This document discusses pedigree analysis in humans. It explains that pedigree analysis involves tracing traits or disorders through family trees to determine patterns of inheritance. The document outlines different patterns seen in pedigrees for autosomal recessive disorders, autosomal dominant disorders, X-linked recessive disorders, and X-linked dominant disorders. It also provides examples like phenylketonuria (PKU), achondroplasia, hemophilia, and testicular feminization syndrome. The document notes that while Mendelian ratios are not always seen in single families due to small sample sizes, pedigree analysis can still reveal inheritance patterns.

1. pedigreeAnalysis
In humans, controlledcrosses cannot be made, so geneticists must resort toscrutinizingfamilyrecords in the hope that informativematings have
been made that canbe usedto deduce dominanceanddistinguish autosomal fromX-linkedinheritance.The investigator traces the historyof
some variant phenotype back through thehistory ofthe familyanddraws up a family tree,or pedigree, usingthestandardsymbols given
in Figure 4-17. The clues in thepedigree havetobe interpreteddifferently dependingonwhetheroneof the contrastingphenotypes is a rare
disorder or whether bothphenotypes of a pair arecommonmorphs of a polymorphism. The geneticdisorders of humanbeings can be dominant
or recessive phenotypes andcanbe eitherautosomal orX-linked. The four categories are discussedin the followingsections.
Figure 4-17
Symbols used in human pedigree analysis.(AfterW. F. BodmerandL. L. Cavalli-Sforza,Genetics, Evolution,andMan.Copyright ©1976by W.
H. Freeman andCompany.)
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Autosomal Recessive Disorders
The unusual phenotype ofa recessivedisorder is determinedby homozygosityfor a recessive allele, andtheunaffectedphenotype is determined
by the corresponding dominant allele. InChapter 3 we sawthat phenylketonuria (PKU) is a recessive phenotype.PKUis determinedby an allele
that we can call p, andthe normal conditionby P. Therefore, sufferers of this disease are of genotype p/p, andunaffectedpeople are
either P/P or P/p. What patterns in a pedigree wouldreveal such an inheritance? Two keypoints are that generallythe disease appears in the
progeny of unaffectedparents andthat the affectedprogeny include both males andfemales equally. Whenwe knowthat both male andfemale
phenotypicproportions are equal, we can assume that we are dealingwith autosomal inheritance, not X-linkedinheritance.Thefollowingtypical
pedigree illustrates the key point that affectedchildren areborn to unaffectedparents:
From this pattern we can immediatelydeduce autosomal inheritance,with the recessiveallele responsible for the
exceptional phenotype(indicatedby shading). Furthermore, we can deduce that the parents must bothbe heterozygotes, P/p. (Both must have
a p allele because each contributedone toeach affectedchild, andbothmust havea P allele because the people are phenotypically normal.) We
can identify thegenotypes of the children(in theorder shown) as P/–,p/p,p/p,andP/–. Hence,the pedigreecan be rewritten
Notice anotherinterestingfeature of pedigree analysis: eventhough Mendelian rules are at work,Mendelian ratios are rarelyobservedin single
families because the samplesizes are too small.In the above example,we see a 1:1 phenotypicratio in theprogenyofwhat is clearly
a monohybridcross, in which we might expect a 3:1ratio.If the couple were tohave, say,20 children, the ratio wouldundoubtedly be something
like 15 unaffectedchildren and5 with PKU(the expectedmonohybrid3:1ratio), but in a sampleof fourany ratio is possible andall ratios are
commonly found.
In the case of a rare recessive allele, in the populationmost of these alleles will be foundin heterozygotes, not in homozygotes. Thereasonis a
matterof probability: toconceive a recessive homozygote, both parents must havehadthep allele, but toconceive a heterozygote all that is
necessary is one parent withthe allele.The formationof an affectedindividual usually depends on the chance unionof unrelatedheterozygotes,
andfor this reasonthe pedigrees of autosomalrecessives lookrather bare,generally withonlysiblings of one cross affected.
Inbreeding(matingbetweenrelatives) increases the chancethat a matingwill be between two heterozygotes.An example ofa cousin marriage is
shown in Figure 4-18. Individuals III-5andIII-6are first cousins andproduce two children. Youcansee fromthe figure that anancestor who is
a heterozygote may produce manydescendants who are also heterozygotes.Matings betweenrelatives thus run a higher riskof producing
abnormal homozygous recessives thando matings between nonrelatives. It is for this reason that first cousin marriages are responsible for a large
portion ofrecessive diseases in humanpopulations.

