raven06b_13

239

13Patterns of Inheritance

Concept Outline

13.1 Mendel solved the mystery of heredity.

Early Ideas about Heredity: The Road to Mendel.Before Mendel, the mechanism of inheritance was not known.Mendel and the Garden Pea. Mendel experimentedwith heredity in edible peas counted his results.What Mendel Found. Mendel found that alternativetraits for a character segregated among second-generationprogeny in the ratio 3:1. Mendel proposed that informationfor a trait rather than the trait itself is inherited.How Mendel Interpreted His Results. Mendel foundthat one alternative of a character could mask the other inheterozygotes, but both could subsequently be expressed inhomozygotes of future generations.Mendelian Inheritance Is Not Always Easy to Analyze.A variety of factors can influence the Mendeliansegregation of alleles.

13.2 Human genetics follows Mendelian principles.

Most Gene Disorders Are Rare. Tay-Sachs disease isdue to a recessive allele.Multiple Alleles: The ABO Blood Groups. The humanABO blood groups are determined by three I gene alleles.Patterns of Inheritance Can Be Deduced fromPedigrees. Hemophilia is sex-linked.Gene Disorders Can Be Due to Simple Alterations ofProteins. Sickle cell anemia is caused by a single aminoacid change.Some Defects May Soon Be Curable. Cystic fibrosismay soon be cured by gene replacement therapy.

13.3 Genes are on chromosomes.

Chromosomes: The Vehicles of MendelianInheritance. Mendelian segregation reflects the randomassortment of chromosomes in meiosis.Genetic Recombination. Crossover frequency reflectthe physical distance between genes.Human Chromosomes. Humans possess 23 pairs ofchromosomes, one of them determining the sex.Human Abnormalities Due to Alterations inChromosome Number. Loss or addition ofchromosomes has serious consequences.Genetic Counseling. Some gene defects can be detectedearly in pregnancy.

Every living creature is a product of the long evolu-tionary history of life on earth. While all organismsshare this history, only humans wonder about theprocesses that led to their origin. We are still far fromunderstanding everything about our origins, but we havelearned a great deal. Like a partially completed jigsawpuzzle, the boundaries have fallen into place, and muchof the internal structure is becoming apparent. In thischapter, we will discuss one piece of the puzzletheenigma of heredity. Why do groups of people from dif-ferent parts of the world often differ in appearance (fig-ure 13.1)? Why do the members of a family tend to re-semble one another more than they resemble members ofother families?

FIGURE 13.1Human beings are extremely diverse in appearance. Thedifferences between us are partly inherited and partly the result of environmental factors we encounter in our lives.

240 Part IV Reproduction and Heredity

Early Ideas about Heredity: The Road to MendelAs far back as written records go, patterns of resemblanceamong the members of particular families have beennoted and commented on (figure 13.2). Some familialfeatures are unusual, such as the protruding lower lip ofthe European royal family Hapsburg, evident in picturesand descriptions of family members from the thirteenthcentury onward. Other characteristics, like the occur-rence of redheaded children within families of redheadedparents, are more common (figure 13.3). Inherited fea-tures, the building blocks of evolution, will be our con-cern in this chapter.

Classical Assumption 1: Constancy of Species

Two concepts provided the basis for most of the thinkingabout heredity before the twentieth century. The first isthat heredity occurs within species. For a very long time peo-ple believed that it was possible to obtain bizarre compos-ite animals by breeding (crossing) widely different species.The minotaur of Cretan mythology, a creature with thebody of a bull and the torso and head of a man, is one ex-ample. The giraffe was thought to be another; its scien-tific name, Giraffa camelopardalis, suggests the belief that itwas the result of a cross between a camel and a leopard.From the Middle Ages onward, however, people discov-ered that such extreme crosses were not possible and thatvariation and heredity occur mainly within the boundariesof a particular species. Species were thought to have beenmaintained without significant change from the time oftheir creation.

Classical Assumption 2: Direct Transmission of Traits

The second early concept related to heredity is that traitsare transmitted directly. When variation is inherited by off-spring from their parents, what is transmitted? The ancientGreeks suggested that the parents body parts were trans-mitted directly to their offspring. Hippocrates called thistype of reproductive material gonos, meaning seed.Hence, a characteristic such as a misshapen limb was theresult of material that came from the misshapen limb of aparent. Information from each part of the body was sup-posedly passed along independently of the informationfrom the other parts, and the child was formed after thehereditary material from all parts of the parents bodies hadcome together.

This idea was predominant until fairly recently. For ex-ample, in 1868, Charles Darwin proposed that all cells andtissues excrete microscopic granules, or gemmules, that

13.1 Mendel solved the mystery of heredity.

FIGURE 13.2Heredity is responsible for family resemblance. Familyresemblances are often stronga visual manifestation of themechanism of heredity. This is the Johnson family, the wife anddaughters of one of the authors. While each daughter is different,all clearly resemble their mother.

FIGURE 13.3Red hair is inherited. Many different traits are inherited inhuman families. This redhead is exhibiting one of these traits.

are passed to offspring, guiding the growthof the corresponding part in the developingembryo. Most similar theories of the directtransmission of hereditary material assumedthat the male and female contributionsblend in the offspring. Thus, parents withred and brown hair would produce childrenwith reddish brown hair, and tall and shortparents would produce children of interme-diate height.

Koelreuter DemonstratesHybridization between Species

Taken together, however, these two con-cepts lead to a paradox. If no variation en-ters a species from outside, and if the varia-tion within each species blends in everygeneration, then all members of a speciesshould soon have the same appearance.Obviously, this does not happen. Individu-als within most species differ widely fromeach other, and they differ in characteris-tics that are transmitted from generation togeneration.

How could this paradox be resolved? Ac-tually, the resolution had been providedlong before Darwin, in the work of theGerman botanist Josef Koelreuter. In 1760,Koelreuter carried out successful hy-bridizations of plant species, crossing dif-ferent strains of tobacco and obtaining fer-tile offspring. The hybrids differed in appearance fromboth parent strains. When individuals within the hybridgeneration were crossed, their offspring were highly vari-able. Some of these offspring resembled plants of the hy-brid generation (their parents), but a few resembled theoriginal strains (their grandparents).

The Classical Assumptions Fail

Koelreuters work represents the beginning of moderngenetics, the first clues pointing to the modern theory ofheredity. Koelreuters experiments provided an impor-tant clue about how heredity works: the traits he wasstudying could be masked in one generation, only toreappear in the next. This pattern contradicts the theoryof direct transmission. How could a trait that is transmit-ted directly disappear and then reappear? Nor were thetraits of Koelreuters plants blended. A contemporary ac-count stated that the traits reappeared in the third gener-ation fully restored to all their original powers andproperties.

It is worth repeating that the offspring in Koelreuterscrosses were not identical to one another. Some resembledthe hybrid generation, while others did not. The alternative

forms of the characters Koelreuter wasstudying were distributed among the off-spring. Referring to a heritable feature as acharacter, a modern geneticist would saythe alternative forms of each character weresegregating among the progeny of a mat-ing, meaning that some offspring exhibitedone alternative form of a character (for ex-ample, hairy leaves), while other offspringfrom the same mating exhibited a differentalternative (smooth leaves). This segrega-tion of alternative forms of a character, ortraits, provided the clue that led GregorMendel to his understanding of the natureof heredity.

Knight Studies Heredity in Peas

Over the next hundred years, other inves-tigators elaborated on Koelreuters work.Prominent among them were Englishgentleman farmers trying to improve vari-eties of agricultural plants. In one such se-ries of experiments, carried out in the1790s, T. A. Knight crossed two true-breeding varieties (varieties that remainuniform from one generation to the next)of the garden pea, Pisum sativum (fig-ure 13.4). One of these varieties had pur-ple flowers, and the other had white flow-ers. All of the progeny of the cross hadpurple flowers. Among the offspring of

these hybrids, however, were some plants with purpleflowers and others, less common, with white flowers. Justas in Koelreuters earlier studies, a trait from one of theparents disappeared in one generation only to reappearin the next.

In these deceptively simple results were the makings of ascientific revolution. Nevertheless, another century passedbefore the process of gene segregation was fully appreci-ated. Why did it take so long? One reason was that earlyworkers did not quantify their results. A numerical recordof results proved to be crucial to understanding the process.Knight and later experimenters who carried out othercrosses with pea plants noted that some traits had astronger tendency to appear than others, but they did notrecord the numbers of the different classes of progeny. Sci-ence was young then, and it was not obvious that the num-bers were important.

Early geneticists demonstrated that some forms of aninherited character (1) can disappear in one generationonly to reappear unchanged in future generations;(2) segregate among the offspring of a cross; and(3) are more likely to be represented than theiralternatives.

Chapter 13 Patterns of Inheritance 241

FIGURE 13.4The garden pea, Pisum sativum. Easy to cultivate and able to produce many distinctivevarieties, the garden pea was apopular experimental subject ininvestigations of heredity as long as a century before GregorMendels experiments.

Mendel and the Garden PeaThe first quantitative studies of inheritance were carriedout by Gregor Mendel, an Austrian monk (figure 13.5).Born in 1822 to peasant parents, Mendel was educated in amonastery and went on to study science and mathematicsat the University of Vienna, where he failed his examina-tions for a teaching certificate. He returned to themonastery and spent the rest of his life there, eventuallybecoming abbot. In the garden of the monastery (figure13.6), Mendel initiated a series of experiments on plant hy-bridization. The results of these experiments would ulti-mately change our views of heredity irrevocably.

