Mendelian Genetics PreMendel Theory Blending theory A permanent

Mendelian Genetics

Pre-Mendel Theory • Blending theory – A permanent blend of each parent – Blend of hereditary material inseparable from that point forward • Problems – If blending is true, then individuals will reach a uniform appearance – Some inheritable traits skip generations and reappear in the next generation.

Particulate Theory • Parents transmit to their offspring discrete inheritable factors (genes) that remain separate factors from one generation to the next. • Mendel influenced by: – Doppler (physicist): quantitative experimental approach to study of natural phenomena – Unger (botanist): interested Mendel in inheritable variations in plants

Mendel’s peas and methods

Genetics terms review • Character = inheritable feature • Trait = variant of an inheritable feature • True-breeding = always same traits in offspring as parents when parents are self-fertilized • P, F 1, F 2 generations (progeny) • Three generations of crosses reveal: – Law of segregation – Law of independent assortment

Law of dominance revealed (Dominant: recessive)

Alleles = alternative variations of same gene • Each locus represented twice in diploid organisms: - equal homologous loci as in true-breeding organisms or two different alleles as in hybrids

Law of Segregation 2 classes Punnett square

More helpful vocabulary

Testcross = breeding of unknown genotype with homozygous recessive

Law of independent assortment Independence of alleles occurs during metaphase I when chromosomes are separated

Segregation and assortment reflect Laws of Probability • Probability scale ranges from: – 1 = event certain to occur – 0 = event certain not to occur • Random events are independent of one another – Rule of multiplication = probability that independent events will occur simultaneously is product of individual probabilities. (e. g. probability of two hybrids producing a homozygous recessive offspring) – Rule of addition = probability of an event that can occur in two or more independent ways is the sum of the separate probabilities of the different ways. (e. g. probability of being a heterozygote)

Using probability in solving genetic problems • Trihybrid cross: what is probability that two organisms of Aa. Bb. Cc will produce an offspring with aabbcc? – Treat as 3 monohybrid crosses • Aa x Aa: probability of aa = 1/4 • Bb x Bb: probability of bb = 1/4 • Cc x Cc: probability of cc = 1/4 – Simultaneous probability for these individual probabilties = 1/4 x 1/4 = 1/64

Another trihybrid question Character Flower color Seed shape Trait & Genotype Purple: PP. Pp White: pp Yellow: YY, Yy Green: yy Round: RR, Rr Wrinkled: rr • If Pp. Yy. Rr x Ppyyrr, what are chances that offspring will show at recessive phenotypes for at least two of the three traits?

Character Flower color Seed shape Trait & Genotype Purple: PP. Pp White: pp Yellow: YY, Yy Green: yy Round: RR, Rr Wrinkled: rr Known genotypes which meet conditions ppyy. Rr 1/4 x 1/2 pp. Yyrr 1/4 x 1/2 Ppyyrr 1/2 x 1/2 PPyyrr 1/4 x 1/2 ppyyrr 1/4 x 1/2 Pp. Yy. Rr x Ppyyrr = = = Probability 1/16 2/16 1/16 6/16 or 3/8 chance of two recessive traits

Using probabilities as predictors • Punnett square results or probability expressions do not guarantee that a F 2 flower from a monohybrid cross will grow out to be white (pp), only that there is a 1/4 chance. • In a large sample, there will be a 25% chance of white flowers • The larger the sample size, the closer the results will conform to predictions.

Other patterns of inheritance • Incomplete dominance produces an intermediate phenotype between dominance and recessiveness • Segregation and independent assortment still apply

Relationships between alleles • Dominance/recessiveness vary along a continuum Complete dominance (A is dominant) AA and Aa have the same phenotype Incomplete dominance (A is incompletely dominant) Aa = Intermediate phenotype between two homozygotes: AA and aa Codominance (no dominance) Aa = Both alleles are equally expressed in phenotype

Levels of gene expression • Codominance: MN blood groups – Blood Type – M – N – MN Genotype MM NN MN • MN blood type expresses both M and N glycoproteins on red blood cell surface

Tay-Sachs Disease • Recessively-inherited disorder (requires both recessive alleles) – One of several “storage disorders”: lipids accumulate in brain because dysfunctional enzymes are produced by recessive genes • Organismal level: heterozygotes are symptom-free – Appears that dominant allele is completely dominant • Biochemical level: intermediate enzyme level occurs half-way between no activity and complete activity – Seems to be a case of incomplete dominance • Molecular level: heterozygotes produce equal quantities of normal and dysfunctional enzymes; they don’t have disease because there is sufficient normal activity to metabolize lipids in the brain.

