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Comparative Genomics and the Evolution of Animal Diversity

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Title: Comparative Genomics and the Evolution of Animal Diversity


1
Chapter 19
  • Comparative Genomics and the Evolution of Animal
    Diversity
  • 04??????? 200431060025
  • ??

2
Outline
  • 1Most animal have essentially the same genes
  • 2Three ways expression is changed during
    evolution
  • 3Experimental manipulations that alter animal
  • Morphology
  • 4Morphological changes in crustaceans and
    insects
  • 5Genome evolution and human origins

3
Topic 1 Most animal have essentially the same
genes
  • 1-1 different animals share essentially the same
    genes.
  • The genetic conservation seen among vertebrates
    extends to the humble sea squirt.
  • The genetic conservation seen among chordates
    appears to extend to other phyla.

4
1-2 How does gene duplication give rise to
biological diversity?
  • There are two ways this can happen
  • 1 The conventional view is that an ancestral gene
    produces multiple genes via duplication ,and the
    new genes undergo mutation.
  • 2 Duplication genes can generate diversity has
    been rather neglected until very recently.

5
Topic 2 Three ways gene expression is changed
during evolution
  • 1. A given pattern determining gene can itself be
    expressed in a new pattern.
  • 2.The regulatory protein encoded by a pattern
    determining gene can acquire new functions.
  • 3.Target genes of a given pattern determining
    gene can acquire new regulatory DNA sequences,
    and thus come under the control of a different
    regulatory gene.

6
Topic 3 Experimental manipulations that alter
animal morphology
  • The first pattern determining gene was identified
    in Drosophila in the Morgan fly lab.
  • A mutation called bxd causes a partial
    transformation of halteres into wings.

7
3-1 Changes in Pax6 expression create Ectopic Eyes
  • The most notorious pattern determining gene is
    Pax6, which control s eye development in most or
    all animals .
  • Pax6 is normally expressed within developing
    eyes but when misexpressed in the wrong
    tissres,Pax6 causes the development of extra eyes
    in those tissues.
  • Evolutionary changes in the regulation of Pax6
    expression have been more important for the
    creation of morphologically diverse eyes than
    have changes in Pax6 protein function.

8
3-2 Changes in Antp expression transform Antennae
into Legs
  • A second Drosophila pattern determining gene,
    Antp, controls the development of the middle
    segment of the thorax, the mesothorax.
  • Antp encodes a homeodomain regulatory protein
    that is normally expressed in the mesothorax of
    the developing embryo .
  • But a dominant Antp mutation caused by a
    chromosome inversion brings the Antp protein
    coding sequence under the control of a foreign
    regulatory DNA that mediates gene expression in
    head tissues ,including the antennae.

9
3-3 Importance of protein function
interconversion of ftz and Antp
  • Pattern determining genes need not be expressed
    in different places to produce changes in
    morphology.
  • A second mechanism for evolutionary diversity is
    changes in the sequence and function of the
    regulatory proteins encoded by pattern
    determining genes .

10
  • The Antp and Ftz proteins recognize distinct
    DNA-binding sites becarse they protein
    interactions are mediated by short peptide motifs
    that map outterapeptide sequence motif, YPWM.

11
  • Ftz-FtzF1 dimers recognize DNA sequences that are
    distinct from those bound by Antp-Exd dimers. As
    a result, Antp and Ftz regulate different target
    genes.

12
3-4 Subtle changes in an enhancer sequence can
produce new patterns of gene expression
  • The third mechanism for evolutionary diversity is
    changes in the target enhancers that are
    regulated by pattern determining genes.

13
  • The principle that changes in enhancers can
    rapidly evolve new patterns of gene expression
    stems from the experimental manipulation of a 200
    bp tissue specific enhancer that is activated
    only in the mesoderm.

14
  • Dorsal functions synergistically with another
    transcription factor Twist to activate gene
    expression in the neurogenic ectoderm.
  • There are no Twist binding sites in the native
    enhancer.
  • A total of eight nucleotide substitutions are
    sufficient to create two Twist binding sites
    (CACATG). When combined with the two nucleotid
    substitutions that produce high-affinity Dorsal
    binding sites,the modified enhancer now directs a
    broad pattern of gene expression in both the
    mesoderm and neurogenic ectoderm.

15
  • A series of 2, 10, and 14 nucleotide
    substitutions produce a spectrm of Dorsal target
    enhancers which direct expression in the
    mesoderm, the mesoderm and neurogenic ectoderm,
    or just in the urogenic ectoderm. These
    observations suggest that enhancers can evolve
    quickly to create new patterns of gene expression.