Why Mendel Chose the Garden Pea

For his experiments, Mendel chose the garden pea, thesame plant Knight and many others had studied earlier.The choice was a good one for several reasons. First, manyearlier investigators had produced hybrid peas by crossingdifferent varieties. Mendel knew that he could expect toobserve segregation of traits among the offspring. Second,a large number of true-breeding varieties of peas wereavailable. Mendel initially examined 32. Then, for furtherstudy, he selected lines that differed with respect to seveneasily distinguishable traits, such as round versus wrinkledseeds and purple versus white flowers, a character thatKnight had studied. Third, pea plants are small and easy togrow, and they have a relatively short generation time.Thus, one can conduct experiments involving numerousplants, grow several generations in a single year, and obtainresults relatively quickly.

A fourth advantage of studying peas is that the sexual or-gans of the pea are enclosed within the flower (figure 13.7).The flowers of peas, like those of many flowering plants,contain both male and female sex organs. Furthermore, thegametes produced by the male and female parts of the sameflower, unlike those of many flowering plants, can fuse toform viable offspring. Fertilization takes place automati-cally within an individual flower if it isnot disturbed, resulting in offspringthat are the progeny from a single indi-vidual. Therefore, one can either letindividual flowers engage in self-fertilization, or remove the flowersmale parts before fertilization and intro-duce pollen from a strain with a differenttrait, thus performing cross-pollinationwhich results in cross-fertilization.


FIGURE 13.5Gregor Johann Mendel. Cultivating his plants in the garden of amonastery in Brunn, Austria (now Brno, Czech Republic), Mendelstudied how differences among varieties of peas were inheritedwhen the varieties were crossed. Similar experiments had beendone before, but Mendel was the first to quantify the results andappreciate their significance.

FIGURE 13.6The garden where Mendel carried outhis plant-breeding experiments. GregorMendel did his key scientific experimentsin this small garden in a monastery.

Mendels Experimental Design

Mendel was careful to focus on only a few specific differ-ences between the plants he was using and to ignore thecountless other differences he must have seen. He also hadthe insight to realize that the differences he selected to ana-lyze must be comparable. For example, he appreciated thattrying to study the inheritance of round seeds versus tallheight would be useless.

Mendel usually conducted his experiments in threestages:

1. First, he allowed pea plants of a given variety to pro-duce progeny by self-fertilization for several genera-tions. Mendel thus was able to assure himself thatthe traits he was studying were indeed constant,transmitted unchanged from generation to genera-tion. Pea plants with white flowers, for example,when crossed with each other, produced only off-spring with white flowers, regardless of the numberof generations.

2. Mendel then performed crosses between varietiesexhibiting alternative forms of characters. For ex-ample, he removed the male parts from the flowerof a plant that produced whiteflowers and ferti l ized it withpollen from a purple-floweredplant. He also carried out thereciprocal cross, using pollenfrom a white-flowered individualto fertilize a flower on a pea plantthat produced purple flowers (fig-ure 13.8).

3. Finally, Mendel permitted the hy-brid offspring produced by thesecrosses to self-pollinate for severalgenerations. By doing so, he al-lowed the alternative forms of acharacter to segregate among theprogeny. This was the same exper-imental design that Knight andothers had used much earlier. ButMendel went an important stepfarther: he counted the numbers ofoffspring exhibiting each trait ineach succeeding generation. Noone had ever done that before.The quantitative results Mendelobtained proved to be of supremeimportance in revealing theprocess of heredity.

Mendels experiments with thegarden pea involved crosses betweentrue-breeding varieties, followed by ageneration or more of inbreeding.


Petals

Anther

Carpel

FIGURE 13.7Structure of the pea flower (longitudinal section). In a peaplant flower, the petals enclose the male anther (containingpollen grains, which give rise to haploid sperm) and the femalecarpel (containing ovules, which give rise to haploid eggs). Thisensures that self-fertilization will take place unless the flower isdisturbed.

Pollen transferred from white flower to stigma of purple flower

Anthersremoved

All purple flowers result

FIGURE 13.8How Mendel conducted his experiments. Mendel pushed aside the petals of a whiteflower and collected pollen from the anthers. He then placed that pollen onto the stigma(part of the carpel) of a purple flower whose anthers had been removed, causing cross-fertilization to take place. All the seeds in the pod that resulted from this pollinationwere hybrids of the white-flowered male parent and the purple-flowered female parent.After planting these seeds, Mendel observed the pea plants they produced. All of theprogeny of this cross had purple flowers.

What Mendel FoundThe seven characters Mendel studied in his experimentspossessed several variants that differed from one another inways that were easy to recognize and score (figure 13.9).We will examine in detail Mendels crosses with flowercolor. His experiments with other characters were similar,and they produced similar results.

The F1 Generation

When Mendel crossed two contrasting varieties of peas,such as white-flowered and purple-flowered plants, thehybrid offspring he obtained did not have flowers of in-termediate color, as the theory of blending inheritancewould predict. Instead, in every case the flower color ofthe offspring resembled one of their parents. It is custom-ary to refer to these offspring as the first filial ( filius is


Character

Flowercolor

Seedcolor

Seedshape

Podcolor

Podshape

Flowerposition

Plantheight

Dominant vs. recessive trait F2 generationDominant form Recessive form

Ratio

3.15:1

3.01:1

2.96:1

2.82:1

2.95:1

3.14:1

2.84:1

705 224

6022 2001

5474 1850

428 152

882 299

651 207

787 277

Purple White

Yellow Green

Round Wrinkled

Green Yellow

Inflated Constricted

Axial Terminal

Tall Dwarf

X

X

X

X

X

X

X

FIGURE 13.9Mendels experimental results. This table illustrates the seven characters Mendel studied in his crosses of the garden pea and presentsthe data he obtained from these crosses. Each pair of traits appeared in the F2 generation in very close to a 3:1 ratio.

Latin for son), or F1, generation. Thus, in a cross ofwhite-flowered with purple-flowered plants, the F1 off-spring all had purple flowers, just as Knight and othershad reported earlier.

Mendel referred to the trait expressed in the F1 plants asdominant and to the alternative form that was not ex-pressed in the F1 plants as recessive. For each of the sevenpairs of contrasting traits that Mendel examined, one of thepair proved to be dominant and the other recessive.

The F2 Generation

After allowing individual F1 plants to mature and self-pollinate, Mendel collected and planted the seeds fromeach plant to see what the offspring in the second filial, orF2, generation would look like. He found, just as Knighthad earlier, that some F2 plants exhibited white flowers, therecessive trait. Hidden in the F1 generation, the recessiveform reappeared among some F2 individuals.

Believing the proportions of the F2 types would pro-vide some clue about the mechanism of heredity, Mendelcounted the numbers of each type among the F2 progeny(figure 13.10). In the cross between the purple-floweredF1 plants, he counted a total of 929 F2 individuals (seefigure 13.9). Of these, 705 (75.9%) had purple flowersand 224 (24.1%) had white flowers. Approximately 14 ofthe F2 individuals exhibited the recessive form of thecharacter. Mendel obtained the same numerical resultwith the other six characters he examined: 34 of the F2 in-dividuals exhibited the dominant trait, and 14 displayedthe recessive trait. In other words, the dominant:recessiveratio among the F2 plants was always close to 3:1. Mendelcarried out similar experiments with other traits, such aswrinkled versus round seeds (figure 13.11), and obtainedthe same result.


FIGURE 13.10A page from Mendels notebook.

FIGURE 13.11Seed shape: a Mendelian character. One of the differences Mendelstudied affected the shape of pea plant seeds. In some varieties, theseeds were round, while in others, they were wrinkled.

A Disguised 1:2:1 Ratio

Mendel went on to examine how theF2 plants passed traits on to subse-quent generations. He found that therecessive 14 were always true-breeding.In the cross of white-flowered withpurple-flowered plants, for example,the white-flowered F2 individuals reli-ably produced white-flowered off-spring when they were allowed to self-fertilize. By contrast, only 13 of thedominant purple-flowered F2 individ-uals (14 of all F2 offspring) provedtrue-breeding, while 23 were not. Thislast class of plants produced dominantand recessive individuals in the thirdfilial (F3) generation in a 3:1 ratio.This result suggested that, for the en-tire sample, the 3:1 ratio that Mendelobserved in the F2 generation was re-ally a disguised 1:2:1 ratio: 14 pure-breeding dominant individuals, 12 not-pure-breeding dominant individuals,and 14 pure-breeding recessive indi-viduals (figure 13.12).

Mendels Model of Heredity

From his experiments, Mendel wasable to understand four things aboutthe nature of heredity. First, theplants he crossed did not produceprogeny of intermediate appearance,as a theory of blending inheritancewould have predicted. Instead, differ-ent plants inherited each alternativeintact, as a discrete characteristic thateither was or was not visible in a par-ticular generation. Second, Mendellearned that for each pair of alterna-tive forms of a character, one alterna-tive was not expressed in the F1 hy-brids, although it reappeared in someF2 individuals. The trait that disap-peared must therefore be latent(present but not expressed) in the F1individuals. Third, the pairs of alter-native traits examined segregatedamong the progeny of a particularcross, some individuals exhibiting onetrait, some the other. Fourth, these al-ternative traits were expressed in theF2 generation in the ratio of 34 domi-nant to 14 recessive. This characteris-tic 3:1 segregation is often referred toas the Mendelian ratio.


P (parental) generation

Cross-fertilize

: :

F1 generation

F3 generation

Purple White

3 : 1

3 : 1

1True-breeding

dominant

1True-breeding

recessive

Self-fertilize

White

Purple

2Not-true-breeding

dominant

Purple

F2 generation

Purple

FIGURE 13.12The F2 generation is a disguised 1:2:1 ratio. By allowing the F2 generation to self-fertilize, Mendel found from the offspring (F3) that the ratio of F2 plants was one true-breeding dominant, two not-true-breeding dominant, and one true-breeding recessive.