2. Figure 4-18
Pedigree of a rare recessivephenotypedeterminedby a recessive allelea.Gene symbols normallyare not includedin pedigree charts, but
genotypes are insertedherefor reference. Note that individuals II-1andII-5marry intothe family; theyare assumed (more...)
Albinism (Figure 4-19) is another rareconditionthat is inheritedin a Mendelianmanner as an autosomal recessivephenotypein many animals,
includinghumans. The striking“white” phenotypeis causedby a defect in an enzymethat synthesizes melanin, the pigment responsible for most
black andbrown colorationof animals. In humans, such colorationis most evident in hair, skin, andretina,andits absence in albinos (who have
the homozygous recessive genotype a/a) leads towhite hair, white skin, andeye pupils that are pinkbecause of the unmaskingof the red
hemoglobin pigment in bloodvessels in the retina. The inheritance andmolecular genetics of albinismare integratedin Figure 4-20.
Figure 4-19
An albino. Thephenotypeis causedby homo-zygosityfora recessiveallele, say,a/a. The dominant alleleAdetermines one step inthe chemical
synthesis of thedark pigment melanin in thecells of skin,hair,andeye retinas. In a/aindividuals this step (more...)
Figure 4-20
Genetics andthe molecularbiology ofalbinism.In the pedigree, parents heterozygous for the recessivealbinism allele produce three A/–
progeny, who havemelanin in their cells, andone a/amale, who is albino. Thethreepanels at thebottomof (more...)
MESSAGE
In pedigrees, an autosomal recessive disorderis revealed by the appearance ofthe phenotype in the male and female progenyof
unaffected individuals.
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Autosomal DominantDisorders
In autosomal dominant disorders, the normal allele is recessive andthe abnormal alleleis dominant. It might seemparadoxical that a rare disorder
can be dominant,but rememberthat dominance andrecessiveness are simplyreflections ofhowalleles act andare not defined in terms
of predominance in thepopulation.An example ofa rare autosomal dominant phenotype is achondroplasia,a type ofdwarfism (see Figure 4-21).
In this case, people withnormal statureare genotypically d/d, andthe dwarf phenotypein principle couldbe D/d or D/D. However,it is believed
that in D/D individuals the two “doses” of the D allele produce such a severeeffect that this genotype is lethal. Iftrue,all achondroplastics are
heterozygotes.
Figure 4-21

3. The humanachondroplasia pheno-type, illustratedby a family offivesisters andtwo brothers. The pheno-type is determinedby a dominant
allele, which we can call D, that interferes withbone growth duringdevelopment. Most members of thehumanpopulation (more...)
In pedigree analysis, the main clues foridentifyingan autosomal dominant disorder are that the phenotype tends toappearin every generationof
the pedigree andthat affectedfathers andmothers transmit thephenotype tobothsons anddaughters. Again, the representationofbothsexes
amongthe affectedoffspringargues against X-linkedinheritance.The phenotype appears in everygenerationbecause generally the
abnormal allele carriedby an individual must have comefroma parent in the previous generation. (Abnormal alleles can arise de novo
by mutation. This is relativelyrare,but must be kept in mindas a possibility.) A typical pedigree fora dominant disorderis shown in Figure 4-22.
Once again, notice that Mendelian ratios are not necessarilyobservedin families. As with recessive disorders,individuals bearingonecopy ofthe
rare allele (A/a) are muchmore common than those bearingtwo copies (A/A), so most affectedpeopleare heterozygotes, andvirtually all matings
involvingdominant disorders areA/a × a/a. Therefore, when theprogenyof such matings are totaled, a 1:1 ratiois expectedof unaffected(a/a)to
affectedindividuals (A/a).
Figure 4-22
Pedigree of a dominant phenotypedeterminedby a dominant allele A.In this pedigree, all the genotypes have been deduced.
Huntington’s disease is an example of anautosomal dominant disorder.The phenotype is one ofneural degeneration, leadingtoconvulsions and
prematuredeath. However, it is a late-onset disease, the symptoms generallynot appearinguntil afterthe personhas begun to have children. Each
childof a carrier of the abnormal allele stands a 50 percent chanceof inheritingthe alleleandtheassociateddisease. This tragic pattern has ledto
a drive to findways of identifyingpeople who carry theabnormal allele before theyexperience the onset ofthe disease. The discovery ofthe
molecular nature of themutant allele, andof neutral DNA mutations that act as “markers” close tothe affectedallele on thechromosome, has
revolutionizedthis sort of diagnosis.
