Extensions to Mendelism

1. Extensions to Mendelism • Mendel's pea experiments used a very simple genetic system: each gene had 2 alleles, one dominant and one recessive, and genes did not interact with each other. • We are going to look at some variations: different forms of dominance, multiple alleles, interactions between genes, and environmental effects.

2. Partial (Incomplete) Dominance • Mendel studied complete dominance: the heterozygote looks exactly like the dominant homozygote. • In partial dominance, the heterozygote has phenotype intermediate between the two homozygotes. • Example: Four o'clock plants. Red flowers x white flowers gives pink F1's. Pink is intermediate between red and white. • Selfing the F1's gives 1/4 red (RR), 1/2 pink (Rr), and 1/4 white (rr)

3. Co-dominance • In co-dominance, both parental alleles are expressed in the heterozygote. • Example: blood groups. Antigens on the surface of red blood cells cause them to clot in the presence of the corresponding antibody. • The MN blood group antigens are coded for by the L gene: the 2 alleles are called LM and LN. • A LM LM homozygote has the M blood type: blood clots in the presence of anti-M antiserum, but not in the presence of anti-N serum. • Similarly, a LN LN homozygote has the N blood type: blood clots in the presence of anti-N antiserum, but not in the presence of anti-M serum. • The LM LN heterozygote has the MN blood type: it clots with both anti-M and anti-N antiserum. These red blood cells have both antigens on their surface. Thus, the MN blood group alleles are co-dominant.

4. Electrophoresis • When an organism's DNA or proteins are examined closely, almost all genes are co-dominant. Both alleles of the gene are present, even if they don't contribute equally to the phenotype. • Electrophoresis is a way of separating the DNA of the genes or the proteins the genes produce. • Electrophoresis depends on a fundamental physical property: charged objects move in an electric field. • DNA and RNA have one negative charge per nucleotide. Most proteins also have a net negative charge, caused by 2 of the 20 amino acids, which have a negative charge. Since opposite charges attract, most nucleic acids and proteins move towards the positive pole. • The speed the molecules move is proportional to their charge and inversely proportional to their size: small, highly charged molecules move faster than large, less charged molecules. • Electrophoresis is done in a gel matrix, to prevent diffusion from confusing the results.

5. More Electrophoresis • As an example, the enzyme "phosphatase" removes phosphate groups from other molecules. When an extract is made of the proteins in an organism, it is possible to separate the proteins by electrophoresis and then stain the gel so only the phosphatase will appear. • In this example, there are 2 alleles of the gene that makes phosphatase. One allele puts more negatively charged amino acids on the protein's surface than the other allele does. Thus, one allele produces a more highly charged protein that moves faster in electrophoresis than the less charged protein from the other allele. These two alleles are called F (Fast) and S (Slow). • After electrophoresis and staining of the gel, an FF homozygote shows a single band, far down the gel. The SS homozygote shows a single band that has only moved a little ways down the gel. The FS heterozygote shows both the F band and the S band. This means that the phosphatase gene is co-dominant: the heterozygote shows both parental types.

6. Multiple Alleles • Mendel used only 2 alleles per gene. Any change in the DNA sequence of a gene is a different allele, so there are millions of possible alleles for any gene. • In reality, many genes have several common alleles: they are polymorphic. Some genes are constrained by natural selection to have only a single allele: they are monomorphic. Having 2 alleles, as in Mendels’ genes, is called dimorphic. • Genes with multiple alleles can have a variety of dominance patterns between the alleles.

7. ABO Blood Group • The ABO blood group is a common multiple allele system. The gene itself is called I, and it has 3 alleles: IA, IB, and iO. • IA and IB are co-dominant, and both IA and IB are dominant to iO. • Thus, IA IA homozygotes and IA iO heterozygotes have type A blood. • Similarly, IB IB homozygotes and IB iO heterozygotes have type B blood. • Because IA and IB are co-dominant, IA IB heterozygotes have AB blood. • Type O blood occurs in people with the iO iO genotype. • Note: O is the most common blood type. Frequency in the population is not related to dominance.

8. Major Histocompatibility Locus • The MHC is the primary determinant of human tissue type, which determines whether organs can be transplanted between people without rejection by the immune system. • The MHC consists of 6 major genes lying close together on one chromosome. These genes are usually inherited as a single unit, called a "haplotype". Taken together, the MHC genes are probably the most polymorphic region of the human genome. There are thousands of known haplotypes. • Most people have 2 different haplotypes, one inherited from each parent. Similarly, mates usually have different haplotypes. The result of this is that each person has one haplotype in common with each parent and one haplotype different. However, a person has a 1/4 chance of having both of the same haplotypes as his/her sibling. Thus, organ transplants between siblings are usually the easiest to perform.

9. Lethal Alleles • Many alleles that cause genetic diseases are called "dominant" because heterozygotes are affected. A common example is achondroplasia, the most common form of dwarfism, with a normal length body trunk but shortened limbs. Another in the Manx cat, which doesn't have a tail. • In fact, these genes would be better described as partially dominant, because the homozygotes are quite different from the heterozygotes: homozygotes are lethal.

