Title: High Mutation Rates Have Driven Extensive Structural Polymorphisms Among Human Y Chromosomes
1High Mutation Rates Have Driven Extensive
Structural Polymorphisms Among Human Y Chromosomes
2Outline
- The Y Chromosome and its Apparent Problems
- Origins of the Y chromosome
- Is the Human Y chromosome degenerating
perniciously? - Homo vs. Pan Y chromosome studies
- High Mutation Rates in Human Y Chromosome
- Repping et al.(2006)
- Distal-Yq heterochromatin and IR3/IR3
- TSPY and AZFc
- Conclusions and Summary
3Evolution of the Y Chromosome
- X and Y diverged from autosomes of mammalian
ancestors ca. 300MYA - Differentiation of X and Y only occurred after
recombination suppression - There are 19 homologous genes on both the X and Y
chromosomes - Located on tip of short arm in X and in 4
contiguous blocks. But are fragmented across
length of Y. - Attributed to four major inversions on the Y
chromosome. Prevented recombination of X-Y
4- ca. 5 of Y is capable of recombining with X.
These areas are known as pseudoautosomal
regions(PAR) located at telomeres.The other 95
is known as the male-specific region(MSY). - MSY contains 78 genes which code for 27 distinct
proteins. - MSY split into three euchromatic classes1
- X-transposed region
- X-degenerate region
- Ampliconic region
5(No Transcript)
6X-transposed region
- Only 2 genes, almost identical with Xq21, a band
on the long arm of the X chromosome - Caused by an eponymous transposition ca. 3MYA
after divergence with chimpanzees - Large inversion within MSY short arm cleaved the
region into two non-contiguous segments (total of
3.4Mb in length) - Do not cross over during male meiosis unlike PARs.
7X-degenerate region
- Replete with single-copy genes or pseudogene
homologues of 27 X-linked genes - Possible remnants of an ancient autosome,homology
indicative of coevolution of both X and Y from
autosome. - e.g Y-linked genes RPS4Y1 and RPS4Y2 are full
length homologues of X-linked gene RPS4X, which
encode two different, full-length isoforms of
ribosomal protein S4. - Contains 16 of 27 protein families in
MSYincluding the sex-determining gene SRY and
all 12 of the ubiquitously expressed genes
8Summary of X-transposed and X-degenerate protein
families
9 Ampliconic region
- By far constitutes more of the MSY than the other
two classes(10.2Mb) and shows a significantly
higher gene density than the other two regions - Consists largely of 99.9 similar sequences which
maintain identity over 10-100Kb - Originated from amplification of X-degenerate
genes (RBMY, VCY) - transposition and amplification of autosomal
genes (DAZ from chromosome 3) - And retroposition and amplification of autosomal
genes (CDY).
10Ampliconic region
- Each of these genes has been amplified, one of
them (TSPY) has multiplied itself 35 times. - 9 of the distinct protein families are expressed
exclusively in testes
11Summary of Ampliconic protein families
12Is the Y Chromosome Degenerating Perniciously?
- Clonal transmission paternally poses a problem
for Y chromosome - Chromosome is greatly emaciated, ca. 30 and less
than 10 length and gene content of X chromosomes - On this notion,it has been proposed that the Y
chromosome will be bereft of functional genes in
10MY(impending demise hypothesis) - Contemporaneously, peers proposed integrity of Y
chromosome is maintained.1
13Is the Y Chromosome Degenerating Perniciously?
- Human ampliconic regions consist of 8 v.large
palindromic sequences(9kb-1.45Mb) - Atleast 6 of these arose before divergence with
Pan - Paired arms of each palindrome separated by
spacer region(2-170kb) - Proposed that integrity of palindromic sequences
is maintained by gene conversion between two arms
of the same palindromic region2 - Found to be true,gene conversion confirmed by
studies of P1.
14Is the Y Chromosome Degenerating Perniciously?
- Gene conversion acts at a slow rate. Balanced
between rates of mutations that cause differences
between arms. - Indicates that process may not be driven by
selective constraints, but rather a weak
direction bias which favours preservation of
original sequences.(at least in humans) - But what about X-degenerate genes?
15Is the Y Chromosome Degenerating Perniciously?
