Читать книгу Welcome to the Genome - Michael Yudell - Страница 16

With only four pairs of chromosomes, the ability to produce offspring at a pace that would make even the most reproductively prolific blush, and the fact that it can live in the austere environment of a laboratory storage bottle, the six‐legged Drosophila melanogaster, or fruit fly, has been the workhorse of genetics for more than 100 years.

Beginning early in the twentieth century, Thomas Hunt Morgan and his students at Columbia University capitalized on Drosophila’s valuable qualities and began breeding fruit flies by the hundreds of thousands, hoping to find variations or mutations in fruit fly traits that would help explain Mendel’s laws in real‐life situations. Morgan’s laboratory, dominated by work with Drosophila, became known as the fly room, a moniker that can only partly suggest the overwhelming number of flies present in a space that measured just 16 × 23 feet. (32) Today the fly room is frequented by one of the present authors—part of it still exists at Columbia University (if you are looking for it, it is now the men’s bathroom on the sixth floor of Schermerhorn Hall).

During the 1910s, thanks in large part to the work conducted in the fly room, genetics shifted from simply testing Mendel’s laws of inheritance to studying the physical arrangement of genes on chromosomes. Interestingly enough, the terminology of what we now call genetics was not even in place. Morgan and his genetically minded colleagues were pioneers in a field that was quickly becoming known as genetics, a word coined by botanist William Bateson in 1906. The word gene was itself first defined by the German biologist Wilhelm Johannsen in 1909. (33) The new terminology and the field of work and entity it describes are still used today.

Morgan, formerly a critic of Mendelian theory, came to embrace the new genetics because of some surprising results in his own research. In 1910 he discovered something startling among one of his breeds of Drosophila—a lone white‐eyed male fly. When it was bred with a normal (red‐eyed) female, all of the offspring had red eyes. When flies from the first generation were crossed, the white‐eyed character reappeared, but surprisingly only in half of the males. Finally, when white‐eyed males were bred with first‐generation females, 50% of both males and females had white eyes. Morgan called this change a mutation and spent much of his career studying such mutations in order to decipher the nature of genes and the structure of chromosomes. (34)

Ultimately Morgan saw that Mendelian laws of segregation and independent assortment easily explained these patterns. Morgan’s biographer Garland Allen suggests that these results were the main factor in Morgan’s acceptance of Mendelism. (35)

The white‐eyed Drosophila was a mutant variation of the normal red‐eyed type. These types of mutations in physical characteristics became the means by which Morgan and his students at Columbia began to describe the physical entities of genes and chromosomes. People tend to think of genetic mutations as frightening, a change caused by exposure to something dangerous or a freakish event or accident. A few things drive this fear. Most obvious is a misunderstanding of what a genetic mutation is and what it means for an organism. The other is that people have often described mutations as the result of exposure to atomic radiation either in real life (Nagasaki, Hiroshima, Chernobyl, or Fukushima) or in science fiction (Godzilla). It is true that the ill‐effects on people exposed to high levels of radiation at atomic bomb sites are real and that cancer rates among survivors of Hiroshima and Nagasaki were substantially higher than normal because of mutations caused by the atomic bomb’s radiation. (36) But mutations are generally not of this type, nor do they create the Godzilla‐like creatures that have appeared in science fiction for the past half‐century. Mutation comes from the Latin word meaning change, so a mutation is simply a change in an organism’s DNA sequence—a change that may have no measurable effect on the organism or may confer either a beneficial or adverse effect. Random errors that occur during cell division are the most common cause of mutation. Most mutations are unpredictable, as are their effects.

Figure 1.5 Most Drosophilia look like the red‐eyed fly on the left. Morgan’s discovery of and breeding experiments with the mutant white‐eyed variety, as seen on the right, confirmed Mendel’s basic laws and expanded them to include the linearity of genes on chromosomes.

Credit: Daniel Marenda, PhD and the Marenda Laboratory

There are two types of mutations. One is somatic (remember these are an organism’s nonreproductive cells)—that is, its effects die with the organism. The other type of mutation occurs in the germline (in reproductive cells) and can be passed between generations. But cells are resilient. During cell division errors do occur, most of which are repaired by cellular mechanisms that are constantly at work to thwart the proliferation of cells with mutated nucleotides. During cell division, repair mechanisms check to make sure that the correct nucleotide has been selected at every stage of DNA synthesis. This is a tremendous task—in the human genome more than 3 billion bases are read and checked each time a cell divides. These repair systems are redundant several times over. During mammalian cell division, for example, a gene called p53 plays an important role as a cellular safety device—it can stop cells with damaged DNA from reproducing themselves. This has earned this gene the nickname “guardian angel of the genome.” (37) Mutations in the p53 gene seem to play a significant role in the development of human cancers. Typically, a mutated p53 is not as effective at controlling the proliferation of cells with damaged DNA, and dangerous mutations can grow over time to become cancers.

The cause of a mutation can be the result of exposure to radiation, but as was the case in the Morgan lab, the causes of mutations for a white‐eyed variation were probably far more ordinary. The white‐eyed trait most likely arose from a random error in the DNA replication process. Less likely, the mutation may have been caused by a mutagen, an agent that can cause mutation. Temperature changes during gestation, environmental exposures, certain viruses, radiation, ultraviolet light, and chemicals can all act as mutagens. By using the mutations found in Drosophila, Morgan was able to begin to map the Drosophila genome. (38) This was not like the modern genome sequence maps that we hear a lot about today. Indeed, although DNA had already been isolated from cellular material, it was not yet even suspected to be the “stuff” of heredity. Thus, there could be no map of the sequence of this genome, as neither science nor technology was even close to accomplishing this feat. Instead, Morgan began to map the location, or linear arrangement, of particular genes along Drosophila chromosomes. Working with a series of mutations, including variations in body color and wing shape, Morgan and his collaborators were able to create chromosome maps showing the location of certain genes on each of Drosophila’s four chromosomes. (39) Morgan’s group, for example, determined that the white‐eyed mutation lies on the X, or Drosophila sex chromosome. (40)

The beauty of Morgan’s work, much like Mendel before him, stemmed from his powers of deduction. Morgan could never actually see the positions of genes on the Drosophila chromosomes, but he could create virtual maps based on his experiments and deductions. Faced with unknown and unpredictable challenges neither he nor his colleagues on the genetic frontier could have anticipated, Morgan’s team was able to organize information in a fashion that is as elegant and relevant today as it was when his discoveries were made. Morgan’s biographer Garland Allen notes that “there have been few research groups in modern biology that have functioned as effectively together as did Morgan’s group in their fly room between 1910 and 1915.” (41) To develop chromosome maps, the Morgan lab used a technique that came to be known as the three‐point cross. Morgan reasoned that two genes very close to each other on a chromosome would appear to stay with each other even when other parts of the chromosome recombined. By looking at thousands and thousands of flies for visible mutations and breedings these mutations in the lab, Morgan was not only able to arrange these into linkage groups on chromosomes based on whether or not they segregated together, but also to say how the traits were organized on the chromosomes. (42)

But all was not well on the genetic frontier. These new and very powerful ideas concerning heredity, just beginning to make sense to some and still unknown to most, became a way to understand the world not only scientifically, but also socially.