10. More Lethal Alleles • Lethal alleles give an unusual inheritance ratio. Consider a mating between two Manx cats. Each is heterozygous Tt, with T the dominant tailless allele and t the recessive normal tail allele. • Using Mendel's Law of Segregation, we see that zygotes form in the ratio of 1/4 TT, 1/2 Tt, and 1/4 tt. • However, all the TT embryos die at a very early stage, and only the Tt (tailless) and tt (tailed) cats are born. • Because there are twice as many Tt as tt, the ratio of offspring in the Tt x Tt cross is 2/3 Tt (tailless) to 1/3 tt (tailled). • Note that pure breeding lines of Manx cats (and achondroplastic dwarves) can't exist, because 1/3 of their offspring are of the incorrect type.

11. Interactions between Two Genes • More than one gene can affect the same trait. Lots of possible interactions: we will look at a few, using only 2 genes and complete dominance for both.

12. Two Genes • 1. Two dominant alleles necessary for the trait. Example: pea purple vs. white flowers. Mendel looked at one gene, but there is another that is also necessary. • Call the genes A and B. Both have two alleles: A and a, B and b. To get a purple flower, the plant must have both a A allele and a B allele. • Selfing a double heterozygote Aa Bb gives 9/16 A_ B_, 3/16 A_ bb, 3/16 aa B_, and 1/16 aa bb. Only the 9/16 A_ B_ have both an A allele and a B allele: these are purple. The rest are white. • The final ratio is thus 9/16 purple to 7/16 white. • Also worth noting: AA bb x aa BB is a cross between two white plants. However, the offspring are all Aa Bb = purple.

13. Two Genes • 2. Duplicate genes. The dominant allele from at least one of the two genes is needed to give the dominant phenotype. • Example: the plant "shepherd's purse" (Capsella bursa-pastoris, in the mustard family). To get a triangular seed pod, you must have a dominant allele from either the A gene or the B gene. The alternative is an ovoid seed capsule. • Thus, the offspring of a selfed Aa Bb plant give 15/16 triangular (9/16 A_ B_, 3/16 A_ bb, 3/16 aa B_) and 1/16 ovoid (aa bb).

14. Two Genes • 3. Two genes with different effects on the trait. Chicken comb types. • Here we have: top left = "pea" comb, from aa B_ genotype. Top right = "rose comb", from A_ bb genotype. Bottom left = "single comb", from aa bb genotype. Bottom right = "walnut comb", from A_ B_ genotype.

15. Two Genes • Epistasis. One gene controls the expression of another gene. • Example: albinism and coat color in dogs. An albino dog lacks all pigment, so it is white. The albinism gene has two alleles: C (normal color) and c (albino). Another gene controls black vs. brown: B is the dominant black allele, and b is the recessive brown allele. • If two Bb Cc dogs are mated (both are black), 9/16 of the offspring are B_ C_ (black), 3/16 are bb C_ (brown), and 4/16 are __ cc (white). The cc dogs can be BB, Bb, or bb: it doesn't matter because the expression of the coat color gene is controlled by the albino gene.

16. Penetrance and Expressivity • Expression of many genes is affected by the environment or by "background" genetic influences. Two closely related concepts are used to describe this. • Penetrance is the percentage of offspring with the mutant genotype that express the mutant phenotype. • Expressivity is the degree to which the mutant phenotype is expressed. • Example. Polydactyly is having extra fingers and toes. There are several forms of this condition. For one form, polydactyly is 65% penetrant: 65% of those who carry the dominant polydactyly allele have extra digits. Examining these people, there is a range of expression: some have 1 extra digit, some have 2, etc. Also, some of the digits are functional: have proper bones, muscles and nerves, while others are missing vital components or connections.

17. Polydactyly • Alfredo Alfonseca "The Six Shooter", former Chicago Cubs relief pitcher. • Six fingers and toes on each hand, all functional.

18. Environmental Effects • Many traits are affected by the environment as well as by genetics. • For example, the hydrangea flower color is controlled first by flower color genes similar to those in the pea: purple vs. white with complete dominance. But, pink vs. purple is controlled by the acidity of the soil in which the plants grow.

19. Phenocopies • A phenocopy is an organism that has a mutant phenotype but a normal (wild type) genotype. It got the mutant appearance through an environmental cause. • Drugs that cause birth defects are a common cause. Nothing is genetically wrong with the child, but it was exposed in utero to toxic chemicals • Another example: my cat Angel, whose tail got run over by a car, looks like a Manx cat (genetically tailless), even though she started out with a normal tail.

20. Pleiotropy • Pleiotropy is one gene affecting several traits. This is quite common: genes make proteins and often affect the overall phenotype in subtle ways that affect many different body systems. • Example: sickle cell anemia causes enlarged spleen, muscle pain, low red blood cell count, resistance to malaria, and early death. All of this is caused by a single mutation in one of the hemoglobin genes.