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Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000.

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An Introduction to Genetic Analysis. 7th edition.

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Human genetics

Human matings, like those of experimental organisms, show inheritance patterns both of the type discovered by Mendel (autosomal inheritance) and of sex linkage. Because controlled experimental crosses cannot be made with humans, geneticists must resort to scrutinizing records in the hope that informative matings have been made by chance. Such a scrutiny of records of matings is called pedigree analysis. A member of a family who first comes to the attention of a geneticist is called the propositus. Usually the phenotype of the propositus is exceptional in some way (for example, the propositus might be a dwarf). The investigator then traces the history of the phenotype in the propositus back through the history of the family and draws a family tree, or pedigree, by using the standard symbols given in Figure 2-16 .

Figure 2-16. Symbols used in human pedigree analysis.

Figure 2-16

Symbols used in human pedigree analysis. (After W. F. Bodmer and L. L. Cavalli-Sforza, Genetics, Evolution, and Man. Copyright © 1976 by W. H. Freeman and Company.)

Many pairs of contrasting human phenotypes are determined by pairs of alleles. Inheritance patterns in pedigree analysis can reveal such allelic determination, but the clues in the pedigree have to be interpreted differently, depending on whether one of the contrasting phenotypes is a rare disorder or whether both phenotypes of a pair are morphs of a polymorphism. Rare inherited disorders are the domain of medical genetics.

Medical genetics

In the study of rare disorders, four general patterns of inheritance are distinguishable by pedigree analysis: autosomal recessive, autosomal dominant, X-linked recessive, and X-linked dominant.

Autosomal recessive disorders

The affected phenotype of an autosomal recessive disorder is determined by a recessive allele, and the corresponding unaffected phenotype is determined by a dominant allele. For example, the human disease phenylketonuria is inherited in a simple Mendelian manner as a recessive phenotype, with PKU determined by the allele p and the normal condition by P . Therefore, sufferers from this disease are of genotype p /p , and people who do not have the disease are either P /P or P /p . What patterns in a pedigree would reveal such an inheritance? The two key points are that (1) generally the disease appears in the progeny of unaffected parents and (2) the affected progeny include both males and females. When we know that both male and female progeny are affected, we can assume that we are dealing with simple Mendelian inheritance, not sex-linked inheritance. The following typical pedigree illustrates the key point that affected children are born to unaffected parents:

Image ch2e18.jpg

From this pattern, we can immediately deduce simple Mendelian inheritance of the recessive allele responsible for the exceptional phenotype (indicated in black). Furthermore, we can deduce that the parents are both heterozygotes, say A /a ; both must have an a allele because each contributed an a allele to each affected child, and both must have an A allele because they are phenotypically normal. We can identify the genotypes of the children (in the order shown) as A /–, a /a , a /a , and A /–. Hence, the pedigree can be rewritten as follows:

Image ch2e19.jpg

Note that this pedigree does not support the hypothesis of X-linked recessive inheritance, because, under that hypothesis, an affected daughter must have a heterozygous mother (possible) and a hemizygous father, which is clearly impossible, because he would have expressed the phenotype of the disorder.

Notice another interesting feature of pedigree analysis: even though Mendelian rules are at work, Mendelian ratios are rarely observed in families, because the sample size is too small. In the preceding example, we see a 1:1 phenotypic ratio in the progeny of a monohybrid cross. If the couple were to have, say, 20 children, the ratio would be something like 15 unaffected children and 5 with PKU (a 3:1 ratio); but, in a sample of 4 children, any ratio is possible, and all ratios are commonly found.

The pedigrees of autosomal recessive disorders tend to look rather bare, with few black symbols. A recessive condition shows up in groups of affected siblings, and the people in earlier and later generations tend not to be affected. To understand why this is so, it is important to have some understanding of the genetic structure of populations underlying such rare conditions. By definition, if the condition is rare, most people do not carry the abnormal allele. Furthermore, most of those people who do carry the abnormal allele are heterozygous for it rather than homozygous. The basic reason that heterozygotes are much more common than recessive homozygotes is that, to be a recessive homozygote, both parents must have had the a allele, but, to be a heterozygote, only one parent must carry the a allele.

