Evolution of Selfishness

1
Evolution of Selfishness
Itai Yanai Department of Biology Technion
Israel Institute of Technology
2
Evolution of Selfishness

• Outline
• C-value paradox
• Selfish genes, Selfish DNA
• Transposons in the human genome
• The function of junk

3
GATCTACCATGAAAGACTTGTGAATCCAGGAAGAGAGACTGACTGGGCAA
CATGTTATTCAGGTACAAAAAGATTTGGACTGTAACTTAAAAATGATCAA
ATTATGTTTCCCATGCATCAGGTGCAATGGGAAGCTCTTCTGGAGAGTGA
GAGAAGCTTCCAGTTAAGGTGACATTGAAGCCAAGTCCTGAAAGATGAGG
AAGAGTTGTATGAGAGTGGGGAGGGAAGGGGGAGGTGGAGGGATGGGGAA
TGGGCCGGGATGGGATAGCGCAAACTGCCCGGGAAGGGAAACCAGCACTG
TACAGACCTGAACAACGAAGATGGCATATTTTGTTCAGGGAATGGTGAAT
TAAGTGTGGCAGGAATGCTTTGTAGACACAGTAATTTGCTTGTATGGAAT
TTTGCCTGAGAGACCTCATTGCAGTTTCTGATTTTTTGATGTCTTCATCC
ATCACTGTCCTTGTCAAATAGTTTGGAACAGGTATAATGATCACAATAAC
CCCAAGCATAATATTTCGTTAATTCTCACAGAATCACATATAGGTGCCAC
AGTTATCCCCATTTTATGAATGGAGTTheCvalueParadoxGATGAAAA
CCTTAGGAATAATGAATGATTTGCGCAGGCTCACCTGGATATTAAGACTG
AGTCAAATGTTGGGTCTGGTCTGACTTTAATGTTTGCTTTGTTCATGAGC
ACCACATATTGCCTCTCCTATGCAGTTAAGCAGGTAGGTGACAGAAAAGC
CCATGTTTGTCTCTACTCACACACTTCCGACTGAATGTATGTATGGAGTT
TCTACACCAGATTCTTCAGTGCTCTGGATATTAACTGGGTATCCCATGAC
TTTATTCTGACACTACCTGGACCTTGTCAAATAGTTTGGACCTTGTCAAA
TAGTTTGGAGTCCTTGTCAAATAGTTTGGGGTTAGCACAGACCCCACAAG
TTAGGGGCTCAGTCCCACGAGGCCATCCTCACTTCAGATGACAATGGCAA
GTCCTAAGTTGTCACCATACTTTTGACCAACCTGTTACCAATCGGGGGTT
CCCGTAACTGTCTTCTTGGGTTTAATAATTTGCTAGAACAGTTTACGGAA
CTCAGAAAAACAGTTTATTTTCTTTTTTTCTGAGAGAGAGGGTCTTATTT
TGTTGCCCAGGCTGGTGTGCAATGGTGCAGTCATAGCTCATTGCAGCCTT
GATTGTCTGGGTTCCAGTGGTTCTCCCACCTCAGCCTCCCTAGTAGCTGA
GACTACATGCCTGCACCACCACATCTGGCTAGTTTCTTTTATTTTTTGTA
TAGATGGGGTCTTGTTGTGTTGGCCAGGCTGGCCACAAATTCCTGGTCTC
AAGTGATCCTCCCACCTCAGCCTCTGAAAGTGCTGGGATTACAGATGTGA
GCCACCACATCTGGCCAGTTCATTTCCTATTACTGGTTCATTGTGAAGGA
TACATCTCAGAAACAGTCAATGAAAGAGACGTGCATGCTGGATGCAGTGG
CTCATGCCTGTAATCTCAGCACTTTGGGAGGCCAAGGTGGGAGGATCGCT
TAAACTCAGGAGTTTGAGACCAGCCTGGGCAACATGGTGAAAACCTGTCT
CTATAAAAAATTAAAAAATAATAATAATAACTGGTGTGGTGTTGTGCACC
TAGAGTTCCAACTACTAGGGAAGCTGAGATGAGAGGATACCTTGAGCTGG
GGACTGGGGAGGCTTAGGTTACAGTAAGCTGAGATTGTGCCACTGCACTC
CAGCTTGGACAAAAGAGCCTGATCCTGTCTCAAAAAAAAGAAAGATACCC
AGGGTCCACAGGCACAGCTCCATCGTTACAATGGCCTCTTTAGACCCAGC
TCCTGCCTCCCAGCCTTCT
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Range of prokaryotic genome sizes
Graur Li. Fundamentals of Molecular Evolution
(1999)
5
Genome size in prokaryotes is correlated with
gene number
E. coli
M. genitalium
Graur Li. Fundamentals of Molecular Evolution
(1999)
6
The genome size, or C-value, of an organism is
defined as the total amount of DNA contained
within its haploid chromosome set.
(Gb) H. sapiens 2.9 M. musculus 2.5 D.
melanogaster 0.18 C. elegans 0.097 S.
cerevisiae 0.012
But!
the single-celled amoeba, one of the simplest
of eukaryotic creatures, has a genome size of
200,000 Mb!
7
The range of genome sizes in various eukaryotic
groups
Eukaryotes vary over a range of 80,000!
Graur Li. Fundamentals of Molecular Evolution
(1999)
8
The C-value paradox
What accounts for the often massive,
counter-intuitive and seemingly arbitrary
differences in genome size observed among
eukaryotic organisms?
The fruit fly Drosophila melanogaster
The mountain grasshopper Podisma pedestris
18,000 Mb
180 Mb
The difference in genome size of a factor of 100
is difficult to explain in view of the apparently
similar levels of evolutionary, developmental and
behavioral complexity of these organisms.
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The 80,000-fold divergence in genome sizes among
eukaryotes represents perhaps the greatest
challenge for genomic holists.
Gregory Hebert. Genome Res. 9, 317-324
(1999). Gregory. Bio. Rev. (2001) 76 65-101
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The key to the C-value paradox lies in the
nongenic regions
Dan Graur lecture
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Junk DNA
Susumu Ohno proposes that the majority of the
genome consisted of now-extinct genes
Not to be confused with the British rock band
(www.junkdna.co.uk)
Triumphs as well as failures of nature's past
experiments appear to be contained in our genome
- Susumu Ohno
Alas, although pseudogenes are not hard to find
in genomes, they correspond to only a small
fraction of them.
12
The phenotype paradigm and genome evolution