Dominant/recessive relationships • A consequence of mechanisms which determine phenotype expression • Are not a result of quantity of alleles in a population; dominant alleles are not necessarily to most abundant in the population – Polydactyly (extra fingers/toes) is dominant, but only occurs in 1 out of 400 births

Molecular basis of blood types

Multiple alleles Codominant alleles

Pleiotropy • Ability of a single gene to have multiple phenotypic effects – Single defective gene gives rise to a complex set of symptoms -- e. g. sickle-cell anemia – Tigers and Siamese cats: gene for fur pigmentation also influences connection between eyes and brain • Defective gene causes abnormal pigmentation and cross-eye condition

Epistasis • Interaction between two nonallelic genes in which one modifies the expression of the other – If one gene suppresses expression of a 2 nd gene then the first gene is said to be epistatic to the 2 nd gene – A dihybrid cross involving epistasis will not yield the typical 9: 3: 3: 1 ratio

Rodent fur pigment genes C = pigment deposition is epistatic to: B = melanin production Black = dominant Brown = recessive Albino = no pigment

Polygenic inheritance • Quantitative character which varies on a continuum within a population – Caused by additive effects of two or more genes expressed in a single phenotype • e. g. human skin coloration – AABBCC = very dark skin – aabbcc = very light skin – Aa. Bb. Cc = intermediate-colored skin » AABbcc also expresses as intermediate since alleles are additive • [summarized on next slide]

“Doses” of pigmentation

Role of environment in expression • Single genotype may have a range of phenotypes called the norm of reaction for the genotype – Hydrangea flowers, tanning of skin, blood cell count (varies with altitude, activity, infection) – Broadest norms occur with polygenic traits (including behaviors) – Himalayan rabbit fur pigmentation Ice bag

Human genetics • Pedigree: device used to study humans – Human generation time about 20 years – Experiments are impossible – Must deduce genetics from family histories • Recall pedigree analysis – – – Squares = Circles = Horizontal lines = Vertical lines = Filled symbol =

Recessively inherited disorders • Defective allele usually codes for malfunctional protein or no protein at all. • Heterozygotes are usually phenotypically normal – Can act as a carrier (transmit gene to next generation) • Range in severity from nonlethal traits (albinism) to lethal traits (cystic fibrosis) • Not usually distributed equally among all racial groups -different genetic histories of world’s people • 1/4 probability of disorder occurring from 2 heterozygote parents (Aa x Aa); 2/3 probability that child will be a heterozygote (carrier) • Increased chance of inheriting recessive disorders if parents are closely related -- consanguinity; most cultures have laws to prevent this.

Cystic fibrosis • 1/2, 500 Caucasians (rarer in other races); most common lethal disorder in U. S. • 4% of Caucasians are carriers • Caused by defective (or absent) chloride channel proteins in membranes of lungs, pancreas, and intestines; allows accumulation of extra thick mucous -- favors bacterial infections • To clear lungs person must be “pounded” regularly to loosen mucous clots

Tay sachs • 1/3, 600 births; 100 X higher incidence in Ashkenazic (central European) Jews than among Sephardic (Mediterranean) Jews and non-Jews. • Lipid accumulation in brain; death after few years • Heterozygotes function normally with half of normal enzyme present

Sickle-cell disease • 1/400 African Americans in US; • Single amino acid substitution in hemoglobin due to point mutation

• Normal hemoglobin gene = A • Sickled hemoglobin gene = S – AS = mild disorder; resistance to malaria (important in equatorial regions of Africa); sickle-cell trait – SS = sickle-cell disease; Hb crystallizes under acidic conditions (when levels of CO 2 rise during exercise); impaired circulation causes severe pains in abdomen, back, head, and extremities; heart enlargement, atrophy of brain cells (about 0. 2% African Americans) • Heterozygotes (carriers; 9% African Americans; 45% African blacks) have a survival advantage and this tends to keep the sickle-cell gene present in the population • Pleiotropic inheritance is demonstrated in the multiple symptoms of the disorder

Phenylketonuria (PKU) • Failure to metabolize amino acid phenylalanine; phenylketones appear in urine (-uria) • Results in poor brain development during infancy – Severe mental retardation – Rarely lives more than 30 years • Sensitive to all foods containing phenylalanine – These foods carry warning labels on them • WARNING PHENYLKETONURICS: This product contains phenylalanine • When caught early in infancy, disorder can be treated nutritionally and normal brain development occurs. Adults are not as sensitive to phenylalanine as infants because their brains are finished being developed. • All newborns in US hospitals are screened for PKU

Dominantly inherited disorders • Achondroplasia: type of dwarfism; affects 1/10, 000 who are heterozygous (Aa); spontaneous mutation in a normal parent’s gamete; 99. 9% of population is pure recessive (aa); pure dominant (AA) embryos usually abort spontaneously

Late-acting lethal dominants • Express too late in life to be eliminated -- children already adults and produced own children • Huntington’s disease: degeneration of nervous system; appears between 35 -40 years; irreversible and lethal. – Children of affected parents (Hh) have 50% chance of developing the disorder in adulthood. – New blood test can detect allele for the disorder before symptoms appear; still not curable

Multifactorial disorders • Disease has a genetic (predisposition) and environmental component – Heart disease – Diabetes – Cancer – Alcoholism – Some mental illnesses • Education helps people avoid environments and behaviors which contribute to these disorders

Tests for carriers • Tay-Sachs • Cystic fibrosis • Sickle-cell disease • Information from tests should be combined with help from genetics counselor (usually in hospitals) to decide course of action

Fetal testing Consumes time Ultrasound and fetoscopy (1% risk of bleeding/fetal death)

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