“We Are All Mutants”: Mutation Basics

In The Ancestor’s Tale: A Pilgrimage to the Dawn of Evolution (2016), Richard Dawkins writes:

The word ‘mutation’ conjures up images of grotesquely distorted creatures, perhaps generated by unscrupulous experimenters, or springing up as a consequence of some radioactive catastrophe. The truth is somewhat different. We are all mutants. The DNA passed on to us from our parents contains novel changes—mutations—which were not present in the DNA that they inherited from their parents. Fortunately so, for mutations provide the raw material, sculpted over millennia by natural selection, used to build the bodies of all the pilgrims on our journey. (126)

I’ve wanted to understand the basics of such a process that provides the “raw material” for evolution as well as a share of diseases and disabilities.  Explaining it here is a step in that direction, so here’s my version of Mutation Made Simple—very simple. I’ve omitted RNA, base pairs, and gene recombination, and I’ve compressed and approximated.

Such simplification notwithstanding, though, the basics of mutations can be difficult to grasp at first for two reasons. One is that DNA duplication, even when it is on track, takes place in several steps that are difficult to visualize and with four kinds of chemical players of whom three bear names unfamiliar to many people. They are nucleotide, codon, and amino acid; the familiar fourth one is protein. Many mutations start with a miscopied nucleotide, which leads to an error in a codon, which corresponds to the wrong amino acid, which may screw up the protein. Such a chain of effects is a lot to wrap one’s head around.

The second difficulty is that there is “slack” in these steps. That is, many of the missteps that could lead to an actual difference in a body are corrected by the cell or produce no  result or produce a result that is harmless. A kind of built-in “forgiveness factor” prevents every single mistake in DNA copying from invariably leading to potentially risky changes in an organism. Such a buffer in the genetic system is part of its complexity.

dna and codons (www2.le.ac.uk)

From the top: the double strand of DNA; the three-letter codons from one of the strands; and the necklace of amino acids designated by each codon. (www2.le.ac.uk)

That said, let’s look at the normal duplication sequence. Mutations exist because cells require replacement. The first step in making a new cell is for the old one to make a copy of its DNA. DNA strands themselves consist of a line-up of basic organic molecules, the nucleotides. There are only four nucleotides, with names that are abbreviated simply A, C, G, and T. This is the DNA “code,” like the dots and dashes in Morse code.

The cell reads the nucleotides in groups of three. That is, the nucleotides constitute a kind of small alphabet that spells out a vocabulary of 64 three-letter “words.”  Each word or triplet, which is the codon, designates one of twenty amino acids.  (So here is one “slack” point: twenty amino acids designated by three times as many codons means each amino acid may be designated by not just one codon but by several. An incorrect codon doesn’t necessarily call up the wrong amino acid. )

Cells then build the protein molecules that will form the new cell by reading each codon in turn, bringing the appropriate amino acid molecule into place, and stringing it like a bead on a necklace in the proper sequence. The finished molecule, the necklace of amino acids, is a particular and complex protein.

But sometimes over billions of nucleotide duplications, a nucleotide miscopies; what should be a copy of an A is a T instead, a C miscopies as a G.

sickle cell (sicklecellanaemia.org)
Sickle cells among normal red blood cells. (sicklecellanemia.org)

Take the codon TTC, for example. Let’s say that a copy of it comes out as TTA instead, one letter off. When this TTA later comes up in the protein production line, which amino acid does it designate and what will the impact be? Is TTA one of the few “nonsense” codons that match no amino acid all and stop the copying process before the protein is complete? Or, if it does result in a changed protein and gene, will the change be limited to one organism, or has the error occurred in a gene for sperm or the ovum that will carry it to offspring?

Point mutation (Pinterest)

The GAG codon, when it miscopies as GTG, puts into the hemoglobin protein an amino acid that creates sickle-shaped cells can bring on painful anemia but also protection against malaria. (Pinterest)

TTA, it turns out, has no such harsh consequences. The amino acid it calls up has the same function as the one that the original TTC corresponded to. The final protein functions normally. No harm, no foul—another example of “forgiveness” in the replication process. But see the illustrations for the much less neutral mutation that produces Sickle cells in the blood.

Besides such mutations that start with the miscopying of a nucleotide, mutations can also occur in another way: through the insertion or deletion of nucleotides and codons, sometimes one codon, sometimes hundreds.