Geneticists have a quantitative way of connecting the rareness of an allele with the commonness or rarity of heterozygotes and homozygotes in a population. They obtain the relative frequencies of genotypes in a population by assuming that the population is in Hardy-Weinberg equilibrium, to be fully discussed in Chapter 24 . Under this simplifying assumption, if the relative proportions of two alleles A and a in a population are p and q , respectively, then the frequencies of the three possible genotypes are given by p 2 for A /A , 2pq for A /a , and q 2 for a /a . A numerical example illustrates this concept. If we assume that the frequency q of a recessive, disease-causing allele is 1/50, then p is 49/50, the frequency of homozygotes with the disease is q 2 =(1/50)2 =1/250, and the frequency of heterozygotes is 2pq  = 2 × 49/50 × 1/50 , or approximately 1/25. Hence, for this example, we see that heterozygotes are 100 times as frequent as disease sufferers, and, as this ratio increases, the rarer the allele becomes. The relation between heterozygotes and homozygotes recessive for a rare allele is shown in the following illustration. Note that the allele frequencies p and q can be used as the gamete frequencies in both sexes.

Image ch2fu3.jpg

The formation of an affected person usually depends on the chance union of unrelated heterozygotes. However, inbreeding (mating between relatives) increases the chance that a mating will be between two heterozygotes. An example of a marriage between cousins is shown in Figure 2-17 . Individuals III-5 and III-6 are first cousins and produce two homozygotes for the rare allele. You can see from Figure 2-17 that an ancestor who is a heterozygote may produce many descendants who also are heterozygotes. Hence two cousins can carry the same rare recessive allele inherited from a common ancestor. For two unrelated persons to be heterozygous, they would have to inherit the rare allele from both their families. Thus matings between relatives generally run a higher risk of producing abnormal phenotypes caused by homozygosity for recessive alleles than do matings between nonrelatives. For this reason, first-cousin marriages contribute a large proportion of the sufferers of recessive diseases in the population.

Figure 2-17. Pedigree of a rare recessive phenotype determined by a recessive allele a .

Figure 2-17

Pedigree of a rare recessive phenotype determined by a recessive allele a . Gene symbols are normally not included in pedigree charts, but genotypes are inserted here for reference. Note that individuals II-1 and II-5 marry into the family; they are assumed (more...)

What are some examples of human recessive disorders? PKU has already served as an example of pedigree analysis, but what kind of phenotype is it? PKU is a disease of processing of the amino acid phenylalanine, a component of all proteins in the food that we eat. Phenylalanine is normally converted into tyrosine by the enzyme phenylalanine hydroxylase:

Image ch2e20.jpg

However, if a mutation in the gene encoding this enzyme alters the amino acid sequence in the vicinity of the enzyme’s active site, the enzyme cannot bind or convert phenylalanine (its substrate). Therefore phenylalanine builds up in the body and is converted instead into phenylpyruvic acid, a compound that interferes with the development of the nervous system, leading to mental retardation.

Image ch2e21.jpg

Babies are now routinely tested for this processing deficiency at birth. If the deficiency is detected, phenylalanine can be withheld by use of a special diet, and the development of the disease can be arrested.

Cystic fibrosis is another disease inherited according to Mendelian rules as a recessive phenotype. The allele that causes cystic fibrosis was isolated in 1989, and the sequence of its DNA was determined. This has led to an understanding of gene function in affected and unaffected persons, giving hope for more effective treatment. Cystic fibrosis is a disease whose most important symptom is the secretion of large amounts of mucus into the lungs, resulting in death from a combination of effects but usually precipitated by upper respiratory infection. The mucus can be dislodged by mechanical chest thumpers, and pulmonary infection can be prevented by antibiotics; so, with treatment, cystic fibrosis patients can live to adulthood. The disorder is caused by a defective protein that transports chloride ions across the cell membrane. The resultant alteration of the salt balance changes the constitution of the lung mucus.

