easy question, right?

It’s the Y chromosome, of course. So you’d think that back in 2003 when former President Bill Clinton announced:

PRES. CLINTON: We are here to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wondrous map ever produced by humankind.

CHAKRABARTI: You would have thought that Clinton meant the entire human genome. Turns out, the map wasn’t exactly complete. More than 10% of human DNA was missing from that first map. Notably, a detailed complete decoding of the Y chromosome. Which is odd to me, when you think about it, the Y is a chromosome in the bodies of 50% of the entire human race.

Well, 20 years later, the Y chromosome is finally getting its due.

This is On Point. I’m Meghna Chakrabarti.

The Y is the tiniest human chromosome. The short, stubby counterpart to the X chromosome. Adam Philippy admits that it’s odd that it hasn’t been fully sequenced until now.

ADAM PHILIPPY: You wouldn't expect it to because it's the smallest chromosome. Why would it take the longest to finish the smallest chromosome?

CHAKRABARTI: Philippy is a senior investigator at the National Human Genome Research Institute at the National Institutes of Health, or NIH. In August of this year, he and his team published a paper in the journal Nature describing the first complete successful sequencing of the Y chromosome.

So back to his question. Why’d it take so long? Philippy says it’s because of something to do with what geneticists call repeats.

PHILIPPY: Repeats are exactly what they sound like. It's a piece of DNA that has a certain sequence, and that sequence is repeated over and over and over, sometimes for millions of bases or characters. And anytime you're putting together a puzzle, figuring out the repeats is always the hardest part because all of the pieces look the same.

CHAKRABARTI: Okay, so let's lay it out as clearly as possible. First, you have to sequence the DNA, or figure out what each piece says. Then you have to assemble those pieces in the right order. For the Y chromosome, Philippy’s team already knew the sequence. They just needed to fit the pieces together.

Let's go back to imagining that puzzle he was talking about. Say it's an actual puzzle on a table in front of you. Philippy’s talking about a ton of pieces that have the same color, like blue for the sky, but those pieces are different shapes. And they only fit together in a certain way.

You know they’re all blue and you know they all fit together, but you’re not sure exactly how.

PHILIPPY: When the Human Genome Project was initiated and completed in the early 2000s, they could only sequence a few hundred bases at a time. So the pieces were much, much smaller 20 years ago. And so small that it was really an impossible problem. They just shoved all of those blue pieces to the side and left them as a big heap.

CHAKRABARTI: Philippy's talking about a giant heap of microscopic, tiny, blue puzzle pieces. Pretty daunting.

But in 2020, the team was using a technology called an assembler. It’s basically a machine that can sort through those confusing puzzle pieces. And it looked like they were on the verge of a breakthrough.

PHILIPPY: We looked at the results on the screen, like a visualization of how well the assembler is doing. And it was putting everything together in a way that we had never seen before. Much more complete, much more continuous. And it was really an 'Aha!' moment. And we saw that visualization and thought, “Wow, we can actually do this.” And we kind of then took everybody in the lab. All hands on deck.

CHAKRABARTI: Roughly two years later, they succeeded. Philippy’s team had finally cracked the code of the full human Y chromosome – the final missing piece in the complete human genome sequence. Their findings were published in the journal Nature in August 2023.

PHILIPPY: I think what the most important takeaway from this study is that we can now do it at all. From end to end, you know, from telomere to telomere, as we call it.

CHAKRABARTI: So what is there to discover across the Y chromosome – between those telomere brackets? As they call them.

What could this complete Y chromosome mean for understanding things like cancer risk, fertility, or biology in general? That's what we want to look at today.

And Pille Hallast joins us. She's a research scientist at the Jackson Laboratory for Genomic Medicine. And she's taken Philippy's team's research a step further.

She's completely sequenced 43 Y chromosomes from men across the world. Pille, welcome to On Point.

PILLE HALLAST: Hello.

CHAKRABARTI: First of all, I would actually like to talk with you before we discuss your research, a little bit more about the fundamental importance of the Y chromosome itself. What are the kinds of things that it determines in human beings?

