GPR33: a short description

1
Did he catch a VHF in Bali?
Some interesting facts and some wild conjectures
PubMed15987686 Römpler H., Schulz A., Pitra
C., Coop G., Przeworski M., Pääbo S., Schöneberg
T. The rise and fall of the chemoattractant
receptor GPR33. JBC 28031068-31075(2005).
2
GPR33 a short description

• GPR33, a G-protein coupled receptor from family
  1
• Closest homologs are CMKLR1 (chemokine
  receptor-like 1) and FRPL1 (FMLP-related receptor
  I)
• Ligand is unknown, but could be a chemoattractant
  receptor
• Has evolved in mammals about 125 to 190 My years
  ago (not found in monotremes such as platypus and
  echidna).
• Found on 14q12 in human
• Swiss-Prot ACs Human Q49SQ1 Mouse O88416

3
A curious case of pseudogenization

• In most individuals a nonsense mutation changes
  Arg-140 into a premature stop codon. Out of 1217
  individuals, 1166 had a stop codon in both
  alleles, 50 were heterozygous and only 1 (from
  the Philippines) had Arg-140 in both alleles
• Inactivated in some chimpanzees by stop mutations
  in either Ser-39 or Arg-140, but intact in the
  bonobo
• Inactivated in some orangutans by a stop mutation
  in His-171
• Inactivated in siamang by a stop mutation in
  Trp-94
• Inactivated in Norway rat by a 14 bp deletion,
  but still intact in black rat
• Also inactivated in two gerbil species, Syrian
  hamster and European mole by frameshifting
  deletions or insertions.

4
And..

• Because they target mammalian species in
  different branches of the taxonomic tree the
  pseudogenization events are independent
• They took place from 700'000 to 1 million year
  ago
• Inactivation could have occurred because
• 1) Loss of constraint due to
• a) Loss of an endogenous ligand
• b) Loss of an exogenous ligand
• c) Emergence of a functional redundancy
• 2) Positive selection

5
What the paper concludes

• Loss of constraint very unlikely for 1a and 1c as
  it cannot explain the "simultaneous"
  pseudogenization
• Loss of an exogenous ligand from the biosphere
  (example disparition of a volatile compound) is
  not very likely as it does not explain why all
  other species have kept GPR33 intact
• Positive selection is therefore very likely
• The selective inactivation may be due to the
  interaction of GPR33 with a putative pathogen
  that could use as a receptor for cell invasion
• This is the case of CXCR4, CXCR6 (Bonzo), CCR3,
  CCR5, CX3CR1, GPR15 for HIV-1/HIV-2/SIV viruses
• But this particular pathogen was quite special as
  it targeted both rodents and primates.

6
Some other facts

• The ancestors of Rattus norvegicus and R. rattus
  diverged from each other about 2 million years
  ago
• Norway rats originated on the plains of Asia,
  probably in what is now northern China and
  Mongolia, where wild rats still live in burrows
  today
• They seem to always have been associated with
  human populations (this type of association is
  called commensalism)
• Both the siamang gibbon and the orangutan
  currently live and seem to originate from
  Southeast Asia
• Homo erectus lived between 1.8 million and
  300000 years ago. It was a successful species
  for a million and a half years. He travelled out
  of Africa into China and Southeast Asia.

7
Does the smoking gun points to Southeast Asia?

• Most of the species concerned by GPR33
  pseudogenization seem to have been present in
  Southeast Asia, except for chimpanzee, but.

8
Are ticks the culprit?

• Some species of ticks can bite both primates and
  rodents
• Ticks are vectors of many bacterial (Lyme
  disease) and viral (tick born encephalitis)
  diseases
• Some of these viruses can cause viral hemorrhagic
  fevers (VHF)
• Many viruses transmitted by ticks seem to be from
  the flavivirus family
• The flavivirus family includes the Dengue
  viruses, Tick-borne encephalitis virus (TBEV),
  hepatitis C, etc.
• As of today the identity of the cellular receptor
  for flaviviruses is not yet known.

9
So maybe he did catchVHF in Bali
Migrations are often accompagnied by the
emergence of new diseases. One can speculate that
somehow in Southeast Asia about 1 million year
ago there was a severy pandemy that is still
visible in the genes of human, rats and some
other rodents and primates.