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0:47

For

0:47

decades, scientists have been

0:50

attempting to read the human genome,

0:52

what makes each of us us in

0:55

its entirety. But

0:57

there's been one mysterious piece

0:59

that has stumped

1:00

them, until now. The

1:04

Y

1:04

chromosome, one of the two

1:06

sex chromosomes, has finally

1:08

been fully sequenced. So

1:11

today we're diving deep into

1:14

the fascinating story of

1:16

the Y chromosome to find

1:18

out about its role in the body, what

1:20

we know about how it influences everything

1:22

from male development, health and fertility,

1:25

all the way to forensics. And

1:27

why some scientists think one day

1:29

it could disappear altogether.

1:34

From The Guardian, I'm Madeline Finlay, and

1:37

this is Science Weekly. Mark

1:44

Jobling, you're Professor of Genetics at

1:46

the University of Leicester. And

1:48

so tell me what you make of these new

1:50

studies finally fully sequencing

1:53

the Y chromosome. How much

1:55

of a step forward is this?

1:56

Well, I think what they've done is something

1:59

that people thought for a long time. time was impossible,

2:01

which is to determine the DNA

2:03

sequence of this very

2:05

difficult little chromosome. So

2:08

the Y chromosome is small, but it's

2:10

full of very weird and difficult,

2:12

knotty bits of DNA that have really

2:15

resisted sequencing for a long time. So

2:18

both of these studies have used really new

2:20

technologies to tackle that problem.

2:24

And although it's a great achievement,

2:26

they don't actually tell us a huge

2:28

amount that's totally new. We had the picture before,

2:30

it was just kind of out of focus. So

2:33

if you like what these have done is it's

2:35

a bit like turning on high definition TV

2:37

and that you can suddenly see absolutely

2:40

everything in its gory details.

2:43

Now, before we get into why that

2:45

has been so difficult and more about

2:47

the Y chromosome itself, perhaps you can

2:49

go over some basics for me. What

2:52

are chromosomes exactly? What do they do?

2:55

Chromosomes are bits of DNA.

2:58

So our DNA is what

3:00

determines many of our features

3:03

and determines the proteins that are

3:05

made in cells and so forth and it's

3:07

information. And our genome

3:09

is about 3,200 million

3:12

DNA letters in length and those

3:14

are G, A, T and C.

3:16

So 3,200 million DNA

3:19

letters, but not in one long

3:21

string, but broken up into

3:24

chromosomes. And these are the packages into

3:26

which genomes are divided. So we've

3:28

actually got two genomes, one from my mum,

3:31

one from my dad. So we have two times 3,200

3:33

million DNA letters and the number of chromosomes

3:37

we have in each genome

3:39

is 23. So considering mum and dad's genome,

3:42

each of us has 46 chromosomes.

3:44

So your chromosomes are like the

3:46

volumes of an encyclopedia.

3:48

They make the whole process of dealing

3:51

with DNA cell division more manageable.

3:54

And so you've got the sex chromosomes,

3:56

the Y and the X and you've said

3:58

the Y is a little weird. it short.

4:00

So give me a picture of this chromosome.

4:03

How does it compare to the X in

4:05

terms of its structure?

4:07

Okay, so the X and the

4:10

Y we find in males because the Y

4:12

determines maleness, whereas females

4:14

have two X chromosomes. If

4:17

you look at the X chromosome, you find a chromosome

4:19

that looks very much like the other 22 chromosomes

4:22

in the genome. It's got about

4:24

a thousand genes on it. It's

4:27

about 150 million DNA

4:30

letters in length. And then

4:32

if you compare it to the Y, you've got a very

4:34

different beast. It's much smaller.

4:37

The length varies a lot between about 45 and 85

4:39

million DNA

4:42

letters in length. It hardly

4:44

contains any genes at all, probably

4:46

fewer than 100. So it's a bit of a gene

4:48

desert. And if you imagine

4:50

it as say a novel, and most chromosomes

4:54

make kind of sense, they start at the

4:56

beginning and they come to the end.

4:58

And some words crop up here and there

5:00

again, because that's the way language works.