16
3-5 The misexpression of Ubx changes the
morphology of the fruit fly
  • New patterns of gene expression are produced by
    changing the Ubx expression pattern, the encoded
    regulatory protein, or its target enhancers.
  • Antp is one of the genes that it regulates Ubx
    represses Antp expression in the metathorax of
    developing embryos.

17
  • The expression of Ubx in the different tissues of
    the metathorax depends on regulatory sequences
    that encompass more than 80 kb of genomic DNA.
  • The consequences of misexpressing a pattern
    determining gene can cause a dramatic change in
    morphology results.

18
3-6 Changes in Ubx function modify the morphology
of fruit fly embryos
  • Ubx protein can function as a transcriptional
    repressor.
  • The Ubx protein contains specific peptide
    sequences that recruit repression complexes.
  • Ubx can be converted into an activator by fusing
    the Ubx DNA-binding domain to the potent
    activation domain from the viral VP-16 protein.

19
  • The protein sequences that mediate
    transcriptional repression map outside the Ubx
    homeodomain and are not present in the Ubx-VP16
    fusion protein .
  • The misexpression of the Ubx-VP16 fusion protein
    causes all of the segments to develop as
    mesothoracic segments.
  • The Ubx-VP16 fusion protein produces the same
    phenotype as that obtained with Antp.

20
3-7 Changes in Ubx target enhancers can alter
patterns of gene expression
  • The Ubx protein contains a homeodomain that
    mediates sequence-specific DNA binding, and
  • it also contains a tetrapeptide motif (YPWM)
    that mediates interactions with Exd.
  • Ubx binds DNA as a Ubx-Exd dimer.

21
  • Exd binds to a half-site with the core sequence,
    TGAT, Hox proteins such as Ybx bind an adjacent
    half-site with a diferent core consensus
    sequence, A-T-T/G-A/G.
  • This obserbation raises the possibility that
    target enhancers regulated by one Hox protein can
    rapidly evolve into a target enhancer for a
    different Hox protein.
  • So ,the altering the function or expression of
    the Ubxprotein or its target enhancers profoundly
    changes patterning in the Drosophila embryos and
    adults.

22
Topic 4 Morphological changes in crustaceans and
insects
  • The first two mechanisms, changes in the
    expression and function of pattern determining
    genes, can account for changes in limb morphology
    seen in certain crustaceans and insects the
    third mechanism, changes in regulatory sequences,
    might provide an explanation for the different
    patterns of wing development in fruit flies and
    butterflies.

23
4-1 Arthropods are remarkably diverse
  • Arthropods embrace five groups trilobites,
    hexapods, crustaceans, myriapods, and
    chelicerates.
  • The success of the arthropods derives from their
    modular architecture.
  • These organisms are composed of a series of
    repeating body segments that can be modified in
    seemingly limitless ways.

24
4-2 changes in Ubx expression explain
modifications in limbs among the crustaceans
  • There are two different groups crustaceans,
    branchiopod and isopod.
  • In branchiopods Scr expression is restricter to
    head regions where it helps promote the
    debelopment of feeding appendages,while Ubx is
    expressed in the thorax where it controls the
    development of swinning limbs.

25
  • In isopods, Scr expression is detected in both
    the head and the first thoracic segment(T1), and
    as a result, the swimming limb in T1 is
    transformed into a feeding appendage.
  • This posterior expansion of Scr was made possible
    by the loss of Ubx expression in T1 since Ubx
    normally represses Scr expression.

26
  • During the divergence of branchiopods and
    isopods, the Ubx regulatory sequence changed in
    isopods. As a result of this change, Ubx
    expression was eliminated in the first thoracic
  • segments, and restricted to segments T2-T8.
  • In Artemia, these head genes are kept off in all
    11thoracic segments, but in isopods the head
    genes can be expressed in the T1 segment due to
    the loss of the Ubx repressor.

27
  • Expression of the Scr gene is restricted to head
    regions of branchiopods, but is expressed in T1of
    isopods. The expression of Scr in T1 causes
    maxillipeds to develop in place of normal
    swimming limbs.

