Genetics

Lecture Series 4
Gene Interaction

Reading: Chapter 6

Assignment or Recommended Problems:

You should work the solved problems that are relevant or similar to ones described in lecture. You should also do the "working with figures" problems taken from figures that were presented in lecture.

In addition to those, the following Chapter 6 problems will be helpful: 14, 15, 16, 17, 18, 19, 22, 35, 40, 45, 55, 62

Other Lecture Supplements:
Lecture Series 4 Presentation Slides (PDF)
Lecture Series 4 Sample Questions

Single Gene Effects on Mendelian Outcomes

Modification of Monohybrid Ratios - Dominance Effects

  • complete dominance - Mendelian phenotypic ratios, heterozygote identical to one of the homozygotes
    • completely dominant wildtype alles are haplosufficient
      • if an allele is haplosufficient - one copy is enough for full expression
      • if an allele is haploinsufficient - one copy is not enough
    • dominant mutations
      • wildtype is haploinsufficient
      • minimum threshold for expression is less than the amount of product from one wildtype allele, the heterozygote will be mutant
  • incomplete dominance - F1 intermediate between parents, 1:2:1 ratio in F2
    • carnations and other flower colors - red, pink, white
      • there is no minimum threshold for expression - product from 1 wildtype allele produces dilute, intermediate phenotype
      • polygenic inheritance is a form of incomplete dominance
  • codominance - usually protein phenotypes, both forms present in F1
    • blood types and other different forms of enzyme express codominance
    • ABO, LMLN, HbAHbS

Genes may exhibit all three kinds of dominance, depending on how the phenotype is defined. Some examples:

  • sickle cell anemia shows three forms of dominance.
    • The table below shows different expressions of dominance for sickle cell anemia. At the individual level dominance is complete; at the red blood cell level it is incomplete; at the protein level there is codominance:

Genotype
Phenotype at different levels
  Individual Red Blood Cell Protein
HbA/HbA normal normal A only
HbA/HbS normal partial sickle A and S
HbS/HbS anemic sickled S only

 

  • the expression of roundness in peas also shows different dominance depending on how it is observed:
    • WW- starch grains are large due to two active alleles of starch branching enzyme, pea does not wrinkle during drying
    • ww - two null alleles of starch branching enzyme leave all starch molecules unbranched, producing small irregular starch grains that allow the skin to wrinkle when the pea dries.
    • Ww - starch grains are large and irregular, intermediate between the two homozygotes (incomplete dominance). One active and one null allele of starch branching enzyme leaves some starch molecules branched, some unbranched (codominance). Large irregular grains sufficient to prevent wrinkling during drying and peas appear round (complete dominance)

Modification of Mendelian Ratios - Lethal Alleles

  • recessive lethal alleles exist for some genes
    • must have a dominant morphological effect to be identified
  • these are examples of pleiotropy - multiple effects from one gene
  • due to recessive lethality these do not breed true, produce 2:1 ratio
    • Cy gene in Drosophila, most other dominant mutations
    • AY allele (yellow fur) in mice
    • ML allele, Manx cat
  • lethality is caused by severe disruption of essential biochemical processes; some recessive lethals carry no dominant morphological effect and so are invisible
    • it has been estimated that all humans carry several recessive lethal alleles, or recessives that cause serious harm.
    • these tend to run in families and can be expressed if they become homozygous through matings of close relatives. therefore incest taboos.

Other Examples of Pleiotropy

  • one mutant protein may have effects in different tissues or organs
    • descendents of northern and central europeans may carry a recessive gene for cystic fibrosis
      • homozygosity results in poor respiration and lung disease, obstruction of small intestine, sterility, very salty sweat
      • results from formation of thick mucus due to lack of channel protein in cell membrane
    • aboriginal new zealanders carry a mutation that produces both sterility and respiratory problems
      • due to protein that is necessary for cilia and flagella to function normally
  • there may be a cascade of events due to one mutation
    • sickle cell anemia has many phenotypes due to multiple effects of sickled red blood cells - anemia, liver damage, joint pain

Modification of Mendelian Inheritance - Multiple Alleles

  • only two alleles may be present in each individual, but for each gene there are many different mutations possible - these different mutations are different alleles and may have different effects
    • white eyes - different allelic mutations produce different colors (allelic mutations are in the same gene, nonallelic mutations are in different genes)
      • w, wa (yellow orange) wbf (buff), wc (crimson), wcf (sepia), wch (pink), waS (light orange), we (yellow pink), wi (yellow), wip (orange)
      • some white alleles are nearly indistinguishable from mutations in different genes, such as sepia
      Himalaya Rabbits
    • C gene in mammals - C, cch, ch, c (at right is the ch phenotype)
      • ch is an example of a conditional temperature sensitive phenotype
    • some allelic mutations produce different phenotypes, some nonallelic mutations produce the same phenotype (see white eyes above)
    • crossing one mutant to another provides a test for allelism
      • if progeny are mutant, the genes are allelic
      • if progeny are wildtype, the mutants are nonallelic