5:02

And that's the same with DNA. But if you

5:04

look at the Y, it's full

5:07

of gobbledygook. So it's full of sections

5:09

in which the same word is repeated

5:11

hundreds or thousands of times, or even

5:13

the same paragraph is repeated hundreds or thousands

5:16

of times. And then even worse than that, it's

5:18

full of bits where an entire

5:20

chapter is repeated, but backwards.

5:23

So it's like a mirror image of itself

5:26

within the DNA sequence.

5:27

Anna, all those features, why

5:29

it's taken so long to get

5:32

to this point where we're able to fully sequence

5:34

the Y chromosome?

5:35

Yes, they are. And when you

5:37

come to sequence large pieces of DNA like

5:39

whole chromosomes, and when you have these

5:41

repeated sequences, then

5:44

that really makes it difficult to

5:46

put the sequence back together. So it's a

5:48

bit like doing a jigsaw puzzle where you've got

5:50

the same pieces, many, many

5:53

times and putting them back together is very

5:55

hard. The other thing that makes it hard

5:57

is because actually, although the X and the Y are the same, they're the same. So they're the same.

6:00

look very different today, they evolved

6:02

from the same pair of chromosomes. So

6:04

about 180 million years ago, these

6:06

were a pair of regular chromosomes. One

6:09

of them started to become the sex-determining

6:11

chromosome, the determinate maleness, and

6:13

then it subsequently underwent process

6:16

of degeneration. So the X chromosome

6:18

has remained as it was, whereas

6:20

the Y chromosome has lost

6:22

a lot of genes, accumulated these

6:24

weird bits that make it hard to sequence,

6:27

but also maintain some similarities

6:29

to the X. And so you need also to be

6:32

able to work out which bits of it are

6:34

on the Y and which are on the X, and then get

6:36

over this horrible repeat sequence structure

6:39

inside it. It makes it extremely

6:41

challenging.

6:43

Given

6:50

how strange and

6:53

unusual the Y chromosome

6:55

is, what's its role in

6:58

the body? What does it do? Because it

7:00

is a very important chromosome.

7:02

It is, yeah, and the main thing it does under

7:05

normal circumstances is give

7:08

rise to maleness. And it does that

7:10

through just one little gene, which

7:12

is called SRY. That

7:14

has the job of triggering the

7:16

development of a testis early

7:19

in development. So when you're developing

7:21

in the uterus, you have

7:23

a structure which can either become a

7:25

testis or an ovary, and it just hasn't

7:27

made its mind up yet. And if there's

7:29

a Y chromosome there, then it

7:32

triggers

7:32

via the action of this little gene, triggers

7:35

differentiation into a testis.

7:37

And if there isn't a Y chromosome, then

7:40

an ovary develops. So femaleness is the default

7:43

option in mammals. So

7:46

what happens next is that once you've got a testis,

7:49

then it produces androgens,

7:52

male hormones, and it's those that

7:54

give rise to the other features of maleness.

7:57

So it's only contained, the Y chromosome only

7:59

contains the trigger.

7:59

for the process. It doesn't contain

8:02

all the other genes you need for the rest

8:04

of the process.

8:05

And so determining your sex

8:08

is either whether you have XX or

8:10

XY, but are there other

8:12

iterations of this? Is it possible to have,

8:15

say, only one X or multiple

8:17

Ys? And in those instances,

8:20

can we learn anything about what the Y

8:22

chromosome does?

8:23

Yes, there are lots of those

8:26

examples. So one thing is that

8:29

you can find women in the

8:31

population who have an X and a Y

8:33

chromosome. And often,

8:36

if you look at that Y chromosome, there's nothing

8:38

wrong with it. When they're born, they appear to be females,

8:40

and they may have issues,

8:43

puberty and so forth, which lead them to be

8:45

undergo medical testing. And

8:48

one of the reasons for that is that there's

8:51

another gene in the genome actually on the X chromosome,

8:53

which is the receptor for testosterone.

