Shadows of Forgotten Ancestors (13 page)

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A particular sequence of As, Cs, Gs, and Ts is in charge of making fibrinogen, central to the clotting of human blood. Lampreys look something like eels (although they are far more distant relations of ours than eels are); blood circulates in their veins too; and their genes also contain instructions for the manufacture of the protein fibrinogen. Lampreys and people had their last common ancestor about 450 million years ago. Nevertheless, most of the instructions for making human fibrinogen and for making lamprey fibrinogen are identical. Life doesn’t much fix what isn’t broken. Some of the differences that do exist are in charge of making parts of the molecular machine tools that hardly matter—something like the handles on two drill presses being made of different materials with different brand names, while the guts of the two are identical.

Or here, to take another example, are three versions of the same message,
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taken from the same part of the DNA of a moth, a fruit fly, and a crustacean:

Moth:

Fruit fly:

Crustacean:

Compare these sequences and recall how different a moth is from a lobster. But these are not the job orders for mandibles or feet—which could hardly be closely similar in moths and lobsters. These DNA sequences specify the construction of the molecular jigs on which newly forming molecules are laid out under the ministrations of the molecular machine tools. Down at this level, it’s not absurd that moths and lobsters might have closer affinities than moths and fruit flies. The comparison of moth and lobster suggests how slow to change, how conservative the genetic instructions can be. It’s a long time ago that the last common ancestor of moths and lobsters scudded across the floor of the primeval abyss.

We know what every one of those three-letter ACGT words means—not just which amino acids they code for, but also the grammatical and lexigraphical conventions employed by life on Earth. We have learned to read the instructions for making ourselves—and everybody else on Earth. Take another look at “START” and “STOP.” In organisms other than bacteria, there’s a particular set of nucleotides that determine when DNA should start making molecular machine tools, which machine tool instructions should be transcribed, and how fast the transcription should go. Such regulatory sequences are called “promoters” and “enhancers.” The particular sequence TATA, for example, occurs just before the place where transcription is to occur.
Other promoters are CAAT and GGGCGG. Still other sequences tell the cell where to stop transcribing.
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You can see that the substitution of one nucleotide for another might have only minor consequences—you could, for example, substitute one structural amino acid for another (in the “handle” of the machine tool) and in no way change what the resulting protein does. But it could also have a catastrophic effect: A single nucleotide substitution might convert the instructions for making a particular amino acid into the signal to stop the transcription; then, only a fragment of the molecular machine in question will be manufactured, and the cell might be in trouble. Organisms with such altered instructions will probably leave fewer offspring.

The subtlety and nuance of the genetic language is stunning. Sometimes there seem to be overlapping messages using the same letters in the same sequence, but with different functional import depending on how it’s read: two texts for the price of one. Nothing this clever occurs in any human language. It’s as if a long passage in English had two completely different meanings,
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something like

ROMAN CEMENT TOGETHER NOWHERE …

and

ROMANCEMENT TO GET HER NOW HERE …

but much better—on and on for pages, perfectly lucid and grammatical in both modes, and, we think, beyond the skill of any human writer. The reader is invited to try.

In “higher” organisms, many long sequences seem to be nonfunctional genetic nonsense. They lie after a “STOP” and before the next “START” and generally remain ignored, forlorn, untranscribed. Maybe some of these sequences are garbled remnants of instructions that, long ago, in our distant ancestors, were important or even keys to survival, but that today are obsolete and useless.
*
Being useless,
these sequences evolve quickly: Mutations in them do no harm and are not selected against. Maybe a few of them are still useful, but elicited only under extraordinary circumstances. In humans some 97% of the ACGT sequence is apparently good for nothing. It’s the remaining 3% that, as far as genetics goes, makes us who we are.

Startling similarities among the
functional
sequences of As, Cs, Gs, and Ts are seen throughout the biological world, similarities that could not have come about unless—beneath the apparent diversity of life on Earth—there was an underlying and fundamental unity. That unity exists, it seems clear, because every living thing on Earth is descended from the same ancestor 4 billion years ago; because we are all kin.

But how could machines of such elegance, subtlety, and complexity ever arise? The key to the answer is that these molecules are able to evolve. When one strand is making a copy of the other, sometimes a mistake occurs and the wrong nucleotide—an A, say, instead of a G—will be inserted into the newly assembled sequence. Some of them are honest replication errors—good as it is, the machinery isn’t perfect. Some are induced by a cosmic ray or another kind of radiation, or by chemicals in the environment. A rise in temperature might slightly increase the rate at which molecules fall to pieces, and this could lead to mistakes. It even happens that the nucleic acid generates a substance that alters itself—perhaps thousands or millions of nucleotides away.