To explain these results, Mendel proposed a simplemodel. It has become one of the most famous models in thehistory of science, containing simple assumptions and mak-ing clear predictions. The model has five elements:

1. Parents do not transmit physiological traits directly totheir offspring. Rather, they transmit discrete infor-mation about the traits, what Mendel called factors.These factors later act in the offspring to produce thetrait. In modern terms, we would say that informationabout the alternative forms of characters that an indi-vidual expresses is encoded by the factors that it re-ceives from its parents.

2. Each individual receives two factors that may code forthe same trait or for two alternative traits for a char-acter. We now know that there are two factors foreach character present in each individual becausethese factors are carried on chromosomes, and eachadult individual is diploid. When the individual formsgametes (eggs or sperm), they contain only one ofeach kind of chromosome (see chapter 12); the ga-metes are haploid. Therefore, only one factor for eachcharacter of the adult organism is contained in thegamete. Which of the two factors ends up in a partic-ular gamete is randomly determined.

3. Not all copies of a factor are identical. In modernterms, the alternative forms of a factor, leading to al-ternative forms of a character, are called alleles.When two haploid gametes containing exactly thesame allele of a factor fuse during fertilization to forma zygote, the offspring that develops from that zygoteis said to be homozygous; when the two haploid ga-metes contain different alleles, the individual off-spring is heterozygous.

In modern terminology, Mendels factors are calledgenes. We now know that each gene is composed of aparticular DNA nucleotide sequence (see chapter 3).The particular location of a gene on a chromosome isreferred to as the genes locus (plural, loci).

4. The two alleles, one contributed by the male gameteand one by the female, do not influence each other inany way. In the cells that develop within the new in-dividual, these alleles remain discrete. They neitherblend with nor alter each other. (Mendel referred tothem as uncontaminated.) Thus, when the individ-ual matures and produces its own gametes, the allelesfor each gene segregate randomly into these gametes,as described in element 2.

5. The presence of a particular allele does not ensurethat the trait encoded by it will be expressed in an in-dividual carrying that allele. In heterozygous individ-uals, only one allele (the dominant one) is expressed,while the other (recessive) allele is present but unex-pressed. To distinguish between the presence of anallele and its expression, modern geneticists refer tothe totality of alleles that an individual contains as theindividuals genotype and to the physical appearanceof that individual as its phenotype. The phenotype ofan individual is the observable outward manifestationof its genotype, the result of the functioning of theenzymes and proteins encoded by the genes it carries.In other words, the genotype is the blueprint, and thephenotype is the visible outcome.

These five elements, taken together, constitute Mendelsmodel of the hereditary process. Many traits in humansalso exhibit dominant or recessive inheritance, similar tothe traits Mendel studied in peas (table 13.1).

When Mendel crossed two contrasting varieties, hefound all of the offspring in the first generationexhibited one (dominant) trait, and none exhibited theother (recessive) trait. In the following generation,25% were pure-breeding for the dominant trait, 50%were hybrid for the two traits and exhibited thedominant trait, and 25% were pure-breeding for therecessive trait.


Table 13.1 Some Dominant and Recessive Traits in Humans

Recessive Traits Phenotypes Dominant Traits Phenotypes

AlbinismAlkaptonuria

Red-green color blindnessCystic fibrosis

Duchenne muscular dystrophyHemophiliaSickle cell anemia

Lack of melanin pigmentationInability to metabolizehomogenistic acidInability to distinguish red or greenwavelengths of lightAbnormal gland secretion, leading toliver degeneration and lung failureWasting away of muscles duringchildhoodInability to form blood clotsDefective hemoglobin that causesred blood cells to curve and sticktogether

Middigital hair

BrachydactylyHuntingtons disease

Phenylthiocarbamide (PTC)sensitivityCamptodactyly

Hypercholesterolemia (the mostcommon human Mendeliandisorder1 in 500)Polydactyly

Presence of hair on middlesegment of fingersShort fingersDegeneration of nervoussystem, starting in middle ageAbility to taste PTC as bitter

Inability to straighten the littlefingerElevated levels of bloodcholesterol and risk of heartattackExtra fingers and toes

How Mendel Interpreted HisResultsDoes Mendels model predict the results he actually ob-tained? To test his model, Mendel first expressed it interms of a simple set of symbols, and then used the symbolsto interpret his results. It is very instructive to do the same.Consider again Mendels cross of purple-flowered withwhite-flowered plants. We will assign the symbol P to thedominant allele, associated with the production of purpleflowers, and the symbol p to the recessive allele, associatedwith the production of white flowers. By convention, ge-netic traits are usually assigned a letter symbol referring totheir more common forms, in this case P for purpleflower color. The dominant allele is written in upper case,as P; the recessive allele (white flower color) is assigned thesame symbol in lower case, p.

In this system, the genotype of an individual that is true-breeding for the recessive white-flowered trait would bedesignated pp. In such an individual, both copies of the al-lele specify the white-flowered phenotype. Similarly, thegenotype of a true-breeding purple-flowered individualwould be designated PP, and a heterozygote would be des-ignated Pp (dominant allele first). Using these conventions,and denoting a cross between two strains with , we cansymbolize Mendels original cross as pp PP.

The F1 Generation

Using these simple symbols, we can now go back and re-examine the crosses Mendel carried out. Because a white-flowered parent (pp) can produce only p gametes, and apure purple-flowered (homozygous dominant) parent(PP) can produce only P gametes, the union of an eggand a sperm from these parents can produce only het-erozygous Pp offspring in the F1 generation. Because theP allele is dominant, all of these F1 individuals are ex-pected to have purple flowers. The p allele is present inthese heterozygous individuals, but it is not phenotypi-cally expressed. This is the basis for the latency Mendelsaw in recessive traits.

The F2 Generation

When F1 individuals are allowed to self-fertilize, the Pand p alleles segregate randomly during gamete forma-tion. Their subsequent union at fertilization to form F2individuals is also random, not being influenced by whichalternative alleles the individual gametes carry. What willthe F2 individuals look like? The possibilities may be visu-alized in a simple diagram called a Punnett square,named after its originator, the English geneticist ReginaldCrundall Punnett (figure 13.13). Mendels model, ana-


P

P p

p

P

P p

p pp pp

(a)

(b)

P

P p

p Pp

P

P p

p

Pp

pp

Pp

Pp pp

PpP PP

P p

p

Gametes

Gametes

FIGURE 13.13A Punnett square. (a) To make a Punnett square, place thedifferent possible types of female gametes along one side of asquare and the different possible types of male gametes along theother. (b) Each potential zygote can then be represented as theintersection of a vertical line and a horizontal line.

lyzed in terms of a Punnett square, clearly predicts thatthe F2 generation should consist of 34 purple-floweredplants and 14 white-flowered plants, a phenotypic ratio of3:1 (figure 13.14).

The Laws of Probability Can Predict Mendels Results

A different way to express Mendels result is to say thatthere are three chances in four (34) that any particular F2individual will exhibit the dominant trait, and one chancein four (14) that an F2 individual will express the recessivetrait. Stating the results in terms of probabilities allowssimple predictions to be made about the outcomes ofcrosses. If both F1 parents are Pp (heterozygotes), theprobability that a particular F2 individual will be pp (ho-mozygous recessive) is the probability of receiving a p ga-mete from the male (12) times the probability of receivinga p gamete from the female (12), or 14. This is the sameoperation we perform in the Punnett square illustrated infigure 13.13. The ways probability theory can be used toanalyze Mendels results is discussed in detail onpage 251.

Further Generations

As you can see in figure 13.14, there are really three kindsof F2 individuals: 14 are pure-breeding, white-flowered indi-viduals (pp); 12 are heterozygous, purple-flowered individu-als (Pp); and 14 are pure-breeding, purple-flowered individ-uals (PP). The 3:1 phenotypic ratio is really a disguised1:2:1 genotypic ratio.

Mendels First Law of Heredity: Segregation

Mendels model thus accounts in a neat and satisfying wayfor the segregation ratios he observed. Its central assump-tionthat alternative alleles of a character segregate fromeach other in heterozygous individuals and remain dis-tincthas since been verified in many other organisms. Itis commonly referred to as Mendels First Law of Hered-ity, or the Law of Segregation. As you saw in chapter 12,the segregational behavior of alternative alleles has a simplephysical basis, the alignment of chromosomes at randomon the metaphase plate during meiosis I. It is a tribute tothe intellect of Mendels analysis that he arrived at the cor-rect scheme with no knowledge of the cellular mechanismsof inheritance; neither chromosomes nor meiosis had yetbeen described.


Purple(Pp)

Purple(PP )

Pp p p

P

P

P

p

F1 generation F2 generation

White(pp)

Purple(Pp)

Pp

ppPp

PP

PpPp

Pp PpGametes

GametesGametes

Gametes

FIGURE 13.14Mendels cross of pea plants differing in flower color. All of the offspring of the first cross (the F1 generation) are Pp heterozygoteswith purple flowers. When two heterozygous F1 individuals are crossed, three kinds of F2 offspring are possible: PP homozygotes (purpleflowers); Pp heterozygotes (also purple flowers); and pp homozygotes (white flowers). Therefore, in the F2 generation, the ratio ofdominant to recessive phenotypes is 3:1. However, the ratio of genotypes is 1:2:1 (1 PP: 2 Pp: 1 pp).