HALLAST: So the most important function of the human Y chromosome is essentially determining the biological gender. So when the human embryo starts developing, if it has the Y chromosome present, it will develop a testis, but if the Y chromosome is not present, the embryo will develop an ovary, meaning that a girl will be born.

CHAKRABARTI: So it determines the sex of a fetus and therefore of a person later on. There are also a lot of sex-linked traits, actually, that are dependent on what either is present or not present on the Y chromosome.

HALLAST: So many of these traits have not been directly associated with the Y chromosome.

We know that there are major differences between males and females in terms of susceptibility to different diseases or disorders, the frequency, the outcome, but we don't necessarily know that this is driven by the Y chromosome or the composition of the Y chromosome. This still remains to be discovered in many cases, because one thing which complicates it is that if we have a biological male, and the male has a testis, the testis produces androgens, male sex hormones.

And they produce testosterone, so the composition of hormones between males and females is completely different. So it's very difficult to actually understand how much of these differences are coming specifically from the presence or absence of the Y chromosome, and how much is coming from differences in the hormonal environment in these specific individuals.

CHAKRABARTI: Okay thank you for that clarification, because you're speaking about hormonal differences between males and females. We will come back to that in a moment, Pille. But I guess what I was referencing, and I apologize for not being as clear as possible, but about sex linked traits such as colorblindness or, I think, hemophilia.

I'm digging back to my middle school and high school biology here, that the presence of, or the lack or presence of certain genes on the Y chromosome in comparison to the X chromosome can lead men to having certain traits or factors more often than women. Isn't that right? Or am I wrong?

Pille, are you with us? Okay. It looks like we have dropped her line. She's in Cambridge in the United Kingdom today. So we're going to come back to Pille Hallast in just a moment, but also joining us now is Richard Reeves. He's president of the American Institute for Boys and Men and author of the book “Of Boys and Men: Why the Modern Male Is Struggling, Why It Matters, and What to Do About It."

Why the modern male is struggling, why it matters and what to do about it. Richard, welcome to On Point.

RICHARD REEVES: Thank you. Thank you for having me. But I think you just misgendered me there.

CHAKRABARTI: I know. I said she and then I corrected it and said he, so I'm so sorry about that. (LAUGHS)

REEVES: That is perfectly fine.

CHAKRABARTI: I should just be settled with he's human.

He's a human, male of the species who joins us today. We will get we will get Pille back on the show in just a moment, apparently the line to the UK is obviously not working in our favor. But Richard, I wanted to invite you on the program today, obviously, because the past several years of your career, you have devoted to studying and investigating the plight or the condition of men and boys in this country. So tell me a little bit about just your first thoughts of, okay now we have this sequence.

We're going to understand a little bit more of what it means. This sequence of the Y chromosome. Do you think that's a breakthrough for understanding men more broadly?

REEVES: Obviously, at a scientific level, it's important, and I'm very interested, for example, in the fact that some of the receptors that helped with COVID were actually found more on the Y than on the X.

And I think that we might just understand more about some diseases, as you've already alluded to, and I'd be interested to hear, I think you've got Pille back now, are there other things we might learn in terms of the different susceptibility just at a biological level? Between men and women, from understanding the Y chromosome.

So I think there's a broader conversation we might get into around masculinity, how far our genes or even our hormones, as you were just discussing, determine who we are as males and females, but it's a broader question, but I think it's exciting just to understand the scientific implications of this to start with, and then we can maybe have a better conversation about the culture of masculinity.

CHAKRABARTI: So we will do that, and I do think we have Pille back, but I'm going to wait, we just have a minute before our first break. So I'm going to actually take advantage of that time. And Richard, ask you, there's always the tension that nature-nurture tension, right? Do you think that we're all actually quite a bit enamored with what we think genetics can tell us about human beings?

Sometimes I think we look to it as an absolutist form of an answer. Are you concerned that the more we understand about what's on the Y, that might happen in understanding masculinity more broadly?

REEVES: Yeah. And I think the danger can go two ways. In one way, do you remember the search for the so-called gay gene? And this sense of if we can just prove this at a biological level, then that will be better. My sense is that we've shown that's not true. And that there's so much diversity of human experience and human identity that looking for a genetic or even sometimes just a biological explanation for human behavior only takes you so far and it turns out not that far.

