Unit 17 · Biology: Genetics and Inheritance

Every cell that has a nucleus keeps its instructions in a molecule called DNA. If you could unwind the DNA from one human cell and lay it out straight, it would be about 2 meters long. Yet it fits inside a nucleus far too small to see without a microscope. It fits because it is a very thin thread, about 2 nanometers wide, coiled and folded again and again.

The shape of the thread is a double helix. Think of a ladder. Now twist the ladder into a spiral. The two rails of the ladder are long chains of sugar and phosphate. The rungs are made of pairs of smaller molecules called bases. There are only four bases: adenine (A), thymine (T), guanine (G) and cytosine (C). Each rung is one base from one rail reaching across to one base on the other.

The bases do not pair at random. A always pairs with T, and G always pairs with C. This is the base-pairing rule. It works because of shape and chemistry. A and T fit together with two weak hydrogen bonds. G and C fit with three. A pair of A with G would be too wide; a pair of C with T would be too narrow. The ladder only stays even when the rule is followed.

The order of the bases along one rail is the information. A stretch reading ATTGCA means something different from ATTGCC. Human DNA holds about 3 billion base pairs. Because of the pairing rule, if you know one rail you can write the other. That simple fact, as you will see, is how a cell copies its instructions.

A cell in your skin divides. Each of the two new cells needs a complete set of DNA. That means the whole 3 billion base pairs must be copied first, with almost no mistakes. The double helix makes this possible. Because each strand is the mirror of the other, each strand can serve as a template, or pattern, for building a new one.

Replication starts when an enzyme called helicase unzips the helix. It breaks the weak hydrogen bonds between the base pairs and pulls the two strands apart. Now each old strand has its bases exposed. A second enzyme, DNA polymerase, moves along each old strand. It grabs free bases floating in the cell and snaps them into place, always following the rule: A across from T, G across from C.

When it is done, there are two double helices where there was one. Each contains one old strand and one new strand. Scientists call this semiconservative copying, because half of each new molecule is conserved from the original. In 1958 Matthew Meselson and Franklin Stahl proved it by growing bacteria in food with heavy nitrogen, then switching to light nitrogen and weighing the DNA after each round of division.

DNA polymerase also checks its work. If it places a wrong base, it usually backs up and fixes it. Even so, a few errors slip through, roughly one for every billion bases copied. Those rare errors are called mutations, and later in this chapter you will see that they are the raw material of change.

DNA stays in the nucleus, but the work of the cell happens outside it. Proteins do that work: they build structures, speed up reactions and carry signals. So the cell needs a way to send the instructions for a protein out of the nucleus without sending the DNA itself. It does this with a messenger.

A gene is a stretch of DNA that holds the instructions for one protein. To read it, an enzyme called RNA polymerase unzips just that stretch and builds a single strand of RNA alongside it. RNA is a close cousin of DNA. It has one strand, not two, and it uses a base called uracil (U) in place of thymine (T). So where DNA reads ATG, the RNA copy reads UAC. This copying step is called transcription, the way a clerk transcribes a document.

In cells with a nucleus, the first RNA copy is edited before it leaves. Some stretches, called introns, are cut out. The remaining pieces are joined. The finished strand, called messenger RNA or mRNA, slips through a pore in the nuclear membrane into the cytoplasm. There it is picked up by a ribosome, the machine that will turn its message into a protein.

Not every gene is transcribed all the time. A cell in your eye and a cell in your liver have the same DNA, but each turns on a different set of genes. That control is what makes the two cells different. A gene that is never read is like a recipe in a closed book: present, but not in use.

The mRNA has reached a ribosome. Now the message must be turned into a protein. A protein is a chain of smaller units called amino acids. There are 20 kinds. The order of amino acids in the chain decides how it folds, and the fold decides what it can do. The job of translation is to read the bases of the mRNA and string the right amino acids together in the right order.

The ribosome reads the mRNA in groups of three bases. Each group is a codon. With four bases there are 4 × 4 × 4 = 64 possible codons, more than enough to name 20 amino acids. Most amino acids have several codons. One codon, AUG, means ’start’ and also stands for the amino acid methionine. Three codons, UAA, UAG and UGA, mean ’stop’. This code is nearly the same in bacteria, oak trees and people, which is why scientists can put a human gene into bacteria and have them make a human protein, such as insulin.

Small molecules called transfer RNA, or tRNA, do the matching. Each tRNA has three bases that fit one codon on one end and carries the matching amino acid on the other. As the ribosome slides along the mRNA, the right tRNA docks at each codon and hands over its amino acid. The chain grows one unit at a time until a stop codon arrives. Then the finished protein is released to fold up and get to work.

