Chapter 14

Mendel and the Gene Idea

Lecture Outline
Overview: Drawing from the Deck of Genes
Every day we observe heritable variations (such as brown, green, or blue eyes) among individuals in a population. o o o These traits are transmitted from parents to offspring. One possible explanation for heredity is a blending hypothesis. This hypothesis proposes that genetic material contributed by each parent mixes in a manner analogous to the way blue and yellow paints blend to ma!e green. "ith blending inheritance, a freely mating population would eventually give rise to a uniform population of individuals. Everyday observations and the results of breeding experiments tell us that heritable traits do not blend to become uniform.

#n alternative hypothesis, particulate inheritance, proposes that parents pass on discrete heritable units, genes, that retain their separate identities in offspring. o $enes can be sorted and passed on, generation after generation, in undiluted form. %odern genetics began in an abbey garden, where a mon! named $regor %endel documented a particulate mechanism of inheritance.

Concept 14.1 Mendel used the scientific approach to identif two laws of inheritance.
%endel discovered the basic principles of heredity by breeding garden peas in carefully planned experiments, carried out several decades before chromosomes were observed under the microscope.

Mendels Experimental, Quantitative Approach

%endel grew up on a small farm in what is today the &'ech (epublic. )n *+,-, %endel entered an #ugustinian monastery.

%endel studied at the .niversity of /ienna from *+0* to *+0-, where he was influenced by a physicist who encouraged experimentation and the application of mathematics to science and by a botanist who stimulated %endel1s interest in the causes of variation in plants. o These influences came together in %endel1s experiments. #fter university, %endel taught school and lived in the local monastery, where the mon!s had a long tradition of interest in the breeding of plants, including peas. #round *+02, %endel began breeding garden peas to study inheritance.
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6ea plants have several advantages for genetic study. 6ea plants are available in many varieties that have distinct heritable features, or characters! with different variant traits. 6eas have a short generation time7 each mating produces many offspring. %endel was able to strictly control the matings of his pea plants. Each pea plant has male (stamens) and female (carpal) sexual organs. )n nature, pea plants typically self8fertili'e, fertili'ing ova with the sperm nuclei from their own pollen. %endel could also use pollen from another plant for cross8pollination.

%endel trac!ed only those characters that varied in an either8or manner, rather than a more8or8less manner. o 9or example, he wor!ed with flowers that were either purple or white. o :e avoided traits such as seed weight, which varied on a continuum. o %endel started his experiments with varieties that were true"#reeding. "hen true8breeding plants self8pollinate, all their offspring have the same traits as their parents.

)n a typical breeding experiment, %endel would cross8pollinate $h #ridi%e& two contrasting, true8breeding pea varieties. o The true8breeding parents are the ' $parental& generation! and their hybrid offspring are the (1 $first filial& generation. %endel would then allow the 9* hybrids to self8pollinate to produce an () $second filial& generation. )t was mainly %endel1s ;uantitative analysis of 9< plants that revealed two fundamental principles of heredity= the law of segregation and the law of independent assortment.

The Law of Segregation

)f the blending hypothesis were correct, the 9* hybrids from a cross between purple8 flowered and white8flowered pea plants would have pale purple flowers. )nstead, the 9* hybrids all have purple flowers, >ust as purple as their purple8flowered parents. "hen %endel allowed the 9* plants to self8fertili'e, the 9< generation included both purple8flowered and white8flowered plants. o The white trait, absent in the 9* generation, reappeared in the 9<. o o %endel used very large sample si'es and !ept accurate records of his results. %endel recorded 2?0 purple8flowered 9< plants and <<, white8flowered 9< plants. This cross produced a ratio of three purple flowers to one white flower in the 9 < offspring.

%endel reasoned that the heritable factor for white flowers was present in the 9 * plants but did not affect flower color. o 6urple flower color is a dominant trait, and white flower color is a recessive trait. @ The reappearance of white8flowered plants in the 9 < generation indicated that the heritable factor for the white trait was not diluted or lost by coexisting with the purple8 flower factor in 9* hybrids.
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 %endel found similar -=* ratios of two traits in 9< offspring when he conducted crosses for six other characters, each represented by two different traits. @ o 9or example, when %endel crossed two true8breeding varieties, one producing round seeds and the other producing wrin!led seeds, all the 9 * offspring had round seeds. )n the 9< plants, 20A of the seeds were round and <0A were wrin!led.