• The phenotype paradigm attempts to explain genome
  structure
• Untranslated mRNA sequences which precede,
  follow, or interrupt protein-coding sequences are
  often assigned a phenotypic roles in regulating
  mRNA
• Discarded portions of transcripts are considered
  to be required for processing.
• Non-transcribed DNA are thought of as regulatory
  or essential to chromosome structure.
• Evolutionary explanations the DNA facilitates
  genetic rearrangements which increase
  evolutionary versatility
• Non-coding DNA is considered a repository from
  which new functional sequences can be recruited.
• It is a yet to be eliminated by-product of past
  chromosomal rearrangements of evolutionary
  significance.
• Doolittle and Spienza. (1980) Nature 284 601-603

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The adaptationist programme
"The Spandrals of San Marco and the Panglossian
Paradigm A Critique of the Adaptationist
Programme" by Gould and Lewontin
Spandrals
The rejection of one adaptive story usually
leads to its replacement by another, rather than
to a suspicion that a different kind of
explanation might be required. Since the range of
adaptive stories is as wide as our minds are
fertile, new stories can always be postulated
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Necessary and unnecessary explanations
When a given DNA, or class of DNAs, of unproven
phenotypic function can be shown to have evolved
a strategy (such as transposition) which ensures
its genomic survival, then no other explanation
for its existence is necessary. The search for
other explanations may prove, if not
intellectually sterile, ultimately futile.
Doolittle and Spienza. (1980) Nature 284 601-603
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A chicken is just an egg's way of making more
eggs
The gene view of evolution genes are the basic
units of evolution
Individuals are not stable things, they are
fleeting. Chromosomes too are shuffled to
oblivion, like hands of cards soon after they are
dealt. But the cards themselves survive the
shuffling. The cards are the genes. The genes are
not destroyed by crossing-over, they merely
change partners and march on. Of course they
march on. That is their business. They are the
replicators and we are their survival machines.
When we have served our purpose we are cast
aside. But genes are denizens of geological time
genes are forever.
The Selfish Gene Richard Dawkins
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The Selfish Gene Richard Dawkins
genes are dynamic entities directly subject to
evolutionary forces
Genes are competing directly with their alleles
for survival, since their alleles in the gene
pool are rivals for their slot on the chromosomes
of future generations. Any gene that behaves in
such a way as to increase its own survival
chances in the gene pool at the expense of its
alleles will, by definition, tautologously, tend
to survive. The gene is the basic unit of
selfishness.
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The Selfish Gene Richard Dawkins
it appears that the amount of DNA in organisms
is more than is strictly necessary for building
them a large fraction of the DNA is never
translated into protein. From this point of view
of the individual organism this seems
paradoxical. As the purpose of DNA is to
supervise the building of bodies, it is
surprising to find a large quantity of DNA which
does no such thing. Biologists are racking their
brains to think what this surplus DNA is doing.
But from the point of view of the selfish genes
themselves, there is no paradox. The true
purpose of DNA is to survive, no more and no
less. The simplest way to explain the surplus DNA
is to suppose that it is a parasite, or at best a
harmless but useless passenger, hitching a ride
in the survival machines created by the other
DNA. pg 156
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Imagine a gene that could duplicate copies of
itself within the genome
time
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Selfish DNA

• A piece of selfish DNA has two distinct
  properties
• Arises when DNA sequence spreads by forming
  additional copies of itself within the genome
• Makes no specific contribution to the phenotype

Selfish sequences spread and make no
contribution to the phenotype of the organism,
except in insofar as it is a slight burden to the
cell that contains it.. The spread of DNA
sequences within the genome can be compared to
the spread of a not-too-harmful parasite within
its host.
Orgel, L. E. Crick, F. H. C. 1980. Nature 284
604-607
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Intra-genomic selection
The idea of selfish DNA is firmly based on this
general theory of natural selection, but it deals
with selection in an unfamiliar context In
short, we may expect a kind of molecular struggle
for existence within the DNA of the chromosomes,
using the process of natural selection.
Orgel, L. E. Crick, F. H. C. 1980. Nature 284
604-607
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Transposable elements are fixed despite being
deleterious

• Probability of fixation of a neutral allele is
  1/2N
• Probability of fixation of an allele with
  selective advantage s is 2s/(1 e4Ns)
• So the probability of fixation of any new mutant
  allele, relative to that of a neutral mutation,
  is 4Ns/(1 e4Ns)
• Note that a deleterious allele with Ns 0.5
  still has a chance of becoming fixed that is 31.3
  per cent of that of a neutral allele

