Mendel's laws describe how invisible factors behave, but not where they are. The answer came from microscopes. By the 1880s biologists could stain cells and watch thread-like bodies in the nucleus, called chromosomes, duplicate and separate as cells divided. They also discovered meiosis, the special division that makes eggs and sperm. Meiosis halves the chromosome number, so that fertilization restores the full set.

The chromosome theory

In 1902 and 1903 the American student Walter Sutton and the German biologist Theodor Boveri each argued that chromosomes behave exactly as Mendel's factors should. Chromosomes come in matching pairs, one from each parent; the members of each pair separate in meiosis; and different pairs line up independently of one another. The proposal that Mendel's factors are carried on chromosomes became known as the Sutton-Boveri chromosome theory of inheritance. It was persuasive, but it needed proof, and it raised an obvious problem. Every organism has far more traits than chromosome pairs. If genes ride on chromosomes, many genes must share each one, and genes on the same chromosome should not assort independently.

The fly room

The proof came from Thomas Hunt Morgan's laboratory at Columbia University, a cramped room crowded with milk bottles of fruit flies. Flies breed in about two weeks, cost almost nothing to keep and produce hundreds of offspring. In 1910 Morgan found a male with white eyes instead of the usual red. When he bred it, the white-eye trait followed a strange pattern: it showed up mostly in males and passed from mothers to sons. Morgan concluded that the white-eye gene lies on the X chromosome. Female flies, like female humans, have two X chromosomes; males have one X and one Y. A male with a single recessive allele on his only X shows the trait, because there is no second copy to mask it. This is called sex-linked or X-linked inheritance, and it tied a specific gene to a specific chromosome for the first time.

Linkage and the first map

Morgan's group soon found many traits that tended to be inherited together. Such genes are linked: they sit on the same chromosome and tend to be inherited together. Yet linkage was never complete. Now and then the combinations broke up. Morgan proposed that during meiosis paired chromosomes swap segments, a process called crossing over, or recombination. The farther apart two genes are, the more likely a crossover will fall between them and separate them.

In 1911 Alfred Sturtevant, a student in the lab, realized this offered a way to measure distance. By his own account he went home, neglected his homework, and stayed up most of the night using recombination frequencies to place genes in a line. Published in 1913, it was the first genetic map, made by Sturtevant while still an undergraduate. Geneticists still measure map distance in centimorgans, named for Morgan: one centimorgan is a one percent chance of recombination between two genes in a generation.

Human chromosomes

Counting human chromosomes proved surprisingly hard. For three decades textbooks said there were 48. In 1956 Joe Hin Tjio and Albert Levan, using better techniques, showed that human cells have 46 chromosomes, in 23 pairs: 22 pairs of autosomes plus the sex chromosomes. In 1959 a French team led by Jérôme Lejeune reported that people with Down syndrome have an extra copy of chromosome 21, the first condition linked to a chromosome number. The researcher Marthe Gautier did much of the laboratory work and later said her role had been played down. Extra or missing chromosomes usually arise from nondisjunction, a failure of a chromosome pair to separate during meiosis, and the risk of it in eggs rises with the mother's age.

Royal blood

X-linked inheritance explains why some conditions are far more common in men. Hemophilia, in which blood fails to clot properly, is caused by a recessive allele on the X chromosome. Queen Victoria was a carrier. One of her sons, Leopold, had hemophilia, and through her daughters the allele reached the royal families of Spain and Russia, including Alexei, heir to the last Russian tsar. The same pattern explains red-green color blindness, which affects about 8 percent of men of northern European ancestry but well under 1 percent of women.

Worked example: a carrier mother

A woman's brother has hemophilia, and she has learned that she carries the allele on one of her X chromosomes. Her husband does not have hemophilia, so his single X is normal. Each son receives his Y from his father and one of his mother's two Xs, so each son has a one in two chance of receiving the allele and having the condition. Each daughter receives her father's normal X, so none will have hemophilia, but each has a one in two chance of being a carrier like her mother. Notice what a father cannot do: a man never passes his X to his sons, so an affected father's sons are unaffected, while all his daughters are carriers. That simple asymmetry, worked out in Morgan's milk bottles, is how genetic counselors trace X-linked conditions through a family tree today.