Introduction

1. Whilepeasareconvenientsubjectsforgeneticresearch,humansarenot.
2. Thegenerationtimeistoolong,fecunditytoolow,andbreedingexperimentsare
unacceptable.
3. Yet,humansaresubjecttothesamerulesregulatinginheritanceasother
organisms.
4. Newtechniquesinmolecularbiologyhaveleadtomanybreakthrough
discoveriesinthestudyofhumangenetics.

PedigreeanalysisrevealsMendelianpatternsinhuman
inheritance
1. Ratherthanmanipulatematingpatternsofpeople,geneticistsanalyzethe
resultsofmatingsthathavealreadyoccurred.
2. Inapedigreeanalysis,informationaboutthepresence/absenceofaparticular
phenotypictraitiscollectedfromasmanyindividualsinafamilyaspossible
andacrossgenerations.
3. Thedistributionofthesecharactersisthenmappedonthefamilytree.
4. Forexample,theoccurrenceofwidowspeak(W)isdominanttoastraighthairline(w).
5. Therelationshipamongallelescanbeintegratedwiththephenotypicappearanceofthese
traitstopredictthegenotypesofmembersofthisfamily.
6. Forexample,ifanindividualinthethirdgenerationlacksawidowspeak,butbothher
parentshavewidowspeaks,thenherparentsmustbeheterozygousforthatgene
7. Ifsomesiblingsinthesecondgenerationlackawidowpeakandoneofthegrandparents
(firstgeneration)alsolacksone,thenweknowtheothergrandparentmustbeheterozygous
andwecandeterminethegenotypeofalmostallotherindividuals.
 8. Wecanusethesamefamilytreetotracethedistributionofattachedearlobes(f),a
recessivecharacteristic.
9. Individualswithadominantallele(F)havefreeearlobes.
10. Someindividualsmaybeambiguous,especiallyiftheyhavethedominantphenotypeand
couldbeheterozygousorhomozygousdominant.

11. Apedigreecanhelpusunderstandthepastandtopredictthefuture.
12. WecanusethenormalMendelianrules,includingmultiplicationandaddition,topredictthe
probabilityofspecificphenotypes.
13. Forexample,theserulescouldbeusedtopredicttheprobabilitythatachildwithWwFf
parentswillhaveawidowspeakandattachedearlobes.
14. Thechanceofhavingawidowspeakis3/4(1/2[WW]+1/4[Ww]).
15. Thechanceofhavingattachedearlobesis1/4[ff].
16. Thiscombinationhasaprobabilityof3/4+1/4=3/16.
ManyhumandisordersfollowMendelianpatternsofinheritance
1. Thousandsofgeneticdisorders,includingdisablingordeadlyhereditarydiseases,areinheritedas
simplerecessivetraits.
2. Theserangefromtherelativelymild(albinism)tolifethreatening(cysticfibrosis).
3. Therecessivebehavioroftheallelesoccursbecausetheallelecodesforeitheramalfunctioning
proteinornoproteinatall.
4. Heterozygoteshaveanormalphenotypebecauseonenormalalleleproducesenoughofthe
requiredprotein.
5. Arecessivelyinheriteddisordershowsuponlyinhomozygousindividualswhoinheritone
recessiveallelefromeachparent.
6. Individualswholackthedisorderareeitherhomozgyousdominantorheterozygotes.
7. Whileheterozygotesmayhavenoclearphenotypiceffects,theyarecarrierswhomaytransmita
recessivealleletotheiroffspring.
8. Mostpeoplewithrecessivedisordersareborntocarrierswithnormalphenotypes.
9. Twocarriershavea1/4chanceofhavingachildwiththedisorder,1/2chanceofacarrier,and
1/4free.
10. Geneticdisordersarenotevenlydistributedamongallgroupsofhumans.
11. Thisresultsfromthedifferentgenetichistoriesoftheworldspeopleduringtimeswhen
populationsweremoregeographically(andgenetically)isolated.
12. Onesuchdiseaseiscysticfibrosiswhichstrikesoneofevery2,500whitesofEuropeandescent.
13. Onein25whitesisacarrier.
14. ThenormalallelecodesforamembraneproteinthattransportsClbetweencellsandthe
environment.
15. Ifthesechannelsaredefectiveorabsent,thereareabnormallyhighextracellularlevelsofchloride
thatcausesthemucuscoatsofcertaincellstobecomethickerandstickierthannormal.
16. Thismucusbuildupinthepancreas,lungs,digestivetract,andelsewherefavorsbacterial
infections.
17. Withouttreatment,affectedchildrendiebeforefive,butwithtreatmentcanlivepasttheirlate
20s.
18. TaySachsdiseaseisanotherlethalrecessivedisorder.
19. Itiscausedbyadysfunctionalenzymethatfailstobreakdownspecificbrainlipids.
20. Thesymptomsbeginwithseizures,blindness,anddegenerationofmotorandmentalperformance
afewmonthsafterbirth.
21. Inevitably,thechilddiesafterafewyears.
22. AmongAshkenazicJews(thosefromcentralEurope)thisdiseaseoccursinoneof3,600births,
about100timesgreaterthantheincidenceamongnonJewsorMediterranean(Sephardic)Jews.
23. Themostcommoninheriteddiseaseamongblacksissicklecelldisease.
24. Itaffectsoneof400AfricanAmericans.
25. Itiscausedbythesubstitutionofasingleaminoacidinhemoglobin.
26. Whenoxygenlevelsinthebloodofanaffectedindividualarelow,sicklecellhemoglobin
crystallizesintolongrods.
27. Thisdeformsredbloodcellsintoasickleshape.
28. Thissicklingcreatesacascadeofsymptoms,demonstratingthepleiotropiceffectsofthisallele.
29. Doctorscanuse
regularblood
transfusionsto
preventbrain
damageandnew
drugstoprevent
ortreatother
problems.