The Testcross

To test his model further, Mendel devised a simple andpowerful procedure called the testcross. Consider a purple-flowered plant. It is impossible to tell whether such a plantis homozygous or heterozygous simply by looking at itsphenotype. To learn its genotype, you must cross it withsome other plant. What kind of cross would provide theanswer? If you cross it with a homozygous dominant indi-vidual, all of the progeny will show the dominant pheno-type whether the test plant is homozygous or heterozygous.It is also difficult (but not impossible) to distinguish be-tween the two possible test plant genotypes by crossingwith a heterozygous individual. However, if you cross thetest plant with a homozygous recessive individual, the twopossible test plant genotypes will give totally different re-sults (figure 13.15):

Alternative 1: unknown individual homozygous dominant (PP). PP pp: all offspring have purple flowers (Pp)

Alternative 2: unknown individual heterozygous (Pp). Pp pp: 12 of offspring have white flowers(pp) and 12 have purple flowers (Pp)

To perform his testcross, Mendel crossed heterozygousF1 individuals back to the parent homozygous for the reces-sive trait. He predicted that the dominant and recessivetraits would appear in a 1:1 ratio, and that is what he ob-served. For each pair of alleles he investigated, Mendel ob-served phenotypic F2 ratios of 3:1 (see figure 13.14) andtestcross ratios very close to 1:1, just as his model predicted.

Testcrosses can also be used to determine the genotypeof an individual when two genes are involved. Mendel car-ried out many two-gene crosses, some of which we will dis-cuss. He often used testcrosses to verify the genotypes ofparticular dominant-appearing F2 individuals. Thus, an F2individual showing both dominant traits (A_ B_) mighthave any of the following genotypes: AABB, AaBB, AABb,or AaBb. By crossing dominant-appearing F2 individualswith homozygous recessive individuals (that is, A_ B_ aabb), Mendel was able to determine if either or both of thetraits bred true among the progeny, and so to determinethe genotype of the F2 parent:

AABB trait A breeds true trait B breeds trueAaBB ________________ trait B breeds trueAABb trait A breeds true ________________AaBb ________________ ________________


if PP if Pp

Dominant phenotype(unknown genotype)

Half of offspring are white;therefore, unknown floweris heterozygous.

All offspring are purple;therefore, unknownflower is homozygousdominant.

PP P p

p

ppp pp

pp

ppPp

Ppp

p

Pp

PpPp

Pp

Alternative 1 Alternative 2

Homozygousrecessive(white)

Homozygousrecessive(white)

?

FIGURE 13.15A testcross. To determine whether an individual exhibiting a dominant phenotype, such as purple flowers, is homozygous orheterozygous for the dominant allele, Mendel crossed the individual in question with a plant that he knew to be homozygous recessive, inthis case a plant with white flowers.


Probability andAllele Distribution

The probability that the three childrenwill be two boys and one girl is:

3p2q = 3 (12)2 (12) = 38

To test your understanding, try to esti-mate the probability that two parents het-erozygous for the recessive allele producingalbinism (a) will have one albino child in afamily of three. First, set up a Punnett square:

Fathers GametesA a

Mothers A AA AaGametes a Aa aa

You can see that one-fourth of the chil-dren are expected to be albino (aa). Thus,for any given birth the probability of an al-bino child is 14. This probability can be sym-bolized by q. The probability of a nonalbinochild is 34, symbolized by p. Therefore, theprobability that there will be one albinochild among the three children is:

3p2q = 3 (34)2 (14) = 2764, or 42%

This means that the chance of havingone albino child in the three is 42%.

Many, although not all, alternative allelesproduce discretely different phenotypes.Mendels pea plants were tall or dwarf, hadpurple or white flowers, and producedround or wrinkled seeds. The eye color of afruit fly may be red or white, and the skincolor of a human may be pigmented or al-bino. When only two alternative alleles existfor a given character, the distribution ofphenotypes among the offspring of a cross isreferred to as a binomial distribution.

As an example, consider the distributionof sexes in humans. Imagine that a couplehas chosen to have three children. Howlikely is it that two of the children will beboys and one will be a girl? The frequencyof any particular possibility is referred to asits probability of occurrence. Let p symbol-ize the probability of having a boy at anygiven birth and q symbolize the probabilityof having a girl. Since any birth is equallylikely to produce a girl or boy:

p = q = 12Table 13.A shows eight possible gender

combinations among the three children. Thesum of the probabilities of the eight possiblecombinations must equal one. Thus:

p3 + 3p2q + 3pq2 + q3 = 1

Table 13.A Binomial Distribution of the Sexes of Children in Human Families

Composition Order of Family of Birth Calculation Probability

3 boys bbb p p p p3

2 boys and 1 girl bbg p p q p2qbgb p q p p2q 3p2qgbb q p p p2q

1 boy and 2 girls ggb q q p pq2

gbg q p q pq2 3pq2

bgg p q q pq2

3 girls ggg q q q q3

erozygous individual with one copy of thatallele has the same appearance as a homozy-gous individual with two copies of it.gene The basic unit of heredity; a se-quence of DNA nucleotides on a chromo-some that encodes a polypeptide or RNAmolecule and so determines the nature ofan individuals inherited traits.genotype The total set of genes presentin the cells of an organism. This term isoften also used to refer to the set of allelesat a single gene.haploid Having only one set of chromo-somes. Gametes, certain animals, protistsand fungi, and certain stages in the life cycleof plants are haploid.

heterozygote A diploid individual carry-ing two different alleles of a gene on twohomologous chromosomes. Most humanbeings are heterozygous for many genes.homozygote A diploid individual carry-ing identical alleles of a gene on both ho-mologous chromosomes.locus The location of a gene on a chromosome.phenotype The realized expression of thegenotype; the observable manifestation of atrait (affecting an individuals structure, phys-iology, or behavior) that results from the bio-logical activity of the DNA molecules.recessive allele An allele whose pheno-typic effect is masked in heterozygotes bythe presence of a dominant allele.

allele One of two or more alternativeforms of a gene.diploid Having two sets of chromo-somes, which are referred to as homologues.Animals and plants are diploid in the dom-inant phase of their life cycles as are someprotists.dominant allele An allele that dictates theappearance of heterozygotes. One allele issaid to be dominant over another if a het-

Vocabulary of Genetics

Mendels Second Law of Heredity:Independent Assortment

After Mendel had demonstrated that different traits of agiven character (alleles of a given gene) segregate inde-pendently of each other in crosses, he asked whether dif-ferent genes also segregate independently. Mendel set outto answer this question in a straightforward way. He firstestablished a series of pure-breeding lines of peas that dif-fered in just two of the seven characters he had studied.He then crossed contrasting pairs of the pure-breedinglines to create heterozygotes. In a cross involving differ-ent seed shape alleles (round, R, and wrinkled, r) and dif-ferent seed color alleles (yellow, Y, and green, y), all theF1 individuals were identical, each one heterozygous forboth seed shape (Rr) and seed color (Yy). The F1 individu-als of such a cross are dihybrids, individuals heterozygousfor both genes.

The third step in Mendels analysis was to allow the di-hybrids to self-fertilize. If the alleles affecting seed shapeand seed color were segregating independently, then theprobability that a particular pair of seed shape alleleswould occur together with a particular pair of seed coloralleles would be simply the product of the individual prob-abilities that each pair would occur separately. Thus, theprobability that an individual with wrinkled green seeds(rryy) would appear in the F2 generation would be equal tothe probability of observing an individual with wrinkledseeds (14) times the probability of observing one with greenseeds (14), or 116.

Because the gene controlling seed shape and the genecontrolling seed color are each represented by a pair ofalternative alleles in the dihybrid individuals, four typesof gametes are expected: RY, Ry, rY, and ry. Therefore, inthe F2 generation there are 16 possible combinations ofalleles, each of them equally probable (figure 13.16). Ofthese, 9 possess at least one dominant allele for each gene(signified R__Y__, where the dash indicates the presenceof either allele) and, thus, should have round, yellowseeds. Of the rest, 3 possess at least one dominant R allelebut are homozygous recessive for color (R__yy); 3 otherspossess at least one dominant Y allele but are homozy-gous recessive for shape (rrY__); and 1 combinationamong the 16 is homozygous recessive for both genes(rryy). The hypothesis that color and shape genes assortindependently thus predicts that the F2 generation willdisplay a 9:3:3:1 phenotypic ratio: nine individuals withround, yellow seeds, three with round, green seeds, threewith wrinkled, yellow seeds, and one with wrinkled,green seeds (see figure 13.16).

What did Mendel actually observe? From a total of 556seeds from dihybrid plants he had allowed to self-fertilize,he observed: 315 round yellow (R__Y__), 108 round green(R__yy), 101 wrinkled yellow (rrY__), and 32 wrinkled green(rryy). These results are very close to a 9:3:3:1 ratio (whichwould be 313:104:104:35). Consequently, the two genesappeared to assort completely independently of each other.

Note that this independent assortment of different genes inno way alters the independent segregation of individualpairs of alleles. Round versus wrinkled seeds occur in aratio of approximately 3:1 (423:133); so do yellow versusgreen seeds (416:140). Mendel obtained similar results forother pairs of traits.

Mendels discovery is often referred to as MendelsSecond Law of Heredity, or the Law of IndependentAssortment. Genes that assort independently of one an-other, like the seven genes Mendel studied, usually do sobecause they are located on different chromosomes, whichsegregate independently during the meiotic process of ga-mete formation. A modern restatement of Mendels SecondLaw would be that genes that are located on different chromo-somes assort independently during meiosis.

Mendel summed up his discoveries about heredity intwo laws. Mendels First Law of Heredity states thatalternative alleles of a trait segregate independently; hisSecond Law of Heredity states that genes located ondifferent chromosomes assort independently.