Hartl. NRG (2000) 1 145-149
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Resolution of the C-value paradox
The C-value of a species is seen as the product
of a balance between an upward mutation pressure
acting to increase DNA content contrasted against
the tolerance of the host cell for the build-up
of functionless DNA.
Genetic drift increases genome size (selfish
elements replicating)
Purifying selection takes out the garbage
http//www.iapht.unito.it/giocattoli/images/fune.j
pg
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GATCTACCATGAAAGACTTGTGAATCCAGGAAGAGAGACTGACTGGGCAA
CATGTTATTCAGGTACAAAAAGATTTGGACTGTAACTTAAAAATGATCAA
ATTATGTTTCCCATGCATCAGGTGCAATGGGAAGCTCTTCTGGAGAGTGA
GAGAAGCTTCCAGTTAAGGTGACATTGAAGCCAAGTCCTGAAAGATGAGG
AAGAGTTGTATGAGAGTGGGGAGGGAAGGGGGAGGTGGAGGGATGGGGAA
TGGGCCGGGATGGGATAGCGCAAACTGCCCGGGAAGGGAAACCAGCACTG
TACAGACCTGAACAACGAAGATGGCATATTTTGTTCAGGGAATGGTGAAT
TAAGTGTGGCAGGAATGCTTTGTAGACACAGTAATTTGCTTGTATGGAAT
TTTGCCTGAGAGACCTCATTGCAGTTTCTGATTTTTTGATGTCTTCATCC
ATCACTGTCCTTGTCAAATAGTTTGGAACAGGTATAATGATCACAATAAC
CCCAAGCATAATATTTCGTTAATTCTCACAGAATCACATATAGGTGCCAC
AGTTATCCCCATTTTATGAATGGAGTTransposableElementsGATG
AAAACCTTAGGAATAATGAATGATTTGCGCAGGCTCACCTGGATATTAAG
ACTGAGTCAAATGTTGGGTCTGGTCTGACTTTAATGTTTGCTTTGTTCAT
GAGCACCACATATTGCCTCTCCTATGCAGTTAAGCAGGTAGGTGACAGAA
AAGCCCATGTTTGTCTCTACTCACACACTTCCGACTGAATGTATGTATGG
AGTTTCTACACCAGATTCTTCAGTGCTCTGGATATTAACTGGGTATCCCA
TGACTTTATTCTGACACTACCTGGACCTTGTCAAATAGTTTGGACCTTGT
CAAATAGTTTGGAGTCCTTGTCAAATAGTTTGGGGTTAGCACAGACCCCA
CAAGTTAGGGGCTCAGTCCCACGAGGCCATCCTCACTTCAGATGACAATG
GCAAGTCCTAAGTTGTCACCATACTTTTGACCAACCTGTTACCAATCGGG
GGTTCCCGTAACTGTCTTCTTGGGTTTAATAATTTGCTAGAACAGTTTAC
GGAACTCAGAAAAACAGTTTATTTTCTTTTTTTCTGAGAGAGAGGGTCTT
ATTTTGTTGCCCAGGCTGGTGTGCAATGGTGCAGTCATAGCTCATTGCAG
CCTTGATTGTCTGGGTTCCAGTGGTTCTCCCACCTCAGCCTCCCTAGTAG
CTGAGACTACATGCCTGCACCACCACATCTGGCTAGTTTCTTTTATTTTT
TGTATAGATGGGGTCTTGTTGTGTTGGCCAGGCTGGCCACAAATTCCTGG
TCTCAAGTGATCCTCCCACCTCAGCCTCTGAAAGTGCTGGGATTACAGAT
GTGAGCCACCACATCTGGCCAGTTCATTTCCTATTACTGGTTCATTGTGA
AGGATACATCTCAGAAACAGTCAATGAAAGAGACGTGCATGCTGGATGCA
GTGGCTCATGCCTGTAATCTCAGCACTTTGGGAGGCCAAGGTGGGAGGAT
CGCTTAAACTCAGGAGTTTGAGACCAGCCTGGGCAACATGGTGAAAACCT
GTCTCTATAAAAAATTAAAAAATAATAATAATAACTGGTGTGGTGTTGTG
CACCTAGAGTTCCAACTACTAGGGAAGCTGAGATGAGAGGATACCTTGAG
CTGGGGACTGGGGAGGCTTAGGTTACAGTAAGCTGAGATTGTGCCACTGC
ACTCCAGCTTGGACAAAAGAGCCTGATCCTGTCTCAAAAAAAAGAAAGAT
ACCCAGGGTCCACAGGCACAGCTCCATCGTTACAATGGCCTCTTTAGACC
CAGCTCCTGCCTCCCAGCCTTCT
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Barbara McClintock discovered jumping genes in
the 1940s and called them activator (Ac) and
dissociation (Ds) elements.
Ds element disrupts the purple pigment

• Ds and Ac are now know to be transposons.
• McClintock studied corn with genetic crosses (no
  molecular techniques invented were yet)
• She received the Nobel Prize in 1981 for this
  work.

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DNA transposons Jumping genes

• Have terminal inverted repeats and encode a
  transposase.
• Transposase mediates a cut-and-paste
  transposition.
• DNA transposons cannot exercise a cis-preference
  the transposase cannot distinguish active from
  inactive elements.
• As inactive copies (in which the transposase no
  longer works) accumulate, transposition becomes
  less efficient.
• DNA transposons eventually spread by horizontal
  transfer (see next lecture).

Graur Li. Fundamentals of Molecular Evolution
(1999)
26
LINEs (long interspersed repetitive elements)
6kb in humans
Encodes an internal polymerase II promoter and
two open reading frames
endonuclease
Endonuclease is not highly sequence specific but
seems to preferentially recognize a DNA junction
between pyrimidines and purines (dTndAn)
Reverse transcription frequently fails to proceed
to the 5 end, resulting in many truncated
nonfunctional insertions.
Graur Li. Fundamentals of Molecular Evolution
(1999)
27
LINEs (long interspersed repetitive elements)

• LINEs are autonomous
• 3 distantly related LINE families are found in
  the human genome, but only LINE1 is active.
• Human genome 515,000 copies of LINE1 (L1),
  365,000 L2, and 37,000 L3 (most are truncated
  or rearranged)
• Only 30-60 are active
• In mouse, 3,000 are active.

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SINEs (short interspersed repetitive elements)

• Short 100-400 bp
• Promoter regions of all known SINEs are derived
  from tRNA sequences except for a single family
  derived from 7SL (an abundant component of the
  signal recognition particle that is essential in
  the process of removing of signal peptides from
  secreted proteins).
• This latter family includes the only active SINE
  in the human genome the Alu element.
• Alus are found more than 1,000,000 times in the
  human genome (10 of the genome).
• What made these pseudogenes so successful? Unlike
  LINEs they are not self-propagating machines.

