The Lazarus Mechanism

Below is an amino acid alignment of IRGM proteins from mouse and humans. IRG proteins are immunity related GTPases and play a role in defending against intracellular parasites. When you look at the two proteins, there doesn’t seem to be much that is remarkable. The human protein is smaller, lacking about 80 of the amino acids at the C-terminal end and about 20 amino acids from the N-terminal end. The two proteins show homology over a region of about 170 amino acids, where approximately 100 of them are identical (green) and another 40 or so are similar (blue).

However, here is one other difference. The human gene was brought back from the dead after being in the genomic grave for over 20 million years.

igm11

A recent paper entitled Death and Resurrection of the Human IRGM Gene outlines an elegant case of historical reconstruction, whereby the researchers determined that the IRGM gene was disrupted by an Alu repeat integration somewhere around 40 million years ago in the lineage that led to New World and Old World monkeys. In other words, it became a non-functional pseudogene.

Then, about 20 million years later, in the common ancestor of man and apes, an ERV9 retroviral element inserted near the 5’ end of the IRGM gene and brought it back on-line. The researchers mention that it is still possible that even though the gene is expressed, it may not have a function. But they cite several lines of circumstantial evidence that indicate it is functional. I would also add that the sequence alignments show the GTPase motifs are still intact.

If it is confirmed that human IRGM is indeed functional, then we have a gene that retained a core function/sequence after experiencing 20 million years of evolution as a pseudogene. Might this be a tip of the iceberg?

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3 responses to “The Lazarus Mechanism

  1. Michael,

    I’m still trying to get my head around biologic homology for a 59% match over a region as opposed to the full protein. In this case metaphors do not translate so well across disciplines from math to biology. Its messy. But, in FLE or MET with varying events, a 59% rate suffices.

    Forgive my ignorance, can homology be cited for less than 50% match?

    OK, so… a function exist today, possibly. What about prior to 40 milloin yrs split? You would look for prescriptive information prior to that in mouse or fish, or sea urchins, correct? Its a hit and miss in some cases, but where is the next logical locatoin to search?

    Also, you doubled up on C-Terminal, leaving out N-terminus?

    “The human protein is smaller, lacking about 80 of the amino acids at the C-terminal end and about 20 amino acids from the C-terminal end.“

  2. ooops, meant to bold the other C-terminal end.

  3. Hi datcg,

    Forgive my ignorance, can homology be cited for less than 50% match?

    The cut-off is usually around 20-25%, unless there is structural matching.

    OK, so… a function exist today, possibly. What about prior to 40 milloin yrs split?

    It functions to defend cells against intracellular infections.

    You would look for prescriptive information prior to that in mouse or fish, or sea urchins, correct? Its a hit and miss in some cases, but where is the next logical locatoin to search?

    IRGM belongs to the Ras-like GTPase family – a versatile, multifunctional switch.

    Also, you doubled up on C-Terminal, leaving out N-terminus?

    Thanks. I corrected it.

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