%endel developed a hypothesis to explain these results that consisted of four related ideas. "e will explain each idea with the modern understanding of genes and chromosomes. *. #lternative versions of genes account for variations in inherited characters. o The gene for flower color in pea plants exists in two versions, one for purple flowers and one for white flowers. o These alternative versions of a gene are called alleles. o Each gene resides at a specific locus on a specific chromosome. o The BC# at that locus can vary in its se;uence of nucleotides. o The purple8flower and white8flower alleles are two BC# variations at the flower8color locus. <. 9or each character, an organism inherits two alleles, one from each parent. o # diploid organism inherits one set of chromosomes from each parent. o Each diploid organism has a pair of homologous chromosomes and, therefore, two copies of each gene. o These homologous loci may be identical, as in the true8breeding plants of the 6 generation. o #lternatively, the two alleles may differ, as in the 9 * hybrids. -. )f the two alleles at a locus differ, then one, the dominant allele, determines the organism1s appearance. The other, the recessive allele, has no noticeable effect on the organism1s appearance. o )n the flower8color example, the 9* plants inherited a purple8flower allele from one parent and a white8flower allele from the other. o The plants had purple flowers because the allele for that trait is dominant. ,. %endel1s law of segregation states that the two alleles for a heritable character segregate (separate) during gamete production and end up in different gametes. o This segregation of alleles corresponds to the distribution of homologous chromosomes to different gametes in meiosis. o )f an organism has two identical alleles for a particular character, then that allele is present as a single copy in all gametes. o )f different alleles are present, then 0?A of the gametes will receive one allele and 0?A will receive the other. %endel1s law of segregation accounts for the -=* ratio that he observed in the 9 < generation. The 9* hybrids produce two classes of gametes, half with the purple8flower allele and half with the white8flower allele. Buring self8pollination, the gametes of these two classes unite randomly to produce four
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e;ually li!ely combinations of sperm and ovum. # 'unnett s*uare may be used to predict the results of a genetic cross between individuals of !nown genotype. 9or the flower8color example, we can use a capital letter to symboli'e the dominant allele and a lowercase letter to symboli'e the recessive allele. o P is the purple8flower allele, and p is the white8flower allele. o o o "hat will be the physical appearance of the 9< offspringD One in four 9< offspring will inherit two white8flower alleles and produce white flowers. :alf of the 9< offspring will inherit one white8flower allele and one purple8flower allele and produce purple flowers. One in four 9< offspring will inherit two purple8flower alleles and produce purple flowers. %endel1s model accounts for the -=* ratio in the 9< generation.

+seful Genetic ,oca#ular #n organism with two identical alleles for a character is homo% gous for the gene controlling that character. @ #n organism with two different alleles for a gene is hetero% gous for that gene. #n organism1s observable traits are called its phenot pe. 6henotype refers to physiological traits as well as traits directly related to appearance.

#n organism1s genetic ma!eup is called its genot pe. Two organisms can have the same phenotype but different genotypes if one is homo'ygous dominant and the other is hetero'ygous. o PP and Pp plants have the same phenotype (purple flowers) but different genotypes (homo'ygous dominant and hetero'ygous).

9or flower color in peas, the only individuals with white flowers are those that are homo'ygous recessive (pp) for the flower8color gene. -he -estcross o o o :ow can we determine the genotype of an individual that has the dominant phenotypeD The organism must have one dominant allele but could be homo'ygous dominant or hetero'ygous. The answer is to carry out a testcross. The mystery individual is bred with a homo'ygous recessive individual. )f any of the offspring display the recessive phenotype, the mystery parent must be hetero'ygous.

The Law of ndependent Assortment

o %endel1s first experiments followed only a single character, such as flower color. #ll the 9* progeny produced in these crosses were monoh #rids! hetero'ygous for one character.
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# cross between two hetero'ygotes is a monohybrid cross.

%endel identified the second law of inheritance by following two characters at the same time. o o )n one such dih #rid cross! %endel studied the inheritance of seed color and seed shape. The allele for yellow seeds (Y) is dominant to the allele for green seeds (y). The allele for round seeds (R) is dominant to the allele for wrin!led seeds ( r).

%endel crossed true8breeding plants that had yellow, round seeds ( YYRR) with true8 breeding plants that had green, wrin!led seeds (yyrr). The 9* plants are dih #rid individuals that are hetero'ygous for two characters ( YyRr). One possible hypothesis is that the two characters are transmitted from parents to offspring as a pac!age. o )n this case, the Y and R alleles and the y and r alleles would stay together. @ @ o )f this were the case, the 9* offspring would produce yellow, round seeds. The 9< offspring would produce two phenotypes (yellow E round7 green E wrin!led) in a -=* ratio, >ust li!e a monohybrid cross. This was not consistent with %endel1s results.