So there isn't an allele or a gene for understanding misogyny or Andrew Tate the online influencer.

CHAKRABARTI: (LAUGHS) There's no Andrew Tate allele!

REEVES: There's no Tate allele. I'm not a scientist.

CHAKRABARTI: Thank God there's no Andrew Tate allele. But Richard Reeves, stand by and thank you for saving us on this technologically challenged Friday, I was thinking it's been such a long but great week. We're going to sail into the weekend, but no, keeping us on our toes is technology. So we'll be back in a moment.

Part II

CHAKRABARTI: Today we are talking about the Y chromosome. It is the last human chromosome to be fully sequenced, and it just happened, or in a paper published just this August. I'm joined today by Richard Reeves. He's president of the American Institute for Boys and Men, and Pille Hallast is with us.

Knock on wood, on a better line, she's a research scientist at the Jackson Laboratory for Genomic Medicine and is first author of a study that sequenced 43 Y chromosomes from men across the world. Now Pille, I'm keeping my fingers crossed. Can you hear me?

HALLAST: I can, yes.

CHAKRABARTI: Okay, good. Thank you so much for your patience while we worked out all those technical problems.

So I want to go back to the question that I was asking you before our line cut off. And that is, again, some Y chromosome basics. I was hoping that you might remind me or correct me about whether things like colorblindness, hemophilia, and some other sex-linked diseases or traits are exclusive to men because of the Y chromosome.

Is that right?

HALLAST: So to be honest, they're not really caused by genes on the Y chromosome, as far as we know. But because men have one X chromosome, this is why there are so many sex linked diseases. So essentially, they have only one X chromosome left, and the X chromosome contains many different genes, which are responsible for many different functions.

So if something goes wrong with that last remaining gene copy on the X chromosome, then this is where the issues come from. Females have two X chromosomes. So the second X chromosome can save the situation.

CHAKRABARTI: Yes.

HALLAST: Classically, what we know is that some men have very hairy ears.

And this phenotype has been associated with the Y chromosome, so it has been a textbook example for a long time, of a Y chromosome linked trait. But then more recent work has actually shown that this is also not necessarily a Y linked phenotype. So again, it is actually influenced by other genes in the genome.

So in that respect it's quite difficult to pinpoint exact phenotypes which are related to the Y chromosome.

CHAKRABARTI: Okay. That makes a lot of sense. Because of course, everything is much more complicated than you learn in elementary or secondary school. But I guess what I was referring to is exactly what you were saying that the X chromosome is so big and so large that it can sometimes contain, let's say, what would usually be a recessive gene for something. And because men don't have another X chromosome, they just have the Y if the Y is lacking, I guess the dominant gene that would have been found on another X chromosome, that recessive trait can be expressed.

So that was what I was trying to get to. But let's move on to the decoding, the fully decoding of the Y chromosome now. Can you tell me your opinion about why it took so long, an additional 20 years, to do that when it is, in fact, the smallest chromosome in the human genome?

HALLAST: So it comes back to the repeat composition of the Y chromosome. So as Adam also mentioned, The Y chromosome is highly repetitive. So if you basically take and sum up all these highly similar repeats in the Y chromosome, you can easily say that 75%, 80% of the whole chromosome is highly repetitive.

And with the old sequencing technologies, which had shorter read length, less than 1,000 base pairs, it was just very difficult to piece, sequence back together in the right order around orientation. So now we have reached the point that we can sequence very large fragments.

So the ... quite new long read sequencing technologies, they can generate sequence fragments, which are 20,000 base pairs in size, and also more than 100,000 base pairs in size. So if you think about it, it's just, if you have tiny pieces of 1,000 base pairs compared to large pieces of 20,000 to 100,000 pieces in length, then, of course, it completely changes how you can piece things together and how accurately.

So this has been a complete game changer in the genomics.

CHAKRABARTI: Okay.

HALLAST: And of course, with the coming of these long-read sequencing technologies, we also needed new software tools that can actually assemble genomes accurately. And this is also an ongoing effort now, but Adam Philippy group has done a great job at coming up with these new tools that can actually assemble genomes very well and very accurately.