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SINEs are similar to LINEs in the 3 end
SINE (400bp)
LINE (6000bp)
Graur Li. Fundamentals of Molecular Evolution
(1999)
30
SINEs are successful LINE freeloaders!
SINEs transpose by using the LINE machinery
Encode an internal polymerase III promoter but no
proteins
LINE machinery
Graur Li. Fundamentals of Molecular Evolution
(1999)c
31
LTR (long terminal direct repeats)
retrotransposons

• Retrotransposons move by a copy and paste
  mechanism but in contrast to transposons, the
  copy is made of RNA, not DNA.
• The LTRs (long terminal direct repeats) contain
  all of the necessary transcriptional regulatory
  elements
• The autonomous also contain gag and pol which
  encode a protease, reverse transcriptase, RNaseH,
  and integrase.
• Reverse transcription occurs in the cytoplasm
  primed by a tRNA (in contrast to nuclear location
  and chromosomal priming of LINEs)

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Human immunodeficiency virus
gtgi9629357refNC_001802.1 Human
immunodeficiency virus 1, complete genome
GGTCTCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACT
AGGGAACCCACTGCTTAAGCC TCAATAAAGCTTGCCTTGAGTGCTTCAA
GTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTAGAGA
TCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTGGCGCCCG
AACAGGGACCTGAAAGCGAA AGGGAAACCAGAGGAGCTCTCTCGACGCA
GGACTCGGCTTGCTGAAGCGCGCACGGCAAGAGGCGAGGGG
CGGCGACTGGTGAGTACGCCAAAAATTTTGACTAGCGGAGGCTAGAAGGA
GAGAGATGGGTGCGAGAGCG TCAGTATTAAGCGGGGGAGAATTAGATCG
ATGGGAAAAAATTCGGTTAAGGCCAGGGGGAAAGAAAAAAT
ATAAATTAAAACATATAGTATGGGCAAGCAGGGAGCTAGAACGATTCGCA
GTTAATCCTGGCCTGTTAGA AACATCAGAAGGCTGTAGACAAATACTGG
GACAGCTACAACCATCCCTTCAGACAGGATCAGAAGAACTT
AGATCATTATATAATACAGTAGCAACCCTCTATTGTGTGCATCAAAGGAT
AGAGATAAAAGACACCAAGG AAGCTTTAGACAAGATAGAGGAAGAGCAA
AACAAAAGTAAGAAAAAAGCACAGCAAGCAGCAGCTGACAC
AGGACACAGCAATCAGGTCAGCCAAAATTACCCTATAGTGCAGAACATCC
AGGGGCAAATGGTACATCAG GCCATATCACCTAGAACTTTAAATGCATG
GGTAAAAGTAGTAGAAGAGAAGGCTTTCAGCCCAGAAGTGA
TACCCATGTTTTCAGCATTATCAGAAGGAGCCACCCCACAAGATTTAAAC
ACCATGCTAAACACAGTGGG GGGACATCAAGCAGCCATGCAAATGTTAA
AAGAGACCATCAATGAGGAAGCTGCAGAATGGGATAGAGTG
CATCCAGTGCATGCAGGGCCTATTGCACCAGGCCAGATGAGAGAACCAAG
GGGAAGTGACATAGCAGGAA CTACTAGTACCCTTCAGGAACAAATAGGA
TGGATGACAAATAATCCACCTATCCCAGTAGGAGAAATTTA
TAAAAGATGGATAATCCTGGGATTAAATAAAATAGTAAGAATGTATAGCC
CTACCAGCATTCTGGACATA AGACAAGGACCAAAGGAACCCTTTAGAGA
CTATGTAGACCGGTTCTATAAAACTCTAAGAGCCGAGCAAG
CTTCACAGGAGGTAAAAAATTGGATGACAGAAACCTTGTTGGTCCAAAAT
GCGAACCCAGATTGTAAGAC TATTTTAAAAGCATTGGGACCAGCGGCTA
CACTAGAAGAAATGATGACAGCATGTCAGGGAGTAGGAGGA
CCCGGCCATAAGGCAAGAGTTTTGGCTGAAGCAATGAGCCAAGTAACAAA
TTCAGCTACCATAATGATGC AGAGAGGCAATTTTAGGAACCAAAGAAAG
ATTGTTAAGTGTTTCAATTGTGGCAAAGAAGGGCACACAGC
CAGAAATTGCAGGGCCCCTAGGAAAAAGGGCTGTTGGAAATGTGGAAAGG
AAGGACACCAAATGAAAGAT TGTACTGAGAGACAGGCTAATTTTTTAGG
GAAGATCTGGCCTTCCTACAAGGGAAGGCCAGGGAATTTTC
TTCAGAGCAGACCAGAGCCAACAGCCCCACCAGAAGAGAGCTTCAGGTCT
GGGGTAGAGACAACAACTCC CCCTCAGAAGCAGGAGCCGATAGACAAGG
AACTGTATCCTTTAACTTCCCTCAGGTCACTCTTTGGCAAC
GACCCCTCGTCACAATAAAGATAGGGGGGCAACTAAAGGAAGCTCTATTA
GATACAGGAGCAGATGATAC AGTATTAGAAGAAATGAGTTTGCCAGGAA
GATGGAAACCAAAAATGATAGGGGGAATTGGAGGTTTTATC
AAAGTAAGACAGTATGATCAGATACTCATAGAAATCTGTGGACATAAAGC
TATAGGTACAGTATTAGTAG GACCTACACCTGTCAACATAATTGGAAGA
AATCTGTTGACTCAGATTGGTTGCACTTTAAATTTTCCCAT
TAGCCCTATTGAGACTGTACCAGTAAAATTAAAGCCAGGAATGGATGGCC
CAAAAGTTAAACAATGGCCA TTGACAGAAGAAAAAATAAAAGCATTAGT
AGAAATTTGTACAGAGATGGAAAAGGAAGGGAAAATTTCAA
AAATTGGGCCTGAAAATCCATACAATACTCCAGTATTTGCCATAAAGAAA
AAAGACAGTACTAAATGGAG AAAATTAGTAGATTTCAGAGAACTTAATA
AGAGAACTCAAGACTTCTGGGAAGTTCAATTAGGAATACCA
CATCCCGCAGGGTTAAAAAAGAAAAAATCAGTAACAGTACTGGATGTGGG