#n alternative hypothesis is that the two pairs of alleles segregate independently of each other. o The presence of a specific allele for one trait in a gamete has no impact on the presence of a specific allele for the second trait. @ @ @ @ @ @ )n our example, the 9* offspring would still produce yellow, round seeds. "hen the 9* offspring produced gametes, genes would be pac!aged into gametes with all possible allelic combinations. 9our classes of gametes (YR, Yr, yR, and yr) would be produced in e;ual amounts. "hen sperm with four classes of alleles and ova with four classes of alleles combine, there are *F e;ually probable ways in which the alleles can combine in the 9 < generation. These combinations produce four distinct phenotypes in a G=-=-=* ratio. This was consistent with %endel1s experimental results.

%endel repeated the dihybrid cross experiment for other pairs of characters and always observed a G=-=-=* phenotypic ratio in the 9< generation. @ @ Each character appeared to be inherited independently. )f you follow >ust one character in these crosses, you will observe a -=* 9 < ratio, >ust as if this were a monohybrid cross.

The independent assortment of each pair of alleles during gamete formation is called %endel1s law of independent assortment: Each pair of alleles segregates independently during gamete formation. Htrictly spea!ing, this law applies only to genes located on different, nonhomologous chromosomes. o $enes located near each other on the same chromosome tend to be inherited together and have more complex inheritance patterns than those predicted for the law of independent assortment.
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Concept 14.) -he laws of pro#a#ilit govern Mendelian inheritance.

%endel1s laws of segregation and independent assortment reflect the same laws of probability that apply to tossing coins or rolling dice. /alues of probability range from ? (an event with no chance of occurring) to * (an event that is certain to occur). o The probability of tossing heads with a normal coin is *4<. o The probability of rolling a - with a six8sided die is *4F, and the probability of rolling any other number is * I *4F J 04F. The outcome of one coin toss has no impact on the outcome of the next toss. Each toss is an independent event, >ust li!e the distribution of alleles into gametes. o 3i!e a coin toss, each ovum from a hetero'ygous parent has a *4< chance of carrying the dominant allele and a *4< chance of carrying the recessive allele. o The same probabilities apply to the sperm. "e can use the multiplication rule to determine the probability that two or more independent events will occur together in some specific combination. o &ompute the probability of each independent event. o %ultiply the individual probabilities to obtain the overall probability of these events occurring together. o The probability that two coins tossed at the same time will both land heads up is *4< K *4< J *4,. o Himilarly, the probability that a hetero'ygous pea plant ( Pp) will self8fertili'e to produce a white8flowered offspring (pp) is the probability that a sperm with a white allele will fertili'e an ovum with a white allele. This probability is *4< K *4< J *4,. "e can use the addition rule to determine the probability that an 9< plant from a monohybrid cross will be hetero'ygous rather than homo'ygous. @ @ @ @ o o o The probability of an event that can occur in two or more different ways is the sum of the individual probabilities of those ways. The probability of obtaining an 9< hetero'ygote by combining the dominant allele from the egg and the recessive allele from the sperm is *L,. The probability of combining the recessive allele from the egg and the dominant allele from the sperm also *L,. .sing the rule of addition, we can calculate the probability of an 9 < hetero'ygote as *L, E *L, J *L<. The rule of multiplication applies to dihybrid crosses. 9or a hetero'ygous parent (YyRr), the probability of producing a YR gamete is *4< K *4< J *4,. "e can now predict the probability of a particular 9< genotype without constructing a *F8 part 6unnett s;uare. The probability that an 9< plant from hetero'ygous parents will have a YYRR genotype is *4*F (*4, chance for a YR ovum K *4, chance for a YR sperm).

