HumanGeneticDisease H man Genetic Disease Todaysquestions:Howdopatternsofinheritance andnaturalselectionaffecthumangenetic and natural selection affect human genetic disease? I. II. II III.

IV. IV Transmissiongeneticsofhumandisease SelectiondynamicsofCF Selection dynamics of CF Selectiononlateonsetillnesses Genexenvironmentinteractionsrevisited G i ti t ti i it d

I.Transmissiongeneticsofhumandisease Howdoesselectionaffectrecessive,dominantandco dominantalleles? Many(ormost)recessivealleleshavelossoffunctionor knockoutmutationstheydonotproduceafunctional knock out mutations they do not produce a functional product.

Explainhowmutationstostopcodons canproducea lossoffunction.

If the stop codon doesn't stop the process, the resulting gene product (mRNA, and protein) will be malfunctioned.

Ifarecessivealleleislossoffunction,whydo heterozygotes haveanormalphenotype?

Because the dominant allele is the one that is selected for expression and protein production which leads to the of the phenotype.

It means that the trait is not selected for since this allele is not expressed.

Whatdoesitmeantosaythatdeleteriousrecessives h d i h d l i i hideout(fromnaturalselection)inheterozygotes?

Whyhaventeugenicsprogramsinhumansbeen y g p g successful?

Impossible to target all those rare excessive alleles. Especially if they aren't typically shown because they are recessive.

II.SelectiondynamicsofCFalleles Observation1:CFallelesareatafrequencyofabout2% inpopulationsofNorthernEuropeanancestry.Giventhe strengthofselectionagainstindividualswiththedisease phenotype,thisisvery higheventhoughthedisease allelesarerecessive. alleles are recessive Observation2:Salmonellatyphi entersgutcells Observation 2: Salmonella typhi enters gut cells throughtheCFgeneproduct.Thiseventstartsan infectionandmayleadtotyphoidfever. infection and may lead to typhoid fever.

Hypothesis:IndividualswhoareheterozygousfortheCF diseasealleleareprotectedagainsttyphoidfever. p g yp Experiment:createmousecellswithCFalleleproducts (aproteincalledCFTR; (a protein called CFTR; normalmicedonthaveit), exposethemtoS.typhi. p yp 1.Whyusemousecells fortheexperiment, p insteadofhumanlung cells(bothinculture)? 2.Interpretthisgraph.

Analysis:Documentfrequencyoftheprotectiveallelein 11Europeancountries,onegenerationaftertyphoidfever p , g yp outbreaksofvaryingintensity.

Interpretthegraph. Whatisplottedonthexaxis? Whatisplottedontheyaxis? h i l d h i? Whatdoestheequation represent? Whatdoesther2 valueindicate?

% disease alleles of protective type

III.Selectiononallelesassociatedwithillness Whichshouldbemorecommon,andwhy? Type2diabetes(adultonset) or Type1diabetes(juvenileonset) Type 1 diabetes (juvenile onset)

Intermsoffitness,arehumanpopulationsinthe industrializedcountriesbecomingweaker(individuals g ( arelessfit,onaverage),duetoimprovedhealthcare?