Sex, Genes and Sequence

Sex chromosomes – most interesting part of genome

Origins, evolution, future of X and Y

Epigenetics and environmental sex

Origins, evolution of sex genes

Jenny GravesLA Trobe University, ANU, U Canberra

Sex chromosomes are weird

X1669 genes

Many different functionsMany sex, intelligence genes

Brains-and-balls genes

YOnly 27 genes specific to YMany copies, pseudogenesMale-specific functions Sex and spermatogenesis

PARShared by X and YContains 24 genes

Smart,Sexy X

Wimpy Y

• Problems at meiosis• Dosage problems• Sex-linked diseases• Sex-reversal syndromes

Why so weird? • so they work optimally?• evolutionary accident?

XXXXXXXXXXXXXXXXX

X Y

Dumb design!

Sex chromosomes–> trouble

• the Y self-destructs!

X Y

proto-XY

XY evolutionOnce the X and Y were an ordinary pair

One partner acquires a male-determining gene

Other male-advantage genes accumulate- recombination suppressed

Y degraded by deletion, mutation

And degraded and degraded

And can even disappear

The Y is a degraded XEvidence: XY homology; independent Y dropouts

Self-destruction of the Y

High variation

• frequent mutation, deletion, insertion

in testis

Inefficient selection and drift• no recombination, no repair

Rate of loss is ~10 genes/MYY will self-destruct in 4.6 mY

How the Y chromosome determines sex

female male

X X X Y

TDF

testis

hormones

=SRY

Y genes are degraded X genes

TSPYSpermatogenesis?

RBMYSpermatogenesis

Y

SRYSex determination

RBMXMental retardation?

X

SOX3Mental retardationspermatogenesis

TSPXCell cycle?

Most Y genes have copies on X

Brains-and-balls genes –> sex and fertility genes

X-Y shared dosage-sensitive genes in added region

Mammals

Fish450

Tetrapods

Amphibians

410

Monotremes

166

Amniotes

Birds andReptiles

310

Placentalmammals

Marsupials

148

Vertebrate relationships

Humanmice

milli

on ye

ars

105

Mammals

Amniotes

Tetrapods

Fish

Amphibians

Reptiles and birds Monotremes Marsupials Placentals

450

410

310

166148

XY

Origin of human sex chromosomes

HumanMouse

105

X

?Elephant

???

Mammals

Y

X

Origin of human XY

Elephant

XX

A

Kangaroo Human

Map orthologues of human X genes

Y

Chicken Platypus Kangaroo Elephant Human

X64

1qA

X

A

X

Origin of human XY

Male FemaleZ Z Z W

Bird sex

W is a degraded Z

Chicken

Emu

XY and ZW chromosomes follow the same evolutionary rules

X Y W Z

humansmice

kangaroos

ratite birds

carinate birds

male femaleZ Z Z W

What is the bird sex-determining gene?No SRY

Dose-dependent sex determination

DMRT1 on Z but not W

Need two doses to make enough male-determining productKnockdown –> ZZ female

Platypus sex chromosomes

X1 Y1 X2 Y2 X3 Y3 X4 Y4 X5 Y5

Female: 26 pairsMale: 21 pairs + 10

Homology to chick ZWNo homology to human XY

No SRYAMH Sex determining?

Mammals

Amniotes

Tetrapods

Fish

Amphibians

Reptiles and birds Monotremes Marsupials Placentals

450

410

310

166148

XYXYTSD,XY,ZW XY ZW

XYXYXYXYXY

Origin of human sex chromosomes

ZW?

SRY

XY and ZW chromosomes follow the same evolutionary rules

X Y W Z

humansmice

kangaroos

ratite birds

carinate birds

boid snakes

colubrid snakes

vipers

Snake sex chromosomes

Vicoso et al, PLoS Biol 2013

Coverage for male ZZ (blue) and female ZW (red)Assembled against Anolis macrochromosomes 1-6

Conserved ZBoids show no ZW differentiationColubrids and viperids show extreme ZW differentiation

Snakes are ZZ male / ZW female

Snake Z = chicken 2

SOX34

2

5

TSD turtle Birds Platypus Kangaroo HumanSnakes1

DMRT1

SOX34

ZW

2

1

DMRT1

SOX3SRY

X Y

4

3,7,10

SOX3

SRYX Y

5

1

3

SOX3

6

15, 18

DMRT1

X Y X Y X Y X Y X Y

?