Codons are read in threes. So the insertion or deletion of even a single nucleotide changes all the codons coming after it in what’s called the frame of the gene, the full sequence of codons. To see the effect, delete just the first letter, t, from this sentence of three-letter words:  “the man won the bet” becomes “hem anw ont heb et…”.  And like such a small deletion, the insertion of a nucleotide has the same chaotic effect.

In other mutations, a codon or group of codons repeats far in excess of the usual number. A gene for brain development, for example, includes from six to fifty repetitions of a CGG codon. That’s normal for that gene. But in a mutation that leads to a form of retardation called Fragile-X Syndrome, the gene repeats the CGG codon from 200 to 1000 times.

So mutations start with nucleotides and codons but may end by altering genes. Some changes are disastrous, some have little or no effect, some are passed on through generations, most are not passed on at all. But in the background, behind the grim or helpful outcomes, mutations keep bringing forth a trickle of variations of all sorts, in all species—the modest but persistent originality of organic life itself. Untypical coloration in an insect or a flower or an animal’s fur may start out as a minor difference. But over generations, if the individuals with the coloring are a little healthier, evade more predators, attract more mates, or produce more offspring, the color mutation will take its place in the species.

 

Genes Are Like Sentences, Genomes Are Like Books

I lose track sometimes of exactly what the common genetic terms mean and how the genetic pieces work together. What’s the difference between a chromosome and a strand of DNA? A gene and a genome? What are those three-letter sets in a DNA diagram called and what do they do? I’m not a scientist, but since I was an English teacher, connecting the names of genetic units to the units of written language—words, sentences, and so on—makes the picture a little clearer.  Maybe it will do the same for the reader.

Let’s start small.  The spiraling rungs on diagrams of a DNA (deoxyribonucleic acid) molecule are each marked with two of four specific letters: A, C, G, and T.  The four DNA letters stand for the four nucleotides—Adenine, Cytosine, Guanine, and Thymine—that make up DNA. Like the letters of the full alphabet, these letters–or rather the four molecules they indicate–are the smallest building blocks of their language.

codons

moodle.clsd.k12.pa.us

In DNA, combinations of the letters for the four nucleotides make up the three-letter codons that are DNA’s version of words. Each three-letter codon/word specifies one amino acid. And most codons are “synonyms” in that several different codons refer to the same amino acid because there are many more codons than there are amino acids. The codons are “read” by a ribosome, a cellular reader/assembly-machine that produces the required amino acid and attaches it to the chain of amino acids that will form a protein.

Groups of these codons make up a gene, much as words make up a sentence. The genes/sentences are long because most proteins are complex; human proteins consist of anywhere from several hundred to several thousand amino acid molecules.  The gene/sentence for red hair says something like “Put this together with that and that and that….”

Genes also include a codon at the start that says “Start the gene here” and another at the end that says “Stop here; gene complete.” Within the gene, however, no actual spaces separate the codons, but since all codons are triplets, it’s always clear where codons themselves begin and end.  (Somewhat similarly, writing in the ancient world often lacked spaces between words.  As long as one could read slowly and figurethewordsoutspacesweren’tessential.)

chromosome (mayoclinic.org)

mayoclinic.org

So, to recap.  The four nucleotides are basic components much like the letters of our alphabet. Groups of three nucleotides spell out codons that can be thought of as words, which in this case are actual amino acid molecules.  And a sequence of codons/amino acids forms a gene that resembles a sentence in a protein recipe for some aspect of the organism.

Finally there are chromosomes and genomes.

A molecule of DNA is very long, a continuous strand of anywhere from a couple of hundred to more than a thousand genes, many of them about related aspects of the organism. Each molecule is a chromosome which, because its genes concern similar aspects of the body, can be compared to a chapter in a book.  But it is a strange book in that each chapter appears twice, in anticipation of the day when the molecule/chapter reproduces itself. Each human cell contain 23 such paired chromosomes, duplicate copies of the assembly instructions for an entire human being. Only the chromosome pair that determines sex contains chromosomes that are different from each other about half the time: females have two identical female chromosomes while males carry one female and one male chromosome.

Finally, our genome is like the book itself, the totality of all our genes on all our chromosomes. The book might be called Me And Us. Your genome book is almost exactly like mine except for about one tenth of one percent of our 20,000 genes that are different. That’s similar to two copies of the same long book that differ only in a few sentences.

Simplified though the comparison is, it’s startling what genetics and written language have in common considering that the second is a recent human invention and the first represents the formation of life almost four billion years ago. Both are composed of the smallest building blocks, then the groupings created from the building blocks, then the meaningful statements/instructions/recipes coded in the groupings, and finally the conversion of the code into organic construction/action/speech.