[This post is part of a series, What Separates Humans from the Animals?]
Before we look at a difference between us and prosimians (lemurs, bushbabies, etc), we need to briefly touch on three genetic concepts. I've tried to make them as painless as possible.
Concept #1: Stop Codons. DNA is made of 4 basic molecules (nucleotides) that are represented by the letters A, T, G, and C. In a gene, every 3 nucleotides codes for an amino acid (the building blocks of proteins). However, there are several combinations that mean, 'Stop. This is the end of the gene.' These are called 'stop codons' and mutations can do two things with respect to them: (i) a mutation in a gene can create a premature stop codon, thus truncating the protein product, or (ii) a mutation can erase a stop codon, thus extending the coding of the gene until a random stop codon in the downstream sequence is reached.
Concept #2: Introns and Exons. Most of your genes are actually fragmented into pieces called exons. After the DNA is transcribed into RNA--but before the RNA is translated into protein--the extra parts (introns) are cut out and the exons are spliced together. The following image from Wikipedia conveys the idea:
The take-home message here is that the introns (the blue lines) were cut out before the RNA was used to make a protein. Simply put, there are signals in the sequence that tell enzymes where the introns are and where the ends of the exons are that should be joined together.
Concept #3: Transposons. Take a course on bacterial genetics and you will be introduced to transposons. Transposons are selfish-DNA elements that are kind of like viruses, except the don't jump from cell to cell. Rather, they spread copies within the genome. They come in various types and have different mechanisms of replication. Your basic cut-and-paste transposon has a simple structure. It consists of a transposase gene, which does the cutting and pasting of DNA, and flanking inverted repeats, which the transposase recognizes. I've made a diagram illustrating the structure and movement of a simple transposon.
Many organisms other than bacteria have transposons in their genome, including us. However, in our case they seem to be remnants of the past because they have sustained mutations that have rendered them inactive. There are other mobile genetic elements in our genome that are different from transposons, but similar in general concept.
Alright, let's proceed.
The basic background to this story is that a gene was discovered in the human genome that is a chimera of a known gene (SET), and a transposase gene from a transposon called Hsmar1. Humans, other apes, and monkeys all have this chimeric gene, which is called SETMAR. Prosimians and other placental mammals only have the SET part, without the addition of the transposase. So the presence of SETMAR sets us apart from prosimians and all other distantly related mammals. So how did SETMAR come to be?
Cordaux et al looked at it and figured out how to get from SET to SETMAR in a few simple steps. I will be referring to their Figure 1. (Click to enlarge.)
Fig. 1. Milestones leading to the birth of SETMAR. The structure of the SETMAR locus (Right) and a simplified chronology of the divergence time of the species examined relative to hominoid primates (Left) are shown. Pink boxes represent the two SET exons, which are separated by a single intron (interrupted black line) and form a “SET-only” gene whose structure is conserved in all nonanthropoid species examined and terminated with a stop codon (∗) located at a homologous position (except in cow; see Fig. 2 a). The Hsmar1 transposon (event 1) was inserted in the primate lineage, after the split between tarsier and anthropoids, but before the divergence of extant anthropoid lineages. The transposon is shown here with its TIRs (black triangles) and transposase coding sequence (red box). The secondary AluSx insertion within the TIR of Hsmar1 (event 2) is represented as a blue diamond. The position of the deletion removing the stop codon of the “SET-only” gene (event 3) is indicated as a lightning bolt. The de novo conversion from noncoding to exonic sequence is shown in green, the creation of the second intron is represented as a dashed blue line (event 4), and the splice sites are shown as thick blue lines.
We'll start at the bottom and work our way up.
Starting point: Other mammals--up to prosimians, have a SET gene that has two exons. The dashed lines indicate sequence that is spliced out of RNA before a protein is made (see Concept #2 above).
Step 1: An Hsmar1 transposon inserted just downstream of the SET gene.
Step 2: An Alu element inserted into one of the Hsmar1 inverted repeats. (I've written about Alu elements before--see here. Briefly, they are like transposons but do not contain any genes, themselves.) The Hsmar1 transposon is now stuck in place; it cannot cut itself out because one of its inverted repeats has been partially deleted.
Step 3: A small deletion occurred, which removed the stop codon at the end of the SET second exon, thus extending the exon (see concept #1 above).
Step 4: The extended SET exon included sequence that could then act as a signal for RNA splicing following transcription. The Hsmar1 transposon also contained a splice signal, so the end of SET could be spliced to Hsmar1.
Finish: The final protein product consists of the original SET, plus a few amino acids gained from the extension of the second exon, plus the transposase gene from the Hsmar1 transposon. Thus a new chimeric gene, SETMAR is born.
The creation of the new gene occurred after the group of primates that gave rise to monkeys and apes diverged from prosimians. Of course, these steps did not all occur in an individual animal!
What does SETMAR do? The answer to that is not yet clear. The SET portion is known to modify histones, which are proteins that provide structural support to DNA and can help determine whether a gene is expressed or not. Interestingly, although the transposase has two functions, natural selection seems to be selecting only one of them: the ability to bind DNA, especially the inverted repeats. Putting the two together suggests that the protein helps to regulate gene expression at specific places in the genome. However, for our purposes here, the function of SETMAR does not matter.
The the main point is that we, other apes, and monkeys have a novel gene that prosimians and other mammals do not, and that the genetic structure of the gene gives us clues as to how it was created: co-option of naturally occurring genetic processes.
Reference:
Cordaux R, Udit S, Batzer MA, Feschotte C. Birth of a chimeric primate gene by capture of the transposase gene from a mobile element. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8101-6.
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