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Modern Genetic Analysis Chapter 4. The Inheritance of Genes
Inheritance Patterns of Individual Genes

The inheritance patterns of individual genes are dictated by the highly programmed movements of chromosomes at mitosis and meiosis.

First let us review mitosis. We will use the alleles A and a as "typical" alleles of a gene. Haploid cells can be of genotype A or a, and the diploids can be homozygous, A/A and a/a, or heterozygous, A/a. Because each of the chromosomes is replicated faithfully, the genotypes of the daughter cells must be identical with the progenitor. We can represent these divisions as follows:

Now let us review the outcomes of meiosis in various genotypes. Logic tells us that meiosis in homozygous meiocytes can produce only one genotype in the four haploid products of meiosis (the tetrad) as follows:

However, starting with a meiocyte of genotype A/a, meiosis produces four haploid cells, of which half are A and half are a, as we saw in Figure 4-9.

The basic reason for this is that in the A/a meiocyte, the A chromosome produces a pair of sister chromatids A/A, and the homologous chromosome produces a pair a/a. These four "copies" of the gene end up in the four meiotic product cells. This result, formally known as equal segregation, was first observed by Gregor Mendel in the nineteenth century (see Genetics in Process 4-4). It is also sometimes called Mendel's first law. The 1:1 segregation is not affected by crossovers.

MESSAGE
Meiosis in a heterozygous meiocyte results in haploid products (for example, gametes) half of which carry one allele, and half the other allele; for example, A/a 1/2 Aand 1/2a .

In animals and plants it is not possible to isolate a meiotic tetrad (the four cells that are the products of meiosis in a single meiocyte). The eggs and sperm that are produced are the result of meioses in manymeiocytes. But the law of equal segregation still holds, so that out of, say, 1000 sperm or eggs produced by many meiocytes in a heterozygote A/a, 500 will be of genotype A and 500 will be a. (Of course sampling might lead to deviations from this 1:1 ratio.) However, some fungi and unicellular algae do have sexual cycles that make it possible to isolate all four products of a single meiosis. Two parental haploid fungi (say, of genotypes A and a) unite sexually to form a transient meiocyte that will be A/a (consult Figure 4-7 for the fungal sexual cycle). Meiosis occurs and the products of meiosis are called sexual spores. The four sexual spores that represent the products of a single meiosis are held together as a tetrad. In yeast (and other ascomycete fungi) the tetrad is contained in a sac called an ascus. Yeast asci from such a parental pair will always contain 2 A and 2 a haploid sexual spores. In the filamentous ascomycete Neurospora crassa and related fungi, the four haploid nuclei resulting from meiosis undergo a mitotic division resulting in 8 sexual spores (an octad); in this case the law of equal segregation would be expressed in the ascus as 4 A and 4 a (see Figure 4-11). Figure 4-12 shows the difference between analysis of the products of single meiocytes (as in fungi) and of randomly sampled products of many meiocytes (as in plants and animals).

Crosses

A cross is a controlled mating between two specific organisms. The purpose of making crosses in genetics is either to obtain progeny of a specific genotype or, working the other way, to use the proportions of different phenotypes of progeny to deduce the genotypes of the parents. Some plants can be selfed; that is, they can be crossed to themselves: pollen is allowed to fall on the stigma in the same flower or another flower of the same plant. Most animals cannot be selfed, but matings of identical genotypes are the equivalent of selfing. Crosses can be made in either diploid or haploid organisms.

Haploid crosses.

These are the simplest to analyze because each gene is present in only one copy in the parents. In genetics, a multiplication symbol is used to designate a cross. Hence for a single gene with two alleles there are only three types of crosses, shown below with their progeny:

(Note that only the progeny of the cross A × a actually illustrate Mendel's first law of equal segregation. Equal segregation is occurring in the crosses A × A and a × a, but since the crosses are homozygous, segregation cannot be observed.)

Diploid crosses.

