Endogenous Retroviruses Health and Evolution

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Endogenous Retroviruses Health and Evolution

• Giri Ramsingh

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Darwins surprise
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(No Transcript)
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Retroviruses are RNA viruses with Reverse
Transcriptase DNA copies of these viruses
inegrate into the genome of the infected cell
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If this happens in the germ line cell,
Retroviral infection of sperm/ova
Inherited by offspring
Fixed in the gene pool Of Host population
1968 Robin Weiss, University College London
identified integrated retroviruses in Healthy
chicken embryos. He then identified the same
virus integrated at same loci in many other
related species ENDOGENOUS RETROVIRUSES
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Infectious (exogenous) retroviruses
Human endogenous retroviruses
Almost all endogenous retroviruses are defective,
however some can still be active
Griffiths, Genomebiology 2001
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Human endogenous retroviruses ( HERVs) were
recognized about 20 years agoBut their
abundance were not predicted till human genome
sequencing was completed in 2003.
Human genome 3 billion base pairs of DNA.
50 are unique and 50 are repititive sequences
Unique/low copy sequences -coding sequences for
proteins- 3 -introns

• Highly repetitive sequences
• -genes encoding riobosomal components
• arranged in tandem repeats 150-200 times
• -very small/small tandem repeats
• Intermediate repititve class
• Transposable elements (includes HERVs)
• ( 46.4 of human genome)

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Transposable elements (TE) mobile Elements
within the genome. Retro-elements require
reverse transcriptase action on RNA for
transposition (copypaste) HERVs are classified
based on their resemblance to other retroviruses.
The nomenclature of the HERV is based on the
aminoacid specificity of The t-RNA that
hybridizes to the primary site. HERV class II is
the newest. Some of them are Human specific (
HERV-K (HLM2)).
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Direct effect of the HERVs on genes -Insertional
mutagenesis and recombinations -Modulation of
gene expression HERV proteins -cell
fusion -inflammation -immune response -control
nuclear factors -cell division? -apoptosis?
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Insertional Mutagenensis
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HERV Proteins in diseases? Cause Vs Effect

• In autoimmune diseases
• HERV particles or antibodies against HERV
  particles have been seen in
• -Multiple sclerosis
• -Diabetes
• -Sjogrens disease
• -Rheumatoid arthritis
• -Systemic Lupus erythematosis.
• In Cancer Expression of HERV-K is activated
• -HERV-K particles are identified in
  teratocarcinoma, melanoma,ovarian cancer
• -High proportion of patients with seminoma have
  antiboides to HERV proteins
• -HERV-K proteins (Rec and Np9) bind to
  promyelocytic leukemia zinc finger,a
• transcriptional repressor of c-myc- role in
  seminoma

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HERV-proteins as tumor specific antigens
Takahashi, JCI March 2008
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Takahashi, JCI March 2008
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Gene modulation in health
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Role in evolution ?
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Molecular Clock Comparing the LTR sequences-
At the time of integration Both LTRs are
identical. Estimated 1 necleotide difference
every 200-450K years Relationship tree random
integration at the same loci at 2 different times
is almost impossible.
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• Human and chimpanzees have 98.5 similarity in
  their coding region and most of those differences
  are in genes related to smell and taste
• The most dramatic difference is seen in Y (and X)
  chromosomes ( between any higher species) Y
  chromosome carries the least genes.
• The differences are largely attributed to
  retroposons ( non coding genes). They are more
  conserved than coding regions

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Spiny anteater
Duck billed platypus
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Can endogenous retroviruses be brought back to
life?
HERV-K(HML2) "endogenization" and present-day
human proviruses
Marie Dewannieux et al. Genome Res. 2006 16
1548-1556
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Electron microscopy of the viral-like particles
generated by the Phoenix provirus
Marie Dewannieux et al. Genome Res. 2006 16
1548-1556
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Infectious properties of Phoenix encoded particles
Marie Dewannieux et al. Genome Res. 2006 16
1548-1556
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Individual immunity Versus Species Immunity
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• Chimps are easily infected by HIV but never
  causes AIDS.

The most dramatic difference between humans and
chimp -Pan Troglodytes, an endogenous retrovirus
(pterv) Chimps 130 copies, Gorillas 8 copies,
Humans none. Got integrated in genome 5 million
years ago. -Human Trim5a suppresses
pterv -Chimp/gorilla/old world monkey Trim5a
suppresses HIV Both mutually exclusive ?Protecti
on from pterv by mutation of Trim5 resulted in
the next step in evolution, but left humans
susceptible to HIV
Kaiser ,Science 2007
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Can HIV become endogenous?

• Belongs to lentivirus family that till recently
  was not found in any genome.
• Recently, first endogenous lentivirus (RELIK)was
  identified in European rabbit- date of
  endogenization 7 million years.

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In late 19th century Kaolas were hunted to near
extinction They were then moved to islands in
south and later brought back to mainland after
100 years to replenish the population Epidemic
of a retrovirus spread among them causing
leukemia and immunodeficiency. Tarlington et al
noted that some babies were infected in the Same
location on DNA as their parents- Virus becoming
endogenous No Kaolas in the Southern islands are
infected.
Tarlinton, Nature, 2006
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• -Viruses in addition to being genetic parasites
  causing diseases
• are a major creative force
• Scenario where AIDS wipes out nearly an entire
  population
• A few will survive without getting sick
• The survivors (people with acquired mutations
• that protect them from the virus and having
  persistent infection )
• would then repopulate the continent. They also
  would have acquired some new
• and complex characteristics.
• - They would be sexually incompatible with
  the rest of the population setting a stage for
• selective inbreeding
• -This population would have acquired a new set of
  complex genes that regulated various
• aspects of cellular molecular and immunology-
  HIV lentivirus genes.
• - Birth of a New species of humans marked by its
  newly acquired endogenous viruses

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Last slide
Chimpanzies will not believe what they have given
rise to