RY

RY Ry rY ry

Ry

rY

ry

RRYY

RRYy

RrYY

RrYy

F1 generation

F2 generation

9/16 are round, yellow3/16 are round, green3/16 are wrinkled, yellow1/16 are wrinkled, green

Wrinkled, greenseeds (rryy)

Round, yellowseeds (RRYY)

X

All round, yellowseeds (RrYy)

RRYy

RRyy

RrYy

Rryy

RrYY

RrYy

rrYY

rrYy

RrYy

Rryy

rrYy

rryy

Sperm

Eggs

FIGURE 13.16Analyzing a dihybrid cross. This Punnett square shows theresults of Mendels dihybrid cross between plants with roundyellow seeds and plants with wrinkled green seeds. The ratio ofthe four possible combinations of phenotypes is predicted to be9:3:3:1, the ratio that Mendel found.

Mendelian Inheritance Is NotAlways Easy to AnalyzeAlthough Mendels results did not receive much noticeduring his lifetime, three different investigators indepen-dently rediscovered his pioneering paper in 1900, 16 yearsafter his death. They came across it while searching the lit-erature in preparation for publishing their own findings,which closely resembled those Mendel had presented morethan three decades earlier. In the decades following the re-discovery of Mendel, many investigators set out to testMendels ideas. However, scientists attempting to confirmMendels theory often had trouble obtaining the same sim-ple ratios he had reported. Often, the expression of thegenotype is not straightforward. Most phenotypes reflectthe action of many genes that act sequentially or jointly,and the phenotype can be affected by alleles that lack com-plete dominance and the environment.

Continuous Variation

Few phenotypes are the result of the action of only onegene. Instead, most characters reflect the action of poly-genes, many genes that act sequentially or jointly. Whenmultiple genes act jointly to influence a character such asheight or weight, the character often shows a range of smalldifferences. Because all of the genes that play a role in de-termining phenotypes such as height or weight segregateindependently of one another, one sees a gradation in thedegree of difference when many individuals are examined(figure 13.17). We call this gradation continuous varia-tion. The greater the number of genes that influence acharacter, the more continuous the expected distribution ofthe versions of that character.

How can one describe the variation in a character suchas the height of the individuals in figure 13.17? Individualsrange from quite short to very tall, with average heightsmore common than either extreme. What one often does isto group the variation into categoriesin this case, bymeasuring the heights of the individuals in inches, round-ing fractions of an inch to the nearest whole number. Eachheight, in inches, is a separate phenotypic category. Plot-ting the numbers in each height category produces a his-togram, such as that in figure 13.17. The histogram ap-proximates an idealized bell-shaped curve, and the variationcan be characterized by the mean and spread of that curve.

Pleiotropic Effects

Often, an individual allele will have more than one effecton the phenotype. Such an allele is said to be pleiotropic.When the pioneering French geneticist Lucien Cuenotstudied yellow fur in mice, a dominant trait, he was unableto obtain a true-breeding yellow strain by crossing individ-ual yellow mice with each other. Individuals homozygousfor the yellow allele died, because the yellow allele was

pleiotropic: one effect was yellow coat color, but anotherwas a lethal developmental defect. A pleiotropic allele maybe dominant with respect to one phenotypic consequence(yellow fur) and recessive with respect to another (lethaldevelopmental defect). In pleiotropy, one gene affectsmany traits, in marked contrast to polygeny, where manygenes affect one trait. Pleiotropic effects are difficult topredict, because the genes that affect a trait often performother functions we may know nothing about.

Pleiotropic effects are characteristic of many inheriteddisorders, such as cystic fibrosis and sickle cell anemia, bothdiscussed later in this chapter. In these disorders, multiplesymptoms can be traced back to a single gene defect. In cys-tic fibrosis, patients exhibit clogged blood vessels, overlysticky mucus, salty sweat, liver and pancreas failure, and abattery of other symptoms. All are pleiotropic effects of asingle defect, a mutation in a gene that encodes a chlorideion transmembrane channel. In sickle cell anemia, a defectin the oxygen-carrying hemoglobin molecule causes anemia,heart failure, increased susceptibility to pneumonia, kidneyfailure, enlargement of the spleen, and many other symp-toms. It is usually difficult to deduce the nature of the pri-mary defect from the range of a genes pleiotropic effects.


Num

ber o

f ind

ividu

als

30

20

10

05'0'' 5'6''

Height6'0''

FIGURE 13.17Height is a continuously varying trait. The photo showsvariation in height among students of the 1914 class of theConnecticut Agricultural College. Because many genescontribute to height and tend to segregate independently of oneanother, the cumulative contribution of different combinationsof alleles to height forms a continuous distribution of possibleheight, in which the extremes are much rarer than theintermediate values.

Lack of Complete Dominance

Not all alternative alleles are fullydominant or fully recessive in het-erozygotes. Some pairs of alleles in-stead produce a heterozygous pheno-type that is either intermediatebetween those of the parents (incom-plete dominance), or representative ofboth parental phenotypes (codomi-nance). For example, in the cross of redand white flowering Japanese four o-clocks described in figure 13.18, all theF1 offspring had pink flowersindicat-ing that neither red nor white flowercolor was dominant. Does this exampleof incomplete dominance argue thatMendel was wrong? Not at all. Whentwo of the F1 pink flowers werecrossed, they produced red-, pink-, andwhite-flowered plants in a 1:2:1 ratio.Heterozygotes are simply intermediatein color.

Environmental Effects

The degree to which an allele is ex-pressed may depend on the environ-ment. Some alleles are heat-sensitive, for example. Traitsinfluenced by such alleles are more sensitive to temperatureor light than are the products of other alleles. The arcticfoxes in figure 13.19, for example, make fur pigment onlywhen the weather is warm. Similarly, the ch allele in Hi-malayan rabbits and Siamese cats encodes a heat-sensitiveversion of tyrosinase, one of the enzymes mediating theproduction of melanin, a dark pigment. The ch version ofthe enzyme is inactivated at temperatures above about33C. At the surface of the body and head, the temperatureis above 33C and the tyrosinase enzyme is inactive, whileit is more active at body extremities such as the tips of theears and tail, where the temperature is below 33C. Thedark melanin pigment this enzyme produces causes theears, snout, feet, and tail of Himalayan rabbits and Siamesecats to be black.


F1 generation

F2 generation

CRCR

CRCR

CRCW

CRCW

CR

CW

CR CW

All CRCW CWCW

CWCW

1 : 2 : 1CRCR:CRCW:CWCW

Eggs

Sperm

FIGURE 13.18Incomplete dominance. In a cross between a red-flowered Japanese four oclock, genotype CRCR, and a white-flowered one (CWCW), neither allele is dominant. The heterozygous progeny have pink flowers and the genotype CRCW. If two of these heterozygotes are crossed, the phenotypes of their progeny occur in a ratio of 1:2:1(red:pink:white).

(a)

(b)

FIGURE 13.19Environmental effects on an allele. (a) An arctic fox in winterhas a coat that is almost white, so it is difficult to see the foxagainst a snowy background. (b) In summer, the same foxs furdarkens to a reddish brown, so that it resembles the color of thesurrounding tundra. Heat-sensitive alleles control this colorchange.

Epistasis

In the tests of Mendels ideas thatfollowed the rediscovery of his work,scientists had trouble obtainingMendels simple ratios particularlywith dihybrid crosses. Recall thatwhen individuals heterozygous fortwo different genes mate (a dihybridcross), four different phenotypes arepossible among the progeny: off-spring may display the dominantphenotype for both genes, either oneof the genes, or for neither gene.Sometimes, however, it is not possi-ble for an investigator to identifysuccessfully each of the four pheno-typic classes, because two or more ofthe classes look alike. Such situationsproved confusing to investigatorsfollowing Mendel.

One example of such difficulty inidentification is seen in the analysis ofparticular varieties of corn, Zea mays.Some commercial varieties exhibit apurple pigment called anthocyanin intheir seed coats, while others do not.In 1918, geneticist R. A. Emersoncrossed two pure-breeding corn vari-eties, neither exhibiting anthocyaninpigment. Surprisingly, all of the F1plants produced purple seeds.

When two of these pigment-producing F1 plants were crossed toproduce an F2 generation, 56% werepigment producers and 44% werenot. What was happening? Emersoncorrectly deduced that two geneswere involved in producing pigment,and that the second cross had thus been a dihybrid cross.Mendel had predicted 16 equally possible ways gametescould combine. How many of these were in each of thetwo types Emerson obtained? He multiplied the fractionthat were pigment producers (0.56) by 16 to obtain 9, andmultiplied the fraction that were not (0.44) by 16 to ob-tain 7. Thus, Emerson had a modified ratio of 9:7 in-stead of the usual 9:3:3:1 ratio.

Why Was Emersons Ratio Modified? When genesact sequentially, as in a biochemical pathway, an allele ex-pressed as a defective enzyme early in the pathway blocksthe flow of material through the rest of the pathway.This makes it impossible to judge whether the later stepsof the pathway are functioning properly. Such gene inter-action, where one gene can interfere with the expressionof another gene, is the basis of the phenomenon calledepistasis.

The pigment anthocyanin is the product of a two-stepbiochemical pathway:

Enzyme 1 Enzyme 2Starting molecule Intermediate Anthocyanin

(Colorless) (Colorless) (Purple)

To produce pigment, a plant must possess at least onefunctional copy of each enzyme gene (figure 13.20). Thedominant alleles encode functional enzymes, but the reces-sive alleles encode nonfunctional enzymes. Of the 16 geno-types predicted by random assortment, 9 contain at leastone dominant allele of both genes; they produce purpleprogeny. The remaining 7 genotypes lack dominant allelesat either or both loci (3 + 3 + 1 = 7) and so are phenotypi-cally the same (nonpigmented), giving the phenotypic ratioof 9:7 that Emerson observed. The inability to see the ef-fect of enzyme 2 when enzyme 1 is nonfunctional is an ex-ample of epistasis.