"e can combine the rules of multiplication and addition to solve complex problems in %endelian genetics. 3et1s determine the probability of an offspring having two recessive phenotypes for at least two of three traits resulting from a trihybrid cross between pea plants that are PpYyRr and Ppyyrr.
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o o

9ive possible genotypes result in this condition= ppyyRr, ppYyrr, Ppyyrr, PPyyrr, and ppyyrr. "e can use the rule of multiplication to calculate the probability for each of these genotypes and then use the rule of addition to pool the probabilities for finding at least two recessive traits. The probability of producing a ppyyRr offspring= The probability of producing pp J *4< K *4< J *4,. The probability of producing yy J *4< K * J *4<. The probability of producing Rr J *4< K * J *4<. Therefore, the probability of all three being present ( ppyyRr) in one offspring is *4, K *4< K *4< J *4*F. 9or ppYyrr= *4, K *4< K *4< J *4*F. 9or Ppyyrr= *4< K *4< K *4< J *4+ or <4*F. 9or PPyyrr= *4, K *4< K *4< J *4*F. 9or ppyyrr= *4, K *4< K *4< J *4*F. Therefore, the chance that a given offspring will have at least two recessive traits is *4*F E *4*F E <4*F E *4*F E *4*F J F4*F.

o o o o o

#lthough we cannot predict with certainty the genotype or phenotype of any particular seed from the 9< generation of a dihybrid cross, we can predict the probability that it will have a specific genotype or phenotype. %endel1s experiments succeeded because he counted so many offspring, was able to discern the statistical nature of inheritance, and had a !een sense of the rules of chance. %endel1s laws of independent assortment and segregation explain heritable variation in terms of alternative forms of genes that are passed along according to simple rules of probability. These laws apply not only to garden peas but to all diploid organisms that reproduce by sexual reproduction. %endel1s studies of pea inheritance are a model not only in genetics but also as a case study of the power of scientific reasoning using the hypothetico8deductive approach.

Concept 14.. Inheritance patterns are often more comple/ than predicted # simple Mendelian genetics.
)n the <?th century, geneticists extended %endelian principles both to diverse organisms and to patterns of inheritance more complex than %endel described. )n fact, %endel had the good fortune to choose a system that was relatively simple genetically. o Each character that %endel studied is controlled by a single gene. o Each gene has only two alleles, one of which is completely dominant to the other. @ The hetero'ygous 9* offspring of %endel1s crosses always loo!ed li!e one of the parental varieties because one allele was dominant to the other. The relationship between genotype and phenotype is rarely so simple.
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Extending Mendelian !enetics for a Single !ene

The inheritance of characters determined by a single gene deviates from simple %endelian patterns when alleles are not completely dominant or recessive, when a gene has more than two alleles, or when a gene produces multiple phenotypes. "e will consider each of these situations.

Degrees of Dominance #lleles show different degrees of dominance and recessiveness in relation to each other. One extreme is the complete dominance characteristic of %endel1s crosses.

Home alleles show incomplete dominance! in which hetero'ygotes show a distinct intermediate phenotype not seen in homo'ygotes. o This is not blending inheritance because the traits are separable (particulate), as shown in further crosses. o Offspring of a cross between hetero'ygotes show three phenotypes= each parental phenotype and the hetero'ygous phenotype. o The phenotypic and genotypic ratios are identical= *=<=*. o o # clear example of incomplete dominance is the flower color of snapdragons. # cross between a white8flowered plant and a red8flowered plant produces all pin! 9 * offspring. Helf8pollination of the 9* offspring produces <0A white, <0A red, and 0?A pin! 9< offspring.

#t the other extreme from complete dominance is codominance! in which two alleles affect the phenotype in separate, distinguishable ways. o 9or example, the %, C, and %C blood groups of humans are due to the presence of two specific molecules on the surface of red blood cells. o 6eople of group % (genotype MM) have one type of molecule on their red blood cells, people of group C (genotype NN) have the other type, and people of group MN (genotype MN) have both molecules present. o The MN phenotype is not intermediate between % and C phenotypes but rather exhibits both the % and the C phenotype. The relative effects of two alleles range from complete dominance of one allele, through incomplete dominance of either allele, to codominance of both alleles. )t is important to recogni'e that a dominant allele does not somehow subdue a recessive allele. @ o #lleles are simply variations in a gene1s nucleotide se;uence. "hen a dominant allele coexists with a recessive allele in a hetero'ygote, they do not interact at all.

To illustrate the relationship between dominance and phenotype, let1s consider %endel1s character of round versus wrin!led pea seed shape. o The dominant allele (round) codes for an en'yme that helps convert an unbranched form of starch to a branched form in the seed. o The recessive allele (wrin!led) codes for a defective form of this en'yme that leads to an accumulation of unbranched starch. Excess water is then drawn into the seed due to osmosis.
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The seeds wrin!le when the excess water dries. Moth homo'ygous dominant and hetero'ygous pea plants produce enough en'ymes to synthesi'e ade;uate amounts of branched starch. #s a result, they do not fill with excess water and they form smooth seeds as they dry.

