Human Y Chromosome Evolution
Group 3: Brian Davis, Ian Davis, Navada
Eagleton, Clayton Knight, and Michelle Mann
The Wimpy, Selfish, Dominant Y
• 57,772,954 bp (1.776% of the
• Genes- 78-400 genes, many
NORFs, SNPs- 71,070
• More than 50%
• 3 MSY gene classes on the Y
Sex chromosome Evolution and Y
Lahn and Page, 1999
Current State of Human Y Evolution
• Y chromosome is considered a haploid element in
a diploid genome.
• Male haplotypes reveal a pattern of human
evolution, originally migrating from Africa.
• The Y chromosome is still undergoing
• It is ultimately trying to preserve itself, but at
what costs? Silencing mechanisms that were once
meant for preservation are now driving its rapid
• The PAR region is the only region of the Y chromosome that
• Loss of PAR1 results in male infertility.
• The PAR region is the product of Addition/Attrition.
• The PAR1 region is a remnant of an addition that appears between 80
and 130 MYA.
• The gene content of the PAR region varies widely between species.
Y Chromosome Intelligence
• Y degeneracy and dosage compensation
evolution are intimately linked.
• Vicious cycle.
• Does the Y have a chance?
Graves, Wakefield and Toder, 1998
-Small 79 amino acid intronless gene
-TDF factor (Testis Determining Factor)
-A member of the SOX (SRY-related HMG-box)
-From Class I SRY genes, which have X
chromosome homologues (from which they
-Present in a single copy
-SRY protein contains a domain (HMG box) that
binds to DNA at a target sequence and bends it
at particular angles
-Almost all sex-reversing mutations occur in this
HMG box Conservation
within HMG box
Relatively impossible to align!
“The genomic structure of SRY coding regions in different species, compared
with the conserved ancestral gene SOX3. The HMG box (blue) is well conserved,
but SRY flanking regions (orange) are hard to align between different species,
and differ from SOX3.”Graves 2002
Mammalian Y Chromosome and SRY
AMELY – A Candidate Gene for Future Y-Linked Decay?
• AMELY is an X-degenerate gene, transposed
onto sex chromosomes 100-180 mya.
• Mutation in AMELX causes recessive
• Evidence for relaxed functional constraint of
1. Low AMELY protein expression
2. AMELY has been deleted in normal human
3. AMELY has been lost in some rodents,
including the mouse, with no apparent effect.
If AMELY is under relaxed functional constraint in humans,
we predict closely related AMELY genes should show
lower sequence conservation than AMELX genes.
Emboss global AMELX Conservation AMELY Conservation
Human/Chimp 95.6%identity, 4.1% gaps 94.3% identity, 5.0% gaps
Human/Cow 77.5% identity,14.7% 84.7% identity, 3.6% gaps
Human/Horse 81.9% identity, 8.0% gaps 80.5% identity, 6.8% gaps
If AMELY is subject to little selective pressure, how does it
retain such high conservation with AMELX?
Grouping X-degenerate genes by Ks values shows AMELX/AMELY
differentiation began recently (30-50 mya).
MYA since X-Y
Group 4: 30-50 mya or
divergence of New
World and Old World
Group 3: 80-130 mya
Group 2: 130-170 mya
Group 1: 130-350 mya
From Lahn et al. 1999
Mechanisms for Survival
Ampliconic Regions - TSPY, DAZ, CDY
• Multi-copy testis-specific genes with highly homogeneous sequences
• Region on the long arm comprising 25% of the MSY has eight large palindromes (9kb-1.45
• Also contain five sets of widely spaced inverted repeats (62kb - 298kb)
• Many long tandem repeats, one 700 kb repeat includes 35 copies of the TSPY gene.