8:57

So in those individuals, they have a testis,

9:00

because they've got a Y chromosome,

9:01

and they make male

9:03

hormones, but they don't have the

9:06

receiver for those male hormones. So the cells

9:08

can't see the hormones. It's called androgen

9:10

insensitivity syndrome. And

9:12

in fact, Joan of Arc was rumored to have had

9:14

that, but I think the evidence is very slim

9:17

on that front. So there's

9:19

that kind of thing that happens. You can have

9:22

a Y chromosome, but not

9:24

be male in some cases. And

9:27

then you can also lack a Y chromosome

9:29

and still be male. And that's due to

9:31

mutations in other genes in

9:33

the pathway of sexual development.

9:36

And then there are also examples where some males

9:38

have two Y chromosomes instead of one.

9:41

And there has been in the past, the

9:44

idea that that led to increased aggressiveness

9:47

and criminality, but that's now being

9:49

debunked. What it does lead to is

9:51

increased stature. So those males are significantly

9:54

taller than other males who have just

9:56

one Y chromosome.

9:58

And you mentioned this. shared

10:00

evolutionary history between the X

10:03

and the Y. So the

10:05

X and the Y chromosomes

10:07

had this same starting point

10:10

and yet the Y developed so differently

10:13

and as you said it degraded. Do we

10:15

know why that is in simple terms?

10:18

It didn't need, if you like, a lot

10:20

of the genes that it already had. So

10:22

each X has a thousand genes on it

10:24

and you might therefore expect that the

10:27

X chromosomes in females

10:29

gave twice as much protein, twice

10:31

as much of the product of those genes

10:34

as in males who only have one X chromosome. But

10:36

in fact in females what happens is a process called

10:39

X inactivation where one of the X

10:41

chromosomes is inactivated. So

10:44

then males and females are now equivalent.

10:47

A male has one X, the female

10:49

has two X's but one is switched off and

10:51

so they're balanced and therefore

10:54

the Y chromosome doesn't really need a whole

10:56

bunch of other genes and just over

10:58

time through rearrangements and being chopped

11:01

up and put back together again it

11:04

has lost a lot of the genes that it didn't

11:06

need. So one idea

11:08

has been that that process might continue

11:11

and we might get to a situation where there is

11:13

no Y chromosome anymore. That's

11:15

been discussed and I think one

11:18

thing that these recent studies show

11:21

is that that's not true because

11:23

if you look you find that there is a set of

11:25

genes on the Y chromosome that are conserved.

11:28

So that means those genes must be important.

11:30

So we're down to, if you like, the minimal

11:32

set and actually we don't know what quite

11:34

a lot of those genes do so that's a question

11:37

that needs to be answered.

11:38

And yet one place we do

11:40

know the Y chromosome can be lost

11:43

is actually within our own cells

11:45

as people with the Y chromosome age

11:48

it seems to

11:49

drop away although that might not be

11:52

quite the right term. So what's going

11:54

on there? Do we know why that

11:56

happens?

11:57

Well you're right it happens and we don't really

11:59

know.

11:59

Y, we know that there are some genetic

12:02

predispositions to losing the Y, but

12:05

if you look at white blood

12:07

cells of elderly males,

12:09

then what you see commonly is the cells

12:12

in which the Y chromosome has been lost. And

12:14

if you look at males who've lost the Y and compare

12:16

the ones who haven't, then

12:19

you can see that they

12:21

have a higher risk of disease of

12:23

all kinds and they have decreased survival

12:26

after hospital admission. You see over-representation

12:29

in cancer patients and

12:31

in males who have Alzheimer disease. And

12:34

you also see that people who smoke

12:36

or males who smoke have a higher risk

12:38

of losing their Y chromosome. So there are some environmental

12:41

factors that increase your risk of

12:43

that loss. It's an interesting aspect.

12:46

The Y chromosome is often regarded as dispensable

12:49

apart from the fact that it triggers

12:51

the testes development, but clearly that's not

12:53

true.

12:54

Men do have different health outcomes

12:57

to women and researchers

12:59

have looked at whether the Y chromosome

13:02

could be playing a role generally,

13:04

but where does the evidence actually stand

13:07

for that at the moment? Almost

13:08

all diseases have statistically

13:11

significant differences between male

13:13

and female incidence or the course

13:15

of disease or disease outcomes and

13:18

a lot of that isn't really understood.