9or any character, dominance4recessiveness relationships depend on the level at which we examine the phenotype. o 9or example, humans with -a "0achs disease lac! a functioning en'yme to metaboli'e certain lipids. o These lipids accumulate in the brain, harming brain cells and ultimately leading to death. o &hildren with two Tay8Hachs alleles (homo'ygotes) have the disease. o Moth hetero'ygotes, with one allele coding for a functional en'yme, and homo'ygotes, with two such alleles, are healthy and normal. #t the organismal level, the allele for the functional en'yme is dominant to the Tay8 Hachs allele. o The activity level of the lipid8metaboli'ing en'yme is reduced in hetero'ygotes. #t the biochemical level, the alleles show incomplete dominance. o :etero'ygous individuals produce e;ual numbers of normal and dysfunctional en'yme molecules. #t the molecular level, the Tay8Hachs and functional alleles are codominant. # dominant allele is not necessarily more common in a population than the recessive allele. o 9or example, one baby in ,?? is born with polydactyly, a condition in which individuals are born with extra fingers or toes. o 6olydactyly is due to a dominant allele. &learly, however, the recessive allele is far more prevalent than the dominant allele. Multiple 1lleles o o %any genes exist in populations in more than two allelic forms. The #MO blood groups in humans are determined by three alleles= I , IB, and i. Moth the I and IB alleles are dominant to the i allele. The I and IB alleles are codominant to each other.

Mecause each individual carries two alleles, there are six possible genotypes and four possible blood types. o )ndividuals who are I I or I i are type # and have type # carbohydrates on the surface of their red blood cells. o )ndividuals who are IBIB or IBi are type M and have type M carbohydrates on the surface of their red blood cells. o )ndividuals who are I IB are type #M and have both type # and type M carbohydrates on the surface of their red blood cells. o )ndividuals who are ii are type O and have neither carbohydrate on the surface of their red blood cells. %atching compatible blood groups is critical for blood transfusions because a person produces antibodies against foreign blood factors. o )f the donor1s blood has an # or M carbohydrate that is foreign to the recipient, then
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antibodies in the recipient1s blood will bind to the foreign molecules, cause the donated blood cells to clump together, and can !ill the recipient. 'leiotrop o The genes that we have covered so far affect only one phenotypic character. %ost genes are pleiotropic! affecting more than one phenotypic character. 9or example, the wide8ranging symptoms of sic!le8cell disease are due to a single gene.

&onsidering the intricate molecular and cellular interactions responsible for an organism1s development, it is not surprising that a gene can affect a number of characteristics.

Extending Mendelian !enetics for Two or More !enes

Epistasis and polygenic inheritance are situations in which two or more genes are involved in determining phenotype. )n epistasis! a gene at one locus alters the phenotypic expression of a gene at a second locus. o 9or example, in mice and many other mammals, coat color depends on two genes. o One, the epistatic gene, determines whether pigment is deposited in hair. 6resence (!) is dominant to absence (c) of pigment. o The second gene determines whether the pigment to be deposited is blac! or brown. The blac! allele (B) is dominant to the brown allele (b). o #n individual that is cc has a white (albino) coat regardless of the genotype of the second gene. o The gene for pigment deposition is said to be epistatic to the gene for pigment color. # cross between two blac! mice that are hetero'ygous ( Bb!c) follows the law of independent assortment. .nli!e the G=-=-=* offspring ratio of a normal %endelian experiment, however, the offspring ratio is nine blac!, three brown, and four white. #ll cc mice are albino, regardless of the alleles they inherit at the M gene. Home characters cannot be classified as either8or, as %endel1s genes were. 2uantitative characters vary in a population along a continuum.

Nuantitative characters are usually due to pol genic inheritance! the additive effects of two or more genes on a single phenotypic character. o 9or example, s!in color in humans is controlled by at least three independent genes. o )magine that each gene has two alleles, one light and one dar!, that demonstrate incomplete dominance. o #n BB!! individual is very dar!7 an aabbcc individual is very light. # cross between two aBb!c individuals (with intermediate s!in shade) produces offspring with a wide range of shades. o )ndividuals with intermediate s!in shades are most common, but some very light and very dar! individuals may be produced as well. o The range of phenotypes forms a normal distribution if the number of offspring is great enough.
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Environmental factors, such as sun exposure, also affect s!in color and contribute to a smooth normal distribution.