Albinism, which served as a model of allelic determination of contrasting phenotypes in Chapter 1 , also is inherited in the standard autosomal recessive manner. The molecular nature of an albino allele and its inheritance are diagrammed in Figure 2-18 . This diagram shows a simple autosomal recessive inheritance in a pedigree and shows the molecular nature of the alleles involved. In this example, the recessive allele a is caused by a base pair change that introduces a stop codon into the middle of the gene, resulting in a truncated polypeptide. The mutation, by chance, also introduces a new target site for a restriction enzyme. Hence, a probe for the gene detects two fragments in the case of a and only one in A . (Other types of mutations would produce different effects at the level detected by Southern, Northern, and Western analyses.)

Figure 2-18. The molecular basis of Mendelian inheritance in a pedigree.

Figure 2-18

The molecular basis of Mendelian inheritance in a pedigree.

In all the examples heretofore considered, the disorder is caused by an allele for a defective protein. In heterozygotes, the single functional allele provides enough active protein for the cell’s needs. This situation is called haplosufficiency.

MESSAGE

In human pedigrees, an autosomal recessive disorder is revealed by the appearance of the disorder in the male and female progeny of unaffected persons.

Autosomal dominant disorders

Here the normal allele is recessive, and the abnormal allele is dominant. It may seem paradoxical that a rare disorder can be dominant, but remember that dominance and recessiveness are simply properties of how alleles act and are not defined in terms of how common they are in the population. A good example of a rare dominant phenotype with Mendelian inheritance is pseudo-achondroplasia, a type of dwarfism (Figure 2-19 ). In regard to this gene, people with normal stature are genotypically d /d , and the dwarf phenotype in principle could be D /d or D /D . However, it is believed that the two “doses” of the D allele in the D /D genotype produce such a severe effect that this is a lethal genotype. If this is true, all the dwarf individuals are heterozygotes.

Figure 2-19. The human pseudoachondroplasia phenotype, illustrated by a family of five sisters and two brothers.

Figure 2-19

The human pseudoachondroplasia phenotype, illustrated by a family of five sisters and two brothers. The phenotype is determined by a dominant allele, which we can call D , that interferes with bone growth during development. Most members of the human population (more...)

In pedigree analysis, the main clues for identifying a dominant disorder with Mendelian inheritance are that the phenotype tends to appear in every generation of the pedigree and that affected fathers and mothers transmit the phenotype to both sons and daughters. Again, the equal representation of both sexes among the affected offspring rules out sex-linked inheritance. The phenotype appears in every generation because generally the abnormal allele carried by a person must have come from a parent in the preceding generation. Abnormal alleles can arise de novo by the process of mutation. This event is relatively rare but must be kept in mind as a possibility. A typical pedigree for a dominant disorder is shown in Figure 2-20 . Once again, notice that Mendelian ratios are not necessarily observed in families. As with recessive disorders, persons bearing one copy of the rare A allele (A /a ) are much more common than those bearing two copies (A /A ), so most affected people are heterozygotes, and virtually all matings concerning dominant disorders are A /a  × a /a . Therefore, when the progeny of such matings are totaled, a 1:1 ratio is expected of unaffected (a /a ) to affected (A /a ) persons.

Figure 2-20. Pedigree of a dominant phenotype determined by a dominant allele A .

Figure 2-20

Pedigree of a dominant phenotype determined by a dominant allele A . In this pedigree, all the genotypes have been deduced.

Huntington disease is an example of a disease inherited as a dominant phenotype determined by an allele of a single gene. The phenotype is one of neural degeneration, leading to convulsions and premature death. However, it is a late-onset disease, the symptoms generally not appearing until after the person has begun to have children (Figure 2-21 ). Each child of a carrier of the abnormal allele stands a 50 percent chance of inheriting the allele and the associated disease. This tragic pattern has led to a great effort to find ways of identifying people who carry the abnormal allele before they experience the onset of the disease. The application of molecular techniques has resulted in a promising screening procedure.