MESSAGE
Pedigrees ofautosomal dominantdisorders show affectedmales and females in each generation and also showaffected men and women
transmittingthe condition to equal proportions of their sons and daughters.
In human populations there are manyexamples of polymorphisms (generally dimorphisms) in whichthe alternative phenotypes of
the character aredeterminedby alleles of a single gene, forexample, thedimorphisms for chindimple versus none,attachedearlobes versus
unattached, widow’s peak versus none, andso on.The interpretation ofpedigrees for dimorphisms is somewhat different fromthose forrare
disorders, because by definition themorphs in a dimorphism arecommon. Let’s lookat a pedigree for aninterestinghuman dimorphism. Most
human populations are dimorphic for the abilitytotaste thechemical phenylthiocarbamide (PTC): people caneitherdetect it as a foul, bitter taste
or—to the great surprise anddisbelief of tasters—cannot tasteit at all. Fromthe pedigree in Figure 4-23, we can see that two tasters sometimes
produce nontasterchildren.This makes it clear that theallele forabilitytotasteis dominant andthat the allelefor nontastingis recessive. Notice,
however, that almost all people who marryintothis family carrythe recessive allele either in heterozygous or in homozygous condition.Such a
pedigree thus differs fromthose of rare recessive disorders,forwhich it is conventional toassume that all who marry intoa familyare
homozygous normal. As bothPTC alleles are common, it is not surprisingthat all but oneof the familymembers in this pedigreemarried
individuals with at least one copyof therecessive allele.
Figure 4-23
Pedigree for the abilitytotastethe chemical PTC.
MESSAGE
In a polymorphism the contrastingmorphs are often determined by alleles ofa single autosomal gene.
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X-LinkedRecessive Disorders

4. Few phenotypes determinedby alleles on the differential region ofthe X chromosome are relatedtosex determination. Phenotypes withX-linked
recessive inheritance typicallyshowthe followingpatterns in pedigrees:
1.
Many moremales thanfemales showthe phenotype under study.This is because a female showingthe phenotype can result only
from a matingin which both the motherandthe father bear the allele (for example,X A
/X a
× X a
/Y), whereas a male with the
phenotypecan be producedwhen onlythe mothercarries the allele.If the recessive alleleis very rare, almost all individuals
showingthe phenotype are males.
2.
None of theoffspringof anaffectedmale are affected, but all his daughters must be heterozygous “carriers” because females
must receive oneof theirX chromosomes fromtheir fathers.Half the sons born to these carrierdaughters are affected(Figure 4-
24).
Perhaps thebest-known example is hemophilia, a maladyin which a person’s bloodfails toclot. Manyproteins must interact in
sequence to make bloodclot.Themost commontype ofhemophilia is causedby the absence or malfunctionofone ofthese
proteins, called factor VIII. The most famous cases of hemophilia are foundin the pedigreeof the interrelatedroyal families of
Europe (Figure 4-25).The originalhemophilia allele in the pedigree arose spontaneously (as a mutation) in thereproductive cells
of Queen Victoria’s parents or ofQueen Victoria herself. Alexis, the sonof the last czarof Russia, inheritedthe allele ultimately
from Queen Victoria, who was the grandmother ofhis motherAlexandra. Nowadays, hemophilia can be treated, but it was
formerlya potentiallyfatal condition.It is interestingtonote that in theJewish Talmudthere are rules about exemptions tomale
circumcision which showclearly that the mode of transmission ofthe disease through unaffected carrier females was well
understoodin ancient times.For example,oneexemptionwas for the sons ofwomenwhose sisters’sons hadbledprofuselywhen
they were circumcised.
Duchenne muscular dystrophy is a fatal X-linkedrecessive disease. The phenotype is a wastingandatrophy ofmuscles.
Generally the onset is before theage of 6, with confinement to a wheelchair by 12anddeathby 20.The gene for Duchenne
muscular dystrophyhas nowbeen isolatedandshown to encode a muscle protein,dystrophin.Such insight holds out hope for a
better understandingof the physiology ofthis conditionand, ultimately, a therapy.