"ature and "urture# The Environmental mpact on $henot%pe

o o o 6henotype depends on both environment and genes. # single tree may have leaves that vary in si'e, shape, and greenness, depending on exposure to wind and sun. 9or humans, nutrition influences height, exercise alters build, sun8tanning dar!ens s!in, and experience improves performance on intelligence tests. Even identical twins, who are genetically identical, accumulate phenotypic differences as a result of their uni;ue experiences.

The relative importance of genes and the environment in influencing human characteristics is a very old and hotly contested debate. The product of a genotype is generally not a rigidly defined phenotype, but a range of phenotypic possibilities, the norm of reaction! determined by the environment. o )n some cases, the norm of reaction has no breadth, and a given genotype specifies a particular phenotype (for example, blood type). o )n contrast, a person1s red and white blood cell count varies with factors such as altitude, customary amount of exercise, and presence of infection. o Corms of reaction are broadest for polygenic characters. 9or these multifactorial characters, genes and environment influence phenotype.

ntegrating a Mendelian &iew of 'eredit% and &ariation

# reductionist emphasis on single genes and single phenotypic characters presents an inade;uate perspective on heredity and variation. # more comprehensive theory of %endelian genetics views organisms as a whole. The term phenotype can refer not only to specific characters such as flower color or blood group, but also to an organism in its entirety, including all aspects of its physical appearance, internal anatomy, physiology, and behavior. "enotype can refer not only to a single genetic locus but also to an organism1s entire genetic ma!eup. #n organism1s phenotype reflects its overall genotype and its uni;ue environmental history.

Concept 14.4 Man human traits follow Mendelian patterns of inheritance.

o "hereas peas are convenient sub>ects for genetic research, humans are not. The human generation time is too long, their fecundity is too low, and breeding experiments are unacceptable. Oet, humans are sub>ect to the same rules governing inheritance as other organisms.

Cew techni;ues in molecular biology have led to many brea!through discoveries in the study of human genetics. )n pedigree analysis, rather than manipulate mating patterns of people, geneticists
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analy'e the results of matings that have already occurred. )nformation about the presence or absence of a particular phenotypic trait is collected from as many individuals in a family as possible, across generations. o o o o The distribution of these characters is then mapped on the family tree. 9or example, the occurrence of a widow1s pea! ( #) is dominant to a straight hairline (w). 6henotypes of family members and !nowledge of dominance4recessiveness relationships between alleles allow researchers to predict the genotypes of members of this family. 9or example, if an individual in the third generation lac!s a widow1s pea! but both her parents have widow1s pea!s, then her parents must be hetero'ygous for that gene. )f some siblings in the second generation lac! a widow1s pea! and one of the grandparents (first generation) also lac!s one, then we !now the other grandparent must be hetero'ygous, and we can determine the genotype of many other individuals.

"e can use the same family tree to trace the distribution of attached earlobes ($), a recessive characteristic. )ndividuals with a dominant allele ( %) have free earlobes. Home individuals may be ambiguous, especially if they have the dominant phenotype and could be hetero'ygous or homo'ygous dominant. # pedigree can help us understand the past and predict the future. "e can use normal %endelian rules, including the multiplication and addition rules of probability, to predict the probabilities of specific phenotypes. o 9or example, the multiplication rule can be used to predict the probability that a child with #w%$ parents will have a widow1s pea! and attached earlobes. The probability of having a widow1s pea! is -4,. The probability of having attached earlobes is *4,. This combination has a probability of -4, K *4, J -4*F.

(ecessivel% nherited )isorders

Thousands of genetic disorders, including disabling or deadly hereditary diseases, are inherited as simple recessive traits. o These conditions range from relatively mild (albinism) to life8threatening (cystic fibrosis). 1l#inism #n allele that causes a recessive condition such as albinism codes for a malfunctioning protein or for no protein at all. :etero'ygotes have a normal phenotype because one normal allele produces enough of the re;uired protein. #lbinism shows up only in homo'ygous individuals who inherit a recessive allele from each parent. )ndividuals who do not have the disorder are either homo'ygous dominant or hetero'ygotes. #lthough hetero'ygotes may lac! obvious phenotypic effects, they are carriers who may transmit a recessive allele to their offspring.
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%ost people with recessive disorders are born to carriers with normal phenotypes. )n a mating between two carriers of albinism, each child has a *4, chance of inheriting the disorder, a *4< chance of being a carrier, and a *4, chance of being homo'ygous dominant. $enetic disorders are not evenly distributed among all groups of humans. This is due to the different genetic histories of the world1s people during times when populations were more geographically and genetically isolated.