The whole route, DNA to RNA to protein, is sometimes called the central dogma of biology. The word dogma is a bit strong, because scientists have found exceptions. Some viruses copy RNA back into DNA. But for the genes in your own cells, the path runs one way, and every protein in your body was built this way.

In the 1940s doctors studying sickle cell disease found that the red blood cells of patients bend into a curved shape when oxygen is low. The bent cells jam in small blood vessels and cause pain. In 1949 Linus Pauling’s team showed that the hemoglobin protein itself was different. Years later the cause was traced to a single base. In one gene, an A had been swapped for a T. That changed one codon, which changed one amino acid, which changed the shape of the whole protein.

A substitution like that swaps one base for another. Some substitutions are silent: the new codon names the same amino acid, so the protein is unchanged. Others change one amino acid, as in sickle cell. Still others create a stop codon in the middle of a gene, cutting the protein short. An insertion or deletion adds or removes bases. If the number is not a multiple of three, every codon after it is read wrong. This is a frameshift, and it usually wrecks the protein.

Where do mutations come from? Some are copying errors that slip past proofreading. Others are caused by damage: ultraviolet light from the sun, certain chemicals in tobacco smoke, or radiation. The cell repairs most damage, but not all. Most mutations land in stretches of DNA that do not code for anything and have no effect. A few are harmful. Rarely, one is helpful.

Which cells the mutation is in matters. A mutation in a skin cell affects only that cell and its descendants in your body. A mutation in a sperm or egg cell can be passed to a child and to every cell in that child. Only those inherited mutations can be passed down through a family.

Your DNA is packed into 46 chromosomes, in 23 pairs. One of each pair came from your mother, the other from your father. A sperm or egg carries only 23, one from each pair. When they join, the count returns to 46. The special kind of cell division that halves the count is called meiosis.

Meiosis begins like ordinary division: the DNA is copied. Then the cell divides twice. In the first division, the paired chromosomes line up side by side and are pulled to opposite ends. In the second, the copies separate. One cell becomes four, each with a single set of 23. Because it happens only in sex cells, meiosis is the bridge between generations.

Two things during meiosis make offspring different from each other. First, while paired chromosomes lie side by side, they swap pieces. This is crossing over. A chromosome that was purely your father’s comes out with stretches from your mother’s copy. Second, when the pairs line up, which member goes left and which goes right is random for each pair. This is independent assortment. With 23 pairs there are 2 to the 23rd power, more than 8 million, possible combinations from one parent alone.

Add crossing over, and then the random meeting of one sperm and one egg, and the number of possible children from two parents is beyond counting. Brothers and sisters share parents but not the same shuffle. Identical twins are the exception: they come from one fertilized egg that split, so they carry the same combination.

In a monastery garden in what is now the Czech Republic, a monk named Gregor Mendel spent eight years crossing pea plants. He chose peas because they have clear traits, like round or wrinkled seeds and tall or short stems, and because he could control which plant pollinated which. Between 1856 and 1863 he grew and counted thousands of plants. He published his results in 1866. Almost no one noticed until 1900.

Here is what he found. Cross a plant with round seeds and a plant with wrinkled seeds, and every offspring has round seeds. The wrinkled trait seems to vanish. But let those offspring pollinate themselves, and wrinkled seeds come back in about one plant in four. Mendel counted 5,474 round to 1,850 wrinkled, close to a 3:1 ratio. He got the same ratio for six other traits.

Mendel explained it with factors that we now call alleles, versions of a gene. Each plant carries two alleles for seed shape, one from each parent. The round allele is dominant: if a plant has even one, its seeds are round. The wrinkled allele is recessive: seeds are wrinkled only when both alleles are wrinkled. When a plant makes pollen or eggs, the two alleles separate, and each sex cell gets one. This matches what you learned about meiosis, though Mendel never saw a chromosome.

A Punnett square shows the possibilities. Write one parent’s alleles across the top, the other’s down the side, and fill in the boxes. For two parents that each carry one round allele (R) and one wrinkled allele (r), the boxes are RR, Rr, Rr and rr. Three of four have at least one R and are round. One is rr and is wrinkled. The 3:1 ratio falls out of the square.

Cross a red snapdragon with a white one and the offspring are pink. Neither allele hides the other. This is incomplete dominance. One red allele makes half as much red pigment as two, so the flower is a lighter color. Cross two pink plants, and you get red, pink and white in a 1:2:1 ratio, which shows the alleles never blended. They just shared the work.

Sometimes both alleles show fully at once. Human blood type is the classic case. The gene for the ABO blood group has three alleles. The A allele and the B allele each put a different marker on red blood cells. A person with one of each has both markers and is type AB. This is codominance. The third allele, O, puts no marker and is recessive to both. So type O people carry two O alleles.

