welcome to the science for the public lecture series science for the public is an organization committed to bringing science information and issues to the general public visit our website for our program evening i mean von stap and i welcome you to contemporary science issues in innovations tonight we welcome one of the great scientists of our time dr david paige director of the whitehead institute for biomedical research at four while working in the mit lab of a leader in the human genome project he subsequently joined the white head institute and i t faculty in one nine hundred eighty eight dr page's lab achieved early distinction by mapping the y chromosome in one thousand nine hundred ninety two and then publishing the complete sequence of the y chromosome in two thousand and three with the collaboration of washington university genome se and center in two thousand and five he was appointed director of the white head institute dr paige founded the white head task force on genetics and public policy and he serves as coeditor an associate editor respectively of the two major journals in the field of genetics he's a member of the national academy of sciences and also the institute of medicine dr pages received a long list of distinguished awards several of which we've listed on the science for the public website for this event but we recommend also that you visit the white head website to see more details of dr page's outstanding contributions to genetic science tonight dr paige will focus on several points about the y chromosome first it's evolution and second why it's diminutive size and the concern among experts for a long time that male miss would disappear and third the relationship between the sex chromosomes and some diseases and conditions that disproportionately affect either males or females it is a very great honor and pleasure to welcome dr david cage welcome sir thank you very much and i'd like to start with the evolution of the y chromosome where did it come from the x in the y chromosomes are usually thought of this completely separate but it turns out that three hundred million years ago when we were reptiles believe it or not we are our x and y chromosomes had their beginnings as a perfectly identical pair and so in fact what live on today on us is the x and y chromosomes where once upon a time exactly the same of a member there were they were members of a an when we had no x and y chromosomes three hundred million years ago our ancestry is i'm referring to sex our sex was probably determined by the temperature which we as an egg incubated like this is really yeah ok so but what happened then so so at that time whether we developed as a male or female was determined by an environmental cue almost you could say in software but we ha was to move sex determination into hardware and a mutation a rose on what had been a perfectly ordinary chromosome to begin to turn it into and so this chromosome now took on a sex determining role a male determining role that it hadn't had before are that that was the beginning of what has been a two hundred or three hundred million year saga a journey of this ordinary unsuspectingly here of chromosomes to become today's x and y along the way to sort of cut to the chase it looks like the x chromosome retained most of the there anything peculiar in that split once you had sexual reproduction this sort of thing so you lost some genes in there was there anything else in there we should know about good by male chromosome the males made sperm the females make made eggs we were reproducing sexually and so it turns out and i think people often get this point very confused yes that it turns out the sex chromosomes were a late addition  evolutionary terms to a perfectly functioning system of sex determination of sexual reproduction it is never taught this way today in the textbooks the textbook always begins with lee explain why madonna but it's important to understand that in reproduce clone only then everybody can have offspring if you have males and females will it's only the females that actually give birth the males are just coming along as a source of a little bit of genetic variability that'll maybe some trouble  the way it makes life much more complicated but no seriously people think that it is the that what males are sexual reproduction adds to the picture is it creates an opportunity to sort of mix and match over the generations and we often think of this is being a source of evolutionary progress but it also turns out it allows it allows organisms to not fall behind so it turns out that during the course of you know as genes are passed down through the generations they often sustain little damaging mutations ok and with sexual reproduction it is possible to swap out or purge a damaged copy of the gene and senshi replace it with a good copy and in fact it is this this problem of the need to purge genes of mildly dilla tyria this bits of damage to them it was the inability of the y chromosome as it began to part ways with the x chromosome that led to the demise of so many of it's so in fact the y chromosome despite it's being called a sex chromosome is actually transmitted with out in a sexual or clone crash so my wife chromosomes from my father from his father his father his father his unlike any of our other chromosomes which are sort of a mishmash the mix of four grandparents yeah eight grade eight grade great grandparents and so on the whole tribe thought oh that's right go all the way back yeah and so it was actually the why i chromosomes going it alone issues was why did that happen and where did those genes go and you were majors well or so what have you learned of that short ok so we had a lot of fun reconstructing how did this how did these two hundred three hundred million years play everybody has an x chromosome males have an x females have two x s since everybody has an x chromosome it meant that everyone had at least one good copy jane ok so it sort of took the pressure off specialties it actually not only last year but especially during the last thirty or forty years of primate evolution the y chromosome has actually gotten in the business of in poor importing new genes to it sure and