What Separates Humans from Monkeys? (Resurrection Edition)

[This post is part of a series, What Separates Humans from the Animals?.]

Many of our genes exist as families. Gene families are groups of genes that have been created through duplications within the genome, and individual members often subsequently take on different functions as a result of mutation or alteration in regulation. Gene families can expand and contract over time, resulting in greater or fewer family members. This story is about a family of genes involved in the immune system called Immunity Related GTPases (IRGs). Most mammals have multiple copies of these genes, but humans have only two: IRGC and IRGM. Our focus here is on IRGM; we have a functional gene but Old and New World Monkeys do not.

Bekpen et al looked at the IRGM gene of a number of primate species and compared it to those of mice and dogs. The first thing to note is that dogs, mice, and prosimians have multiple copies of IRGM (although not all are functional). Now, here's where things get interesting.

(Click to enlarge.)

Figure 5. A model for the evolution of primate IRGM genes is depicted. The mammalian IRGM tandem gene family contracts to a single-copy gene after the divergence of prosimians and anthropoids. The single-copy gene is pseudogenized in the anthropoid ancestor due to an AluSc repeat integration into the second exon, disrupting the ORF of the sole remaining IRGM gene. Multiple stop codons and frameshift mutations accrue in all Old World and New World monkey lineages. Three mutation events restore the IRGM gene in the common ancestor of apes and humans: integration of the ERV9 element to serve as a new promoter, a single-nucleotide mutation that introduces a new ATG codon (green arrow) after the Alu repeat and the loss of a stop codon that is shared with Old World monkey species. The latter event is polymorphic in orangutans rendering both functional and nonfunctional copies in this species. (*) of the five gibbon species analyzed, H. gabriellae shows a heterozygote stop codon. In the human and African great ape, the functional copy becomes fixed. Frameshift mutation (Fs) and stop codons are indicated. The genomic loci are not drawn to scale with the exception of the full-length sequence of IRGM ORF.

Step 1 - Death: Around 40 million years ago, the ancestor of anthropoids (i.e. monkeys and apes) lost IRGM when there was a contraction down to one copy, followed by the insertion of an Alu element that disrupted the single remaining gene and turned it into a non-functional pseudogene.

Step 2 - Decay: With the single copy of IRGM now broken, mutations in it could begin to accumulate without resulting in a selective disadvantage, and the relative order of the mutations can be determined by looking at which lineages share them. All Old World Monkeys share a mutation that created a premature stop codon in the gene. Remember, a stop codon indicates the end of a gene and the creation of one in the middle of a gene leads to a truncated protein that may be non-functional. However, in this case the stop codon had no real effect because the beginning of the gene was already broken by the Alu element.

Step 3 - Resurrection begins: At least 8% of our genome consists of endogenous retroviruses (ERVs). Retroviruses are a family of viruses that integrate into DNA as part of their life-cycle. If they find their way to a germ-line cell, they can remain in the genome permanently and be passed on as though they were just another gene. Lucky for IRGM, about 20 million years ago an ERV inserted upstream of the Alu element. The reason this was lucky is because the ERV contains a sequence that acts as a promoter, which is a stretch of DNA that promotes the transcription of a gene. In other words, the ERV helped turn IRGM back on. The ERV insertion was accompanied by an independent mutation just after the Alu element that created a new start codon--a new beginning of the gene.

Step 4 - Resurrection complete: Alright, the gene has been turned back on and has a new start codon, but what about that premature stop codon? A simple mutation turned it from a stop codon back to a codon for an amino acid. The gene was thus restored, though shorter than the original. Interestingly, the version of the gene with the stop codon (still broken) and the version without it (functional) can both be found in a species of gibbon and among orangutans. Gorillas, chimpanzees, and humans appear to have completely lost the broken version; they only have the resurrected IRGM. Analysis of the sequence of the resurrected gene suggests that it has been under positive selection (i.e. natural selection favors it).

So the next time you hear someone claim that mutations only destroy genetic information, remember the mutational resurrection of IRGM.


Reference:

Bekpen C, Marques-Bonet T, Alkan C, Antonacci F, Leogrande MB, et al. (2009) Death and Resurrection of the Human IRGM Gene. PLoS Genet 5(3).

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