Whitehead High School Teachers Program
October 5, 2009
What do sex chromosomes
have to do with sex?
Evolution of Sexual Reproduction: 4 Big Innovations
1. sexual
recombination
3 - 4 bya
2. genes in pairs
(meiosis)
diploid / haploid
once
1.5 - 2 bya
3. dimorphic
gametes
egg / sperm
(female / male)
several
animals
times
700 mya
4. sex
chromosomes
XX / XY
ZW / ZZ
many
times
mammals
300 mya
1957
Sex Chromosome Evolution:
Y as Rotting X
SRY
A pair of
autosomes
X Y
SRY
X Y
SRY
X Y
Nature 415, 963 (2002)
The future of sex
R. John Aitken and
Jennifer A. Marshal Graves
“The Y chromosome is particularly vulnerable … because
it is not a matching partner for the X chromosome, so it cannot
retrieve lost genetic information by recombination.”
“At the present rate of decay, the Y chromosome will selfdestruct in around 10 million years.”
“Feeling that they were better off without
males, the women of Earth decided to outlaw
men because they were too violent.
… a weapon called the "Y-bomb" was used,
which resulted in the deaths of 97% of men.
20 years later, scientist Hope Chase conducts
a cloning experiment to produce a new male,
whom she names Adam.
When Adam reaches maturity, he finds
himself on the run, hiding out with rebel
bands of the last remaining men.”
From Internet Movie Database (IMDb)
Spermatogenic Specialization of
Y Revealed by Genomic Analyses
• DNA sequence of chromosome
• Catalog of genes
• Y deletions ! spermatogenic failure
The Human Y Chromosome
Euchromatin
23 Mb ! 1% of human genome
Heterochromatin
p
q
The Y differs from other nuclear
chromosomes:
--specific to one sex
--no crossing over
Old and new understandings of the human Y
genetic wasteland
~76 protein-coding genes !
27 distinct proteins;
spermatogenic specialization
merely a rotting copy of
an ancient autosome
many genes imported (from
autosomes and X) during primate
evolution; gene amplification
full of junky repeats
gene-rich palindromes of
unprecedented scale + precision
no productive recombination
! all genes disintegrating
gene conversion ! better
maintenance of genes in pairs?
headed for extinction
even single-copy genes
preserved through natural selection
Old and new understandings of the human Y
genetic wasteland
~76 protein-coding genes !
27 distinct proteins;
spermatogenic specialization
merely a rotting copy of
an ancient autosome
many genes imported (from
autosomes and X) during primate
evolution; gene amplification
full of junky repeats
gene-rich palindromes of
unprecedented scale + precision
no productive recombination
! all genes disintegrating
gene conversion ! better
maintenance of genes in pairs?
headed for extinction
even single-copy genes
preserved through natural selection
Structure of a Y palindrome
up to 1.45 million bp
1 or more testis genes
1 or more testis genes
99.94 - 99.997 % identity
( < 0.06 % divergence)
Kuroda-Kawachuchi et al., Nature Genet. 29: 279 (2001)
Skaletsky et al., Nature 423: 825 (2003)
< 0.06% arm-to-arm divergence in Y palindromes
implies either:
1) very recent origin (< 500K years ago)
or
2) ongoing homogenization via nonreciprocal
recombination (gene conversion)
Do the “same” (orthologous) palindromes exist
on chimp Y chromosome?
Chimp orthologs of human Y palindromes
Human
Chimpanzee
1.44 %
0.021 %
0.028 % nucleotide divergence
Palindrome existed in chimp/human ancestor 6 MYA
Arm-to-arm gene conversion in both human and chimp lineages
Rozen et al., Nature 423: 873 (2003)
Palindromes comprise 25% of Y euchromatin
and carry all intact copies of the long arm!s
testis-specific gene families
Yq
Yp
VCY
XKRY
HSFY
RBMY
PRY
CDY
BPY2
DAZ
All subject to arm-to-arm gene conversion
Skaletsky et al., Nature 423: 825 (2003)
What if the whole chromosome
turned into a palindrome?