30. Attheorganismallevel,thenonsicklealleleisincompletelydominanttothesicklecellallele.
31. Carriersaresaidtohavethesicklecelltrait.
32. Theseindividualsareusuallyhealthy,althoughsomesuffersomesymptomsofsicklecelldisease
underbloodoxygenstress.
33. Atthemoleculelevel,thetwoallelesarecodominantasbothnormalandabnormalhemoglobins
aresynthesized.
34. Thehighfrequencyofheterozygoteswiththesicklecelltraitisunusualforanallelewithsevere
detrimentaleffectsinhomozygotes.
35. Interestingly,individualswithonesicklecellallelehaveincreasedresistancetomalaria,a
parasitethatspendspartofitslifecycleinredbloodcells.
36. IntropicalAfrica,wheremalariaiscommon,thesicklecellalleleisbothaboonandabane.
37. Homozygousnormalindividualsdieofmalaria,homozygousrecessiveindividualsdieofsickle
celldisease,andcarriersarerelativelyfreeofboth.
38. ItsrelativelyhighfrequencyinAfricanAmericansisavestigeoftheirAfricanroots.
39. Normallyitisrelativelyunlikelythattwocarriersofthesamerareharmfulallelewillmeetand
mate.
40. However,consanguineousmatings,thosebetweencloserelatives,increasetherisk.
41. Theseindividualswhosharearecentcommonancestoraremorelikelytocarrythesame
recessivealleles.
42. Mostsocietiesandcultureshavelawsortaboosforbiddingmarriagesbetweencloserelatives.
43. Althoughmostharmfulallelesarerecessive,manyhumandisordersareduetodominantalleles.
44. Forexample,achondroplasia,aformofdwarfism,hasanincidenceofonecasein10,000people.
45. Heterozygousindividualshavethedwarfphenotype.
46. Thosewhoarenotachodroplasticdwarfs,99.99%ofthepopulationarehomozygousrecessive
forthistrait.
47. Lethaldominantallelesaremuchlesscommonthanlethalrecessivesbecauseifalethaldominant
killsanoffspringbeforeitcanmatureandreproduce,theallelewillnotbepassedontofuture
generations.
48. Alethaldominantallelecanescapeeliminationifitcausesdeathatarelativelyadvancedage,
aftertheindividualhasalreadypassedonthelethalalleletohisorherchildren.
49. OneexampleisHuntingtonsdisease,adegenerativediseaseofthenervoussystem.
50. Thedominantlethalallelehasnoobviousphenotypiceffectuntilanindividualsisabout35to45
yearsold.
51. Thedeteriorationofthenervoussystemisirreversibleandinevitablyfatal.
52. AnychildborntoaparentwhohasthealleleforHuntingtonsdiseasehasa50%chanceof
inheritingthediseaseandthedisorder.
53. Recently,moleculargeneticistshaveusedpedigreeanalysisofaffectedfamiliestotrackdownthe
Huntingtonsalleletoalocusnearthetipofchromosomes4.
54. WhilesomediseasesareinheritedinasimpleMendelianfashionduetoallelesatasinglelocus,
manyotherdisordershaveamultifactorialbasis.
55. Thesehaveageneticcomponentplusasignificantenvironmentalinfluence.
56. Multifactorialdisordersincludeheartdisease,diabetes,cancer,alcoholism,andcertainmental
illnesses,suchaschizophreniaandmanicdepressivedisorder.
57. Thegeneticcomponentistypicallypolygenic.
58. Atpresent,littleisunderstoodaboutthegeneticcontributiontomostmultifactorialdiseases
59. Thebestpublichealthstrategyiseducationabouttheenvironmentalfactorsandhealthybehavior.
Technologyisprovidingnewtoolsforgenetictestingand
counseling
1. ApreventativeapproachtosimpleMendeliandisordersissometimespossible.
2. Theriskthataparticulargeneticdisorderwilloccurcansometimesbeassessedbeforeachildis
conceivedorearlyinpregnancy.
