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High Mutation Rates Have Driven Extensive Structural Polymorphisms Among Human Y Chromosomes

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Title: High Mutation Rates Have Driven Extensive Structural Polymorphisms Among Human Y Chromosomes


1
High Mutation Rates Have Driven Extensive
Structural Polymorphisms Among Human Y Chromosomes
  • Matthew Byrnes

2
Outline
  • 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

3
Evolution 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
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6
X-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.

7
X-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

8
Summary 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).

10
Ampliconic 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

11
Summary of Ampliconic protein families
12
Is 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

13
Is 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.

14
Is 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?

15
Is 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

16
Homo 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

17
Homo 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

18
Homo 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

19
High 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?

20
High 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
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22
Regions of Y chromosome and conserved elements in
Pan
23
Distal-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

24
IR3/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?)

25
TSPY
  • 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

26
TSPY
  • 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.

27
AZFc
  • 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

28
AZFc
  • 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?

29
Conclusions
  • 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.

30
References
  • 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
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