TGATGCATATTTTTCAGTTC CCTTAGATGAAGACTTCAGGAAGTATACT
GCATTTACCATACCTAGTATAAACAATGAGACACCAGGGAT
TAGATATCAGTACAATGTGCTTCCACAGGGATGGAAAGGATCACCAGCAA
TATTCCAAAGTAGCATGACA AAAATCTTAGAGCCTTTTAGAAAACAAAA
TCCAGACATAGTTATCTATCAATACATGGATGATTTGTATG
TAGGATCTGACTTAGAAATAGGGCAGCATAGAACAAAAATAGAGGAGCTG
AGACAACATCTGTTGAGGTG GGGACTTACCACACCAGACAAAAAACATC
AGAAAGAACCTCCATTCCTTTGGATGGGTTATGAACTCCAT
CCTGATAAATGGACAGTACAGCCTATAGTGCTGCCAGAAAAAGACAGCTG
GACTGTCAATGACATACAGA AGTTAGTGGGGAAATTGAATTGGGCAAGT
CAGATTTACCCAGGGATTAAAGTAAGGCAATTATGTAAACT
CCTTAGAGGAACCAAAGCACTAACAGAAGTAATACCACTAACAGAAGAAG
CAGAGCTAGAACTGGCAGAA AACAGAGAGATTCTAAAAGAACCAGTACA
TGGAGTGTATTATGACCCATCAAAAGACTTAATAGCAGAAA
TACAGAAGCAGGGGCAAGGCCAATGGACATATCAAATTTATCAAGAGCCA
TTTAAAAATCTGAAAACAGG AAAATATGCAAGAATGAGGGGTGCCCACA
CTAATGATGTAAAACAATTAACAGAGGCAGTGCAAAAAATA
ACCACAGAAAGCATAGTAATATGGGGAAAGACTCCTAAATTTAAACTGCC
CATACAAAAGGAAACATGGG AAACATGGTGGACAGAGTATTGGCAAGCC
ACCTGGATTCCTGAGTGGGAGTTTGTTAATACCCCTCCCTT
AGTGAAATTATGGTACCAGTTAGAGAAAGAACCCATAGTAGGAGCAGAAA
CCTTCTATGTAGATGGGGCA GCTAACAGGGAGACTAAATTAGGAAAAGC
AGGATATGTTACTAATAGAGGAAGACAAAAAGTTGTCACCC
TAACTGACACAACAAATCAGAAGACTGAGTTACAAGCAATTTATCTAGCT
TTGCAGGATTCGGGATTAGA AGTAAACATAGTAACAGACTCACAATATG
CATTAGGAATCATTCAAGCACAACCAGATCAAAGTGAATCA
GAGTTAGTCAATCAAATAATAGAGCAGTTAATAAAAAAGGAAAAGGTCTA
TCTGGCATGGGTACCAGCAC ACAAAGGAATTGGAGGAAATGAACAAGTA
GATAAATTAGTCAGTGCTGGAATCAGGAAAGTACTATTTTT
AGATGGAATAGATAAGGCCCAAGATGAACATGAGAAATATCACAGTAATT
GGAGAGCAATGGCTAGTGAT TTTAACCTGCCACCTGTAGTAGCAAAAGA
AATAGTAGCCAGCTGTGATAAATGTCAGCTAAAAGGAGAAG
CCATGCATGGACAAGTAGACTGTAGTCCAGGAATATGGCAACTAGATTGT
ACACATTTAGAAGGAAAAGT TATCCTGGTAGCAGTTCATGTAGCCAGTG
GATATATAGAAGCAGAAGTTATTCCAGCAGAAACAGGGCAG
GAAACAGCATATTTTCTTTTAAAATTAGCAGGAAGATGGCCAGTAAAAAC
AATACATACTGACAATGGCA GCAATTTCACCGGTGCTACGGTTAGGGCC
GCCTGTTGGTGGGCGGGAATCAAGCAGGAATTTGGAATTCC
CTACAATCCCCAAAGTCAAGGAGTAGTAGAATCTATGAATAAAGAATTAA
AGAAAATTATAGGACAGGTA AGAGATCAGGCTGAACATCTTAAGACAGC
AGTACAAATGGCAGTATTCATCCACAATTTTAAAAGAAAAG
GGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGACATAATAGCA
ACAGACATACAAACTAAAGA ATTACAAAAACAAATTACAAAAATTCAAA
ATTTTCGGGTTTATTACAGGGACAGCAGAAATCCACTTTGG
AAAGGACCAGCAAAGCTCCTCTGGAAAGGTGAAGGGGCAGTAGTAATACA
AGATAATAGTGACATAAAAG TAGTGCCAAGAAGAAAAGCAAAGATCATT
AGGGATTATGGAAAACAGATGGCAGGTGATGATTGTGTGGC
AAGTAGACAGGATGAGGATTAGAACATGGAAAAGTTTAGTAAAACACCAT
ATGTATGTTTCAGGGAAAGC TAGGGGATGGTTTTATAGACATCACTATG
AAAGCCCTCATCCAAGAATAAGTTCAGAAGTACACATCCCA
CTAGGGGATGCTAGATTGGTAATAACAACATATTGGGGTCTGCATACAGG
AGAAAGAGACTGGCATTTGG GTCAGGGAGTCTCCATAGAATGGAGGAAA
AAGAGATATAGCACACAAGTAGACCCTGAACTAGCAGACCA
ACTAATTCATCTGTATTACTTTGACTGTTTTTCAGACTCTGCTATAAGAA
AGGCCTTATTAGGACACATA GTTAGCCCTAGGTGTGAATATCAAGCAGG
ACATAACAAGGTAGGATCTCTACAATACTTGGCACTAGCAG
CATTAATAACACCAAAAAAGATAAAGCCACCTTTGCCTAGTGTTACGAAA
CTGACAGAGGATAGATGGAA CAAGCCCCAGAAGACCAAGGGCCACAGAG
GGAGCCACACAATGAATGGACACTAGAGCTTTTAGAGGAGC
TTAAGAATGAAGCTGTTAGACATTTTCCTAGGATTTGGCTCCATGGCTTA
GGGCAACATATCTATGAAAC TTATGGGGATACTTGGGCAGGAGTGGAAG
CCATAATAAGAATTCTGCAACAACTGCTGTTTATCCATTTT
CAGAATTGGGTGTCGACATAGCAGAATAGGCGTTACTCGACAGAGGAGAG
CAAGAAATGGAGCCAGTAGA TCCTAGACTAGAGCCCTGGAAGCATCCAG
GAAGTCAGCCTAAAACTGCTTGTACCAATTGCTATTGTAAA
AAGTGTTGCTTTCATTGCCAAGTTTGTTTCATAACAAAAGCCTTAGGCAT
CTCCTATGGCAGGAAGAAGC GGAGACAGCGACGAAGAGCTCATCAGAAC
AGTCAGACTCATCAAGCTTCTCTATCAAAGCAGTAAGTAGT
ACATGTAATGCAACCTATACCAATAGTAGCAATAGTAGCATTAGTAGTAG
CAATAATAATAGCAATAGTT GTGTGGTCCATAGTAATCATAGAATATAG
GAAAATATTAAGACAAAGAAAAATAGACAGGTTAATTGATA
GACTAATAGAAAGAGCAGAAGACAGTGGCAATGAGAGTGAAGGAGAAATA
TCAGCACTTGTGGAGATGGG GGTGGAGATGGGGCACCATGCTCCTTGGG
ATGTTGATGATCTGTAGTGCTACAGAAAAATTGTGGGTCAC
AGTCTATTATGGGGTACCTGTGTGGAAGGAAGCAACCACCACTCTATTTT
GTGCATCAGATGCTAAAGCA TATGATACAGAGGTACATAATGTTTGGGC