Figure 2-21. The age of onset of Huntington disease.

Figure 2-21

The age of onset of Huntington disease. The graph shows that people carrying the allele generally do not express the disease until after child-bearing age.

Some other rare dominant conditions are polydactyly (extra digits) and brachydactyly (short digits), shown in Figure 2-22 , and piebald spotting, shown in Figure 2-23 .

Figure 2-22. Some rare dominant phenotypes of the human hand.

Figure 2-22

Some rare dominant phenotypes of the human hand. (a) (right) Polydactyly, a dominant phenotype characterized by extra fingers, toes, or both, determined by an allele P . The numbers in the accompanying pedigree (left) give the number of fingers in the (more...)

Figure 2-23. Piebald spotting, a rare dominant human phenotype.

Figure 2-23

Piebald spotting, a rare dominant human phenotype. Although the phenotype is encountered sporadically in all races, the patterns show up best in those with dark skin. (a) The photographs show front and back views of affected persons IV-1, IV-3, III-5, (more...)

MESSAGE

Pedigrees of Mendelian autosomal dominant disorders show affected males and females in each generation; they also show that affected men and women transmit the condition to equal proportions of their sons and daughters.

X-linked recessive disorders

Phenotypes with X-linked recessive inheritance typically show the following patterns in pedigrees:

1.

Many more males than females show the phenotype under study. This is because a female showing the phenotype can result only from a mating in which both the mother and the father bear the allele (for example, X A X a ×X a Y), whereas a male with the phenotype can be produced when only the mother carries the allele. If the recessive allele is very rare, almost all persons showing the phenotype are male.

2.

None of the offspring of an affected male are affected, but all his daughters are “carriers,” bearing the recessive allele masked in the heterozygous condition. Half of the sons of these carrier daughters are affected (Figure 2-24 ). Note that, in common X-linked phenotypes, this pattern might be obscured by inheritance of the recessive allele from a heterozygous mother as well as the father.

3.

None of the sons of an affected male show the phenotype under study, nor will they pass the condition to their offspring. The reason behind this lack of male-to-male transmission is that a son obtains his Y chromosome from his father, so he cannot normally inherit the father’s X chromosome too.

Figure 2-24. Pedigree showing that X-linked recessive alleles expressed in males are then carried unexpressed by their daughters in the next generation, to be expressed again in their sons.

Figure 2-24

Pedigree showing that X-linked recessive alleles expressed in males are then carried unexpressed by their daughters in the next generation, to be expressed again in their sons. Note that III-3 and III-4 cannot be distinguished phenotypically.

In the pedigree analysis of rare X-linked recessives, a normal female of unknown genotype is assumed to be homo-zygous unless there is evidence to the contrary.

Perhaps the most familiar example of X-linked recessive inheritance is red-green colorblindness. People with this condition are unable to distinguish red from green and see them as the same. The genes for color vision have been characterized at the molecular level. Color vision is based on three different kinds of cone cells in the retina, each sensitive to red, green, or blue wavelengths. The genetic determinants for the red and green cone cells are on the X chromosome. As with any X-linked recessive, there are many more males with the phenotype than females.

Another familiar example is hemophilia, the failure of blood to clot. Many proteins must interact in sequence to make blood clot. The most common type of hemophilia is caused by the absence or malfunction of one of these proteins, called Factor VIII. The most well known cases of hemophilia are found in the pedigree of interrelated royal families in Europe (Figure 2-25 ). The original hemophilia allele in the pedigree arose spontaneously (as a mutation) either in the reproductive cells of Queen Victoria’s parents or of Queen Victoria herself. The son of the last czar of Russia, Alexis, inherited the allele ultimately from Queen Victoria, who was the grandmother of his mother Alexandra. Nowadays, hemophilia can be treated medically, but it was formerly a potentially fatal condition. It is interesting to note that, in the Jewish Talmud, there are rules about exemptions to male circumcision that show clearly that the mode of transmission of the disease through unaffected carrier females was well understood in ancient times. For example, one exemption was for the sons of women whose sisters’ sons had bled profusely when they were circumcised.