Once again considering one gene with two alleles, there are only three genotypes, A/A, A/a, and a/a. Crosses between homozygotes have the simplest outcomes because only one type of meiotic product (shown below as gametes) is possible. Furthermore, each cross produces only one type of zygote (fertilized egg) and, hence, only one type of progeny. There are three types of such crosses:

Crosses involving heterozygotes are slightly more complex, but the law of equal segregation can be used to predict the proportions of gametes. The following grids show graphically how the progeny are produced in the three different crosses involving heterozygotes. The gamete ratios produced by the two parents are drawn along the top and side of the grid, then the grid itself portrays the cells that result from gamete fusion (the zygotes).

Note that underlying the 3:1 phenotypic ratio in this cross there is a 1:2:1 genotypic ratio of A/A:A/a:a/a.

In analyzing single genes, a testcross can be made to deduce whether an individual with the dominant phenotype is homozygous (A/A) or heterozygous (A/a). The individual of dominant phenotype A/ (that is, A/A or A/a) is crossed to a homozygous recessive a/a (called the tester in this context). If there is a 1:1 ratio of dominant to recessive phenotypes in the progeny, then we can infer the cross must have been of the type A/a × a/a and that the strain under test must have been heterozygous. If all the progeny are of the dominant phenotype, then the strain must have been homozygous A/A and the testcross was A/A × a/a, giving progeny of genotype A/a.

For example, in mice the difference between black coat and brown coat is determined by a pair of alleles, B (black) and b (brown), for which B is dominant to b. A black male of unknown ancestry is testcrossed to a brown female. The cross results in eight babies, of which three are black and five are brown. This result tells us the male must have been heterozygous B/b because the brown babies must have received a b allele from both their mother and their father. Therefore the cross was B/b × b/b. Of course Mendel's law of equal segregation leads to an expectation of equal numbers of black and brown progeny (4:4), but a chance deviation such as 3:5 is likely in such a small sample size.

Animals and plants used for genetic analysis are often maintained as pure lines (also called pure-breeding lines, stocks, or strains). These are populations that when interbred or selfed will always breed true for some particular phenotype. Such lines must be homozygous. The genotypes A/A and a/a are both pure-breeding genotypes, but A/a is not.

Using crosses to deduce genotypes and dominance and recessiveness.

In deriving the above ratios we used known parental genotypes involving alleles with known dominance and recessiveness in order to make predictions about the phenotypic ratios expected in progeny. To deduce genotypes and dominance when they are unknown, we have to make the appropriate crosses. Mendel was the first to establish this sort of experimental procedure, so we can use an example from his work, involving the color of pea seeds. The crossing procedure is shown in Figure 4-13. In describing this procedure the symbol P is the conventional designation for the parental generation, and F1 and F2 stand for the first and second filial generations (from the Latin filius, "son," and filia, "daughter").

To explore the genetics underlying the character of seed color, we cross two pure-breeding lines of peas, one yellow and one green, to produce the F1. An F2 is then derived by selfing, or intercrossing, the F1 plants. We find that the F1 plants all have yellow seeds, and that of the F2 plants 3/4 have yellow seeds and 1/4 have green seeds, a 3:1 phenotypic ratio. From these results two deductions can be made:

1. The green phenotype disappears in the F1 but reappears in the F2, so we can deduce that yellow must have dominated green in the F1.Therefore yellow is the dominant phenotype and green the recessive.
2. Since we know that a 3:1 ratio found in the F2 is diagnostic of a cross between two heterozygotes for a single gene, we can infer that the two phenotypes yellow and green are determined by alleles of a single gene and that the F1 plants must have been of genotype Y/y, where Y is a dominant allele determining yellow and y is a recessive allele determining green. (Note: a cross between two heterozygotes for a single gene is sometimes referred to as a monohybrid cross.)

MESSAGE
Genetic analysis works in two directions: 1. Crossing parents of known genotypes and dominance relations to obtain specific progeny types 2. Observing progeny phenotypes and ratios to infer parental genotypes and dominance

This analytical technique has revealed the genotype and dominance patterns for characters in many different organisms. Some more examples follow.