Sjoerd Repping
Academic Medical Center
University of Amsterdam
Julian Lange
Sherman Silber
St. Luke"s Hospital, St. Louis
Robert Oates
Boston University School of Medicine
Y deletions
Spermatogenic failure
Infertility
Y-chromosome interstitial deletions
cause spermatogenic failure
1 common deletion
Yp
Our unpublished results
Repping et al., Nature Genet. (2003)
Repping et al., Am. J. Hum. Genet. (2002)
Kuroda-Kawachuchi et al., Nature Genet. (2001)
Reijo et al., Nature Genet. (1995)
Yq
AZFc
Y-chromosome interstitial deletions
cause spermatogenic failure
1 common deletion & 4 infrequent deletions
Yp
Yq
AZFc
AZFb
AZFa
Our unpublished results
Repping et al., Nature Genet. (2003)
Repping et al., Am. J. Hum. Genet. (2002)
Kuroda-Kawachuchi et al., Nature Genet. (2001)
Reijo et al., Nature Genet. (1995)
3.5 Mb
7.0 Mb
7.7 Mb
6.2 Mb
0.8 Mb
Y-chromosome interstitial deletions
cause spermatogenic failure
1 common deletion & 4 infrequent deletions
Big: 0.8 million base pairs to 7.7 million base pairs
Y"s
New: fathers have intact Ys
Recurrent: 83 unrelated AZFc cases
Yp
Yq
AZFc
AZFb
AZFa
Our unpublished results
Repping et al., Nature Genet. (2003)
Repping et al., Am. J. Hum. Genet. (2002)
Kuroda-Kawachuchi et al., Nature Genet. (2001)
Reijo et al., Nature Genet. (1995)
3.5 Mb
7.0 Mb
7.7 Mb
6.2 Mb
0.8 Mb
Y-chromosome interstitial deletions
cause spermatogenic failure
1 common deletion & 4 infrequent deletions
Big: 0.8 million base pairs to 7.7 million base pairs
Y"s
New: fathers have intact Ys
Recurrent: 83 unrelated AZFc cases
Delete many genes: 2 – 25
Yp
Yq
AZFc
AZFb
AZFa
Our unpublished results
Repping et al., Nature Genet. (2003)
Repping et al., Am. J. Hum. Genet. (2002)
Kuroda-Kawachuchi et al., Nature Genet. (2001)
Reijo et al., Nature Genet. (1995)
3.5 Mb
7.0 Mb
7.7 Mb
6.2 Mb
0.8 Mb
Other men with spermatogenic failure have
deletions with only one breakpoint
Yp
Y
Are these terminal deletions?
Why do most breakpoints fall within palindromes?
Lange et al., Cell (2009)
Reijo et al., Nature Genet. (1995)
Vollrath et al., Science (1992)
SRY
Hypothesis: palindrome - palindrome recombination
yields a mirror-image Y,
an isodicentric chromosome
Yp
SRY
Yq
Yp
Yp
Lange et al., Cell (2009)
SRY
SRY
Yq
Yp
Isodicentric chromosomes confirmed by
fluorescence in situ hybridization
normal chromosome
Yp
Yq
Yp
Yp
Lange et al., Cell (2009)
Yp
Yp
Reexamined Y chromosomes
and phenotypes of 2380 patients
studied for any of three reasons:
1. Discordance between sex chromosome
constitution and anatomy
2. Microscopically detectable anomaly of Y
chromosome
3. Men with little or no sperm production
Lange et al., Cell (2009)
Identified 60 patients with
idicY or isoY chromosomes
51 of these arose through crossing over at palindromes
8 different Y palindromes “hit” (targets for crossing over)
A significant cause of spermatogenic failure in men
However, 20 of these patients were anatomically feminized
2 patients: SRY not present on idicY chromosome
18 patients: SRY present in two copies on idicY
Lange et al., Cell (2009)
Hypothesis…
Mitotic instability of idicY chromosomes --> XO cells
in embryonic gonad --> feminization of external genitalia
Prediction…
The greater the distance between the centromeres,
the higher the probability of anatomic feminization
Correlation between sexual development & location of
targeted palindrome (distance between centromeres)
Yp
Anatomically
male (n=40)
Anatomically
feminized (n=18)
In human beings with idicY chromosomes,
more Y DNA --> greater likelihood of feminization
Lange et al., Cell (2009)
Yq
Speculations arising…
Could mitotic instability of idicY chromosomes be a
significant cause of XO state in girls & women with
Turner syndrome?
(No maternal age effect in XO Turner syndrome,
unlike trisomy 21)
(In 3/4 of XO girls and women, the X chromosome
is of maternal origin)
Could Y palindrome-palindrome recombination be a
significant cause of Turner syndrome?