Figure 2-25. The inheritance of the X-linked recessive condition hemophilia in the royal families of Europe.

Figure 2-25

The inheritance of the X-linked recessive condition hemophilia in the royal families of Europe. A recessive allele causing hemophilia (failure of blood clotting) arose in the reproductive cells of Queen Victoria, or one of her parents, through mutation. (more...)

Duchenne muscular dystrophy is a fatal X-linked recessive disease. The phenotype is a wasting and atrophy of muscles. Generally the onset is before the age of 6, with confinement to a wheelchair by 12, and death by 20. The gene for Duchenne muscular dystrophy has now been isolated and shown to encode the muscle protein dystrophin. This discovery holds out hope for a better understanding of the physiology of this condition and, ultimately, a therapy.

A rare X-linked recessive phenotype that is interesting from the point of view of sexual differentiation is a condition called testicular feminization syndrome, which has a frequency of about 1 in 65,000 male births. People afflicted with this syndrome are chromosomally males, having 44 autosomes plus an X and a Y, but they develop as females (Figure 2-26 ). They have female external genitalia, a blind vagina, and no uterus. Testes may be present either in the labia or in the abdomen. Although many such persons marry, they are sterile. The condition is not reversed by treatment with the male hormone androgen, so it is sometimes called androgen insensitivity syndrome. The reason for the insensitivity is that the androgen receptor malfunctions, so the male hormone can have no effect on the target organs that contribute to maleness. In humans, femaleness results when the male-determining system is not functional.

Figure 2-26. Four siblings with testicular feminization syndrome (congenital insensitivity to androgens).

Figure 2-26

Four siblings with testicular feminization syndrome (congenital insensitivity to androgens). All four subjects in this photograph have 44 autosomes plus an X and a Y chromosome, but they have inherited the recessive X-linked allele conferring insensitivity to (more...)

X-linked dominant disorders.

These disorders have the following characteristics:

1.

Affected males pass the condition to all their daughters but to none of their sons (Figure 2-27 ).

2.

Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters (Figure 2-28 ).

Figure 2-27. Pedigree showing that all the daughters of a male expressing an X-linked dominant phenotype will show the phenotype.

Figure 2-27

Pedigree showing that all the daughters of a male expressing an X-linked dominant phenotype will show the phenotype.

Figure 2-28. Pedigree showing that females affected by an X-linked dominant condition are usually heterozygous and pass the condition to half their sons and daughters.

Figure 2-28

Pedigree showing that females affected by an X-linked dominant condition are usually heterozygous and pass the condition to half their sons and daughters.

There are few examples of X-linked dominant phenotypes in humans. One example is hypophosphatemia, a type of vitamin D-resistant rickets.

X-chromosome inactivation

Early in the development of female mammals, one of the X chromosomes in each cell becomes inactivated. The inactivated X chromosome becomes highly condensed and is visible as a darkly staining spot called a Barr body (Figure 2-29 ). Surprisingly, this chromosomal inactivation persists through all the subsequent mitotic divisions that produce the mature body of the animal. The inactivation process is random, affecting either of the X chromosomes. As a result of this inactivation, the adult female body is a mixture, or mosaic, of cells with either of the two different X chromosome genotypes (Figure 2-30 ). During the growth and development of tissues, the mitotic descendants of a progenitor cell often stay next to each other, forming a cluster; so, if a female is heterozygous for an X-linked gene that has its effect in that tissue, the two alleles of the heterozygote are expressed in patches, or sectors. A mosaic phenotype familiar to most of us is the coat pigmentation pattern of tortoiseshell and calico cats (Figure 2-31 ). Such cats are females heterozygous for the alleles O (which causes fur to be orange) and o (which causes it to be black). Inactivation of the O -bearing X chromosome produces a black patch expressing o , and inactivation of the o -bearing X chromosome produces an orange patch expressing O .

