Disappearance of the Y Chromosome

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Disappearance of the Y Chromosome

Dr. Bill Courtney Past Researcher, The Genome Institute at Washington University

Dr. Darren Griffin Professor of Genetics, University of Kent



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The Disappearing Y Chromosome: Are our (genetic) male bits disappearing?

Human Y chromosome

• Why do we… – Need men? – Have sex? – Have sexes? • What does our genome look like? – What is the difference between boys and girls? – The human Y chromosome and shrinkage • How did the Y come to shrink? • What is the argument all about? • The Jenny Graves Case – The Y is disappearing • The Jenn Hughes Case – In defense of the Y • Rebuttals and Conclusions

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Audience Question “Do you think the human Y chromosome will eventually disappear?” • Yes • No • Undecided • Yes, Good riddance


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Why do we need men? • Women – Do “all” the work from conception to delivery – Usually are responsible for weaning and early upbringing

• Women rarely – Participate in violent crime – Become tyrants – Start wars

• In animal breeding female: male ratios can be 100:1 – There is a distinct advantage to manipulate the sex ratio

• Wouldn’t the world be a better place without men? – If we could solve the reproduction issue

• Is there a genetic or evolutionary reason why we need all this “excess baggage?”

Why do we have sexual reproduction? • Short term losses – – – –

Costly Time consuming Expends energy But has many long term gains

• Reshuffles our genetic composition – Brings together advantageous genes – Increases likelihood of survival – Ability to cope with changing environment

• Accelerates evolution – Creates unique individuals – With a wider pool of ancestors

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But why do we have sexes? • Resource Allocation – More time and resources spent in producing one type of gamete instead of two – One small, mobile and numerous (sperm) – One large, nutrient-rich and rare (egg)

• Encourages outbreeding, avoids inbreeding – Which can only be healthy

• A 50:50 sex ratio avoids all sorts of issues

• •

– Mate competition – When the sex ratio gets skewed, it tends to “correct” itself So males are here to stay (in natural populations at least) But, ironically being male, tends to shrink our (genetic) “male bits” over evolutionary time


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This is what our genome looks like

All our DNA comes in pairs One from mum, one from dad.

x

x x x x

x x

x x

x

x

x

x x

x x

x

x x

x

x

x

x x

x

x

x

x

x x

x

x

All our DNA comes in pairs One from mum, one from dad

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x

x x x x

x x

x

x

x

x

x

x x

x x

x

x x

x

x

x

x x

x

x

x

x

x x

x

x

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How does this make us all different? • Either the left or the right hand of each pair (but not normally both) could find its way into the sperm or egg • Genetic exchange of DNA following crossing-over of chromosomes • “Random mating” • This is how we “do” evolution

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But what is the difference between boys and girls?

Spot the odd couple

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Spot the odd couple

The mere presence of a Y chromosome is the “mark of maleness”

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BUT The X chromosome is big (but not too big), functional, and gene-rich.

The Y chromosome is tiny, full of junk DNA and gene-poor.

Wimpy Y

Sexy X

Ohno (Oh no!)’s hypothesis: Males used to look like this:

But their (genetic) male bits shrunk over time

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Will the Y eventually disappear?

Y

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Degrees of Y Degradation turtles alligators

frogs many fish some deer

most mammals Inc. humans

kangaroos

spiny rats mole voles

X

Y

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How did the Y come to shrink in the first place? Identical sex chromosomes exchange genetic material Sex determining region

Suppression of genetic exchange around the sex determining region

Sex determining region

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Mutations

Mutations Sex determining region

Mutations

Mutations

Absence of “mutual support mechanism” causes mutations on both chromosomes They start to differentiate


One of the chromosomes (in mammals it’s the “Y”) starts to lose genetic material

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X

Y

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One of the chromosomes (in mammals it’s the “Y”) starts to accumulate “Junk DNA”

Further reduction in genetic exchange

X

Y

Mutations

Mutations


Mutations

Mutations

X

Y

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It’s a vicious circle!