CHAKRABARTI: Yeah. So it sounds like you're saying that there's actually more, there are many more repeats in the Y chromosome than. I suppose in the X. First of all, is that right? And second of all is the fact of just the existence of the high number of repeats significant in understanding what the Y chromosome does?

HALLAST: So the X chromosome definitely contains a lot less repeats. And actually, the Y chromosome in the human genome is by far the most repeat rich chromosome. So it's in its own, it's a completely different genetic entity. I guess you could say so, because it's so different in the sequence composition and repeat composition.

CHAKRABARTI: And can you tell me if that's significant in terms of understanding, perhaps the greater influence that the Y chromosome has on male biology, or not? Is it maybe too early to even ask that question?

HALLAST: I would say it's even a bit too early. For a long time, people thought that these kinds of repetitive regions were essentially junk and they did nothing.

But I think that unless we look, we don't really know. So we know by now that in the human genome, there are repetitive regions, which do have important functions and they do influence traits and disease outcomes and all sorts of things. But with the Y chromosome, essentially, large parts, more than half of the Y chromosome sequence was missing until now from the reference genome.

So we have not been able to study it. Maybe it does something, maybe it does not, maybe it doesn't do anything, but we just haven't been able to look into it properly.

CHAKRABARTI: Yeah, I've never, I have to say, I've never understood why there may be such large chunks of the genome that are, let me put it this way, empty of meaning to us.

Right now, because it's hard for me to imagine that any set of base pairs after billions of years of evolution wouldn't have some kind of purpose. But it's very, it's interesting to me that we can't quite yet figure out what the supposedly junk parts of the genome do. But Pille, and Richard, I promise I'll get back to you here.

Feel free to jump in anytime with a question if you have one. But I just wanted to get a little bit more of the science laid out before us. So Pille, you then went ahead and actually sequenced 43 Y chromosomes from men across the world, different continents, different races, etc. What was revealed to you with the additional sequencing of so many more Y chromosomes from different kinds of men?

HALLAST: What surprised me the most was essentially the high level of size and structural variation. We know quite a lot about the Y chromosome despite the fact that the reference was incomplete. From studies which were made in '80s, '90s, even '70s. So for example, we do know that the size varies, but what was very surprising to me was we only sequenced 43 Y chromosomes, and yet we saw such a huge range of variations.

So just the size of the Y chromosome, among a relatively small sample size, let's be honest, ranged from 45 million base pairs to 85 million base pairs. And maybe even more interestingly, roughly quarter of the whole Y chromosome composition, especially in the regions which contain genes, important genes for testicular functions, spermatogenesis, they basically flip in orientation, and they also contain additional large scale structural variations.

So some of these variations we knew about, but what we now have accomplished is really the base pair level understanding of these regions, the base pair level representation. So this now gives us the possibility to go a step further and try to understand, "Okay we see this sort of variation, what does it do?"

Again, maybe it does nothing, but I'm pretty sure it does something.

CHAKRABARTI: Oh, yeah. Yes, I would I'd stake money on that right now, Pille, but let me go back to something you said. So you said that in the 43 Y chromosomes that you studied, you found a very powerful fundamental variation in the sheer number of base pairs from 40 million to 80 million.

So some of these Y chromosomes had double the number of base pairs. That seems amazing to me. Do we see the same variability in the number of base pairs in X chromosomes?

HALLAST: No, absolutely not. The X chromosome is, of course, much larger. It's roughly 150 million base pairs in size. And of course there are repetitive regions which vary in size between individuals, but nothing to that extent.

And this is also true for the other human chromosomes. None of the human chromosomes vary in size to such extent.

CHAKRABARTI: Just the Y.

HALLAST: Just the Y.

CHAKRABARTI: That's mind blowing. Okay, again, this is so new that I don't expect you to have answers, but then what are some of the questions that are raised in your mind from the sheer fact of this base pair variability in the Y chromosome? What else would you like to learn about what that variability means?

HALLAST: So there are many questions. I think the main question I would like to focus on is what does this variation do? Does it do anything? Because as I mentioned, even in the regions which do contain genes, that's code proteins, which are, for example, important in spermatogenesis, we see extensive variation in the sequence composition.

