Blogging the Human Genome: Muscular dystrophy, Cri du Chat, “immigration delay disease”—When DNA fails.

Muscular dystrophy, Cri du Chat, “immigration delay disease”: When DNA fails.

Chromosomes 4 & 5

Illustration by Andrew Morgan

We’ve seen already how freely genetics borrows from grammar books to describe how DNA works. Linguistic analogies also help make sense of mutations, cases where DNA fails.

Most mutations involve typos: Something bumps a cell’s elbow as it’s copying DNA and the wrong letter appears in a triplet—CAG becomes CCG. In “silent” mutations, no harm is done: Because the DNA code is partly redundant, sometimes the before and after triplets call for the same protein building block (an amino acid). So the net effect is like mistyping “grey” for “gray.” But if CAG and CCG call for different amino acids—a “missense” mutation—the protein can change shape and become disfigured.

Worse are “nonsense” mutations. When making proteins, cells keep on adding amino acids until they encounter a “stop” triplet, which terminates the process like a period terminates a sentence. A nonsense mutation converts a normal triplet into a period. Which truncates. The protein prematurely. Nonsense mutations can also erase periods, so the protein rambles on and on.

Cells can correct simple typos straightaway, but if something goes wrong (and it will) the flub can become permanent. All human beings are in fact born with dozens of mutations their parents lacked, and a few of those mutations could well be lethal if we didn’t have two copies of every gene, so one can pick up the slack if the other malfunctions. But that backup plan doesn’t always work. Especially if their parents are related, people can easily get slipped two bad copies of a harmful, recessive gene. (This is one drawback of incest.)

The backup plan also fails if you get a single copy of a dominant trait. Whereas recessive traits require two bad copies of a gene to become noticeable, a dominant trait expresses itself no matter what the other copy does. A benign example of dominance: If you inherit one gene for sticky wet earwax and one gene for dry earwax, the sticky earwax gene wins out every time. A less benign example: The first dominant human gene discovered, in 1905, left victims with excessively stubby fingers. For a malignant example, consider the mutant gene on chromosome 4 that causes Huntington’s disease. Because the mutated version dominates, you cannot escape even if you have a healthy second copy.

Typos aren’t the only type of mutation. A “frameshift” mutation is basically an old-fashioned typesetting mistake: a DNA letter either gets deleted (CTG→CG), or an extra base fat-fingers its way in (AGA→AGCA). Because cells read DNA in consecutive groups of three, an insertion or deletion screws up not only that triplet but every triplet down the line, a cascading catastrophe: “The dog ate the bug leg” becomes “Thd oga tet heb ugl eg.”

Sometimes cells erase not just one base, but huge chunks of DNA. This can happen because DNA is a very, very long and very, very coiled molecule. If multiple coils get snipped at once (a streaking radioactive particle can do this), multiple free ends will be hanging loose in close proximity. Cells can repair this disaster, but they don’t always “know” which ends to solder back together in which order. And if they solder the wrong coils together, vital DNA can get left out.

For instance, if certain DNA on human chromosome 5 goes missing, newborns develop Cri du Chat (“cry of the cat”) syndrome. These poor things often have severe mental problems, low birth weights, and difficulty doing even basic baby tasks like sucking. They also mew uncannily like cats for a few years, probably due to voice box trouble. In fact, while the mental handicaps of Cri du Chat have largely been traced to a certain million letters missing near the end of chromosome 5, the mewing region lies slightly farther afield, in an area designated as 5p15.3, or the “cat-like cry critical region.”

Another source of mutations is poor DNA splicing. When cells turn DNA into RNA, they copy the DNA by rote, skipping no letters. But with the full RNA manuscript in hand, cells narrow their eyes, lick a red pencil, and start slashing—think Gordon Lish hacking down Raymond Carver. This editing consists mostly of chopping out superfluous segments of RNA (segments called introns), then stitching the remaining, important bits (called exons) back together. As an example, raw RNA containing both usable exons (capital letters) and unusable introns (lowercase) might read, abcdefGHijklmnOpqrSTuvwxyz. Edited down, it says GHOST.

The key point is that not all cells use RNA the same way. Brain cells might opt to keep an “e” or “m” in GHOST, or liver cells might cut the “O” and substitute “ij.” This differential splicing gives cells versatility: They can customize RNA and proteins for different environments in the body. But splicing can also cause problems. The gene for the largest human protein, titin, contains 178 fragments totaling 80,000 bases, all of which must be stitched together precisely. An even more sprawling gene—dystrophin, the Jacksonville of human DNA—contains 14,000 bases of coding DNA spread among 2.2 million bases of intron cruft. Transcription alone takes 16 hours. And mistakes in making dystrophin can cause muscular dystrophy.

Probably the most interesting splicing error involves chromosome 4. One stretch of DNA on this chromosome helps form the grooves and whorls on fingerprints. So guess what happens if the splicing gets screwed up? You end up without fingerprints—the tips of your fingers are bald. Based on family inheritance patterns, scientists know this condition is dominant. It really doesn’t cause people many difficulties day-to-day—except for the guff they get at border crossings. Hence, scientists have dubbed this chromosome-4 disorder “immigration delay disease.”