Some genes sit on the X chromosome. Women have two X chromosomes; men have one X and one Y. A recessive allele on the X is usually masked in a woman by her other X. A man has no second X, so if his one X carries it, the trait shows. These are sex-linked traits. Red-green color blindness works this way. It affects about 1 in 12 men but only about 1 in 200 women. A colorblind man’s sons never inherit it from him, because sons get his Y; his daughters get his X and become carriers.

Most human traits are more tangled still. Height, skin color and the risk of many diseases depend on many genes at once, plus food, sunlight and other conditions. That is why children are not simple averages of their parents and why a Punnett square cannot predict how tall you will be.

Geneticists cannot cross people the way Mendel crossed peas. Instead they draw a pedigree: a family tree that marks who has a trait. Squares stand for males and circles for females. A horizontal line joins parents; a vertical line leads down to their children. A shaded shape means the person shows the trait. Half-shading or a dot can mark a carrier, someone who has one copy of a recessive allele but does not show it.

The pattern tells the story. If two unaffected parents have an affected child, the trait must be recessive: both parents were carriers. If a trait appears in every generation and every affected child has an affected parent, it is likely dominant. If it shows up mostly in males and skips generations through unaffected mothers, it is probably recessive and on the X chromosome.

The most famous pedigree in history is Queen Victoria’s. She carried an allele for hemophilia, a disease in which blood does not clot properly, on one of her X chromosomes. She had no symptoms. But one of her sons had the disease, and two of her daughters were carriers. Through royal marriages the allele reached the ruling families of Spain, Germany and Russia. The pattern, affected sons and carrier daughters, is exactly what a sex-linked recessive trait produces.

Pedigrees have practical uses today. A genetic counselor can use one, along with a DNA test, to tell a couple the odds that a child will inherit a condition that runs in the family. The chart cannot say what will happen to one particular child. It can only say what fraction of many such children would be expected to inherit it.

A genome is the complete set of DNA in one organism. In 1990 a large team of scientists in the United States and other countries set out to read all 3 billion base pairs of the human genome. This was the Human Genome Project. It took 13 years and about 3 billion dollars, and it finished in April 2003. Today a person’s genome can be sequenced in a day or two for a few hundred dollars.

The results held surprises. Scientists had guessed humans would have around 100,000 genes. The count came in at only about 20,000 protein-coding genes, similar to a mouse and fewer than some plants. Only about 1 to 2 percent of the genome codes for protein. Much of the rest controls when and where genes are turned on. And any two people are about 99.9 percent identical in their DNA. All human variety fits in the other 0.1 percent.

Reading genomes changed medicine. Doctors can test for the alleles behind cystic fibrosis, sickle cell disease and many cancers. Some drugs are now matched to a patient’s genes. Genome tests can also confirm family relationships and help identify the cause of rare inherited diseases.

Reading your own code raises questions. Who should see it? Could an employer or an insurer use it against you? In the United States a 2008 federal law bars health insurers and most employers from using genetic information to discriminate. But privacy of DNA stored in company databases remains an open issue.

Bacteria get infected by viruses, and some bacteria keep a memory of past infections. They store short pieces of viral DNA in their own genome, in a region called CRISPR. When the same virus returns, the bacterium makes an RNA copy of the stored piece. That RNA guides a protein called Cas9 to the matching spot in the virus’s DNA, and Cas9 cuts it. It is an immune system made of DNA.

In 2012 Jennifer Doudna and Emmanuelle Charpentier showed that this system could be aimed anywhere. Give Cas9 a guide RNA that matches any sequence you choose, and it will cut there. The cell then repairs the cut, and scientists can supply a new piece of DNA for it to use as a patch. This is gene editing. For this work the two shared the Nobel Prize in Chemistry in 2020.

The first cures came fast. Sickle cell disease is caused by one changed base, as you saw. In December 2023 the U.S. Food and Drug Administration approved a treatment that edits a patient’s own blood-forming cells and returns them to the body. Researchers are also editing crops for drought tolerance and disease resistance. Illinois, where more than 90 percent of corn acres are planted with genetically engineered varieties, is watching closely.

The hard questions come with the power. Editing a patient’s blood cells changes one person. Editing an embryo would change every cell of a person not yet born, and their children too. In 2018 a scientist in China announced he had edited the genes of twin girls before birth. Scientists worldwide condemned it, and he was sent to prison. Most countries now ban editing embryos that will be carried to birth. Who decides which conditions to edit, who can afford it, and what counts as a disease rather than a difference are questions the science alone cannot answer.