Many of these regions are in different orientation. We have copy number variations, in some men, some regions have more copies than in others. So there are so many different questions that we could be asking. As I mentioned as well before, we knew about many of these structural variants, but now that we have the sequence resolution, I really do believe that this will help to explain at least some of these variable phenotypes that we see, as well.

So maybe if we see the similar structure across different men, but maybe the exact break point where something happens is actually different. But we didn't know this before, we couldn't determine it before, because we didn't have the full sequence, but we can do it now.

CHAKRABARTI: Okay, Pille, stand by for just a moment, because Richard, you've been listening very patiently, and I hope you can forgive me just nerding out on some of the details here of Pille's research. But I don't know if you have any response or reaction to what she's been sharing so far?

REEVES: It's fascinating. Of course, in some ways this can just make for great copy or great jokes, right?

What we're hearing is that the male chromosome is short, repetitive, and a bit confused. And we hear scientists like Pille saying, "Does it do anything?" (LAUGHS) And actually, in science fiction, there's like why the last man, there's this sense that maybe the Y will disappear and so on too.

And that's one reaction. I think. At a more serious level though, I am very interested in understanding how it interacts with things like hormone expression, which in turn interacts with behavior. I have a question for, maybe Pille can help with this. One of the things that we've struggled to understand is the huge difference in mortality rates from COVID-19, for example.

And as far as my science takes me, which is not very far, it looks like there's something about the expression of ACE2 receptors. So I'm nerding out now, but on the Y much more so than on the X. And so could it be that even something like the much higher death rate, so in the U. S. for example, twice as many middle-aged men died from COVID as middle-aged women.

And globally, there was at least a 50% higher risk of death. Pille, is that something that, that we would hope to understand some of the differences in the responses to diseases as well from understanding the chromosomes better?

HALLAST: I do think so. Yes. So for example, there was a paper recently in June, published in Nature as well.

Which showed that the loss of Y chromosome makes a huge difference how invasive is bladder cancer in men who have lost the Y chromosome. And also, the loss of the Y chromosome specifically in the tumor tissue made these tumors much more prone to a specific treatment.

So I think like these sorts of studies are now coming up more and more, showing that there is something on the Y chromosome that is also impacting immune responses, cancer, development, all these kinds of things. So I think we just need to dig deeper and really try to understand what is the difference. I think there is something on the Y chromosome. Many studies have shown that, for example, the loss of the Y chromosome in men, it makes a huge difference in even life expectancy, risk for different cancers, Alzheimer disease.

CHAKRABARTI: Wow. So somehow, something on the Y is important. Pille, let me just step in here for just a moment and say, I'm Meghna Chakrabarti. This is On Point. Can you explain briefly what you mean by the loss of the Y chromosome? I'm a little confused by that.

HALLAST: So it has been known for quite some time now, decades, that aging men lose the Y chromosome in the white blood cells.

And this loss of white blood, loss of Y chromosome in the blood cells has been associated with many different risk factors, lower life expectancy, as I mentioned. So again, we don't really understand it very well. And it is definitely impacted by environmental factors, as well. For example, we know that men who smoke, they have a higher risk of losing the Y chromosome and therefore they're also at a higher risk of all these other increased risks of cancer and Alzheimer's disease.

CHAKRABARTI: Oh, Pille, but when you mean when they lose the white blood cells in the Y, sorry, when they lose the Y chromosomes in the white blood cells, you mean like the Y chromosome actually just physically is not there in white blood cells from man after.

CHAKRABARTI: Really? How does that happen?

HALLAST: I guess it happens during the cell division so that the Y chromosome is just lost.

If you think about it, it doesn't necessarily have very important roles in the viability of a human being, once it determines the gender, the individuals can well survive without the Y chromosome.

CHAKRABARTI: Wow.

HALLAST: So it's not strictly necessary. But clearly there is something on the Y chromosome that is making it important.

CHAKRABARTI: Okay.

HALLAST: But now that we have the full sequences, maybe we can also understand it better. What is it exactly that is making the white chromosome important?

CHAKRABARTI: Richard, are you looking down at your hands or arms right now and wondering what's in your white blood cells at the moment?