A rare X-linkedrecessivephenotypethat is interestingfromthe point of viewof sexual differentiation is a condition
calledtesticular feminizationsyndrome, whichhas a frequencyof about 1 in 65,000malebirths. People afflictedwith this
syndrome are chromosomallymales, 44A + XY, but theydevelopas females (Figure 4-26).Theyhave femaleexternal genitalia,
a blind vagina, andno uterus. Testes maybe present eitherin the labia or in theabdomen. Although manysuch people are
happily married, they are, ofcourse, sterile. Theconditionis not reversedby treatment withmale hormone (androgen),so it is
sometimes calledandrogeninsensitivity syndrome.Thereasonforthe insensitivity is that the causative allele codes for a
malfunctioningandrogen receptorprotein, so malehormone canhave no effect onthe target organs that are involvedin maleness.
In humans, femaleness results when the male-determiningsystemis not functional.
Figure 4-24
Pedigree showingthat X-linkedrecessive alleles expressedin males are thencarriedunexpressedby theirdaughters in thenext generation, to be
expressedagain in their sons.Note that III-3 andIII-4cannot be distinguishedphenotypically.
Figure 4-25
The inheritance ofthe X-linkedrecessiveconditionhemophilia in the royal families of Europe. A recessive allele causinghemophilia (failure of
bloodclotting) arose in the reproductive cells ofQueen Victoria,or one ofher parents, through mutation. (more...)
Figure 4-26

5. Four siblings with testicularfeminizationsyndrome (congenitalinsensitivitytoandrogens). All four subjects in this photographhave 44
autosomes plus an X anda Y, but theyhaveinheritedthe recessiveX-linkedallele conferringinsensitivity to androgens (more...)
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X-LinkedDominantDisorders
Pedigrees of rare X-linkeddominant phenotypes showthe following characteristics:
1.
Affectedmales pass the condition ontoall theirdaughters but to noneof theirsons (Figure 4-27).
2.
Females marriedtounaffected males pass theconditionon to half theirsons anddaughters.
Figure 4-27
Pedigree of an X-linkeddominant disorder.
There are fewexamples of X-linkeddominant phenotypes in humans. One is hypophosphatemia,a type ofvitamin D–resistant rickets.
The mechanisms of X-linkeddominance andrecessiveness in humans aresomewhat complicatedby the phenomenonof X chromosome
inactivationfoundin mammals. This topicwill be coveredin Chapter16.
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Calculating Risks in PedigreeAnalysis
When a disease allele is known to be present in a family,knowledge of simple genetransmissionpatterns can be usedto calculatethe probability
of prospective parents’ havinga childwith thedisorder. Forexample, a marriedcouple finds out that eachhadan uncle withTay-Sachs disease (a
severe autosomal recessive disease).The pedigree is as follows:
The probabilityof their havinga childwith Tay-Sachs can be calculatedin the followingway. The question is whetheror not the manandwoman
are heterozygotes (it is clear that theydo not havethe disease) because if theyare bothheterozygotes thentheystanda chance of havingan
affectedchild.
1.
The man’s grandparents must havebothbeen heterozygotes T/t because they produceda t/t child(theuncle).Therefore, they
effectively constituteda monohybridcross. The man’s fathercouldbe T/T or T/t, but we knowthat the relativeprobabilities of
these genotypes must be 1/4 and1/2,respectively (the expectedprogenyratioin a monohybridcross is 1/4 T/T, 1/2 T/t, and
1/4 t/t). Therefore, there is a 2/3 probability that the father is a heterozygote [calculatedas 1/2 dividedby ( + 1/4+1/2)].
2.
The man’s mothermust be assumedto be T/T, since she marriedintothe family anddisease alleles generallyare rare. Thus if the
father is T/t, thenthe matingtothe motherwas a cross T/t × T/T andthe expectedprogenyproportions are 1/2 T/T and1/2 T/t.
3.
The overall probabilityof the man’s beinga heterozygote must be calculatedusinga statistical rule calledtheproduct rule, which
states that the probability of two independent events bothoccurring is the product of their individual probabilities. Hence the
probability ofthe man’s beinga heterozygoteis the probabilityof his father’s beinga heterozygote times the probabilityof the
father havinga heterozygous son, whichis 2/3 × 1/2 = 1/3.

6. 4.
Likewise the probabilityof the man’s wife beingheterozygous is also 1/3.
5.
If they are bothheterozygous (T/t),thenthe probability oftheirhavinga t/t childis 1/4, so overall the probabilityof the couple
havingan affectedchildis 1/3 × 1/3 × 1/4 = 1/36; in other words, a 1 in 36 chance.
By agreement withthe publisher, this bookis accessible by the search feature, but cannot be browsed.
Copyright ©1999, W. H. FreemanandCompany.
Bookshelf ID: NBK21257
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