CACACATGCCTGTGTACCCACAGACCCCAACCCACAAGAAG
TAGTATTGGTAAATGTGACAGAAAATTTTAACATGTGGAAAAATGACATG
GTAGAACAGATGCATGAGGA TATAATCAGTTTATGGGATCAAAGCCTAA
AGCCATGTGTAAAATTAACCCCACTCTGTGTTAGTTTAAAG
TGCACTGATTTGAAGAATGATACTAATACCAATAGTAGTAGCGGGAGAAT
GATAATGGAGAAAGGAGAGA TAAAAAACTGCTCTTTCAATATCAGCACA
AGCATAAGAGGTAAGGTGCAGAAAGAATATGCATTTTTTTA
TAAACTTGATATAATACCAATAGATAATGATACTACCAGCTATAAGTTGA
CAAGTTGTAACACCTCAGTC ATTACACAGGCCTGTCCAAAGGTATCCTT
TGAGCCAATTCCCATACATTATTGTGCCCCGGCTGGTTTTG
CGATTCTAAAATGTAATAATAAGACGTTCAATGGAACAGGACCATGTACA
AATGTCAGCACAGTACAATG TACACATGGAATTAGGCCAGTAGTATCAA
CTCAACTGCTGTTAAATGGCAGTCTAGCAGAAGAAGAGGTA
GTAATTAGATCTGTCAATTTCACGGACAATGCTAAAACCATAATAGTACA
GCTGAACACATCTGTAGAAA TTAATTGTACAAGACCCAACAACAATACA
AGAAAAAGAATCCGTATCCAGAGAGGACCAGGGAGAGCATT
TGTTACAATAGGAAAAATAGGAAATATGAGACAAGCACATTGTAACATTA
GTAGAGCAAAATGGAATAAC ACTTTAAAACAGATAGCTAGCAAATTAAG
AGAACAATTTGGAAATAATAAAACAATAATCTTTAAGCAAT
CCTCAGGAGGGGACCCAGAAATTGTAACGCACAGTTTTAATTGTGGAGGG
GAATTTTTCTACTGTAATTC AACACAACTGTTTAATAGTACTTGGTTTA
ATAGTACTTGGAGTACTGAAGGGTCAAATAACACTGAAGGA
AGTGACACAATCACCCTCCCATGCAGAATAAAACAAATTATAAACATGTG
GCAGAAAGTAGGAAAAGCAA TGTATGCCCCTCCCATCAGTGGACAAATT
AGATGTTCATCAAATATTACAGGGCTGCTATTAACAAGAGA
TGGTGGTAATAGCAACAATGAGTCCGAGATCTTCAGACCTGGAGGAGGAG
ATATGAGGGACAATTGGAGA AGTGAATTATATAAATATAAAGTAGTAAA
AATTGAACCATTAGGAGTAGCACCCACCAAGGCAAAGAGAA
GAGTGGTGCAGAGAGAAAAAAGAGCAGTGGGAATAGGAGCTTTGTTCCTT
GGGTTCTTGGGAGCAGCAGG AAGCACTATGGGCGCAGCCTCAATGACGC
TGACGGTACAGGCCAGACAATTATTGTCTGGTATAGTGCAG
CAGCAGAACAATTTGCTGAGGGCTATTGAGGCGCAACAGCATCTGTTGCA
ACTCACAGTCTGGGGCATCA AGCAGCTCCAGGCAAGAATCCTGGCTGTG
GAAAGATACCTAAAGGATCAACAGCTCCTGGGGATTTGGGG
TTGCTCTGGAAAACTCATTTGCACCACTGCTGTGCCTTGGAATGCTAGTT
GGAGTAATAAATCTCTGGAA CAGATTTGGAATCACACGACCTGGATGGA
GTGGGACAGAGAAATTAACAATTACACAAGCTTAATACACT
CCTTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAGAATTA
TTGGAATTAGATAAATGGGC AAGTTTGTGGAATTGGTTTAACATAACAA
ATTGGCTGTGGTATATAAAATTATTCATAATGATAGTAGGA
GGCTTGGTAGGTTTAAGAATAGTTTTTGCTGTACTTTCTATAGTGAATAG
AGTTAGGCAGGGATATTCAC CATTATCGTTTCAGACCCACCTCCCAACC
CCGAGGGGACCCGACAGGCCCGAAGGAATAGAAGAAGAAGG
TGGAGAGAGAGACAGAGACAGATCCATTCGATTAGTGAACGGATCCTTGG
CACTTATCTGGGACGATCTG CGGAGCCTGTGCCTCTTCAGCTACCACCG
CTTGAGAGACTTACTCTTGATTGTAACGAGGATTGTGGAAC
TTCTGGGACGCAGGGGGTGGGAAGCCCTCAAATATTGGTGGAATCTCCTA
CAGTATTGGAGTCAGGAACT AAAGAATAGTGCTGTTAGCTTGCTCAATG
CCACAGCCATAGCAGTAGCTGAGGGGACAGATAGGGTTATA
GAAGTAGTACAAGGAGCTTGTAGAGCTATTCGCCACATACCTAGAAGAAT
AAGACAGGGCTTGGAAAGGA TTTTGCTATAAGATGGGTGGCAAGTGGTC
AAAAAGTAGTGTGATTGGATGGCCTACTGTAAGGGAAAGAA
TGAGACGAGCTGAGCCAGCAGCAGATAGGGTGGGAGCAGCATCTCGAGAC
CTGGAAAAACATGGAGCAAT CACAAGTAGCAATACAGCAGCTACCAATG
CTGCTTGTGCCTGGCTAGAAGCACAAGAGGAGGAGGAGGTG
GGTTTTCCAGTCACACCTCAGGTACCTTTAAGACCAATGACTTACAAGGC
AGCTGTAGATCTTAGCCACT TTTTAAAAGAAAAGGGGGGACTGGAAGGG
CTAATTCACTCCCAAAGAAGACAAGATATCCTTGATCTGTG
GATCTACCACACACAAGGCTACTTCCCTGATTAGCAGAACTACACACCAG
GGCCAGGGGTCAGATATCCA CTGACCTTTGGATGGTGCTACAAGCTAGT
ACCAGTTGAGCCAGATAAGATAGAAGAGGCCAATAAAGGAG
AGAACACCAGCTTGTTACACCCTGTGAGCCTGCATGGGATGGATGACCCG
GAGAGAGAAGTGTTAGAGTG GAGGTTTGACAGCCGCCTAGCATTTCATC
ACGTGGCCCGAGAGCTGCATCCGGAGTACTTCAAGAACTGC
TGACATCGAGCTTGCTACAAGGGACTTTCCGCTGGGGACTTTCCAGGGAG
GCGTGGCCTGGGCGGGACTG GGGAGTGGCGAGCCCTCAGATCCTGCATA
TAAGCAGCTGCTTTTTGCCTGTACTGGGTCTCTCTGGTTAG
ACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTT
AAGCCTCAATAAAGCTTGCC TTGAGTGCTTC
33
LTR retrotransposons are close relatives of
retroviruses
Envelope protein
Human immunodeficiency virus
34
Evolution of Viruses
Gain structural genes (env)
Retrotransposon ? ? ?
Retrovirus
Do viruses challenge our definitions of life?
The modest scope of viruses on the tree of life
35
Transposable elements employ different strategies