these have actually helped drive the y chromosome in our species and other primates towards a very strongly specialized role in sperm production i  l fertility today depends to a very significant degree on genes on the y chromosome many of which have been acquired by the y chromosome during the last thirty forty million years of evolution that's rather rapid isn't it i you know and this was and this actually flew in the face there had been a lot of ideas saying oh my gosh if the y chromosome has gone its own way this this helps us not only understand that the war that the y chromosome is going to lose genes that helps us understand the loss of genes but there had been it came as a complete surprise to us and the scientific community that despite this going it alone has that the y chromosome was in occasional communication with other chromosomes and grab and occasionally they're actually acquiring of imperial or young bright but in the i think in the scientific community where you know well respected scientists were concerned about this diminished thing which they assume was happening like every other week or something yeah rather it but you said no it happened much earlier well how did that come about yeah yeah so there's been for decades now there's been a debate about the the the past y chromosome and predict and and also predictions of its future and so i've often said i thought i'd spent the better part of my career defending the honor of the white in the face of many insults to its character but especially to its future prospects and so so the question was yes the y chromosome has lost so many genes that it once shared with the x chromosome but what if but could we actually reconstruct the trajectory of the laws and so about about ten years ago or twelve years ago it was actually editorialized in the pages of  the given that the chromosome had only had been around for maybe two hundred three hundred million years this was a fairly short order short period of time doing our job to try and that that model was based on the found in recent years by comparing the y chromosome of the human with the y chromosome especially of the chimpanzee and our rhesus monkey so we're separated from chimps by seven million years by the route from the rhesus monkey of about twenty five million years by studying those and more recently some additional now yes we've been able to reconstruct the jack terry did that that trajectory of gene loss on the y chromosome and what we found is that most of the gene  out yeah it has been sailing along pretty happily with a small but stable set of genes for actually on the order of about one hundred million years and but it sounds as though because it was so much on the x that it didn't need so prediction of the wise imminent demise was that the genes the loss of genes from the y chromosome had been sort of a willy nilly random exercise but what we've come to understand very recently is that the shared with the x chromosome we think there's a small set of genes for which it's quite important to the to the individual to have t very small set maybe as few as a dozen genes that are shared between the egg there are why we're having two copies is critically important that is amazing it seems really that those were smart  part but the other thing there is that could you even have figured this out like even twenty years ago or maybe sabella was modern sequencing or did that give you the ability to see this well so great great question so the the only reason we've come to understand the y chromosome at all or is through the age of the error of genome x and the era of gene and geno genetics all the things that mendel taught us and that anybody who ever takes a genetics course learns those things apply to genes and chromosomes that come in pairs one from mom one from  i chromosome doesn't follow those rules so it could never be understood through the standard tools and ways of thinking of genetics so it absolutely had to wait until genomes d sequencing came along and even as the era of genome sequencing opened up we and we've you know it's about twelve years ago we started to get a handle on the sequence of the human y chromosome we thought when we had the sequence of the human y comes who are so excited that this is telling us so much but then it's more recently when we've added been able to add the sequence of the y chromosome of other primates  and x chromosomes with the y and x chromosomes of our sister brother species right yeah let me get this clear then so what you see and now you can you can  of verify it is that this loss curt at least across mammals very early so it's the same thing that why did the same thing it didn't bird as an as an outgroup to mammals yeah so it turns out that again all of these mammals and many many more share to a first approximation they share our yeah but in some cases we've been split from some of these other mammals for eighty ninety one hundred million years so they're there x and y chromosomes and specialized away from ours a bit but it's all one establishing the reference sequence of a y chromosome is particularly difficult because as we found we didn't know this before we got deeply into it it turns out that y chromosomes carry massive mirror images of their own sequence so for instance the human y chromosome carries eight very large palindromes oh for million letters and then another copy flipped around in the opposite direction and the stan methods of sequencing which involve taking our d n a and chopping it up into little bits sequencing all these little bits  is that it has required a much more painstaking approach and a much more sort of deliberate and maybe compulsive i should say approach to actually and this helps explain why i actually bite bite today we know that we have a rough cut sequence of the of the genomes of many dozens of mammals but we today have the pace you know at least that we understand why this is such a challenge and i was thinking that it was because recently the whole mess was a challenge but then there was some extra difficulty are around the why there is well there were there were a couple to sequence than the other chromosomes but then there was another for a variety