DMRT1

SOX34

2

ZW

1

Different genome regions became sex chromosomes in different vertebrates

Sex in frogsYoshimoto & Ito, FEBS J 2011

Conclude DMW inhibits DMRT12 DMRT1 –> male2 DMRT1 + DMW –> femaleDMW defines new W

Xenopus laevis has ZZ / ZW Found DMRT1 homologue on WDMW knockdown –> ZW males

ZW=XY=human XqSOX3 is sex determining

Rana rugosa has ZZ / ZW and XY / XX

Miura et al 2010

Sex in FishLinkage analysis –> chr 1=XYY Positional cloning –>DMRT1 copy

XX female XX+DMY male XY male

Transgenic DMY –> XX male

Matsuda et al, Nature 2002; PNAS 2007

soma testis

Conclude:2 DMRT1 female2 DMRT1 + DMY maleDMY defines a new Y

Medaka Oryzias latipes

MALE FEMALEZ Z

X Y

Z ZZ W

X X

Z W

A A

A A

A A

A A

Neo-Y

Neo-W

Origin of new sex genes?

from copy

from inactive copy

Sex in other medaka species

O. latipes LG1 DMY

O. curvinotos LG1 DMY

=> Change in expression level or timing

O. dancera LG10 ?

Oda (XY=LG10)Sox3 on X, Y –> same protein

Overexpression of Sox3 –>male

Olu ( XY=LG12)Gsdf on X, Y–>same protein Overexpression of GsdfY –>male

O. luzonensis LG12 ?

Ope (XY=LG12)Gsdf on X, Y–>same protein Early expression of GsdfbY –>male

O. pectoralis LG12 ?

A A

A A

X Y

X Y

A A

A A

Z W

Z W Overexpression of one allele

MALE FEMALE

testis ovary

New sex genes from expression change

testis ovary

Change in timing or tissue of expression

Ectopic expression in testis–>XX males

SOX3active in brain, germ-cells

Evolution of SRY

Fusion

expression in gonad

SRYtestis determination

New function

Sato et al Mol Cell Biol 2010; Sutton et al J Clin Invest 2011

Mammals

Amniotes

Tetrapods

Fish

Amphibians

Reptiles and birds Monotremes Marsupials Placentals

450410

310

166148

XYXYTSD,XY,ZW XY ZW

XYXYXYXYXY

Independent recruitment of sex genes

MY

DMYO. latipes

DMWX. laevis

DMRT1birds

SRY

SOX3

SOX3R. rugosa

SOX3O. dancera

AMHsea bass

AMH?

DMRT1tongue sole

Mammals

Temperature Sex Determination - TSDe.g. Crocodiles and marine turtles

No sex chromosomes

Chick Z

6

6

Dragon lizard Pogona vitticeps

%m

ales

Temperature –>

50

0

GSD TSDIdentification of ZW by CGH

W

Quinn et alScience ‘07

A dragon with ZW and TSD

GSD–> TSDZW –> XY

male femaleZ Z Z W

Normaltemperature

female femaleZ Z Z W

Hightemperature

Sex in dragons

Finding dragon sex determining gene….

dose-dependent

and temperature-dependent

Microdissected W, screened for W BACs Sequenced W BAC –> RCC1, OPRD1, syntenic with RSPO1…Sequenced ZZ male, ZW female, ZZ female at BGI

ZZ ZW ZWmale female pseudomale

dmrt1 dmrt1 dmrt1

Epigenetic sex determinationHalf smooth tongue soleChen et al Nature, Shao et al Genome Res

AUTOSOMES SEX CHROMOSOMES

methylation

Conclusions

Vertebrate genome is very conserved

Different genome regions became sex chromosomes

New sex genes evolve, often from same autosomal gene

Sex chromosomes specialize, then self-destruct

Sex can be determined or modified by environment