28
4-3 Why insects lack abdominal limbs?
  • The loss of abdominal limbs in insects is due to
    functional changes in the Ubx regulatory protein.
  • In insects, Ubx and abd-A repress the expression
    of a critical gene that is required for the
    development of limbs, call Dll.
  • Although Ubx is expressed in metathorax, it does
    not interfere with the expression of Dll in that
    segment, because Ubx is not expressed in the
    developing T3 legs until after the time when Dll
    is activated, as a result, Ubx does not interfere
    with limb development in T3.

29
  • The misexpression of Ubx throughout all of the
    tissues of the presumptive thorax in transgenic
    Drosophila embryos suppresses limb development
    due to the repression of Dll.
  • The misexpression of the crustacean Ubx protein
    in transgenic flies does not interfere with Dll
    gene expression and the formation of thoracic
    limbs.

30
4-4 modification of flight limbs might arise from
the evolution of regulatory DNA sequences
  • Changes in the Ubx expression pattern appear to
    be responsible for the transformation of swimming
    limbs into maxillipeds in crustaceans.

31
  • Ubx in crustaceans, the C-terminal antirepression
    peptide blocks the activity of the N-terminal
    repression domain.
  • Ubxin insects ,the C-terminal antirepression
    peptide was lost throught mutation.

32
  • Two possibilities
  • First, the Ubx protein is functionally distinct
    in flies and butterfiles.
  • Second, each of the approximately five to ten
    target genes that are repressed by Ubx in
    Drosophila have evolved changes in their
    regulatory DNAs so that they are no longer
    repredded by Ubx in butterflies.

33
  • The Ubx repressor is expressed in the halters of
    dipterans and hindwings of lepidopterans.
  • Different target fenes contain Ubx repressor
    sites in dipterans. These habe been lost in
    lepidopterans.
  • An implication of the preceding arguments is that
    evolutionary changes regulatory DNAs.

34
Topic 5 Genome evolution and human origins
  • The genomes of mice and humans have been
    sequenced and assembled, and their comparison
    should shed light on our own human origins.

35
5-1 Humans contain surprisingly few genes
  • The human genome contains only 25000-30000
    protein coding genes. Before the human genome was
    sequenced, there were popular estimates for
    100000 protein coding genes.
  • Organismal complexity is not correlated with gene
    number, but instead depends on the number of gene
    expression patterns.

36
5-2 The human genome is very similar to that of
the mouse and virtually identical to the chimp
  • Mice and humans contain roughly the same number
    of genes, approximately 80 of these genes
    possess a clear and unique one-to-one sequence
    alignment with one another between the two
    species.
  • Most of the remaining 20 of the genes in mice
    and humans differ by virtue of lineage-specific
    gene duplication events.

37
  • The chimp and human genomes are even more highly
    conserved, they vary by an average of just 2
    sequence divergence.
  • The regulatory DNA evolve more rapidly than
    proteins.

38
5-3 the evolutionary origins of human speech
  • Speech depends on the precise coordination of the
    small muscles in our larynx and mouth.
  • Reduced levels of a regulatory protein called
    FOXP2 cause severe defects in speech.
  • Changes in the expression pattern or changes in
    FOXP2 target genes might be responsible for the
    ability of FOXP2 to promote speech in humans.

39
5-4 How FOXP2 fosters speech in humans
  • Changes in the FOXP2 expression pattern, changes
    in its amino acid sequence, and changes in FOXP2
    target fenes might explain its emergence as an
    important mediator of human speech.
  • Some might encode neurotransmitters or other
    critical signals that are expressed within the
    developing larynx.
  • FOXP2 is just one example of a regulatory fene
    that underlies human speech.

40
  • A scenario for the evolution of speech in humans.
  • A hypothetical regulatory protein is expressed in
    the neocortex of both chimps and humans.
  • The human gene is strongly expressed at the
    critical time in the development of the speech
    center and activates all three hypothetical
    target genes in the neocortex, these target gene
    might encode neurotransmitters important for the
    formation of the speech center.

41
5-5 The future of comparative genome analysis
  • There is a glaring limitation in our ability to
    infer the function of regulatory DNA from simple
    sequence inspection .
  • In the future it might also be possible to
    identify changes in the expression profiles of
    homologous genes.

42
Summary
  • The same concept of differential gene expression
    can explain the evolution of animal diversity.
  • Changes in gene expression during evolution
    depend on altering the activities of a special
    class of regulatory genes, called pattern
    determining genes.
  • There are three major strategies for altering the
    activities of pattern determining genes.
  • We are fast entering a golden era of comparative
    genome analysis.

43
The End
  • Thank you!
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