REEVES: I am literally on another screen booking a blood test. (LAUGHS)

This is getting more depressed by the moment; these things can disappear. But it's also, I think it's also important, it's not just in the beginning, right? It's also in adolescence, I think. I think some of the interactions with hormones and environment. So what's interesting about this is the more, I think the more we learn about biology, the more important we realize the environment is.

CHAKRABARTI: Yeah.

REEVES: And how it makes culture and environment more important, not less important, as we understand how they interact with biology. So there's no magic gene answer.

CHAKRABARTI: No.

REEVES: And instead, what we learn is that actually how we interact in the world becomes more important. The more we understand.

Part III

CHAKRABARTI: I want to now bring in Dr. Stephen Leslie. He's with us from Omaha, Nebraska, and he's associate professor of urology at the Creighton University School of Medicine. Dr. Leslie, my deep appreciation for your patience, and welcome to On Point.

STEPHEN LESLIE: Thank you and hello, Meghna.

CHAKRABARTI: First of all, as a urologist, what, give me one or two of the big questions that you would like to ask that understanding the Y chromosome might help answer.

LESLIE: How soon can we find out how to turn on or turn off some of these genes that will actually make a difference in human health and particularly male infertility?

CHAKRABARTI: Okay, so why male infertility in particular? First, that's the main function of the Y chromosome. To create the testes and to determine male physical characteristics, as well as healthy sperm.

The sperm counts among men worldwide has been declining steadily. And I'm afraid I'm going to make Richard even more depressed. In 1940, the average sperm count was over 110 million sperm per milliliter. In the 1990s, this dropped to 66 million. In 2018, it was around 50 million. And currently we consider the normal average to be anything over 40.

If this continues, eventually we're not going to have a viable number of sperm to continue procreating the human race.

CHAKRABARTI: I have read those similar numbers before. We actually have done several shows about the reduction, the dramatic reduction in male fertility worldwide. I want to emphasize that.

But Dr. Leslie, what confuses me about this rapid decline is that I didn't think that evolution works on that kind of very tight timeline. Certainly, there has to be some kind of environmental piece to this, that would so quickly be, if we're presuming that there's something being turned off and on in the Y chromosome, it can't just be evolution.

Is there something we're doing to our environment that's having an impact on chromosomal activity in men now?

LESLIE: We're not absolutely sure, but the overwhelming evidence is that exposure to more and more environmental chemicals and toxins, pollution, particularly pesticides, poor diet, COVID-19 didn't help, obesity tends to affect hormone production and has an effect.

Smoking damages the most rapidly reproducing cells and the cells that make sperm are the fastest growing in the body. We now have vastly improved medical care worldwide compared to what we had 50 or 100 years ago. And as wonderful as that is, it's allowing more men with marginal health and borderline genetics and really poor sperm production to reproduce.

We have assisted reproductive techniques where we use a lot of high-tech microscopes and inject sperm into eggs and then re-implant them in ladies and all sorts of other fancy things. Where in the past, those people who had very marginal sperm counts just could not procreate. Now they're able to, and that just allows marginal genes to remain in the population.

And marginal genes don't produce good sperm.

CHAKRABARTI: I'm going to come back to this in a second because thinking about the Y chromosome and the human race more broadly has happened before in the past, and I promise to come back to that. But Pille, first of all, actually, let me turn to you.

Because what Dr. Leslie is talking about is, is it plausible that we would, if we don't already know, we would determine where in the Y chromosome the genes for activating or deactivating spermatogenesis happen? And that perhaps we could, we could tweak those genes to keep them on even in the face of environmental assaults to the Y chromosome, Pille?

HALLAST: I guess it's not impossible, but it will be a long path and a lot of work. Especially if we want to use these kinds of therapies on human beings, it will definitely need a lot of work and a lot of time to make sure that we are not messing something else up while trying to solve one issue and then maybe we will cause 10 others.

CHAKRABARTI: Well, Richard, since Dr. Leslie mentioned your name quite often. Your response to his actually pointed and database concern about male fertility.