Cormally, it is relatively unli!ely that two carriers of the same rare, harmful allele will meet and mate. o o &onsanguineous matings between close relatives increase the ris!. )ndividuals who share a recent common ancestor are more li!ely to carry the same recessive alleles. $eneticists disagree about the extent to which human consanguinity increases the ris! of inherited diseases.

%ost societies and cultures have laws or taboos forbidding marriages between close relatives. C stic (i#rosis o o C stic fi#rosis stri!es one of every <,0?? whites of European descent. One in <0 people (,A) of European descent is a carrier for this condition. The normal allele at this gene codes for a membrane protein that transports chloride between cells and extracellular fluid. o )f these channels are defective or absent, abnormally high extracellular levels of chloride accumulate. o Then the mucous coats of certain cells become thic!er and stic!ier than normal. o This mucous buildup in the pancreas, lungs, digestive tract, and elsewhere causes poor absorption of nutrients, chronic bronchitis, and bacterial infections. o The extracellular chloride also contributes to infection by disabling a natural antibiotic made by some body cells. "ithout treatment, affected children die before age 0, but with treatment, they can live past their late <?s or even -?s. 0ickle"Cell Disease The most common inherited disease among people of #frican descent is sickle"cell disease! which affects one of ,?? #frican8#mericans. o Hic!le8cell disease is caused by the substitution of a single amino acid in hemoglobin. o "hen oxygen levels in the blood of an affected individual are low, sic!le8cell hemoglobin aggregates into long rods that deform red blood cells into a sic!le shape. o This sic!ling creates a cascade of symptoms, demonstrating the pleiotropic effects of this allele, as sic!led cells clump and clog capillaries throughout the body. Boctors can use regular blood transfusions to prevent brain damage and new drugs to prevent or treat other problems. #t the organismal level, the nonsic!le allele is incompletely dominant to the sic!le8cell allele.
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&arriers are said to have sic&le-cell trait. These individuals are usually healthy, although some may suffer symptoms of sic!le8cell disease under blood8oxygen stress.

#t the molecular level, the two alleles are codominant because both normal and abnormal (sic!le8cell) hemoglobin molecules are synthesi'ed. o #bout one in ten #frican8#mericans has sic!le8cell trait. The high fre;uency of hetero'ygotes is unusual for an allele with severe detrimental effects in homo'ygotes. )ndividuals with one sic!le8cell allele have increased resistance to the malaria parasite, which spends part of its life cycle in red blood cells. o )n tropical #frica, where malaria is common, the sic!le8cell allele is both a boon and a bane. @ :omo'ygous normal individuals die of malaria and homo'ygous recessive individuals die of sic!le8cell disease, while carriers are relatively free of both. The relatively high fre;uency of sic!le8cell trait in #frican8#mericans is a vestige of their #frican roots.

)ominantl% nherited )isorders

#lthough most harmful alleles are recessive, a number of human disorders are due to dominant alleles. 1chondroplasia o o o o o chondroplasia' a form of dwarfism, has a prevalence of one case in <0,??? people. :etero'ygous individuals have the dwarf phenotype. The GG.GGA of the population who are not achondroplastic dwarfs are homo'ygous recessive for this trait. #chondroplasia is another example of a trait for which the recessive allele is far more prevalent than the dominant allele. 3ethal dominant alleles are much less common than lethal recessive alleles. )f a lethal dominant allele !ills an offspring before he or she can mature and reproduce, the allele will not be passed on to future generations. )n contrast, a lethal recessive allele can be passed on by hetero'ygous carriers who have normal phenotypes. 3untington4s Disease # lethal dominant allele can escape elimination if it causes death at a relatively advanced age, after the individual has already passed on the lethal allele to his or her children. o o One example is 3untington4s disease! a degenerative disease of the nervous system. The dominant lethal allele has no obvious phenotypic effect until the individual is about -0 to ,0 years old. Then the deterioration of the nervous system is irreversible and inevitably fatal.

#ny child born to a parent who has the allele for :untington1s disease has a 0?A chance of inheriting the disease and the disorder.
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)n the .nited Htates, this devastating disease afflicts one in *?,??? people.

(ecently, molecular geneticists have used pedigree analysis of affected families to trac! the :untington1s allele to a locus near the tip of chromosome ,. o The gene has now been se;uenced. o This has led to the development of a test that can detect the presence of the :untington1s allele in an individual1s genome.