Figure 2-29. A Barr body, a condensed inactivated X chromosome, in the nucleus of a cell of a normal woman.

Figure 2-29

A Barr body, a condensed inactivated X chromosome, in the nucleus of a cell of a normal woman. Men have no Barr bodies. The number of Barr bodies in a cell is always equal to the total number of X chromosomes minus one. (Karen Dyer Montgomery.)

Figure 2-30. X-chromosome inactivation in mammals.

Figure 2-30

X-chromosome inactivation in mammals. The zygote of a female mammal heterozygous for an X-linked gene becomes a mosaic adult composed of two cell lines expressing one or the other of the alleles of the heterozygous gene because one or the other X chromosome (more...)

Figure 2-31. A calico cat.

Figure 2-31

A calico cat. Both calico and tortoiseshell cats are females heterozygous for two alleles of an X-linked coat-color gene, O (orange) and o (black). The orange and black sectors are caused by X-chromosome inactivation. The white areas are caused by a (more...)

Although all human females have one of their X chromosomes inactivated in every cell, this inactivation is detectable only when a female is heterozygous for an X-linked gene. This is particularly striking when, as in tortoiseshell cats, the phenotype is expressed on the exterior of the body. Such a condition is anhidrotic ectodermal dysplasia. Males carrying the responsible allele (let us call it d ) in its hemizygous condition have no sweat glands. A heterozygous (D/d ) female has a mosaic of D and d sectors across her body, as shown in Figure 2-32 .

Figure 2-32. Somatic mosaicism in three generations of females heterozygous for sex-linked anhidrotic ectodermal dysplasia (absence of sweat glands).

Figure 2-32

Somatic mosaicism in three generations of females heterozygous for sex-linked anhidrotic ectodermal dysplasia (absence of sweat glands). Areas without sweat glands are shown in green. The extent and location of the different tissues is determined by chance, (more...)

Interestingly, the X-chromosome location of the gene causing testicular feminization was confirmed when it was shown microscopically that, in females heterozygous for the gene, half their fibroblast cells bind androgen but the other half do not. It should be noted that X inactivation is canceled in the female germinal tissue, so both X chromosomes are passed into the eggs.

Y-linked inheritance

Genes on the differential region of the human Y chromosome are inherited only by males, with fathers transmitting the region to their sons. The gene that plays a primary role in maleness is the TDF gene, which codes for testis-determining factor. The TDF gene has been located and mapped on the differential region of the Y chromosome (see Chapter 23 ). However, other than maleness itself, no human phenotype has been conclusively proved to be Y linked. Hairy ear rims (Figure 2-33 ) has been proposed as a possibility. The phenotype is extremely rare among the populations of most countries but more common among the populations of India. An Indian geneticist, K. Dronamraju, studied the phenotype in his own family. Every male in the family descended from a certain male ancestor showed the phenotype. In other Indian families, however, males seem to transmit the phenotype to only some of their sons, which is part of the reason that the evidence for Y-linked inheritance is considered to be inconclusive.

Figure 2-33. Hairy ear rims.

Figure 2-33

Hairy ear rims. This phenotype has been proposed to be be caused by an allele of a Y-linked gene. (From C. Stern, W. R. Centerwall, and S. S. Sarkar, The American Journal of Human Genetics 16, 1964, 467. By permission of Grune & Stratton, Inc.) (more...)

MESSAGE

Inheritance patterns with an unequal representation of phenotypes in males and females can locate the genes concerned to one or both of the sex chromosomes.

Human autosomal polymorphisms

Recall from Chapter 1 that a polymorphism is the coexistence of two to several common phenotypes of a character in a population. The alternative phenotypes of polymorphisms are often inherited as alleles of a single gene. In humans, there are many examples; consider, for example, the dimorphisms brown versus blue eyes, dark versus blonde hair, chin dimples versus none, widow’s peak versus none, and attached versus free earlobes.