In yeast (haploid) the colonies are normally white in color. However, a rare strain arose that had pink colonies. A cross was made between a white and a pink strain and a tetrad analysis was performed. All tetrads showed 2 white spores and 2 pink spores. This result shows the 1:1 segregation expected of heterozygous meiocytes. Therefore we can deduce that the phenotypic difference was determined by two alleles of one gene. Let p = pink and p+ = white (wild type). Then the cross must have been as follows:

Fruit flies normally have relatively large wings. In the laboratory population a fly was found that had miniature wings. When this was crossed to the wild type, the F1 all had normal large wings. When F1 flies were allowed to interbreed, thus producing an F2, 400 flies were counted, and of these, 305 had normal wings and 95 had miniature wings. This result tells us that

1. The two phenotypes must be determined by two alleles of one gene, because the observed 3:1 F2 ratio is based on 1:1 meiotic segregation in a heterozygote (that is, it is a single-gene ratio).
2. Large must be dominant to miniature, because the F1 were all large-winged.

If we let m = miniature and m+ = large, the cross must have been

Autosomal and Sex-Linked Genes

Sex is chromosomally determined in many animals, such as humans and fruit flies, and in dioecious plants (those with male and female sex organs on separate plants). In these cases it is necessary to distinguish between the sex chromosomes (those that are involved in sex determination) and the autosomes (the remaining "regular" chromosomes). Generally there is only one pair of sex chromosomes. In human females the sex chromosomes are a pair of X chromosomes, and in males they are an X and a Y chromosome. Hence using a letter A to represent an autosome, a female is designated 44A + XX and a male is 44A + XY. The set of human chromosomes is shown in Figure 4-14. In females, the pair of homologous X chromosomes segregates at meiosis, so all eggs have a single X. In males, the X and the Y are only homologous in a small region at one end, but at meiosis they pair in this region and segregate equally so that 1/2 the sperm bear an X and 1/2 bear a Y. When these sperm fuse randomly with the X-bearing eggs, 50 percent male (XY) and 50 percent female (XX) progeny result.

Hence the numerical equality of the two sexes is based on equal segregation at meiosis. In humans, sex is determined by the presence or absence of the Y chromosome. However, in fruit flies sex is determined by the number of X chromosomes in relation to the autosomes. This difference is demonstrated by the sexes of aberrant conditions, as shown in Table 4-1.

Autosomal genes are inherited in the simple way described for, say, pea seed color or mouse coat color. Both male and female progeny show exactly the same phenotypic ratios for characters controlled by autosomal genes. For example, in a cross of A/a × A/a both male and female progeny will show a 3:1 ratio of A/:a/a. This is not the case for genes on the X chromosome because in certain crosses there are different phenotypic ratios in male and female progeny. Indeed the observation of different phenotypic ratios in male and female progeny is an experimental diagnostic for genes on the sex chromosomes. The precise pattern of inheritance is determined by where a gene is on the sex chromosomes (these regions are distinguished in Figure 4-15).

The differential region of the X has no counterpart on the Y. It contains many genes with alleles that produce distinct phenotypes. These genes for the most part are not involved in sex determination. Genes on this region are called X-linked genes, and they are said to show X-linked inheritance. A typical case of X-linked inheritance is illustrated by the red and white alleles of an eye color gene in Drosophila (Figure 4-16 on the next page). Note the crosses in which the male and female progeny show different phenotypic ratios. For example, in the F2 of the first cross, there is a 3:1 ratio of red to white, but unlike cases of autosomal gene inheritance, the white flies are all males. Furthermore in the second cross the female progeny in the F1 are all red but the males are all white. Such inheritance patterns illustrate the diagnostic for inferring X-linked inheritance.

There are few genes in the homologous (pairing) region, so we will not consider these further at this point, other than to point out that there are obligatory pairing events, and in some cases obligatory crossover events as well, in this region in each meiocyte. Likewise the differential region of the Y contains few genes with alleles that cause distinct phenotypic variants. One crucial gene in this region in humans is the maleness-determining gene, calledTDF (testis-determining factor). The role of this gene in sex determination will be discussed in Chapter 16.

In most cases of chromosomal sex determination the male is the heterogametic sex (that is, he is the bearer of the pair of different sex chromosomes), but there are some exceptions. For example, in chickens and moths, the female is the heterogametic sex.

© 1999 by W. H. Freeman and Company. All rights reserved.