3. Manyhospitalshavegeneticcounselorstoprovideinformationtoprospectiveparentswhoare
concernedaboutafamilyhistoryofaspecificdisease.
4. Considerahypotheticalcouple,JohnandCarol,whoareplanningtohavetheirfirstchild.
5. InbothoftheirfamilieshistoriesarecessivelethaldisorderispresentandbothJohnandCarol
hadbrotherswhodiedofthedisease.
6. WhileneitherJohnandCarolnortheirparentshavethedisease,theirparentsmusthavebeen
carriers(AaxAa).
7. JohnandCaroleachhavea2/3chanceofbeingcarriersanda1/3chanceofbeinghomozygous
dominant.
8. Theprobabilitythattheirfirstchildwillhavethedisease=2/3(chancethatJohnisacarrier)x
2/3(chancethatCarolisacarrier)x1/4(chancethattheoffspringoftwocarriersishomozygous
recessive)=1/9.
9. Iftheirfirstchildisbornwiththedisease,weknowthatJohnandCarolsgenotypemustbeAa
andtheybotharecarriers.
10. Thechancethattheirnextchildwillalsohavethediseaseis1/4.
11. Mendelslawsaresimplytherulesofprobabilityappliedtoheredity.
12. Becausechancehasnomemory,thegenotypeofeachchildisunaffectedbythegenotypesof
oldersiblings.
13. WhilethechancethatJohnandCarolsfirstfourchildrenwillhavethedisorder(1/4x1/4x1/4x
1/4),thelikelihoodofhavingafifthchildwiththedisorderisonechanceinsixtyfour,still1/4.
14. Mostchildrenwithrecessivedisordersareborntoparentswithanormalphenotype.
15. Akeytoassessingriskisidentifyingifprospectiveparentsarecarriersoftherecessivetrait.
16. Recentlydevelopedtestsforseveraldisorderscandistinguishbetweennormalphenotypesin
heterozygotesfromhomozygousdominants.
17. Theresultsallowindividualswithafamilyhistoryofageneticdisordertomakeinformed
decisionsabouthavingchildren.
18. However,issuesofconfidentiality,discrimination,andadequateinformationandcounseling
arise.
19. Testsarealsoavailabletodetermineinuteroifachildhasaparticulardisorder.
20. Onetechnique,amniocentesis,canbeusedbeginningatthe14thto16thweekofpregnancyto
assessthepresenceofaspecificdisease.
21. Fetalcellsextractedfromamnioticfluidareculturedandkaryotypedtoidentifysomedisorders.
22. Otherdisorderscanbeidentifiedfromchemicalsintheamnioticfluids.
23. Asecondtechnique,chorionicvillussampling(CVS)canallowfasterkaryotypingandcanbe
performedasearlyastheeighthtotenthweekofpregnancy.
24. Thistechniqueextractsasampleoffetaltissuefromthechrionicvillioftheplacenta.
25. Thistechniqueisnotsuitablefortestsrequiringamnioticfluid.

26. Othertechniques,ultrasoundandfetoscopy,allowfetalhealthtobeassessedvisuallyinutero.
27. Bothfetoscopyandamniocentesiscausecomplicationsinabout1%ofcases.
28. Theseincludematernalbleedingorfetaldeath.
29. Therefore,thesetechniquesareusuallyreservedforcasesinwhichtheriskofageneticdisorder
orothertypeofbirthdefectisrelativelygreat.
30. Iffetaltestsrevealaseriousdisorder,theparentsfacethedifficultchoiceofterminatingthe
pregnancyorpreparingtocareforachildwithageneticdisorder.
31. Somegenetictestscanbedetectedatbirthbysimpleteststhatarenowroutinelyperformedin
hospitals.
32. Onetestcandetectthepresenceofarecessivelyinheriteddisorder,phenyketonuria(PKU).
33. Thisdisorderoccursinonein10,000to15,000births.
34. Individualswiththisdisorderaccumulatetheaminoacidphenylalanineanditsderivative
phenypyruvateinthebloodtotoxiclevels.
35. Thisleadstomentalretardation.
36. Ifthedisorderisdetected,aspecialdietlowinphenyalalanineusuallypromotesnormal
development.