AB

AB Ab aB ab

Ab

aB

ab

AABB

AABb

AaBB

AaBb

F2 generation

9/16 purple7/16 white

F1 generation

All purple(AaBb)

X

AABb

AAbb

AaBb

Aabb

AaBB

AaBb

aaBB

aaBb

AaBb

Aabb

aaBb

aabb

Eggs

Sperm

White(aaBB)

White(AAbb)

FIGURE 13.20How epistasis affects grain color. The purple pigment found in some varieties of corn isthe product of a two-step biochemical pathway. Unless both enzymes are active (the planthas a dominant allele for each of the two genes, A and B), no pigment is expressed.

Other Examples of Epistasis

In many animals, coat color is the result of epistatic inter-actions among genes. Coat color in Labrador retrievers, abreed of dog, is due primarily to the interaction of twogenes. The E gene determines if dark pigment (eumelanin)will be deposited in the fur or not. If a dog has the geno-type ee, no pigment will be deposited in the fur, and it willbe yellow. If a dog has the genotype EE or Ee (E_), pigmentwill be deposited in the fur.

A second gene, the B gene, determines how dark thepigment will be. This gene controls the distribution ofmelanosomes in a hair. Dogs with the genotype E_bb willhave brown fur and are called chocolate labs. Dogs with thegenotype E_B_ will have black fur. But, even in yellowdogs, the B gene does have some effect. Yellow dogs with

the genotype eebb will have brown pigment on their nose,lips, and eye rims, while yellow dogs with the genotypeeeB_ will have black pigment in these areas. The interactionamong these alleles is illustrated in figure 13.21. The genesfor coat color in this breed have been found, and a genetictest is available to determine the coat colors in a litter ofpuppies.

A variety of factors can disguise the Mendeliansegregation of alleles. Among them are the continuousvariation that results when many genes contribute to atrait, incomplete dominance and codominance thatproduce heterozygotes unlike either parent,environmental influences on the expression ofphenotypes, and gene interactions that produceepistasis.


No dark pigment in furee

eebb eeB_Yellow fur,

brown nose,lips, eye rims

Yellow fur,black nose,

lips, eye rims

Yellow Lab

Dark pigment in furE_

E_bb E_B_

Brown fur,nose, lips,eye rims

Black fur,nose, lips,eye rims

Chocolate Lab Black Lab

FIGURE 13.21The effect of epistatic interactions on coat color in dogs. The coat color seen in Labrador retrievers is an example of the interaction oftwo genes, each with two alleles. The E gene determines if the pigment will be deposited in the fur, and the B gene determines how darkthe pigment will be.

Random changes in genes, called mutations, occur in anypopulation. These changes rarely improve the functioningof the proteins those genes encode, just as randomly chang-ing a wire in a computer rarely improves the computersfunctioning. Mutant alleles are usually recessive to other al-leles. When two seemingly normal individuals who are het-erozygous for such an allele produce offspring homozygousfor the allele, the offspring suffer the detrimental effects ofthe mutant allele. When a detrimental allele occurs at a sig-nificant frequency in a population, the harmful effect itproduces is called a gene disorder.

Most Gene Disorders Are RareTay-Sachs disease is an incurable hereditary disorder inwhich the nervous system deteriorates. Affected childrenappear normal at birth and usually do not develop symp-toms until about the eighth month, when signs of mentaldeterioration appear. The children are blind within a yearafter birth, and they rarely live past five years of age.

Tay-Sachs disease is rare in most human populations,occurring in only 1 of 300,000 births in the United States.However, the disease has a high incidence among Jews ofEastern and Central Europe (Ashkenazi), and amongAmerican Jews, 90% of whom trace their ancestry to East-ern and Central Europe. In these populations, it is esti-mated that 1 in 28 individuals is a heterozygous carrier ofthe disease, and approximately 1 in 3500 infants has thedisease. Because the disease is caused by a recessive allele,most of the people who carry the defective allele do notthemselves develop symptoms of the disease.

The Tay-Sachs allele produces the disease by encoding anonfunctional form of the enzyme hexosaminidase A. Thisenzyme breaks down gangliosides, a class of lipids occurringwithin the lysosomes of brain cells (figure 13.22). As a re-sult, the lysosomes fill with gangliosides, swell, and eventu-ally burst, releasing oxidative enzymes that kill the cells.There is no known cure for this disorder.

Not All Gene Defects Are Recessive

Not all hereditary disorders are recessive. Huntingtonsdisease is a hereditary condition caused by a dominant al-lele that leads to the progressive deterioration of brain cells(figure 13.23). Perhaps 1 in 24,000 individuals develops thedisorder. Because the allele is dominant, every individualthat carries the allele expresses the disorder. Nevertheless,the disorder persists in human populations because itssymptoms usually do not develop until the affected individ-uals are more than 30 years old, and by that time most ofthose individuals have already had children. Consequently,the allele is often transmitted before the lethal conditiondevelops. A person who is heterozygous for Huntingtons

disease has a 50% chance of passing the disease to his or herchildren (even though the other parent does not have thedisorder). In contrast, the carrier of a recessive disordersuch as cystic fibrosis has a 50% chance of passing the alleleto offspring and must mate with another carrier to riskbearing a child with the disease.

Most gene defects are rare recessives, although someare dominant.


13.2 Human genetics follows Mendelian principles.

Perc

ent o

f nor

mal

enz

yme

func

tion 100

50

Tay-Sachs(homozygous

recessive)

Carrier(heterozygous)

Normal(homozygous

dominant)

0

FIGURE 13.22Tay-Sachs disease. Homozygous individuals (left bar) typicallyhave less than 10% of the normal level of hexosaminidase A (rightbar), while heterozygous individuals (middle bar) have about 50%of the normal levelenough to prevent deterioration of thecentral nervous system.

Age in years

Huntingtonsdisease

Perc

ent o

f tot

al w

ith H

untin

gton

's al

lele

affe

cted

by

the

dise

ase

00

25

50

75

100

10 20 4030 50 60 70 80

FIGURE 13.23Huntingtons disease is a dominant genetic disorder. It isbecause of the late age of onset of this disease that it persistsdespite the fact that it is dominant and fatal.

Multiple Alleles: The ABO Blood GroupsA gene may have more than two alleles in a population, andmost genes possess several different alleles. Often, no singleallele is dominant; instead, each allele has its own effect,and the alleles are considered codominant.

A human gene with more than one codominant allele isthe gene that determines ABO blood type. This gene en-codes an enzyme that adds sugar molecules to lipids on thesurface of red blood cells. These sugars act as recognitionmarkers for the immune system. The gene that encodes theenzyme, designated I, has three common alleles: IB, whoseproduct adds galactose; IA, whose product adds galac-tosamine; and i, which codes for a protein that does not adda sugar.

Different combinations of the three I gene alleles occurin different individuals because each person possesses twocopies of the chromosome bearing the I gene and may behomozygous for any allele or heterozygous for any two. Anindividual heterozygous for the IA and IB alleles producesboth forms of the enzyme and adds both galactose andgalactosamine to the surfaces of red blood cells. Becauseboth alleles are expressed simultaneously in heterozygotes,the IA and IB alleles are codominant. Both IA and IB aredominant over the i allele because both IA or IB alleles leadto sugar addition and the i allele does not. The differentcombinations of the three alleles produce four differentphenotypes (figure 13.24):

1. Type A individuals add only galactosamine. They areeither IAIA homozygotes or IAi heterozygotes.

2. Type B individuals add only galactose. They are ei-ther IBIB homozygotes or IBi heterozygotes.

3. Type AB individuals add both sugars and are IAIB het-erozygotes.

4. Type O individuals add neither sugar and are ii ho-mozygotes.

These four different cell surface phenotypes are calledthe ABO blood groups or, less commonly, the Land-steiner blood groups, after the man who first describedthem. As Landsteiner noted, a persons immune systemcan distinguish between these four phenotypes. If a type Aindividual receives a transfusion of type B blood, the recip-ients immune system recognizes that the type B bloodcells possess a foreign antigen (galactose) and attacks thedonated blood cells, causing the cells to clump, or aggluti-nate. This also happens if the donated blood is type AB.However, if the donated blood is type O, no immune at-tack will occur, as there are no galactose antigens on thesurfaces of blood cells produced by the type O donor. Ingeneral, any individuals immune system will tolerate atransfusion of type O blood. Because neither galactose norgalactosamine is foreign to type AB individuals (whose redblood cells have both sugars), those individuals may re-ceive any type of blood.

The Rh Blood Group

Another set of cell surface markers on human red bloodcells are the Rh blood group antigens, named for the rhe-sus monkey in which they were first described. About 85%of adult humans have the Rh cell surface marker on theirred blood cells, and are called Rh-positive. Rh-negativepersons lack this cell surface marker because they are ho-mozygous for the recessive gene encoding it.

If an Rh-negative person is exposed to Rh-positiveblood, the Rh surface antigens of that blood are treated likeforeign invaders by the Rh-negative persons immune sys-tem, which proceeds to make antibodies directed againstthe Rh antigens. This most commonly happens when anRh-negative woman gives birth to an Rh-positive child(whose father is Rh-positive). At birth, some fetal red bloodcells cross the placental barrier and enter the mothersbloodstream, where they induce the production of anti-Rh antibodies. In subsequent pregnancies, the mothersantibodies can cross back to the new fetus and cause its redblood cells to clump, leading to a potentially fatal conditioncalled erythroblastosis fetalis.

