Within a few years, many other traits turned out to be transmitted together. Experiments with millions of flies showed that all Drosophila genes could be arranged into groups on the basis of whether or not their patterns of inheritance were independent. Some combinations behaved as Mendel expected. For others, pairs of traits from one parent tended to stay together in later generations. The genes involved were, as Morgan put it, in the same linkage group. The number of groups was the same as the number of chromosomes. This discovery began the ‘linkage map’ of Drosophila and became the connection between Mendelism and molecular biology.
Linkage is the tendency of groups of genes to travel together down the generations. It is not absolute. Genes may be closely associated or may show only a feeble preference for each other’s company. Such incompleteness is explained by some odd events when sperm and egg are formed. Every cell contains two copies of each of the chromosomes. The number is halved during a special kind of cell division in testis or ovary. The chromosomes lie together in their pairs and exchange parts of their structure. Sperm or egg cells hence contain combinations of chromosomal material that differ from those in the cells of the parents who made them.
That is why, within a linkage group, certain genes are inherited in close consort while others have a less intimate association. If genes are near each other they are less likely to be parted when chromosomes exchange material. If they are a long way apart, they split more often. Pairs of genes that each follow Mendel are on different chromosomes. Recombination, as the process is called, is like shuffling a red and a black hand of cards together. Two red cards a long way apart in the hand are more likely to find themselves split from each other when the new deck is divided than are two such cards close together. Such rearrangements mean that each chromosome in the next generation is a new mixture of the genetic material made up of reordered pieces of the chromosome pairs of each parent.
Recombination helped make the first genetic maps. Like the cards in a hand held by a skilled player, genes are arranged in a sequence. Their original position can be determined by how much this is disturbed each generation as the inherited cards are shuffled. By studying the inheritance of groups of genes Morgan worked out their order and their relative distance apart. Combining the information from small sets of inherited characters allowed what he called a ‘linkage map’ to be made.
Linkage maps, based as they are on exceptions to Mendelism, are very useful. They have been made for bacteria, tomatoes, mice and many other beings. Thousands of genes have been mapped in this way. In Drosophila almost all have been arranged in order along the chromosomes and in mice almost as many.
Because this work needs breeding experiments, the human linkage map remained for many years almost a perfect and absolute blank. Most families are too small to look for deviations from Mendel’s rules and too few variants were known to look for them. There seemed little hope that a genetic chart of humankind could be made.
The one exception to this terra incognita was sex linkage. If genes are linked to the X chromosome, they must be linked to each other. It did not take long for dozens of traits to be mapped there. To draw the linkage map for other chromosomes was a painfully slow business. The gene for colour-blindness was mapped to the X in 1911, but the first linkage on other chromosomes did not emerge until 1955, when the gene for the ABO blood groups was found to be close to that for an abnormality of the skeleton. The actual number of human chromosomes was established in the following year and the first non-sex linked gene mapped onto a specific chromosome in 1968.
Now, genetics has been transformed. The technology involved is as to linkage mapping as satellites are to sextants. It does not depend on crosses and comes up with much more than a biological chart based on patterns of inheritance. Geneticists have now made a more conventional (but much more detailed) kind of chart, a physical map of the actual order of all the bases along the DNA. The new atlas of ourselves has changed our views of what genes are.
In the infancy of human genetics, thirty years ago, biologists had a childish view of what the world looks like. As in the mental map of an eleven year-old (or of Herodotus) linkage was based on a few familiar landmarks placed in relation with each other. The tedious but objective use of a measure of distance changed all that. Thirty years ago, molecular biologists were full of hubris. They had, they thought, solved the problems of inheritance. The new ability to read the DNA message would do the job that family studies and linkage mapping had failed to complete; it would show where all our genes were in relation to each other. The edifice whose foundations were laid by Mendel would then be complete. Optimism was, at the time, reasonable. It seemed a fair guess that the physical map of the genes would look much like a biological map based on patterns of inheritance and might in time replace it.
Such optimism was soon modified. The first explorations of the unknown territory which lay along the DNA chain showed that the physical map was quite different from the linkage map as inferred from peas or fruit-flies. The genes themselves are not beads lined up on a chromosomal string, but have a complicated and unexpected structure.
The successes of the molecular explorers depended, like those of their geographical predecessors, on new surveying instruments which made the world a bigger and more complicated place. The tools used in molecular geography deserve a mention.
The first device is electrophoresis, the separation of molecules in an electric field. Many biological substances, DNA included, carry an electrical charge. When placed between a positive and a negative terminal they move towards one or the other. A gel (which acts as a sieve) is used to improve the separation. Gels were once made of potato starch, while modern ones are made of chemical polymers. I have tried strawberry jelly, which works quite well. The gel separates molecules by size and shape. Large molecules move more slowly as they are pulled through the sieve while smaller ones pass with less difficulty. Various tricks improve the process. Thus, a reversal of the current every few seconds means that longer pieces of DNA can be electrophoresed, as they wind and unwind each time the power is interrupted. The latest technology uses arrays of fine glass tubes filled with gel, into each of which a sample is loaded. With various tricks the whole process becomes a production line and tens of thousands of samples can be analysed each day.
The computer on which I wrote this book has some fairly useless talents. It can – if asked – sort all sentences by length. This sentence, with its twenty words, would line up with many otherwise unrelated sentences from the rest of the book. Electrophoresis does this with molecules. The length of each DNA piece can be measured by how far it has moved into the gel. Its position is defined with ultraviolet light (absorbed by DNA), with chemical stains, fluorescent dyes that light up when a laser of the correct wavelength is shone on them, or with radioactive labels. Each piece lines up with all the others which contain the same number of DNA letters.
Another tool uses enzymes extracted from bacteria to divide the landscape into manageable pieces. Bacteria are attacked by viruses which insert themselves into their genetic message and force the host to copy the invader. They have a defence: enzymes which cut foreign DNA in specific places. These ‘restriction enzymes’ can be used to slice human genes into pieces. Dozens are available, each able to cut a particular group of DNA letters. The length of the pieces that emerge depends on how often the cutting-site is repeated. If each sentence in this volume was severed whenever the word ‘and’ appeared, there would be thousands of short fragments. If the enzyme recognised the word ‘but’, there would be fewer, longer sections; and an enzyme that sliced through the much less frequent word ‘banana’ (which, I assure you, does appear now and again) would produce just a few fragments thousands of letters long.
The positions of the cuts (like those of the words and, but and banana) provide a set of landmarks along the DNA. To track them down is a first step to reconstituting the book itself. The process is close to that carried out by the students