DNA copying is astonishingly accurate, but not perfect. Errors also come from radiation, some chemicals and the natural wear of molecules. A permanent change in DNA sequence is a mutation. Each of us carries several dozen new mutations that neither parent had, most of them arising in the father's sperm, whose parent cells divide many more times than those of eggs. Most new mutations have no noticeable effect, because they fall outside genes or make silent changes. A few are harmful, and a very few are helpful. Mutation is the ultimate source of all genetic variation, the raw material of evolution and of inherited disease alike.
Kinds of change
A substitution swaps one base for another. As the last level showed, it can be silent, can replace one amino acid with another (missense), or can create an early stop (nonsense). Insertions and deletions add or remove bases; unless they come in multiples of three, they cause a frameshift that garbles every codon downstream. Some mutations are repeat expansions, in which a short sequence such as CAG, normally repeated a modest number of times, grows longer. Repeats can grow further as they pass to children, which can make a condition start earlier or hit harder in each generation, a pattern called anticipation. Fragile X syndrome, myotonic dystrophy and Huntington's disease are repeat disorders. Larger changes involve whole chunks of chromosome.
Three patterns of inheritance
Single-gene conditions follow Mendel's rules. In autosomal recessive conditions a person must inherit two faulty copies, one from each parent. Parents are usually healthy carriers, so the condition seems to appear from nowhere. Cystic fibrosis, which clogs the lungs and gut with thick mucus, is the most common serious example among people of northern European ancestry, of whom about one in 25 is a carrier. Its gene was identified in 1989, and its most common mutation, called delta F508, deletes three bases, removing a single amino acid from a protein that moves chloride through cell membranes.
In autosomal dominant conditions one faulty copy is enough, so an affected parent has a one in two chance of passing it to each child. Dominant conditions can also arise fresh. About 80 percent of children with achondroplasia, the most common form of dwarfism, have average-height parents, because the mutation arose new in a parent's sperm or egg. X-linked conditions, such as hemophilia and Duchenne muscular dystrophy, follow the pattern from the second level.
The sickle cell puzzle
If a recessive allele is harmful, why would it be common? Sickle cell disease is the classic answer. Two copies of the sickle allele distort red blood cells into stiff crescents that block small blood vessels. Yet the allele is common across much of Africa and in parts of the Middle East and India. In 1954 the British doctor Anthony Allison showed that its distribution matches the historic range of malaria, and that carriers with one copy are partly protected against severe malaria. Where malaria is common, carriers survive and have children more often than people with no copy, so the allele stays frequent even though people with two copies suffer. This is called heterozygote advantage: carriers of one copy survive better than people with none. It is a reminder that "good" and "bad" alleles depend on the environment.
Genetic does not mean fixed
Phenylketonuria, or PKU, is a recessive condition in which the body cannot break down the amino acid phenylalanine, which builds up and damages the developing brain. The Norwegian doctor Asbjørn Følling identified it in 1934. In the early 1960s Robert Guthrie developed a cheap blood test from a heel prick, and newborn screening spread across many countries. Babies found to have PKU are put on a special low-phenylalanine diet and grow up with normal intelligence. PKU is entirely genetic and largely preventable, a powerful answer to the idea that genetic means destiny.
Carrier screening offers another kind of choice. Tay-Sachs disease, a fatal recessive condition of the nervous system, was once far more common among Ashkenazi Jews than in other groups. Voluntary community screening, beginning in the early 1970s, cut affected births among Jewish families in the United States and Canada by more than 90 percent. One Orthodox program, Dor Yeshorim, tests young people confidentially and tells two prospective partners only whether both are carriers.
Worked example: two carriers
Two healthy parents learn from newborn screening that their first baby has sickle cell disease, so both must be carriers. Call the usual allele A and the sickle allele S; each parent is AS. For each pregnancy there is a one in four chance the child will be SS and have the disease, a one in two chance of being a carrier, and a one in four chance of being AA. Chance has no memory: having one affected child does not make the next any safer. Now consider their second child, who is healthy. She cannot be SS, so only three equally likely outcomes remain: AA, AS or SA. Two of the three are carriers, so her chance of carrying the allele is two in three, not one in two. Removing outcomes that the facts have ruled out is the everyday reasoning of genetic counseling.