Many blood group genes possess multiple alleles,several of which may be common.


IAIA

IAIB

IAi

IAIA

IBIB

IBi

IAi

IBi

ii

IA

IA

or

IB

or

i

or IB or i

Possible alleles from female

Poss

ible

alle

les

from

mal

e

A AB BBlood types O

FIGURE 13.24Multiple alleles control the ABO blood groups. Differentcombinations of the three I gene alleles result in four differentblood type phenotypes: type A (either IAIA homozygotes or IAiheterozygotes), type B (either IBIB homozygotes or IBiheterozygotes), type AB (IAIB heterozygotes), and type O(ii homozygotes).

Patterns of Inheritance Can BeDeduced from PedigreesWhen a blood vessel ruptures, the blood in the immediatearea of the rupture forms a solid gel called a clot. The clotforms as a result of the polymerization of protein fibers cir-culating in the blood. A dozen proteins are involved in thisprocess, and all must function properly for a blood clot toform. A mutation causing any of these proteins to lose theiractivity leads to a form of hemophilia, a hereditary condi-tion in which the blood is slow to clot or does not clot at all.

Hemophilias are recessive disorders, expressed onlywhen an individual does not possess any copy of the nor-mal allele and so cannot produce one of the proteins nec-essary for clotting. Most of the genes that encode theblood-clotting proteins are on autosomes, but two (desig-nated VIII and IX) are on the X chromosome. These twogenes are sex-linked: any male who inherits a mutant alleleof either of the two genes will develop hemophilia becausehis other sex chromosome is a Y chromosome that lacksany alleles of those genes.

The most famous instance of hemophilia, often called theRoyal hemophilia, is a sex-linked form that arose in one ofthe parents of Queen Victoria of England (18191901; figure13.25). In the five generationssince Queen Victoria, 10 of hermale descendants have had he-mophilia. The present Britishroyal family has escaped thedisorder because Queen Victo-rias son, King Edward VII, didnot inherit the defective allele,and all the subsequent rulers ofEngland are his descendants.Three of Victorias nine chil-dren did receive the defectiveallele, however, and they car-ried it by marriage into manyof the other royal families ofEurope (figure 13.26), where itis still being passed to futuregenerationsexcept in Russia,where all of the five children ofVictorias granddaughterAlexandra were killed soonafter the Russian revolution in1917. (Speculation that onedaughter, Anastasia, survivedended in 1999 when DNAanalysis confirmed the identityof her remains.)

Family pedigrees canreveal the mode ofinheritance of a hereditarytrait.


FIGURE 13.25Queen Victoria of England, surrounded by some of herdescendants in 1894. Of Victorias four daughters who lived tobear children, two, Alice and Beatrice, were carriers of Royalhemophilia. Two of Alices daughters are standing behindVictoria (wearing feathered boas): Princess Irene of Prussia(right), and Alexandra (left), who would soon become Czarina ofRussia. Both Irene and Alexandra were also carriers ofhemophilia.

George III

EdwardDuke of Kent

Louis IIGrand Duke of Hesse

KingEdward VII

Duke ofWindsor

QueenElizabeth II

PrincePhilip

Margaret

PrincessDiana

PrinceCharles

Anne Andrew Edward

William Henry

KingGeorge VI

KingGeorge V

Earl ofMountbatten

ViscountTremation

Alfonso Jamie GonzaloPrinceSigismond

PrussianRoyalHouse

British Royal HouseSpanish Royal House

RussianRoyalHouse

Henry Anastasia Alexis? ?

? ?

? ?

?

Waldemar

Queen VictoriaPrince Albert

FrederickIII

I

II

III

IV

V

VI

VII

Gen

erat

ion

Victoria Alice Alfred Arthur Leopold Beatrice PrinceHenry

HelenaDuke ofHesse

No hemophilia No hemophiliaGermanRoyalHouse

Juan

King JuanCarlos

No evidenceof hemophilia

No evidenceof hemophilia

Irene CzarNicholas II

CzarinaAlexandra

Earl ofAthlone

PrincessAlice

QueenEugenie

AlfonsoKing ofSpain

Maurice Leopold

FIGURE 13.26The Royal hemophilia pedigree. Queen Victorias daughter Alice introduced hemophilia into theRussian and Austrian royal houses, and Victorias daughter Beatrice introduced it into the Spanishroyal house. Victorias son Leopold, himself a victim, also transmitted the disorder in a third line ofdescent. Half-shaded symbols represent carriers with one normal allele and one defective allele; fullyshaded symbols represent affected individuals.

Gene Disorders Can Be Due toSimple Alterations of ProteinsSickle cell anemia is a heritable disorder first noted inChicago in 1904. Afflicted individuals have defective mol-ecules of hemoglobin, the protein within red blood cellsthat carries oxygen. Consequently, these individuals areunable to properly transport oxygen to their tissues. Thedefective hemoglobin molecules stick to one another,forming stiff, rod-like structures and resulting in the for-mation of sickle-shaped red blood cells (figure 13.27). Asa result of their stiffness and irregular shape, these cellshave difficulty moving through the smallest blood vessels;they tend to accumulate in those vessels and form clots.People who have large proportions of sickle-shaped redblood cells tend to have intermittent illness and a short-ened life span.

The hemoglobin in the defective red blood cells dif-fers from that in normal red blood cells in only one ofhemoglobins 574 amino acid sub-units. In the defective hemoglobin,the amino acid valine replaces a glu-tamic acid at a single position in theprotein. Interestingly, the positionof the change is far from the activesite of hemoglobin where the iron-bearing heme group binds oxygen.Instead, the change occurs on theouter edge of the protein. Why thenis the result so catastrophic? Thesickle cell mutation puts a very non-polar amino acid on the surface ofthe hemoglobin protein, creating asticky patch that sticks to othersuch patchesnonpolar amino acidstend to associate with one another inpolar environments like water. Asone hemoglobin adheres to another,ever-longer chains of hemoglobinmolecules form.

Individuals heterozygous for thesickle cell allele are generally indis-tinguishable from normal persons.However, some of their red bloodcells show the sickling characteristicwhen they are exposed to low levelsof oxygen. The allele responsible forsickle cell anemia is particularlycommon among people of African descent; about 9% ofAfrican Americans are heterozygous for this allele, andabout 0.2% are homozygous and therefore have the dis-order. In some groups of people in Africa, up to 45% ofall individuals are heterozygous for this allele, and 6%are homozygous. What factors determine the high fre-quency of sickle cell anemia in Africa? It turns out thatheterozygosity for the sickle cell anemia allele increases

resistance to malaria, a common and serious disease incentral Africa (figure 13.28). We will discuss this situa-tion in detail in chapter 21.

Sickle cell anemia is caused by a single-nucleotidechange in the gene for hemoglobin, producing a proteinwith a nonpolar amino acid on its surface that tends tomake the molecules clump together.


FIGURE 13.27Sickle cell anemia. In individuals homozygous for the sickle celltrait, many of the red blood cells have sickle or irregular shapes,such as the cell on the far right.

Sickle cellallele in Africa

15%510%1020%

P. falciparummalaria in Africa

Malaria

FIGURE 13.28The sickle cell allele increases resistance to malaria. The distribution of sickle cellanemia closely matches the occurrence of malaria in central Africa. This is not acoincidence. The sickle cell allele, when heterozygous, increases resistance to malaria, avery serious disease.

Some Defects May Soon Be CurableSome of the most common and serious gene defects resultfrom single recessive mutations, including many of thedefects listed in table 13.2. Recent developments in genetechnology have raised the hope that this class of disor-ders may be curable. Perhaps the best example is cysticfibrosis (CF), the most common fatal genetic disorderamong Caucasians.

Cystic fibrosis is a fatal disease in which the body cellsof affected individuals secrete a thick mucus that clogs theairways of the lungs. These same secretions block theducts of the pancreas and liver so that the few patients whodo not die of lung disease die of liver failure. There is noknown cure.

Cystic fibrosis results from a defect in a single gene,called cf, that is passed down from parent to child. One in20 individuals possesses at least one copy of the defectivegene. Most carriers are not afflicted with the disease; onlythose children who inherit a copy of the defective genefrom each parent succumb to cystic fibrosisabout 1 in2500 infants.

The function of the cf gene has proven difficult to study.In 1985 the first clear clue was obtained. An investigator,Paul Quinton, seized on a commonly observed characteris-tic of cystic fibrosis patients, that their sweat is abnormallysalty, and performed the following experiment. He isolateda sweat duct from a small piece of skin and placed it in a so-lution of salt (NaCl) that was three times as concentrated asthe NaCl inside the duct. He then monitored the move-ment of ions. Diffusion tends to drive both the sodium(Na+) and the chloride (Cl) ions into the duct because ofthe higher outer ion concentrations. In skin isolated from

normal individuals, Na+ and Cl ions both entered the duct,as expected. In skin isolated from cystic fibrosis individuals,however, only Na+ ions entered the ductno Cl ions en-tered. For the first time, the molecular nature of cystic fi-brosis became clear. Cystic fibrosis is a defect in a plasmamembrane protein called CFTR (cystic fibrosis transmem-brane conductance regulator) that normally regulates pas-sage of Cl ions into and out of the bodys cells. CFTRdoes not function properly in cystic fibrosis patients (seefigure 4.8).

