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The Genius of Alternative Reading Frames

Image credit: Emmanuel Douzery, [CC BY-SA 4.0], via Wikimedia Commons.

A reader, Charles, asks a good question:

I’ve been wondering about this for some time and haven’t been able to find an answer. In protein production in an organism having a diploidal genome, do both strands contribute to protein production? In particular, does the complementary segment of a translated gene also get translated? It seems to me that it would be a real miracle if that were to be the case, since the chances of a sequence being useful and its complement being useful in the reversed direction would be quite small.

Best regards,

My reply: 

Hi Charles,

You are actually asking two questions.

We each have two sets of chromosomes, as you pointed out. You ask whether both sets of genes can be expressed. So for example, if you get a gene for blue eyes from your mom and a gene for brown eyes from your dad, are they both expressed? The answer is most probably yes. There is an exception however. In female mammals the X chromosome is different. A female has 2 X chromosomes and the male has 1 X chromosome. To equalize the amount of gene product being made, the female inactivates one of her X chromosomes in each cell. 1 X is inactivated (silenced), and the other is active and being transcribed. Which X is an activated in each cell is random. This method of dosage compensation, as it’s called, is common to mammals. Other kinds of animals may do it differently. 

But that’s off the track. Now you probably know more than you wanted to about whether genes from each chromosome can be expressed. Indeed they can, and it is enough of an issue that there are ways to compensate for gene dosages that are too high or too low.

Now for the second part of your question. You ask about expression from the complementary strand. That is different from talking about the other chromosome. When you talk about the complementary strand you are talking about the same chromosome, but the opposite strand of DNA. DNA is made up of two strands of nucleotides running in opposite directions, and coiled about each other, the so called double helix. One strand has typically been called the coding strand because nearly all genes were thought to be encoded on that strand.

But as techniques for detecting transcripts have gotten better, and scientists have begun to scan for “alternative reading frames,” they are finding them.

If you look at the figure at the top of this post,you’ll see the sequence of DNA from a human mitochondrion: AAATGAACGAAA and so on. Above in red you see the nucleotides (ATCG) have been grouped in threes, and a letter assigned to each. Each group of three is a codon, and each unique codon specifics a particular amino acid, indicated by the red letters: K W T K I, etc. That is the protein sequence that the DNA specifies for that particular way of reading the DNA. That way of reading the DNA, with that set of groups of three, is called a reading frame, because it establishes the frame for the way we read the information in the gene. In this case it encodes the protein ATP8.

If DNA were a human code, then it would be inconceivable to have a code that could be read in more than one frame at a time. By this I mean starting at one nucleotide and getting one sequence and starting at another nucleotide and getting another sequence with a different meaning.

But that is exactly what happens in this stretch of mitochondrial DNA. Look below the nucleotides to a different set of letters in blue. Notice that they are offset from the first reading frame by two nucleotides. This changes the way the nucleotides are read. The first codon is ATG, the second AAC, and so on. And the resulting protein, ATP6, has a very different sequence from that of the first, ATP8.

And for toppers it is also possible to start on the complementary strand and get yet another reading in the opposite direction. Theoretically it is possible to have a code that reads in all six frames, three forward and three reverse. We see overlapping genes in everything from viruses to humans, sometimes offset from each other on the same strand, and sometimes from the complementary strand.

So in answer to your question, yes, it is possible to get some protein from the complementary strand as well as the “coding strand.” You can have more than one protein produced from the same stretch of DNA — and I haven’t even mentioned splicing yet… but I’ll leave that for another time.

This is amazing! Here we have multiple meanings being read from one stretch of digital code. Here it is A T C G combinations, but on a computer it would be 01001, etc. Can anyone write a string of 0s and 1s that can be read in different frames and have each of those readings make sense?

Only a design genius could do it.

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