• LINEs and SINEs rely on vertical transmission
  within the host genome and its progeny.
• DNA transposons require frequent horizontal
  transfer
• LTR retrotransposons use both strategies some
  are long term residents of the genome and others
  have only short-residence times.

36
Repeats dominate the human genome
One megabase from chromosome 7
Interspersed repeats
UCSC Genome Browser http//genome.cse.ucsc.edu
37
Census of human repeats
Over 40 of the human genome corresponds to
interspersed repeats
IHGSC. Nature (2001) 409 860-921
38
Number and nature of interspersed repeats in
human, fly and worm
The euchromatic portion of the human genome has a
much higher density of transposable element
copies than fly and worm
39
The fossil record of human repeats
IHGSC. Nature (2001) 409 860-921
Time (as are generally not under functional
constraint)
Human divergence from prosimians
Eutherian radiation
Human divergence from gibbon
Human divergence from old world monkeys
40
The fossil record of human repeats
Time (as are generally not under functional
constraint)
IHGSC. Nature (2001) 409 860-921
41
The fossil record of human repeats
In earlier times, the reigning transposons were
LINE2 and MIR (a SINE)
Time (as are generally not under functional
constraint)
The SINE MIR was perfectly adapted to LINE2 (it
carried the same 50-base sequence at its 3 end).
When LINE2 became extinct 80-100 Myr ago, it also
spelled the doom of MIR.
IHGSC. Nature (2001) 409 860-921
42
The fossil record of human repeats
There has been significant slowdown in human
transposition in recent evolution
Time (as are generally not under functional
constraint)
IHGSC. Nature (2001) 409 860-921
43
The fossil record of mouse repeats
A slowdown is also found in mouse but not as
significant as in human
MGSC. Nature (2002) 420 520-562
44
The human genome is filled with copies of ancient
transposons, while the transposons in the other
genomes tend to be of more recent origin
Comparison of the age of interspersed repeats in
eukaryotic genomes
IHGSC. Nature (2001) 409 860-921
45
Variation in the distribution of repeats
Exons Repeats
Transposons are blocked certain crucial regions
IHGSC. Nature (2001) 409 860-921
46
LINE1 are popular in GC poor regions, while
ALUs are popular in GC rich regions
Density of the major repeat classes as a function
of local GC content, in windows of 50kb
IHGSC. Nature (2001) 409 860-921
47
Alu elements target AT-rich DNA, but accumulate
in GC-rich DNA
Same distribution but with only for Alus and
sorted according to different age groups
Age groups
IHGSC. Nature (2001) 409 860-921
48
LINE elements also target AT-rich DNA, but have
not changed in the past 100 million years
GC content distribution of LINE1 according to
different age groups
Age groups
IHGSC. Nature (2001) 409 860-921
49
Do Alus have a function?
Schmid proposed that SINEs function a promoters
of protein translation under stress. This
hypothesis is based on the observation that

• In many species SINEs are transcribed under
  conditions of stress.
• The resulting RNAs specifically bind a particular
  protein kinase (PKR) and block its ability to
  inhibit protein translation
• SINE RNAs would thus promote protein translation
  under stress.
• SINE would be appropriate for this function since
  they
• Can be quickly transcribed in large quantities
  from thousands of elements.
• Can function without protein translation.
• Positive selection for SINEs in readily
  transcribed open chromatin would explain Alus
  proximity to genes (GC-rich regions).

