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Did he catch a VHF in Bali?

This article explores the pseudogenization of GPR33, a G-protein coupled receptor, and its potential connection to a pandemic in Southeast Asia. It discusses various pseudogenization events in different species and suggests the involvement of a putative pathogen and the role of ticks as vectors. The article also speculates on the emergence of new diseases during migrations and the impact on human, rodent, and primate genes.

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Did he catch a VHF in Bali?

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  1. Did he catch a VHF in Bali? Some interesting facts and some wild conjectures PubMed=15987686; Römpler H., Schulz A., Pitra C., Coop G., Przeworski M., Pääbo S., Schöneberg T. The rise and fall of the chemoattractant receptor GPR33. JBC 280:31068-31075(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 1’217 individuals, 1’166 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 300’000 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.

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