Sex determining region • • •

More structural differentiation of chromosomes

X

More loss of DNA More accumulation of “junk” More reduction of genetic exchange

Y


• • •


More differentiation

X

Y

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• • •



X

Y


• • •



X

Y

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X

Y

Remaining region of genetic exchange


Great pile of junk

Regions of similarity

X

Y

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What is the argument all about? • There is a “debate” in the genome evolution community about whether the mammalian (including the human) Y chromosome will eventually disappear (and when) – Some would call it an argument

• The press like to extrapolate that to ask “will males eventually disappear” – Sorry, but the answer to that one is almost certainly “no” – No-one in the scientific community is seriously suggesting that males will disappear

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Debate • 18th International Chromosome Conference, • Manchester August 31st 2011 • Jenny Marshall-Graves – LaTrobe University, Melbourne, Australia

• Jennifer Hughes – Howard Hughes Medical Institute, Cambridge, Massachusetts, USA

The Basis of the Argument • Clearly the Y is a “degraded X” but

• Has it – Reached the point of equilibrium such that it can go no further? or – Got to the cliff edge, clinging on by its fingernails, about to fall at any moment?

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Linear Model? # genes left (MY)

1600

45 0

-166

Time (MY)

0

“Y Forever” Model

# genes left (MY)

1600

Y forever!!!!? 0

-166

Time (MY)

0

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Sudden Collapse Model

# genes left (MY)

1600

0

-166

Time (MY)

0

Extinction next week

“Skin of Teeth” Model

# genes left (MY)

1600

0

-166

Time (MY)

0

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The Jenny Graves case: the Y is disappearing

Wimpy Y Sexy X

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Genes on the Y Chromosome

Genes that survive on the Y Most Y genes have similar versions on the X 18 identical genes

SOX3 Mental retardation

SRY(sex determining region Y) Sex determination

RBMY

Similar genes

Sperm development

RBMX

TSPY

Mental retardation

Y

Sperm development

TSPX

Many functions

X

Brains genes (1700 in total)

Testis functions Balls genes (27 in total)

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When did it all happen? Reptiles and birds

Temperature Some sex chromosomes (ZW)

Platypus

Marsupials Humans

XYXYXYXYXY

Amphibians

XY

XY

SRY

148 166 Mammals

Fish 310

410

Million years ago

450

When will the human Y disappear?

166 Million years ago – the Y had ~1669 genes Today – the Y has 45 genes Genes lost per Million years = About 10 At this rate Y will disappear in 4.6 Million years

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Linear Model? # genes left (MY)

1600

45 0

-166

Time (MY)

0

Extinction in 4.6mY

Has it happened already?

Mole voles - males have no Y, no SRY E. fuscocapillus - XY males, XX females E. lutescens - XO males, XO females E. tancrei - XX males, XX females

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Has it happened already? Japanese spiny rats have survived loss of Y no SRY

female male X X Amami-Osima Island Amami spiny rat (T. osimensis) Tokunoshima Island

Tokunoshima spiny rat (T. tokunoshimensis)

no SRY Okinawa-jima Island

female male X X

SRY Okinawa spiny rat (T. muenninki )

female XX

male XY

What could happen to Y genes? intact mutation inactivation amplification deletion move to another chromosome

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Y loss in spiny rat Could it happen in humans? X

KDM5C

Y

KDM5 EIF2S3Y TSPY ZFX SRY RBMY

SRY replaced by ??

EIF2S3X TSPX

Other Y genes relocated

ZFX RBMY-RT SOX3

KDM5

RBMX

EIF2S3Y TSPY ZFX

XX

What if

woman

spiny rat

man

New human species? 34

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The human Y is disappearing because: • It is subject to higher rates of change than other chromosomes • There is evidence from across the animal kingdom that “Y”’s degrade irreversibly – Spiny rats and mole voles – Some say fruit flies are on their 3rd Y chromosomes

• There is evidence that there is practically nothing left of the original human Y – A few bits have since been added, and they are also degrading


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The Jenn Hughes Case In defense of the Y

Jennifer Hughes Whitehead Institute for Biomedical Research Cambridge, MA

A Tale of Three Primate Y’s ~25 mya

~6 mya

Rhesus macaque Chimpanzee

Human

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She studied the human Y chromosome in great detail

Genes on the Human Y

Gene type

Where does it act?

Origin

Single-copy

Brains

X-Y ancestor

Multi-copy

Balls

X-Y ancestor or transposition

Single-copy: Multi-copy:

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Genes and sequences on the human Y

Many Palindromes

Audience Question “Which of the following is a palindrome?”

