Mutations: The Good, The Bad and The Others

Mutations—irregular versions of genes—can bring disease and disability to organisms, or improve their fitness, or have no visible effect at all.  The word evokes cancer, mental limitations, handicap. In the long term, though, many mutations prove benign. The countless small variations among living bodies over billions of years usually began with mutations. Mutations kept evolution moving.

I’ve wanted to understand how a single process could have both such dire and essential effects on living things. How do mutations work that they can play such opposite roles?  So here is my version of Mutation-Made-Simple. Very simple. I’ve omitted RNA, base pairs, and gene recombination. I’ve compressed and approximated. Biologists may cringe. But I wanted, as writers say, to get at the character of the protagonist.

This “character” in mutations includes a kind of naive power. From a random copying error or from an inherited inclination, they can drive the fate of an organism. They intervene in the short term and mold change in the long run. They can be placated for the moment (cells correct most mutations early on) or aggravated (by radiation, chemicals). Their curses are more blatant than their favors, which reveal themselves over generations. The ancient Greeks might have pictured Mutation as an elusive deity, changeable in garb and expression, subterranean, disruptive, though at times sighted in a shining mist, when even Zeus holds His breath.

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

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

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 called nucleotides. The nucleotides come in four variations, abbreviated A, C, G, and T. The cell “reads” the nucleotides in groups of three. That is, the nucleotides constitute a kind of four-letter alphabet that spells out a vocabulary of 64 three-letter “words”. Each word or triplet, called a codon, designates one of twenty amino acids (so several codons may designate the same amino acid). Cells build their all-important protein molecules 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 protein.

But once in roughly every thousand duplications of a nucleotide, there’s a glitch. Glitches may be random, may result from damage or radiation, may go on to effect many cells or none, and are often “corrected” later by the cell itself. But the inaccuracy in the copy alters the nucleotide “spelling” and puts the proper bead-stringing of amino acids at risk. Enter Mutation.

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, one letter off. When this TTA later comes up in the protein production line for the next bead of amino acid, which amino acid will be selected? Will the final protein be affected? Will the genetic code have been changed only this once, or has the error occurred in a reproductive gene, which means it will be handed down to offspring? Will Mutation scowl, smile, yawn, or laugh?

Point mutation (Pinterest)

The GAG codon, when it miscopies as GTG, can bring on anemia or protection against malaria. (Pinterest)

A miscopied codon may do damage or it may provide a benefit—or it may do both. It does the last two, for example, in the seventh codon of the gene for hemoglobin, the protein in red blood cells. This GAG codon is sometimes miscopied as GTG. The GAG codon puts into the hemoglobin protein chain an amino acid that creates sickle-shaped cells that can block small blood vessels. When people with sickle-cell anemia exert themselves strenuously or at high altitudes, the shortage of oxygen is painful and exhausting. But the same sickle mutation, when it doesn’t cause anemia, also provides heightened resistance to malaria. From the view of evolution, the benefits have outweighed the costs.

But back to the TTA misspelling. In addition to having an effect on physiology, another possibility  is that Mutation may have absent-mindedly tossed in a codon miscopy that matches no amino acid at all, a “nonsense” codon which stops the copying process for that gene. The result is an incomplete and functionless protein. Mutation yawns.

In actuality, however, with TTA, Mutation has teased us. Often, a miscopied codon does no damage because it either refers to the same amino acid as the original one or, as it does with TTA, it calls up a different amino acid but one with the same properties as the original. The final protein functions normally. No harm, no foul.

So the results of the start of a mutation, the miscopying of a single nucleotide when a DNA strand is reproduced, are many and varied.

But besides such “point mutations,” codons can inaccurately duplicate in other ways, many of them less forgiving. Sometimes nucleotides are deleted or added to a gene, sometimes singly, sometimes by the thousands. Such changes play havoc with the “frame” of the gene, the sequence of codons from beginning to end that is meaningful by three’s. Even the deletion of a single nucleotide can render codons meaningless—and the rest of the gene useless. To see the effect, delete just the first letter, t, from this sentence:  “the man won the bet” becomes “hem anw ont heb et…”.

In other “frameshift mutations,” a codon repeats far in excess of the usual number. The gene that guides the construction of a protein for brain development, for example, normally includes from six to fifty repetitions of a CGG codon. That’s normal for that gene. But in the mutation that leads to a form of retardation called Fragile-X Syndrome, the gene repeats the codon from 200 to 1000 times.

So mutations consist of changing codons and altering genes. Some changes are disastrous, some have little or no effect, some are passed on for generations, most are not passed on at all. But in the background, behind the grim outcomes, mutations continually create a repository of variations of all sorts. They do the groundwork for natural selection. Variations—even slight ones in how an organism looks or functions— are the raw material for evolution. Untypical coloration in a leaf or a flower or an animal’s fur may start out as a minor variation. But over generations, if the individuals with the coloring are a little healthier, evade more predators, attract more mates, or produce more offspring, the variation in the coloring may be here to stay—at least, until the predators or mates or other conditions of the environment change.

I envision Mutation, face half hidden beneath a hood, with a weary eye and a patient smile.

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