The interpretation of pedigrees for polymorphisms is somewhat different from that of rare disorders, because, by definition, the morphs are common. Let’s look at a pedigree for an interesting human dimorphism. Most human populations are dimorphic for the ability to taste the chemical phenylthiocarbamide (PTC). That is, people can either detect it as a foul, bitter taste, or—to the great surprise and disbelief of tasters—cannot taste it at all. From the pedigree in Figure 2-34 , we can see that two tasters sometimes produce nontaster children, which makes it clear that the allele that confers the ability to taste is dominant and that the allele for nontasting is recessive. Notice that almost all people who marry into this family carry the recessive allele either in heterozygous or in homozygous condition. Such a pedigree thus differs from those of rare recessive disorders for which it is conventional to assume that all who marry into a family are homozygous normal. Because both PTC alleles are common, it is not surprising that all but one of the family members in this pedigree married persons with at least one copy of the recessive allele.

Figure 2-34. Pedigree for the ability to taste the chemical PTC.

Figure 2-34

Pedigree for the ability to taste the chemical PTC.

Polymorphism is an interesting genetic phenomenon. Population geneticists have been surprised at how much polymorphism there is in natural populations of plants and animals generally. Furthermore, even though the genetics of polymorphisms is straightforward, there are very few polymorphisms for which there is satisfactory explanation for the coexistence of the morphs. But polymorphism is rampant at every level of genetic analysis, even at the DNA level; indeed, polymorphisms observed at the DNA level have been invaluable as landmarks to help geneticists find their way around the chromosomes of complex organisms.

One useful type of molecular chromosomal landmark, or marker, is a restriction fragment length polymorphism (RFLP). In Chapter 1 , we learned that restriction enzymes are bacterial enzymes that cut DNA at specific base sequences in the genome. The target sequences have no biological significance in organisms other than bacteria—they occur purely by chance. Although the target sites generally occur quite consistently at specific sites, sometimes, on any one chromosome, a specific site is missing or there is an extra site. If such restriction-site presence or absence flanks the sequence hybridized by a probe, then a Southern hybridization will reveal a length polymorphism, or RFLP. Consider this simple example in which one chromosome of one parent contains an extra site not found in the other chromosomes of that type in that cross:

Image ch2fu4.jpg

The Southern hybridizations will show two bands in the female and only one in the male. The “heterozygous” fragments will be inherited in exactly the same way as a gene. The preceding cross could be written as follows:

Image ch2e22.jpg

according to the law of equal segregation.

MESSAGE

Populations of plants and animals (including humans) are highly polymorphic. Contrasting morphs are generally determined by alleles inherited in a simple Mendelian manner.

Mendel’s work has withstood the test of time and has provided us with the basic groundwork for all modern genetic study. He was the first person to draw attention to the mathematical regularity of inheritance patterns. From these patterns, he was able to make deductions about the fundamental nature of inheritance. Mendel’s approach is still used by geneticists today. Yet his work went unrecognized and neglected for 35 years after its publication. Why? There are many possible reasons, but here we shall consider just one. Perhaps it was because biological science at that time could not provide evidence for any real physical units within cells that might correspond to Mendel’s genetic particles. Chromosomes had certainly not yet been studied, meiosis had not yet been described, and even the full details of plant life cycles had not been worked out. Without this basic knowledge, it may have seemed that Mendel’s ideas were mere numerology.

Above the doorway into the Mendel museum in Brno there is a wistful quip by Mendel inscribed in Czech, “MÁ DOBA PŘRIJDE,” meaning “My time will come.” Mendel’s time did come; in the twentieth century, research and the understanding of heredity flowered, all stemming from Mendel’s seminal studies in the tiny monastery garden. His hypothetical “factors” (genes, as we now call them) are a well-understood molecular reality, and even whole genomes are becoming characterized. It is possible to take the latest dramatic research on cloning, gene therapy, transgenics, the human genome project, and so forth, and trace it all back through the research literature to that single paper entitled “Experiments on Plant Hybridization,” presented in 1865 to the Brünn Natural History Society.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, W. H. Freeman and Company.
Bookshelf ID: NBK21977

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