REEVES: First of all, I need to go, I've got eight medical tests that I need to go and schedule like, immediately. But more seriously this question about declining male fertility is an interesting one and it's sometimes wrapped up into this whole debate about the decline of men, do we need men, et cetera. But when I've looked at the evidence, and I want to ask Stephen this, I've always thought it's a bit overstated. Because even though there's been a big drop and you have dramatic numbers, like the ones you just shared, the truth is you just don't need that many.

And so, what is it, 66 million or something, but you just don't need that many. And so there's still, there's no reason to panic. And there's also no reason to assume the line will keep going down. And so I've come away from that evidence much less concerned than you sound. And so what do you make of the argument that actually, sure, that we've got many fewer, but we've still got millions more than we need.

LESLIE: That's true. In theory, yes, but in theory, you only really need one, assuming that sperm is really healthy and chooses the right fallopian tube to use. In practice, what we find is anything less than 20 million per ML is really iffy. So as long as we're above that kind of red line threshold, we're probably okay.

But since we don't know for sure what the cause is, and we're no further along in correcting it, I have no reason to think that the trend will not continue. And the factors I mentioned, pollution, pesticide, chemical exposure. Maintaining a population pool of poor and poorer genes overall, paradoxically, through better medical care.

I don't see anything changing that, and therefore, I'm not quite as optimistic as you are. I'm a little concerned that we need to pay attention to this.

REEVES: So the precautionary principle would suggest better to act now and get ahead of what could potentially be a very bad outcome, i.e. the end of the human race, rather than say, "We're fine for now."

You would say, look, "Let's try and get ahead of it, figure out what's going on before we get close to that threshold."

LESLIE: I don't see anyone arguing in favor of obesity and smoking and poor health and more and more pollution or pesticides. We should do a better job in taking care of it now. And what I see happening is that little by little, fewer and fewer men will have sufficient normal sperm counts with enough healthy sperm to have reasonable or normal fertility.

And more and more males in the population will either need assisted reproductive techniques or just give up and not have children at all. It's going to happen little by little and incrementally, I think.

CHAKRABARTI: It does sound, though, that Dr. Leslie you're seeing finally the full sequencing of the Y chromosome as the first significant step that could potentially lead to a breakthrough in answering some of these questions about male fertility.

LESLIE: Absolutely, we already know about these environmental factors and the other things I mentioned. Now that we know what the gene sequence is in the Y chromosome, we also know that since it's passed down from father to son and father to son and so on, that it does undergo relatively few mutations.

If we can figure out how to stabilize or make it more stable, perhaps it can work. Slow the decline in the sperm count, or maybe even reverse it. We know how to turn on specific areas in genes and turn them off. Promote or stop enzymes. We're just at the beginning of that. And I'm hopeful that sometime in the future we'll be able to fix borderline spermatogenic problems.

If we can fix the Y chromosome, the issue that is causing it.

CHAKRABARTI: Dr. Stephen Leslie, Associate Professor of Urology at the Creighton University School of Medicine with us from Omaha. Thank you so much for joining us today.

LESLIE: Oh, you're quite welcome.

CHAKRABARTI: And Pille Hallast, Research Scientist at the Jackson Laboratory for Genomic Medicine who studied the full genome of 43 different Y chromosomes from across the world.

Pille, thank you so much for your research and for joining us today.

HALLAST: Thank you so much for having me.

CHAKRABARTI: Okay, Richard, I actually wanted to spend the last few minutes of the show with you. Because we could, of course, have spent the entire time talking about the genomic reality now in terms of better understanding the Y chromosome and the scientific future.

But I think we need to get back to what you were saying earlier about the question of biology and environment and how those things actually work together. To produce this thing called masculinity at various ages that we're still trying, that we should care more about and think more clearly about. Because I do, as much as I love science, I practice a little bit of caution and being a genetic determinist.

Because in the past, we've looked to the Y chromosome as being, even before we came anywhere close to sequencing it, a century ago people were talking about super males, if they had two Y chromosomes, that might have led them to be more violent, for example, there was no proof to that whatsoever.

So do you worry that there may be some, maybe not in the scientific community, but those of us outside of it who are trying to interpret the findings? A yearning to say we can understand these aspects of masculinity because of what we find on the Y.