• Naomi, did I moan? • As I pee, sir, I see Pisa • Kay, a red nude, peeped under a yak • All of the above • None of the above

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What is a palindrome? • • • • • • • • • •

Elle Eve Dumb mud Senile felines Mad as Adam A Santa at Nasa Strap on no parts Naomi, did I moan? As I pee, sir, I see Pisa Kay, a red nude, peeped under a yak

Genes and Sequences on the Human Y

Many Palindromes

Eve

Madam

Elle Strap on no parts

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How the Y saves itself • Palindromes undergo “self genetic exchange” – Essentially they cause the Y to “do it with itself”

Human-chimp-rhesus comparison ~25 mya

~6 mya

Rhesus macaque

Chimpanzee

Human

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The rhesus Y is incredibly simple

But when we look at the number of genes………

Surviving “ancestral” genes in human Y, chimp Y, and rhesus Y 25 mya

Z

6 mya

Z

14 genes 19 genes

20 genes chimp Y rhesus Y

human MSY

One gene lost from human Y in last 25 million years. In human lineage, Y gene loss essentially ceased > 25 mya. The same is true for rhesus lineage. Y gene loss in chimp lineage is an exception, not the rule.

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The human Y is not going to disappear because: • It hasn’t disappeared yet and it has been around for hundreds of millions of years. • The Y chromosome has shown it has ways to outsmart genetic decay in the absence of “normal” recombination. – Palindromes cause Y to “do it with itself”

• The human Y has added at least 8 different genes, many of which are in multiple copy. • The human Y has not lost any genes since human and rhesus monkey diverged 25 million years ago.

“Y Forever” Model

# genes left (MY)

1600

Y forever!!!!? 0

-166

Time (MY)

0

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Rebuttals •

In analysing primates – –

•

Harbingers of our future –

two rodents already lost both Y & TDF •

–

• •

•

provide good examples of the Y chromosome “clinging on to life.”

once it’s gone, it’s gone, the process is irreversible

Palindromes and gene duplication by themselves will not save the Y without evolutionary selection –

Palindromes can preserve Y genes. – –

natural selection will swiftly remove Ys that contain mutated copies palindromes are evolving significantly slower

•

There has not been any decay of genes in at least 25 million years,

•

Each individual part of the X shows a “Y forever” model Most of genes that remain on human Y are probably indispensible

spiny rat and mole vole.

Some fruit fly species are on their third Y chromosome. Gene conversion is not directional –

•

tiny evolutionary interval need to consider the issue in a broader evolutionary context.

–

•

– – –

not a “tiny” fraction.

not just for determining maleness, for sperm development and other basic biological functions, Therefore to Y is here to stay!

Therefore the Y is on it’s way out

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Conclusion 1: Summary • No-one (apart from certain sections of the press) is suggesting that males are disappearing – Just because the male “bits” are disappearing, does not mean that males themselves are

• Everyone agrees that the “Y” is “degenerate X” – So it has shrunk considerably

• Everyone agrees that the “Y” has evolved some pretty clever mechanisms to “put the brakes on” • What we can’t agree on is how effective the brakes are

Conclusion 2: Do we need males? •

•

•

There are lots of studies of skews from 1:1 sex ratios – But they are relatively rare – The skew from 1:1 is usually quite small – By and large 1:1 ratios are here to stay in natural populations Clinically, attempts at female: female fertilization would be very dangerous – Natural conceptions with only female genomes do not survive – If we tried to get over the problem using science, this would almost certainly lead to clinically affected children Humans could, theoretically, just survive with a few males – As in some farm animal breeding regimes – But how would we choose the “lucky” guys? – Imagine the fights – Good luck in trying to get that through Parliament 

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Audience Question “Do you think the human Y chromosome will eventually disappear?” • Yes • No • Undecided

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ACS Fellows Series: The Increasing Importance of Informatics in the Pharmaceutical Industry Dr. Wendy Cornell, Head of Informatics IT Proprietary Information & Knowledge Management, Merck Dr. William Carroll, VP of Industry Issues, Occidental Chemical Corporation


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ACS Fellows Series: The Increasing Importance of Informatics in the Pharmaceutical Industry Dr. Wendy Cornell, Head of Informatics IT Proprietary Information & Knowledge Management, Merck Dr. William Carroll, VP, Industry Issues for Occidental Chemical Corporation


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Disappearance of the Y Chromosome

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