The defective cf gene was isolated in 1987, and its posi-tion on a particular human chromosome (chromosome 7)was pinpointed in 1989. In 1990 a working cf gene was suc-cessfully transferred via adenovirus into human lung cellsgrowing in tissue culture. The defective cells were cured,becoming able to transport chloride ions across theirplasma membranes. Then in 1991, a team of researcherssuccessfully transferred a normal human cf gene into thelung cells of a living animala rat. The cf gene was first in-serted into a cold virus that easily infects lung cells, and thevirus was inhaled by the rat. Carried piggyback, the cf geneentered the rat lung cells and began producing the normalhuman CFTR protein within these cells! Tests of genetransfer into CF patients were begun in 1993, and while agreat deal of work remains to be done (the initial experi-ments were not successful), the future for cystic fibrosis pa-tients for the first time seems bright.

Cystic fibrosis, and other genetic disorders, arepotentially curable if ways can be found to successfullyintroduce normal alleles of the genes into affectedindividuals.


Table 13.2 Some Important Genetic Disorders

Dominant/ Frequency among Disorder Symptom Defect Recessive Human Births

Cystic fibrosis

Sickle cell anemia

Tay-Sachs disease

Phenylketonuria

Hemophilia

Huntingtons disease

Muscular dystrophy (Duchenne)Hypercholesterolemia

Mucus clogs lungs, liver,and pancreasPoor blood circulation

Deterioration of centralnervous system in infancyBrain fails to develop ininfancyBlood fails to clot

Brain tissue graduallydeteriorates in middle ageMuscles waste away

Excessive cholesterol levelsin blood, leading to heartdisease

Failure of chloride iontransport mechanismAbnormal hemoglobinmoleculesDefective enzyme(hexosaminidase A)Defective enzyme(phenylalanine hydroxylase)Defective blood clotting factorVIIIProduction of an inhibitor ofbrain cell metabolismDegradation of myelin coatingof nerves stimulating musclesAbnormal form of cholesterolcell surface receptor

Recessive

Recessive

Recessive

Recessive

Sex-linkedrecessiveDominant

Sex-linkedrecessiveDominant

1/2500 (Caucasians)1/625 (African Americans)1/3500 (Ashkenazi Jews)1/12,000

1/10,000 (Caucasian males)1/24,000

1/3700 (males)1/500

Chromosomes: The Vehicles of Mendelian InheritanceChromosomes are not the only kinds of structures that seg-regate regularly when eukaryotic cells divide. Centriolesalso divide and segregate in a regular fashion, as do the mi-tochondria and chloroplasts (when present) in the cyto-plasm. Therefore, in the early twentieth century it was byno means obvious that chromosomes were the vehicles ofhereditary information.

The Chromosomal Theory of Inheritance

A central role for chromosomes in heredity was first sug-gested in 1900 by the German geneticist Karl Correns, inone of the papers announcing the rediscovery of Mendelswork. Soon after, observations that similar chromosomespaired with one another during meiosis led directly to thechromosomal theory of inheritance, first formulated bythe American Walter Sutton in 1902.

Several pieces of evidence supported Suttons theory. Onewas that reproduction involves the initial union of only twocells, egg and sperm. If Mendels model were correct, thenthese two gametes must make equal hereditary contribu-tions. Sperm, however, contain little cytoplasm, suggestingthat the hereditary material must reside within the nuclei ofthe gametes. Furthermore, while diploid individuals havetwo copies of each pair of homologous chromosomes, ga-metes have only one. This observation was consistent withMendels model, in which diploid individuals have twocopies of each heritable gene and gametes have one. Finally,chromosomes segregate during meiosis, and each pair of ho-mologues orients on the metaphase plate independently ofevery other pair. Segregation and independent assortmentwere two characteristics of the genes in Mendels model.

A Problem with the Chromosomal Theory

However, investigators soon pointed out one problem withthis theory. If Mendelian characters are determined bygenes located on the chromosomes, and if the independentassortment of Mendelian traits reflects the independent as-sortment of chromosomes in meiosis, why does the numberof characters that assort independently in a given kind oforganism often greatly exceed the number of chromosomepairs the organism possesses? This seemed a fatal objec-tion, and it led many early researchers to have seriousreservations about Suttons theory.

Morgans White-Eyed Fly

The essential correctness of the chromosomal theory ofheredity was demonstrated long before this paradox was re-

solved. A single small fly provided the proof. In 1910Thomas Hunt Morgan, studying the fruit fly Drosophilamelanogaster, detected a mutant male fly, one that differedstrikingly from normal flies of the same species: its eyeswere white instead of red (figure 13.29).

Morgan immediately set out to determine if this newtrait would be inherited in a Mendelian fashion. He firstcrossed the mutant male to a normal female to see if red orwhite eyes were dominant. All of the F1 progeny had redeyes, so Morgan concluded that red eye color was domi-nant over white. Following the experimental procedurethat Mendel had established long ago, Morgan thencrossed the red-eyed flies from the F1 generation with eachother. Of the 4252 F2 progeny Morgan examined, 782(18%) had white eyes. Although the ratio of red eyes towhite eyes in the F2 progeny was greater than 3:1, the re-sults of the cross nevertheless provided clear evidence thateye color segregates. However, there was something aboutthe outcome that was strange and totally unpredicted byMendels theoryall of the white-eyed F2 flies were males!

How could this result be explained? Perhaps it was im-possible for a white-eyed female fly to exist; such individu-als might not be viable for some unknown reason. To testthis idea, Morgan testcrossed the female F1 progeny withthe original white-eyed male. He obtained both white-eyedand red-eyed males and females in a 1:1:1:1 ratio, just asMendelian theory predicted. Hence, a female could havewhite eyes. Why, then, were there no white-eyed femalesamong the progeny of the original cross?


13.3 Genes are on chromosomes.

FIGURE 13.29Red-eyed (normal) and white-eyed (mutant) Drosophila. Thewhite-eyed defect is hereditary, the result of a mutation in a genelocated on the X chromosome. By studying this mutation,Morgan first demonstrated that genes are on chromosomes.

Sex Linkage

The solution to this puzzle involved sex. In Drosophila, thesex of an individual is determined by the number of copiesof a particular chromosome, the X chromosome, that anindividual possesses. A fly with two X chromosomes is a fe-male, and a fly with only one X chromosome is a male. Inmales, the single X chromosome pairs in meiosis with a dis-similar partner called the Y chromosome. The female thusproduces only X gametes, while the male produces both Xand Y gametes. When fertilization involves an X sperm, theresult is an XX zygote, which develops into a female; whenfertilization involves a Y sperm, the result is an XY zygote,which develops into a male.

The solution to Morgans puzzle is that the gene caus-ing the white-eye trait in Drosophila resides only on the Xchromosomeit is absent from the Y chromosome. (Wenow know that the Y chromosome in flies carries almostno functional genes.) A trait determined by a gene on theX chromosome is said to be sex-linked. Knowing the

white-eye trait is recessive to the red-eye trait, we cannow see that Morgans result was a natural consequenceof the Mendelian assortment of chromosomes (fig-ure 13.30).

Morgans experiment was one of the most important inthe history of genetics because it presented the first clearevidence that the genes determining Mendelian traits doindeed reside on the chromosomes, as Sutton had pro-posed. The segregation of the white-eye trait has a one-to-one correspondence with the segregation of the X chromo-some. In other words, Mendelian traits such as eye color inDrosophila assort independently because chromosomes do.When Mendel observed the segregation of alternative traitsin pea plants, he was observing a reflection of the meioticsegregation of chromosomes.

Mendelian traits assort independently because they aredetermined by genes located on chromosomes thatassort independently in meiosis.


Y chromosome X chromosome withwhite-eye gene

X chromosome withred-eye gene

FemaleMale

FemaleMale

FemalesMales

Parents

F1 generation

F2 generation

FIGURE 13.30Morgans experiment demonstratingthe chromosomal basis of sex linkagein Drosophila. The white-eyed mutantmale fly was crossed with a normalfemale. The F1 generation flies allexhibited red eyes, as expected for fliesheterozygous for a recessive white-eyeallele. In the F2 generation, all of thewhite-eyed flieswere male.

Genetic RecombinationMorgans experiments led to the gen-eral acceptance of Suttons chromoso-mal theory of inheritance. Scientiststhen attempted to resolve the paradoxthat there are many more indepen-dently assorting Mendelian genes thanchromosomes. In 1903 the Dutch ge-neticist Hugo de Vries suggested thatthis paradox could be resolved only byassuming that homologous chromo-somes exchange elements duringmeiosis. In 1909, French cytologistF. A. Janssens provided evidence tosupport this suggestion. Investigatingchiasmata produced during amphibianmeiosis, Janssens noticed that of thefour chromatids involved in each chi-asma, two crossed each other and twodid not. He suggested that this cross-ing of chromatids reflected a switch inchromosomal arms between the pater-nal and maternal homologues, involv-ing one chromatid in each homologue.His suggestion was not acceptedwidely, primarily because it was diffi-cult to see how two chromatids couldbreak and rejoin at exactly the sameposition.

Crossing Over

Later experiments clearly establishedthat Janssens was indeed correct. Oneof these experiments, performed in1931 by American geneticist CurtStern, is described in figure 13.31.Stern studied two sex-linked eye char-acters in Drosophila strains whose Xchromosomes were visibly abnormalat both ends. He first examined manyflies and identified those in which anexchange had occurred with respect tothe two eye characters. He then stud-ied the chromosomes of those flies to see if their X chro-mosomes had exchanged arms. Stern found that all of theindividuals that had exchanged eye traits also possessedchromosomes that had exchanged abnormal ends. Theconclusion was inescapable: genetic exchanges of charac-ters such as

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