REEVES: Yeah, I think there's a real human need to try and find the answer to various things and just explain it.

And if there are science, science-y words. That you can use. And I think it's true for genetics. And I mentioned earlier the hunt for the so-called gay gene, but it's also true of things like hormones. So testosterone androgens are triggered by the chromosome. When it, what does that mean?

And clearly that has an effect on behavior, but it's also clear that culture and environment interacts with those differences in biology in ways that make culture more important. Understanding biology, even understanding something like the role of hormones doesn't make culture less important, it makes it more important.

For example, if, as a result of the testosterone and androgen production that comes from the Y chromosome, men are, have more potential for physical aggression, which is true, that doesn't mean that men are physically aggressive. Look at what's happened in the last few decades. Look at one country compared to another country, right?

The levels of male aggression vary significantly. And so actually the thing is that if you're like a more of a men's rights person and you're looking for a genetic explanation for like male superiority. The more we learn about the Y chromosome the weaker that argument gets. Right? It's not the super chromosome, it's, if anything, a little bit of a weakling chromosome.

And that can be used on the other side to be eye rollingly dismissive of men. And the truth is that we're just all a little bit sometimes entranced by the possibility of a biological explanation. And whilst I think it's a mistake not to understand the biological roots of human behavior, it is also a mistake to overweigh it.

To think that's the allele for whatever, when it comes to things like behavior. So the difference between maleness, as a biological condition and what that means for say testicular cancer or fertility or some of the things that we heard, that's important. But masculinity is and always has been much more of a social construction, much more of a cultural construction varying over time and place.

And it's super interesting to me, actually, that there's a lot, there's more variation on the Y than on the X. I thought, wasn't that interesting?

CHAKRABARTI: Totally fascinating. REEVES: No one really knows why. But look by way of analogy, rather than causality, I would say in a way, that's a hopeful finding. Because what it suggests is that maybe there's also lots of variability in masculinity and that it's not fixed either in time or place or fixed in some way deep, deep within our DNA without denying the fact that there are some differences.

So I love this way of talking about it, the way you've just been talking about it for the last hour or so, which is, look, biology matters, understanding matters, health matters for everybody, men and women, but also when it comes to the social questions, of women and men and how we behave and who should be president and who can be nurses. We're not going to find that on a DNA map.

CHAKRABARTI: Yeah. So not overweighting the importance of genetics is critical here, but I'd also say not underweighting it is important. Because I read so many chapters of your book put together, the research that shows that, for example, in early education, when you came on the show, we talked about this a lot, that there is on average.

There'll always be outliers on either side of a curve, but on average, boys in K through 5 they learn at different rates and different subjects than the girls do. And so maybe, you've advocated like taking another look at what's expected of kids in early education, especially of boys, or maybe changing the thinking around how to best educate boys.

When you have that kind of on average difference, it can't exclusively be environment, right? I still think we have to understand the genetic part played here.

REEVES: I agree. And the understandable fear of looking at biology, looking at these differences in biology that are related to behavior, is that it will be used in some way to discriminate against a certain group.

And of course, historically against women. And so actually we've had this understandable fear that we're going to, in some way, treat females like defective males. And it took quite a long time to make sure that women were even included in clinical trials of drugs. But I think it's equally important that we don't make the opposite mistake of saying men are defective females.

And what's different about? So what we want is a way of thinking about this from every level, from the very biological roots of our existence, DNA, up to what's happening in society, which is cognizant of these on average differences without being trapped by them, they can become traps and they can become excuses for discrimination.

And so I think for a lot of people, they're understandably wary of anything that explains anything by biology. Because of how it's been used historically. But we're not there anymore, and it's very important that we're able to have a good faith conversation about the actual evidence. And not treat, just because boys are different to girls, say, at the age of five, or men have some differences to women at the age of 50, and we've just heard a lot about those.

It doesn't mean one's better than the other, it just means we are different. And can we be, can we have equality without androgyny? That's the test I think in front of us and this science should help us in that course.

CHAKRABARTI: Yeah, I will say also that it is quite exciting to see if, as research progresses, we do find why associated reasons for you know that the health differences that we were talking about, that men do face, especially in later age.