September 18, 2006

The Movability of Genes

Barbara McClintock, Mutable Loci in Maize, 1948

I often forget just how much research into genetics went on before the structure of DNA was discovered. My education in biology covered the Abbot Gregor Mendel's discovery of dominant and recessive traits, the rediscovery of his work in 1900, and then jumped straight to Watson and Crick. I am not alone in this: many scientists neglected earlier work in the decades after the DNA revolution.

Barbara McClintock is one of the least-known great scientists of the 20th century. Her work on genetics was ground-breaking, from her proof of the link between genetic recombination and chromosomal crossover in 1930 right through to her discoveries about transposable genes in the 1950s. Although well regarded by those of her colleagues who understood her work, many of her discoveries weren't well known until the early 1980s. Indeed, in 1953 she actually stopped publishing her work on gene regulation through sheer frustration with the fuzzy assumptions and dull incomprehension she encountered in geneticists at the time.

Basically, most geneticists started out believing that all genes follow Mendel's simple model: each gene produces one trait, in either a dominant or a recessive form. Genes were known to reside on the chromosomes, those tiny structures in cells which later turned out to be huge bundles of DNA. Most cells contain two copies of each chromosome, and thus two copies of each gene, which also fits Mendel's model.

During sexual reproduction, cells divide differently than they normally do, and sister chromosomes can be observed exchanging parts. As mentioned above, McClintock was the first to show that this "crossover" process causes genetic traits to be exchanged between chromosomes. The consequences of this are useful: if two genes happen to be near each other on the same chromosome, they are much less likely to end up in different offspring. That is, most offspring will have both traits, or neither. If they are far apart, or on different chromosomes, offspring will tend to have one trait and not the other as often as having both or neither.

Using this statistical information, one can map the chromosomes, showing which chromosome each gene is on and where it is relative to other genes. McClintock did this with maize (corn), a plant she studied for most of her career. This is sort of like an early version of gene sequencing. Most geneticists knew about this kind of work, and believed as a result that genes are lined up linearly on chromosomes, and stay in the same position.

McClintock added all kinds of wrinkles to this model. For starters, she discovered a gene on the 9th chromosome of maize whose dominant form frequently caused the chromosome to break at the gene's location. (This was observed with a microscope.) As you can imagine, this caused havoc with the development of the plant. Corn kernels on the same plant often look quite different from each other, in part because chromosome breakage causes large mutations in the different kernels during the lifetime of a single plant.

McClintock then discovered that this gene was controlled by a second gene. When the recessive form of the control gene was present, breakages never happened, no matter whether the breakage gene was dominant or recessive. When the dominant form of the control gene was present, the breakage gene behaved normally. The discovery of genes whose only effect is to control the action of other genes is a major step forward all by itself.

But McClintock didn't stop there. During her detailed study of maize, she noticed that some corn kernel mutations appear in paired patches: one patch with a higher mutation rate than normal, and an adjacent patch with a lower mutation rate than normal. (McClintock was known for her incredible eye for detail. Admittedly, she was using a microscope, but still!) These paired patches, she theorized, must have arisen from a single ancestral cell, early in the growth of the kernel, that divided in such a way that one daughter cell gained something from the other daughter cell. The two neighboring patches then, represent all the descendants of the two daughter cells.

She quickly discovered that the differing mutation rates were governed by the same gene that controlled the breakage gene. The gains and losses appeared at many different strengths, and with time McClintock came to realize that the control gene was composed of a repeating segment of DNA, and the paired patches were being caused when some of the repeated units got moved from one chromosome to its sister. Along the way, she discovered that the breakage gene sometimes moved to a different position on the chromosome!

In short, McClintock destroyed the notion that chromosomes are immutable lists of dominant and recessive traits. It seems they are better understood as collections of genes, many having variable strength, and many of which cause other genes to be activated, deactivated, moved about, and even edited. These phenomenon are not restricted to maize; one estimate has 45% of the human genome composed of transposons (genes known to change location). Bacteria are particularly good at this trick, even going so far as to take genes from other bacteria and incorporate them into their own genome.

In many ways, genetic systems actually resemble incredibly messy, self-modifying computer programs.


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