13:21

So one possibility is that actually

13:23

it's the presence of the Y chromosome in males

13:25

that's making those differences happen. And

13:28

it's actually quite hard to get to the bottom of this

13:30

because you've got the Y chromosome there,

13:33

it has its set of genes,

13:35

we don't know quite what they do, so yeah sure some

13:37

of those could be causing issues

13:39

with males or giving rise to differences

13:42

between the sexes. The other big problem

13:44

is that the Y triggers the testes development

13:46

and then the testes makes hormones. And

13:49

so you've got a different hormonal environment,

13:51

you've got lots of other differences that have arisen

13:53

through the life course because of the presence

13:56

of testosterone

13:57

and deconvoluting the effect of

14:00

you know, the Y just being there, and

14:02

then the testis being there and all the hormones being

14:05

there has been a really hard problem.

14:13

Now

14:13

another reason we might want to

14:16

understand more about the Y chromosome is

14:18

because it can be really useful in

14:20

forensics. So tell

14:22

me about that.

14:23

Most criminals are males.

14:25

That's just the statistics. Most violent

14:28

criminals are males and the very, very

14:30

large proportion of sexual offenses

14:33

are committed by males. So that means

14:35

if those perpetrators are going to leave

14:37

behind DNA, they're going to leave behind a Y chromosome.

14:40

And particularly in sexual assault casework,

14:42

you've got often DNA mixtures with

14:45

a majority of female DNA

14:48

and a minority of male DNA. And

14:50

so if you use a DNA profiling,

14:52

forensic profiling method that targets the Y

14:55

chromosome, then you can actually pick up

14:57

a male specific profile

15:00

relatively easily. There are some other

15:02

more kind of arcane ways in

15:04

which it could be useful, which is males

15:06

get their surnames from their fathers as

15:09

well as their Y chromosomes. And

15:11

if you think about that going back through time,

15:13

if you collect a set of men

15:16

called, for example, Attenborough, then

15:18

if they all descend from some

15:21

medieval Attenborough, then

15:24

they should share a Y chromosome with each other.

15:27

And to a good approximation they do. So about 90%

15:29

of men called Attenborough who are

15:32

not relatives, as far as they know, they're not brothers

15:34

or uncle nephew or anything like that.

15:36

If you look at their Y chromosomes, they're all

15:38

the same. So if you have a Y

15:40

chromosome type,

15:42

you find it a crime scene, you can ask,

15:45

can you predict the surname of the individual

15:47

carries it? So if you had a good database, you'd be able

15:49

to do that. And it's not perfect,

15:51

but it does work to some degree. So

15:54

it's actually an interesting link between

15:56

DNA

15:57

and genetics and a kind of social.

16:00

people. So

16:05

Mark, we've got a picture

16:07

of the Y chromosome in HD

16:10

now. What do you think is left to

16:12

learn about it? What are some of the big questions

16:14

that researchers are still interested

16:16

in answering?

16:18

I think there's still a lot of work to do on what the

16:20

genes are doing and that includes the

16:22

spermatogenesis genes. We're still

16:24

not clear about how mutations in

16:26

those genes give rise to different

16:28

kinds of problems in making

16:30

sperm and whether any of those can

16:33

be treated or fixed using, say,

16:35

gene editing technology. I

16:37

think that

16:38

looking at the human Y chromosome in this

16:41

high definition provides

16:43

us with the optimism that we can do

16:45

the same in other organisms. So

16:48

mammals all have XY chromosome

16:51

sex determining systems. But then

16:53

there are other parts of the kingdom of life that do things

16:55

differently. So for example, in birds, they

16:58

have what are called ZW chromosomes.

17:01

So I think with these technologies, we'll be able to

17:03

learn a lot more about how those different

17:06

chromosomes arise and the common and different

17:08

features

17:08

in the structures

17:11

and sequences of chromosomes that come about because

17:13

of this weird role

17:16

in sex determination.

17:18

Well Mark, from an XX to an XY,

17:20

it's been absolutely fascinating. Thank

17:23

you so much.

17:24

Thanks. Thanks

17:26

again to Professor Mark Jobling. This

17:29

episode was produced by me, Madeline

17:31

Finley. The sound design was by Tony

17:33

Onachuku and the executive producer

17:35

is Ellie Burey. We'll be back on Tuesday.

17:38

See you then.

17:49

This is The Guardian.