Multifactorial )isorders
"hile some diseases are inherited in a simple %endelian fashion due to alleles at a single locus, many other disorders have a multifactorial basis. o Huch disorders have a genetic component plus a significant environmental influence. o %ultifactorial disorders include heart disease, diabetes, cancer, alcoholism, and certain mental illnesses, such as schi'ophrenia and manic8depressive disorder. o The genetic component of such disorders is typically polygenic. #t present, little is understood about the genetic contribution to most multifactorial diseases. o The best public health strategy is education about relevant environmental factors and promotion of healthy behavior.

!enetic Testing and *ounseling

# preventive approach to simple %endelian disorders is sometimes possible. The ris! that a particular genetic disorder will occur can sometimes be assessed before a child is conceived or early in pregnancy. %any hospitals have genetic counselors to provide information to prospective parents who are concerned about a family history of a specific disease. Counseling 5ased on Mendelian Genetics and 'ro#a#ilit 6ules &onsider a hypothetical couple, Pohn and &arol, who are planning to have their first child. o o o o o o o Moth Pohn and &arol had brothers who died of the same recessive disease. Pohn, &arol, and their parents do not have the disease. Their parents must have been carriers ( a K a). Pohn and &arol each have a <4- chance of being carriers and a *4- chance of being homo'ygous dominant. The probability that their first child will have the disease is <4- (chance that Pohn is a carrier) K <4- (chance that &arol is a carrier) K *4, (chance that the offspring of two carriers is homo'ygous recessive) J *4G. )f their first child is born with the disease, we !now that Pohn and &arol1s genotype must be a and they are both carriers. )n that case, the chance that their next child will also have the disease is *4,. %endel1s laws are simply the rules of probability applied to heredity. Mecause chance has no memory, the genotype of each child is unaffected by the genotypes of older siblings.
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The chance that Pohn and &arol1s first three children will have the disorder is *4, K *4, K *4, J *4F,. Hhould that outcome happen, the li!elihood that a fourth child will also have the disorder is still *4,. -ests for Identif ing Carriers

Mecause most children with recessive disorders are born to parents with a normal phenotype, the !ey to assessing ris! is identifying whether prospective parents are hetero'ygous carriers of the recessive trait. (ecently developed tests for many disorders can distinguish normal phenotypes in hetero'ygotes from homo'ygous dominants. o These results allow individuals with a family history of a genetic disorder to ma!e informed decisions about having children. o )ssues of confidentiality, discrimination, and counseling may arise. (etal -esting Tests are available to determine in utero whether a child has a particular disorder. One techni;ue, amniocentesis! can be used from the *,th to *Fth wee! of pregnancy to assess whether the fetus has a specific disease. o 9etal cells extracted from amniotic fluid are cultured and !aryotyped to identify some disorders. o Other disorders can be identified from chemicals in the amniotic fluids. # second techni;ue, chorionic villus sampling $C,0&! allows faster !aryotyping and can be performed as early as the eighth to tenth wee! of pregnancy. o # sample of fetal tissue is extracted from the chorionic villi of the placenta. o This techni;ue is not suitable for tests that re;uire amniotic fluid. (ecently, techni;ues have been developed for isolating and culturing fetal cells from the mother1s blood. Other techni;ues, ultrasound and $etoscopy' allow fetal health to be assessed visually in utero. o .ltrasound uses sound waves to produce an image of the fetus. o )n fetoscopy, a needle8thin tube containing fiber optics and a viewing scope is inserted into the uterus. o Moth fetoscopy and amniocentesis cause complications such as maternal bleeding or fetal death in about *A of cases. o Therefore, these techni;ues are usually reserved for cases in which the ris! of a genetic disorder or other type of birth defect is relatively great. )f fetal tests reveal a serious disorder, the parents face the difficult choice of terminating the pregnancy or preparing to care for a child with a genetic disorder. 7ew#orn 0creening Home genetic traits can be detected at birth by simple tests that are now routinely performed in hospitals.
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One test can detect the presence of a recessively inherited disorder, phenyl!etonuria
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(6Q.). o This disorder occurs in one in *?,??? to *0,??? births. o )ndividuals with this disorder accumulate the amino acid phenylalanine and its derivative phenylpyruvate in the blood to toxic levels, which leads to mental retardation. o )f the disorder is detected, a special diet low in phenylalanine usually promotes normal development. .nfortunately, few other genetic diseases are so treatable.

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