4 Genetic counselingPedigree can help us understand the past & predict the futureThousands of genetic disorders are inherited as simple recessive traitsfrom benign conditions to deadly diseasesalbinismcystic fibrosisTay sachssickle cell anemiaPKU
6 Recessive diseasesThe diseases are recessive because the allele codes for either a malfunctioning protein or no protein at allHeterozygotes (Aa)carriershave a normal phenotype because one “normal” allele produces enough of the required protein
7 Heterozygote crosses Aa x Aa A a Aa A a AA Aa AA Aa A a A a Aa Aa aa Heterozygotes as carriers of recessive allelesAa x AaAaAaAamale / spermAAAaAAAaAafemale / eggscarrierAaAaAaaaAaaacarrierdisease
8 Cystic fibrosis (recessive) Primarily whites of European descentstrikes 1 in 2500 births1 in 25 whites is a carrier (Aa)normal allele codes for a membrane protein that transports Cl- across cell membranedefective or absent channels limit transport of Cl- & H2O across cell membranethicker & stickier mucus coats around cellsmucus build-up in the pancreas, lungs, digestive tract & causes bacterial infectionswithout treatment children die before 5; with treatment can live past their late 20snormal lung tissueCystic fibrosis is an inherited disease that is relatively common in the U.S. Cystic fibrosis affects multiple parts of the body including the pancreas, the sweat glands, and the lungs. When someone has cystic fibrosis, they often have lots of lung problems. The cause of their lung problems is directly related to basic problems with diffusion and osmosis in the large airways of the lungs.People without cystic fibrosis have a small layer of salt water in the large airways of their lungs. This layer of salt water is under the mucus layer which lines the airways. The mucus layer in the airways helps to clear dust and other inhaled particles from the lungs.
9 bacteria & mucus build up mucus secreting glands Chloride channeltransports salt through protein channel out of cellOsmosis: H2O follows Cl–Effect on Lungsnormal lungsairwayCl–Cl– channelH2Ocells lining lungscystic fibrosisCl–H2OIn people without cystic fibrosis, working cystic fibrosis proteins allow salt (chloride) to enter the air space and water follows by osmosis. The mucus layer is dilute and not very sticky.In people with cystic fibrosis, non-working cystic fibrosis proteins mean no salt (chloride) enters the air space and water doesn't either. The mucus layer is concentrated and very sticky.People with cystic fibrosis have lung problems because:Proteins for diffusion of salt into the airways don't work. (less diffusion)Less salt in the airways means less water in the airways. (less osmosis)Less water in the airways means mucus layer is very sticky (viscous).Sticky mucus cannot be easily moved to clear particles from the lungs.Sticky mucus traps bacteria and causes more lung infections.Therefore, because of less diffusion of salt and less osmosis of water, people with cystic fibrosis have too much sticky mucus in the airways of their lungs and get lots of lung infections. Thus, they are sick a lot.bacteria & mucus build upthickened mucus hard to secretemucus secreting glands
11 Tay-Sachs (recessive) Primarily Jews of eastern European (Ashkenazi) descent & Cajuns (Louisiana)strikes 1 in 3600 births100 times greater than incidence among non-Jewsnon-functional enzyme fails to breakdown lipids in brain cellsfats collect in cells destroying their functionsymptoms begin few months after birthseizures, blindness & degeneration of muscle & mental performancechild usually dies before 5yo
12 Sickle cell anemia (recessive) Primarily Africansstrikes 1 out of 400 African Americanshigh frequencycaused by substitution of a single amino acid in hemoglobinwhen oxygen levels are low, sickle-cell hemoglobin crystallizes into long rodsdeforms red blood cells into sickle shapesickling creates pleiotropic effects = cascade of other symptoms
13 hydrophilic amino acid hydrophobic amino acid Sickle cell anemiaSubstitution of one amino acid in polypeptide chainhydrophilic amino acidhydrophobic amino acid
14 Doctors can use regular blood transfusions to prevent brain damage and new drugs to prevent or treat other problems.
15 Sickle cell phenotype 2 alleles are codominant both normal & mutant hemoglobins are synthesized in heterozygote (Aa)50% cells sickle; 50% cells normalcarriers usually healthysickle-cell disease triggered under blood oxygen stressexercise
16 Heterozygote advantage Malariasingle-celled eukaryote parasite spends part of its life cycle in red blood cellsIn tropical Africa, where malaria is common:homozygous dominant individuals die of malariahomozygous recessive individuals die of sickle cell anemiaheterozygote carriers are relatively free of bothreproductive advantageHigh frequency of sickle cell allele in African Americans is vestige of African roots
17 Prevalence of MalariaPrevalence of Sickle Cell Anemia
18 Huntington’s chorea (dominant) 1872Dominant inheritancerepeated mutation on end of chromosome 4mutation = CAG repeatsglutamine amino acid repeats in proteinone of 1st genes to be identifiedbuild up of “huntingtin” protein in brain causing cell deathmemory lossmuscle tremors, jerky movements“chorea”starts at age 30-50early death10-20 years after startTesting… Would you want to know?
19 Genetics & culture Why do all cultures have a taboo against incest? laws or cultural taboos forbidding marriages between close relatives are fairly universalFairly unlikely that 2 unrelated carriers of same rare harmful recessive allele will meet & matebut matings between close relatives increase risk“consanguineous” (same blood) matingsindividuals who share a recent common ancestor are more likely to carry same recessive alleles
20 A hidden disease reveals itself AaxAA x AaAamale / spermAmale / spermAAAAAaAaAAAAAafemale / eggsAafemale / eggsAaAaaaaaAaAa• increase carriers in population • hidden disease is revealed
21 Speaking of hidden diseases… The “Blue People” of Troublesome Creek, KentuckyThe Fugate family pedigree“There’s BLUE people up in them thar hills!”
25 Blue People of Troublesome Creek French orphan Martin Fugate settled in Troublesome CreekMarried Elizabeth Smith - 7 children of whom 4 reported to be ‘blue’Many consanguineous marriages (normally cousin - cousin)One of their sons married an aunt
26 Blue People of Troublesome Creek Generation 1: Mom and DadGeneration 2: SiblingsReproduce with non-carrierGeneration 3: CousinsTesting to see what happens
27 Blue People of Troublesome Creek 6 generations later Ben Stacy born (1975)Ben’s skin blue - no apparent cause(1998) lips and fingernails still blue when stressedWhat is the cause? Treatment?Madison Cawein (1960 ) proposed answers