of well for a variety of reasons when genomes were beings when the genomes of new organisms were being sequenced the of the rationale was well let's just do the female because we don't really want the why and it won't really add that much anyway and i'm not making this up and but there was another reason which was that the methods for sequencing the were designed to with with the realization that for most of the chromosomes in our genomes there would be two copies in the mix yeah yeah and so there was a statistical sampling method that was put in place that said i'm going to ask that you have two copies of the chromosome i will fold them in as if they were together as it were at one hand i will call that the reference sequence and so the decision was taken amazed that it took a long time to get past some of these obstacles that are also the thinking and i would say that these mental obstacles are actually still there and it's why i say it's all in vogue but it just changed very quickly but it's a wonderful story a wonderful story of science a correction mechanism that people go along for a number of reasons with certain assumptions and when you're completely wrong you have very prestigious journals you know telling you what's right one day and that's wrong you had had a good time with it well it's been you know that it's i felt really privileged to travel with and then but the chance you know yeah yeah yeah i mean there were you know i've been traveling with the y chromosome for i don't know thirty thirty five years now and it's a lot of fun to look back at what did people say about the y chromosome thirty years ago right and it wasn't it wasn't very favorable even with recently it was that or so it's actually very interest i think if we take the clock back two or three decades it was generally assumed that there was one function of the y chromosome maybe one gene that was involved in in directing the has come to light in recent decades is this incredible specialization of the white cross well i should say first of all that that original surmise is correct there is in fact recently is a set of a dozen genes that are that are shared with the x chromosome that are actually expressed that appear to be active you know all the tissues and then all types of the body and that have no obvious connection to sex differentiation is classically taught in medical schools and still in medical skills yeah y and that is really do i hope you don't have the big battle there but yeah i believe that that has that been the source of your interest in these male female you know it's actually almost the rule not the exception that even for diseases outside the reproductive tract so let me back to that day that you know obviously things like prostate cancer yeah that affects m but then there are many diseases outside the reproductive tract that affect two shoes in organs that are common to men and women many diseases that are occurring much more frequently or more severely yet in males immune disorders yeah and think about them as a group and what i'm suggesting we now need to take this whole sweep right of disorders and diseases that show strong sex or gender bias in inciden or severe o t and we need to begin to disentangle the underlying causes by his biases right and so i think there are many we don't have and we have very few if any answers today right but you're asking the question it sounds like that's the important thing because it's for the first time that something that you're out there saying why you know so i would say the prevailing view when i talk to my  high but we begin to wonder whether some of these genes that are shared between the x and y chromosomes whose significance was not appreciated until very recently where and i mean this year oh wow and we recognize that these x y gene pairs are actually expressed throughout the body yes so we begin to say oh my gosh it could be that the that even the cells of our skin your toes areas of our gut some level they may know whether they're x y or x x and could that and perhaps that contributes to these very different predispositions on the part of males and females to a wide variety of diseases outside the reproductive will let me ask maybe it's still very new but this is another thing to do you see this in other species as well even in our ape relatives do would you see this difference between male and female diseases that such a thing exists or is it just us i think we you know i think the it may well exist i wouldn't start that i know by surprised if it doesn't it certainly exists in it certainly exists in ice  argument that no we need to be looking at this genetic thing that at these chromosomes are playing a very large role because it from the public view we hear hormones all the time and this is one of the questions basic fundamental research done in that space that i can't so it's almost i think actually our public storytelling and i have a c s is actually it has foundation in the scientific literature yeah but the scientific literature in that in that space is so meager needs so much more research in that arena and it is a it is it the whole question of the underground disruptors and such is it presents questions of the will direct scientific complexity yet because of the number of chemicals there as a species have introduced into our environment right and probing how each of those many many chemicals might disrupt our our systems is far beyond the capacity of the very limited  corner of the scientific enterprise that's devoted to those questions at present what is striking though is how fragile our capacity and the capacity of of our species capacity  and of other species capacity for sexual reproduction is to environmental destruction or what i'm saying is that there's something about sex the mechanisms of sexual reproduction that make them than we do and i think we're just again beginning to scratch the surface of those questions and how this all works and of course with an eye towards what can we do about well that's true but also then the question going back to these why so many diseases outside the reproductive tract with a strong male or female and that's where you're add so that's one whole set of