Schmid NAR (1998) 26 4541-4550
IHGSC. Nature (2001) 409 860-921
50
GATCTACCATGAAAGACTTGTGAATCCAGGAAGAGAGACTGACTGGGCAA
CATGTTATTCAGGTACAAAAAGATTTGGACTGTAACTTAAAAATGATCAA
ATTATGTTTCCCATGCATCAGGTGCAATGGGAAGCTCTTCTGGAGAGTGA
GAGAAGCTTCCAGTTAAGGTGACATTGAAGCCAAGTCCTGAAAGATGAGG
AAGAGTTGTATGAGAGTGGGGAGGGAAGGGGGAGGTGGAGGGATGGGGAA
TGGGCCGGGATGGGATAGCGCAAACTGCCCGGGAAGGGAAACCAGCACTG
TACAGACCTGAACAACGAAGATGGCATATTTTGTTCAGGGAATGGTGAAT
TAAGTGTGGCAGGAATGCTTTGTAGACACAGTAATTTGCTTGTATGGAAT
TTTGCCTGAGAGACCTCATTGCAGTTTCTGATTTTTTGATGTCTTCATCC
ATCACTGTCCTTGTCAAATAGTTTGGAACAGGTATAATGATCACAATAAC
CCCAAGCATAATATTTCGTTAATTCTCACAGAATCACATATAGGTGCCAC
AGTTATCCCCATTTTATGAATGGAGTConsequencesofMovementGA
TGAAAACCTTAGGAATAATGAATGATTTGCGCAGGCTCACCTGGATATTA
AGACTGAGTCAAATGTTGGGTCTGGTCTGACTTTAATGTTTGCTTTGTTC
ATGAGCACCACATATTGCCTCTCCTATGCAGTTAAGCAGGTAGGTGACAG
AAAAGCCCATGTTTGTCTCTACTCACACACTTCCGACTGAATGTATGTAT
GGAGTTTCTACACCAGATTCTTCAGTGCTCTGGATATTAACTGGGTATCC
CATGACTTTATTCTGACACTACCTGGACCTTGTCAAATAGTTTGGACCTT
GTCAAATAGTTTGGAGTCCTTGTCAAATAGTTTGGGGTTAGCACAGACCC
CACAAGTTAGGGGCTCAGTCCCACGAGGCCATCCTCACTTCAGATGACAA
TGGCAAGTCCTAAGTTGTCACCATACTTTTGACCAACCTGTTACCAATCG
GGGGTTCCCGTAACTGTCTTCTTGGGTTTAATAATTTGCTAGAACAGTTT
ACGGAACTCAGAAAAACAGTTTATTTTCTTTTTTTCTGAGAGAGAGGGTC
TTATTTTGTTGCCCAGGCTGGTGTGCAATGGTGCAGTCATAGCTCATTGC
AGCCTTGATTGTCTGGGTTCCAGTGGTTCTCCCACCTCAGCCTCCCTAGT
AGCTGAGACTACATGCCTGCACCACCACATCTGGCTAGTTTCTTTTATTT
TTTGTATAGATGGGGTCTTGTTGTGTTGGCCAGGCTGGCCACAAATTCCT
GGTCTCAAGTGATCCTCCCACCTCAGCCTCTGAAAGTGCTGGGATTACAG
ATGTGAGCCACCACATCTGGCCAGTTCATTTCCTATTACTGGTTCATTGT
GAAGGATACATCTCAGAAACAGTCAATGAAAGAGACGTGCATGCTGGATG
CAGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAGGCCAAGGTGGGAGG
ATCGCTTAAACTCAGGAGTTTGAGACCAGCCTGGGCAACATGGTGAAAAC
CTGTCTCTATAAAAAATTAAAAAATAATAATAATAACTGGTGTGGTGTTG
TGCACCTAGAGTTCCAACTACTAGGGAAGCTGAGATGAGAGGATACCTTG
AGCTGGGGACTGGGGAGGCTTAGGTTACAGTAAGCTGAGATTGTGCCACT
GCACTCCAGCTTGGACAAAAGAGCCTGATCCTGTCTCAAAAAAAAGAAAG
ATACCCAGGGTCCACAGGCACAGCTCCATCGTTACAATGGCCTCTTTAGA
CCCAGCTCCTGCCTCCCAGCCTTCT
51
What are the effects of transposition on the host
genome?

• Insertions.
• Transduction.
• Recombination.

Deleterious Potentially advantageous
52
Insertions
L1 insertions have turned up in several
genetic disorders including Duchenne muscular
dystrophy, type 2 retinitis pigmentosa, ß
-thalassaemia and chronic granulomatous disease
Prak Kazazian. (2000) NRG. 1 134-144
53
Transduction.
In addition to duplicating themselves, L1s
can carry with them genomic flanking sequences
that are downstream of their 3UTRs.
Prak Kazazian. (2000) NRG. 1 134-144
54
Recombination
Apart from influencing gene expression and
function through insertions, the large number of
Alu elements, and to a lesser extent L1 elements,
may promote homologous recombination events.
Prak Kazazian. (2000) NRG. 1 134-144
55
The End, Thanks.
Transposon art. Mobile genetic elements caused
these prized color patterns in morning glories.
56
Inteins are selfish DNA elements found within
coding regions
Pietrokovski, S. TIGs 2001 Aug17(8)465-72