- No gene conversion takes place in X-degenerate
regions. So extensive gene decay is expected - 16 X-degenerate and 11 pseudogenes both present
in chimpanzees and humans - Therefore, none or little gene decay has occurred
in human lineage since divergence with Pan. - Functional proteins exhibit less interspecies
divergence(Homo vs pan) than intronic DNA
sequences - Suggests stabilizing selection is imperative to
maintaining functionality of human X-degenerate
regions
16Homo vs Pan Y Chromosome Studies
- In significant contrast, pernicious X-degenerate
gene decay was prevalent in chimpanzee - Of the 8 genes found to have gt1.0 divergence, 5
had undergone truncations, which was either
caused by splice-site disruption, or expression
of stop codons. - e.g USP9Y is vital for spermatogenesis
in humans,but in Pan, it only codes for
a 675 amino acid chain(cf.2555) - TMSB4Y (ubiquitous in humans) is not
transcriptionally active at all. - Both differ by negligible differences in
humans
17Homo vs Pan Y Chromosome Studies
- Why have chimpanzees suffered gene decay
severely, and humans negligibly? - Strong positive selection at another locality on
Y? (genetic hitchhiking) - Natural selection acts on Y as a unit,as it has
nothing else with which to recombine. - Deleterious mutations can be selected until
fixation has occurred
by linkage to beneficial
mutations on other
Y-linked genes
18Homo vs Pan Y Chromosome Studies
- Ampliconic regions bear many testes-restricted
genes - These play a vital role in spermatogenesis and
spermatogenic failure, therefore these regions
may be under intense selection pressure - Especially in taxa such as Pan which exhibit a
complex mating system,mainly promiscuity. This
gives rise to intense sperm competition - Monogamy, the prevailing strategy in humans, may
allow for higher preservation of
testes-restricted genes
19High Mutation Rates in Human Y
ChromosomeRepping et al.(2006)
- Use of ampliconic DNA sequences to determine
causes of frequently recurring polymorphisms in
Human male genealogy. - Are these polymorphisms recurrent independent
mutations are do they originate from a single
ancestor? - How are these polymorphisms governed? And what
effect does natural selection have on these areas?
20High Mutation Rates in Human Y Chromosome
- 47 chromosomes were collected, each representing
a major branch of global diversity and major
genealogical lineages - 9 categories of potential structural variation
were investigated. And four of these showed
sufficient variation to be further considered - Minimum-mutation histories and lower bound
mutation rates over 52,000 generations were
calculated - Distal-Yq heterochromatin
- IR3/IR3
- TSPY
- AZFc
21(No Transcript)
22Regions of Y chromosome and conserved elements in
Pan
23Distal-Yq heterochromatin
- Showed large-scale length variation (29-54 of
the length of metaphase Y) - Consists of low-complexity sequences in tandem
arrays - Distinct lengths must be due to
multiple mutations - gt12 large-scale changes equate to a
rate of gt2.3 X 10-4 per father-to-son
transmission
24IR3/IR3
- Was inverted in proximal Yp in 16 of the 47
chromosomes - 3.6Mb inversion
- Attributed to ectopic homologous recombination
- 12 independent inversion events
- gt2.3 X 10-4 per father-to-son transmission (same
as Yq, why is this so?)
25TSPY
- Testes-specific protein Y-linked
- Often expressed in testicular cancer
- Showed large scale length variation. Ranged in
size from 0.47Mb-1.3Mb - Highly similar 20.4Kb repeat units of gene and
transcription factor - Result of multiple mutations
26TSPY
- gt23 changes in length gt4.4 X 10-4 per
father-to-son transmission - Specimens who displayed frequent changes also
showed limited copy number variation.
27AZFc
- Highest mutation rates(20 rearrangements and
mutation rate of 3.8X 10-4) . Higher variation of
copy number (does this correspond with
significant mutations in this region?) - Very important as it bears many testes-specific
genes - Many common deletions result in large sections of
AZFc being removed - b2/b4 deletion removes entire region most common
cause of spermatogenic failure
28AZFc
- gr/gr mutation removes 1.6Mb, it has arose 14
times independently in human genealogy. - And as deleterious mutations are usually not
able to become polymorphic this is an indicator
of haploid selection being in balance with
homologous recombination - b2/b3 similar to gr/gr, does not delete full
copies on genes, and retains some copies.4,5 - Are ampliconic regions so duplicated to withstand
intense natural selection? - Are these deleterious mutations selected in
conjunction with other Y-linked genes with
positive effects on fitness?
29Conclusions
- Natural selection acts on Y in a v.different way
to autosomes,and selects it as one unit. This
allows for different kinetics which must be
further elucidated. - High duplication in the MSY allows many
functional genes to be retained by homologous
recombination - Direct and indirect natural selection on certain
genetic units play in integral role - Natural selection may help preserving vital
spermatogenic genes by exerting a stabilizing
selection on gene copy variance - Contemporary evidence points away from impending
demise hypothesis for humans.
30References
- 1.Helen Skaletsky et al(2003) The male-specific
region of the human Y chromosome is a
mosaic of discrete sequence classes. NATURE VOL
423 www.nature.com/nature - 2.Jennifer F. Hughes, Helen Skaletsky et al
(2005) Conservation of Y-linked genes during
human evolution revealed by comparative
sequencing in chimpanzee. Nature vol 437 - 3.Repping et al(2006) High mutation rates have
driven extensive structural polymorphism among
human Y chromosomes.Nature Genetics.Advanced
online publication - 4. Repping et al.(2004)A family of human Y
chromosomes has dispersed throughout northern
Eurasia despite a 1.8-Mb deletion in the
azoospermia factor c region. Genomics vol 83
10461052 - 5.Repping et.al(2003) Polymorphism for a 1.6Mb
deletion of human Y chromosome through balance
between recurrent mutation and haploid
selection.Nature genetics.vol 35 3