rides another set of questions is what is happening in our environment that is  disrupting the sexual reproduction of so many species and in many cases we actually look to other species actually even including alligators yes temperature deprive the disruption of sexual reproduction in these many species is sort of serving as the canary in the environment to raise our own concerns but what i'm saying is these two storm systems sex bias and disease and environmental disruption of sex reproduction diseases so we're in that we're we're barely out of the starting block ok so but beginning we're trying to figure out actually how to approach these questions  so we need new tools we need new ways of thinking and one of what i'll say one of the ways we're beginning to think about simply catalogue the molecular i ask this then is that when you were working on the why you really i think were a pioneer out there sort of on your own you didn't have an army of people saying yes this is right in fact there were detractors but now with this it was something that's been just ignored really i guess if you're in terms of do you is it is difficult to convince people  that we need to look at this chromosomal factor i have heard of these disparities and i see really only been talking with colleagues in medicine and our science about this within the last year lot really is new it is very new yeah but i would say the reception has been exhilarating oh wonderful i mean people were excited for this idea and i think actually the time is right to to get serious yes about trying to understand and actually trying to understand these sex biases and it's worth recognizing it's you against the backdrop of now in this era of sequence of someone's geno together with other information about diseases which they might be at particular risk and out which we might guess something in a preventative sense for instance but i would argue that actually the way we been we've had a unisex model of personalized medicine and that will have changed and i think that absolutely has to change yeah when in fact the single greatest identifiable risk factor for many diseases is are you a male or are you a female we could actually acknowledge there and take that into our thinking and and see what we can make of it right you know so there may actually for some of these diseases the disease in males and the disease in females may in some sense be different disorders oh that is even if we give them the say yes exactly how interesting what she would uncover as a result of this because it just sounds like a whole new direction it does come at an opportune time when there is this sense of we need to personalized medicine and it's within our capacity certainly in the in the future but what an exciting prospect this time i'm glad we got to meet you before you get t theme among these twelve genes they look to be global regulators of gene activity ok so they include chromosome modifiers transcription factors translation factors so these are what it really blew our minds when we began to see this sort of commonality among them so it looks like they you know i would i think we describe them as global regulators of gene activity ok and it turns out that actually the x member of many of these x y pairs  in some cases the the x side of the pair is already being input has already been implicated in some in some diseases so it's the why side hasn't been looked at so much but these what i'm saying is these twelve x y gene pairs are very very from a from a modern biologist point of view these are very sexy pairs they're really they have a lot of name recognition already xchange already have name recognition already have developing literatures and so it's very exciting for us because in some cases some of these x y gene pairs we had discovered that long ago  seventeen years ago but in the ensuing seventeen years the cell biologist and the biochemist have been hard at work telling us what these what these gene peers do what that what the products of these  peers do and so when we come back and put it all together and look at it now it's these are very exciting pair of jeans you get it and then i think this actually contributes to the enthusiasm of the you know it's actually so surprising i finally have something which meets with an almost immediately enthusiastic response and people i think you know and it's actually very gratifying  because in the for so many years the view was that this research into the white chromosome it has you know it's of some you know it's sort of curious but it's and you start saying oh you mean all of medicine might be the playground now for thinking about this it completely changes the way completely changes the way people think about and receive the information  is now looking at precisely that question so so the interesting thing is now if we think about these twelve x y gene pairs the question becomes are the products of these genes identical  function do they function equivalently but maybe even if they even if they function equivalently maybe they're not expressed in quite the same way and so so we're very interested in the possibility that that evolution has yielded has resulted in slightly different regulations of the x and y flavors of these these genes really great question you know it's right at the let me make sure i understand so you're saying if in some cases an old aeration in the sequence of these genes causes a disease then were you asking how should we correct  how should we correct well ok so you know i think there is a lot of excitement in just the last year or two around new genome editing  s no actually actually d n a so some methods for actually changing the spelling or maybe correcting the spelling now this these methods have in the few just in the last two or three years actually in the last year or two become the rage all the rage in modern biology they've been they've been incorporated into many many experiments people are just beginning to think about and just beginning to apply these to the possibility of correcting the facts responsible for human to seize but i think we're going to be hearing a lot lot more in the near future about actually correcting spelling errors