Single-Gene Inheritance

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What kinds of research do biologists do? One central area of research in the biology of all organisms is the attempt to understand how an organism develops from a fertilized egg into an adult—in other words, what makes an organism the way it is. Usually, this overall goal is broken down into the study of individual biological properties such as the development of plant flower color, or animal locomotion, or nutrient uptake, although biologists also study some general areas such as how a cell works. How do geneticists analyze biological properties? The genetic approach to understanding any biological property is to find the subset of genes in the genome that influence that property, a process sometimes referred to as gene discovery. After these genes have been identified, their cellular functions can be elucidated through further research.

There are several different types of analytical approaches to gene discovery, but one widely used method relies on the detection of single-gene inheritance patterns, and that is the topic of this chapter.

All of genetics, in one aspect or another, is based on heritable variants. The basic approach of genetics is to compare and contrast the properties of variants, and from these comparisons make deductions about genetic function. It is similar to the way in which you could make inferences about how an unfamiliar machine works by changing the composition or positions of the working parts, or even by removing parts one at a time. Each variant represents a “tweak” of the biological machine, from which its function can be deduced.

In genetics, the most common form of any property of an organism is called the wild type, that which is found “in the wild,” or in nature. The heritable variants observed in an organism that differs from the wild type are mutants, individual organisms having some abnormal form of a property. As examples, the wild type and some mutants in two model organisms are shown in Figure 2-1. The alternative forms of the property are called phenotypes. In this analysis we distinguish a wild-type phenotype and a mutant phenotype.

Compared to wild type, mutants are rare. We know that they arise from wild types by a process called mutation, which results in a heritable change in the DNA of a gene. The changed form of the gene is also called a mutation. Mutations are not always detrimental to an organism; sometimes they can be advantageous, but most often they have no observable effect. A great deal is known about the mechanisms of mutation (see Chapter 16), but generally it can be said that they arise from mistakes in cellular processing of DNA.

Most natural populations also show polymorphisms, defined as the coexistence of two or more reasonably common phenotypes of a biological property, such as the occurrence of both red- and orange-fruited plants in a population of wild raspberries. Genetic analysis can (and does) use polymorphisms, but polymorphisms have the disadvantage that they generally do not involve the specific property of interest to the researcher. Mutants are much more useful because they allow the researcher to zero in on any property.

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Simply stated, the general steps of functional analysis by gene discovery are as follows:

Of these steps, only 1 and 2 will be covered in the present chapter.

Gene discovery starts with a “hunt” to amass mutants in which the biological function under investigation is altered or destroyed. Even though mutants are individually rare, there are ways of enhancing their recovery. One widely used method is to treat the organism with radiation or chemicals that increase the mutation rate. After treatment, the most direct way to identify mutants is to visually screen a very large number of individuals, looking for a chance occurrence of mutants in that population. Also, various selection methods can be devised to enrich for the types sought.

Armed with a set of mutants affecting the property of interest, one hopes that each mutant represents a lesion in one of a set of genes that control the property. Hence, the hope is that a reasonably complete gene pathway or network is represented. However, not all mutants are caused by lesions within one gene (some have far more complex determination), so first each mutant has to be tested to see if indeed it is caused by a single-gene mutation.

The test for single-gene inheritance is to mate individuals showing the mutant property with wild-type and then analyze the first and second generation of descendants. As an example, a mutant plant with white flowers would be crossed to the wild type showing red flowers. The progeny of this cross are analyzed, and then they themselves are interbred to produce a second generation of descendants. In each generation, the diagnostic ratios of plants with red flowers to those with white flowers will reveal whether a single gene controls flower color. If so, then by inference, the wild type would be encoded by the wild-type form of the gene and the mutant would be encoded by a form of the same gene in which a mutation event has altered the DNA sequence in some way. Other mutations affecting flower color (perhaps mauve, blotched, striped, and so on) would be analyzed in the same way, resulting overall in a set of defined “flower-color genes.” The use of mutants in this way is sometimes called genetic dissection, because the biological property in question (flower color in this case) is picked apart to reveal its underlying genetic program, not with a scalpel but with mutants. Each mutant potentially identifies a separate gene affecting that property.

After a set of key genes has been defined in this way, several different molecular methods can be used to establish the functions of each of the genes. These methods will be covered in later chapters. Hence, genetics has been used to define the set of gene functions that interact to produce the property we call flower color (in this example).

This type of approach to gene discovery is sometimes called forward genetics, a strategy to understanding biological function starting with random single-gene mutants and ending with their DNA sequence and biochemical function. (We shall see reverse genetics at work in later chapters. In brief, it starts with genomic analysis at the DNA level to identify a set of genes as candidates for encoding the biological property of interest, then induces mutants targeted specifically to those genes, and then examines the mutant phenotypes to see if they indeed affect the property under study.)

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Gene discovery is important not only in experimental organisms but also in applied studies. One crucial area is in agriculture, where gene discovery can be used to understand a desirable commercial property of an organism, such as its protein content. Human genetics is another important area: to know which gene functions are involved in a specific disease or condition is useful information in finding therapies.

The rules for single-gene inheritance were originally elucidated in the 1860s by the monk Gregor Mendel, who worked in a monastery in the town of Brno, now part of the Czech Republic. Mendel’s analysis is the prototype of the experimental approach to single-gene discovery still used today. Indeed, Mendel was the first person to discover any gene! Mendel did not know what genes were, how they influenced biological properties, or how they were inherited at the cellular level. Now we know that genes work through proteins, a topic that we shall return to in later chapters. We also know that single-gene inheritance patterns are produced because genes are parts of chromosomes, and chromosomes are partitioned very precisely down through the generations, as we shall see later in the chapter.