Uncorrected mistakes in the message are propagated down to future generations. They “breed true.” These changes in the sequence of As, Cs, Gs, and Ts, including alterations of a single nucleotide, are called mutations. They introduce a fundamental and irreducible randomness into the history and nature of life. Some mutations may neither help nor hinder, occurring, for example, in long, repetitive sequences—containing redundant information—or in what we’ve called the handles of the molecular machine tools, or in untranscribed sequences
between STOP and START. Many other mutations are deleterious. If you’re crafting superb machine tools and, while you’re not looking, someone introduces a few random changes into the computer instructions for manufacture, there isn’t much chance that the resulting machines, built according to the new, garbled instructions, will work better than the earlier model. Enough random changes in a complex set of instructions will cause serious harm.

But a few of the random changes, by luck, prove advantageous. For example, the sickle-cell trait we mentioned in the last chapter is caused by the mutation of a single nucleotide in the DNA, generating a difference of a single amino acid in the hemoglobin molecules that nucleotide helps code for; this in turn changes the shape of the red blood cell and interferes with its ability to carry oxygen, but at the same time it eventually kills the plasmodium parasites those cells contain. A lone mutation, one particular T turning into an A, is all it takes.

And, of course, not just the hemoglobin in red blood cells, but every part of the body, every aspect of life, is instructed by a particular DNA sequence. Every sequence is vulnerable to mutation. Some of these mutations cause changes more far-reaching than the sickle-cell trait, some less. Most are harmful, a few are helpful, and even the helpful ones may—like the sickle-cell mutation—represent a tradeoff, a compromise.

This is a principal means by which life evolves—exploiting imperfections in copying despite the cost. It is not how we would do it. It does not seem to be how a Deity intent on special creation would do it. The mutations have no plan, no direction behind them; their randomness seems chilling; progress, if any, is agonizingly slow. The process sacrifices all those beings who are now less fit to perform their life tasks because of the new mutation—crickets who no longer hop high, birds with malformed wings, dolphins gasping for breath, great elms succumbing to blight. Why not more efficient, more compassionate mutations? Why must resistance to malaria carry a penalty in anemia? We want to urge evolution to get to where it’s going and stop the endless cruelties. But life doesn’t
know
where it’s going. It has no long-term plan. There’s no end in mind. There’s no mind to keep an end in mind. The process is the opposite of teleology. Life is profligate, blind, at this level unconcerned with notions of justice. It can afford to waste multitudes.

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The evolutionary process could not have gone very far, though, if the mutation rate had been too high. In any given environment, there must be a delicate balance—simultaneously avoiding mutation rates so high that instructions for essential molecular machine tools are quickly garbled, and mutation rates so low that the organism is unable to retool when changes in the external environment require it to adapt or die.

There is a vast molecular industry that repairs or replaces damaged or mutated DNA. In a typical DNA molecule, hundreds of nucleotides are inspected every second and many nucleotide substitutions or errors corrected. The corrections are then themselves proofread, so that there is only about one error in every billion nucleotides copied. This is a standard of quality control and product reliability rarely reached in, say, publishing or automobile manufacture or microelectronics. (It is unheard of that a book this size, containing around a million letters would have no typographical errors; a 1% failure rate is common in automobile transmissions manufactured in America; advanced military weapons systems are typically down for repair some 10% of the time.) The proofreading and correction machinery devotes itself to DNA segments that are actively involved in controlling the chemistry of the cell, and mainly ignores nonfunctioning, largely untranscribed, or “nonsense” sequences.

The unrepaired mutations steadily accumulating in these normally silent regions of the DNA may lead (among other causes) to cancer and other illnesses, should the “STOP” be ignored, the sequence turned on, and the instructions carried out. Long-lived organisms such as humans devote considerable attention to repairing the silent regions; short-lived organisms such as mice do not, and often die filled with tumors.
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Longevity and DNA repair are connected.

Consider an early one-celled organism floating near the surface of the primeval sea—and thereby flooded with solar ultraviolet radiation. A small segment of its nucleotide sequence reads, let’s say,

When ultraviolet light strikes DNA, it often binds two adjacent T nucleotides together by a second route, preventing DNA from exercising
its coding function and getting in the way of its ability to reproduce itself:

The molecule literally gets tied up in knots. In many organisms enzymatic repair crews are called in to correct the damage. There are three or four different kinds of crews, each specialized for repairing a different kind of damage. They snip out the offending segment and its adjacent nucleotides (C
C, say) and replace it with an unimpaired sequence (CTTC). Protecting the genetic information and making sure it can reproduce itself with high fidelity is a matter of the highest priority. Otherwise, useful sequences, tried-and-true instructions, essential for the adaptation of organism to environment, may be quickly lost by random mutation. Proofreading and repair enzymes correct damage to the DNA from many causes, not just UV light. They probably evolved very early, at a time before ozone, when solar ultraviolet radiation was a major hazard to life on Earth. Early on, the rescue squads themselves must have undergone fierce competitive evolution. Today, up to a certain level of irradiation and exposure to chemical poisons, they work extremely well.