Mary Lyon

Even in England’s mild climate, summer temperatures rise enough to make telephone wires sag—and young Mary Lyon wondered why. She soon realized that science explains such enigmas. At age ten, she won an essay contest in honor of King George V’s Silver Jubilee. The prize—a set of books about nature—ensnared her in biology. She learned about amoebae in pond water and marveled at the complex lives of butterflies and honeybees.

In college at Cambridge University, Lyon studied zoology. The notion that genes control embryonic development—a new idea in the mid 1940s—intrigued her. Her graduate work on mice led her to join a government project that explored the harmful effects of radiation. As part of this enterprise, Lyon studied mouse mutants—those that had acquired changes in their genetic blueprints. Occasionally, a so-called spontaneous mutant turned up in the control group.

In 1960, Lyon reported on such a mouse whose splotchy coat perplexed her. Its appearance typified females that carry particular coat-color genes on one of their two X chromosomes. The creature was male, however, and males with such X-linked traits typically died before birth or sported solid coats. In keeping with that trend, breeding studies showed that the gene carried by Lyon’s original dappled mouse killed would-be male descendants in utero. She puzzled over how the animal had survived and gotten his spots. Perhaps, she speculated, a genetic oddity arose in a single cell during early embryonic life. In Lyon’s scenario, the other—normal and healthy—cells divided and gave rise to most of the animal’s body. Fur from the perturbed cell differed in color from fur that came from the original cells. Because every cell spawns many others and the two cell types duplicated adjacent to each other, patches developed.

Lyon wondered whether this phenomenon might also create the coat patterns of females with X-linked pigment genes. She delved into the scientific literature and learned that female mice with a single X chromosome in each cell could survive and reproduce. Therefore, gene activity from only one X chromosome is needed. A second, even more tantalizing finding made her ideas coalesce. In 1960, researchers reported that the so-called Barr body, a structure that appears in the nuclei of female mammals, was a single X chromosome. This observation revealed that an X chromosome can behave differently from its partner. Furthermore, the Barr body stained darkly with certain dyes, suggesting a highly condensed and genetically silent state.

Lyon realized that the inactivation of one X chromosome might be the early event that produced the mottled coats of females with sex-linked coat-color mutations. In each cell, she proposed, the paternal or maternal X chromosome would randomly turn off and remain dormant. The blotchy pattern resulted because pigment-production genes on only one X chromosome fire in any given cell.

Lyon subsequently tested this 1961 hypothesis and extended it to humans. The discovery of X inactivation—also called “lyonization”—has established the cornerstone for insights into human sex-linked disorders, sex determination, and general health differences between men and women.

Author Profile: Evelyn Strauss, Ph.D.