Intrachromosomal gene conversion:
- Decrease variation by correcting mutant alleles to wild-type or vice versa within the Y -
• Intrachromosomal repeats have less than .03% variation in both humans and chimps
• When inter-species comparison is made, however variation was 1.4 - 2.3%
• The near uniformity of arm-to arm sequence in the palindromes of both humans and
chimpanzees suggests that gene conversion must be frequent enough to erase new
mutations almost as quickly as they occur.
• This makes it a profound selective force for maintaining the Y chromosome population.
DAZ is a candidate for the human Y-chromosomal azoospermia factor (AZF).
• Expressed in premeiotic germ cells, spermatogonia and encodes an RNA-binding protein (spermatogenesis)
– Deletions cause azoospermia / oligospermia
• The DAZ proteins (DAZ, DAZ2, DAZ3 and DAZ4) are all encoded by a strongly repeated region
– One pair of genes is part of the P2 palindrome, second is part of the P1 palindrome.
• Within the RNA recognition motif (RRM), the mouse DAZL differs from human DAZL by far less amino acids than
the mouse DAZL differs from the DAZ domain. This divergence increases outside the RRM.
• Comparing the 5’ and 3’ UTRs of human DAZL and human DAZ mRNA shows 75% 5’ and 87% 3’ similarity
• Comparing the 5’ and 3’ UTRs of human DAZL and mouse DAZL mRNA shows 17% 5’ and 59% 3’ similarity
– This indicates that the DAZ gene family arose from its DAZL homolog on chromosome 3 during primate
evolution by transposition of a complete transcription unit.
• Chromodomain protein 1 is involved in chromatin assembly/disassembly
– Contains a histone acetyltransferase catalytic domain
– CDY1 is localized to the nucleus of late spermatids
• where histone hyperactelyation occurs, which is usually associated with gene activation.
• Two identical copies of CDY1 located at the same position on opposite arms of P1
• CDY gene family are derivatives of a single-copy gene, CDYL (human 13 & mouse 6)
• CDY genes contain the exonic sequences present in CDYL but no introns
• Again, much greater amino acid divergence between CDY and CDYL than intra-species
• In mice, the autosomal Cdyl gene produces two transcripts
• In humans, CDY1 has two isoforms that with different roles in spermatogenesis
• In humans, autosomal CDYL produces only a ubiquitous housekeeping transcript
• The Y homolog produces the testis-specific transcript.
TSPY was discovered over 15 years ago and was the first gene to be isolated from any Y chromosome
• TSPY homologues with similar gene structure
– Found on the Y chromosome in primates, artiodactyls and rodents
– Suggest TSPY has been on the Y chromosome since before the eutherian radiation more than 80
– There have been no homologs found in marsupials
• Has been extensively amplified
– Present in 20-40 copies on the human, primate and artiodactyl
– 50-200 copies have been found on the bovine Y
– Only a single functional copy on mouse and rat Y chromosomes
• Unlike other amplified testis-specific genes on the human Y (DAZ, CDY)
– TSPY is found outside the palindromic sequences.
– Several TSPY-like genes have been identified on autosomes in human and mouse but lack introns
• TSPX, A ubiquitously transcribed gene with an identical intron-exon structure maps to the X
chromosome syntenic with SMCX
– Appears to have evolved from a ubiquitously expressed gene on the proto-sex chromosome pair
– Its transcription was limited to the testis during evolution
– No sequence available for comparison
The Future of the Human Y
• Y degeneracy and the evolution of dosage
compensation are intimately linked.
• Vicious cycle.
• The genetic isolation of Y also means that the
selection of the fittest Y is inefficient.
• Only genes with a male selectable function can
ultimately resist degradation.
• Does the Y have a chance?
– Will survival mechanisms be able to counteract
• You cannot only look at the genomic side.
• Combination of mechanisms- selection, drift,
environmental factors, high mutation rate,
haploid state, etc.
• Will Y disappear? What will happen to human
• Does it matter if the male genes are on the X
chromosome, because there is no Y
chromosome? highly evolved dosage
Thank you for listening.