Modificantion of Mendelian Inheritance - Other Genetic Effects

  • not all individuals with a particular genotype have full expression of the phenotype:
    • penetrance - % of individuals w/ gene that express phenotype
    • expressivity - degree to which individuals w/genotype express it

 

Multiple Gene Effects on Single Phenotypes: Genes in Pathways

The One Gene-One Enzyme Hypothesis - genes act on separate steps in biochemical pathways

  • G. Beadle and E. Tatum produced 3 different mutants in bread mold that could not synthesize the essential amino acid argenine, and therefore could not grow without an argenine supplement
    • microorganisms can typically synthesize essential amino acids, but can also acquire them from their diet
    • supplementation with arginine allowed the mutants to grow
  • independent assortment of the mutants showed they were different genes (not allelic)Argenine Precursor Structures
  • all these mutants required argenine to grow, but some could also grow on simpler amino acids that were chemically similar to argenine
  • Beadle and Tatum showed that these amino acids allowed growth for different sets of mutants, indicating that each gene affected a different step in the biochemical pathway for argenine synthesis

these were their results

Supplement
Mutant 1
Mutant 2
Mutant 3
ornithine growth none none
citrulline growth growth none
argenine growth growth growth

 

    • if a gene for a step in a pathway is defective, then the pathway stops at that point. if a supplement is added, the pathway can continue as long as genes for subsequent steps are intact
    • since each step is controlled by a different enzyme, and each mutant affected a different step, this indicated that each gene functions by specifying a particular enzyme (one gene - one enzyme)
    • the one gene-one enzyme hypothesis has been modified to one gene-one polypeptide, because some enzymes consist of two or more polypeptides, each coded by a different gene.  i.e. hemoglobin
  • Summary:
    • single genes direct the synthesis of single polypeptides, two or more of which may combine to produce an active protein.   usually, multiple enzymes work together in a single pathway to produce a single biosynthetic product. for a more complete description of how components of a genome work together to produce a phenotype see The Alternative Genome

Multiple Phenotypes from Single Gene; Single Phenotype due to Multiple Genes  (how confusing!)

  • one gene often contributes to more than one phenotype - pleiotropy
    • one mutant protein may have effects in different tissues or organs - cystic fibrosis, sickle cell anemia
    • a special case of pleiotropy - when a morphological mutation is also a recessive lethal
  • a single phenotype is often the product of multiple genes
    • genes usually work together in biochemical pathways to produce a phenotype
      • argenine biosynthesis, melanin synthesis, other enzyme interactions
    • a mutation in any of the genes could result in a null phenotype
      • white eyes in Drosophila can result from mutations in different genes
      • inability to synthesize argenine or other amino acids, vitamins
  • Summary
    • two different phenotypes may be due to one gene
    • mutations in two different genes may cause the same phenotype

How to determine whether different mutant phenotypes are allelic (due to mutations in the same gene)

  • test for allelism - pleiotropy and multigenic contributions to a single phenotype can make it difficult to determine whether different mutants are the same gene or different genes
    • two fruitfly eye color mutants with the same phenotypes could be different genes
    • two fruitfly eye color mutants with different phenotypes could be the same gene
    • complementation tests can determine whether different mutations are alleles or mutations in different genes in diploids
      • if mutant 1 crossed with mutant 2 = wildtype, then these are different genes
      • if mutant 1 crossed with mutant 2 = mutant phenotype, these are the same gene
      • when two mutations complement, they are in different genes; when they fail to complement, they are in the same gene
Interactions Between Genes

Interactions between Genes in the Same Biochemical Pathway

  • genes in the same biochemical pathway interact to produce a modified 9:3:3:1 ratio
  • complementation - 9:7 ratio in the F2

Ratio
Partial Genotype
Phenotype
Ratio
9/16 A-/B- purple 9/16
3/16 A-/bb white 7/16
3/16 aa/B- white
1/16 aa/bb white
  • recessive epistasis - 9:3:4 ratio in the F2 - B gene and C gene in mammals - recessive expression of one gene masks variation in the other

Ratio
Partial Genotype
Phenotype
Ratio
9/16 C-/B- black 9/16
3/16 C-/bb brown 3/16
3/16 cc/B- white 4/16
1/16 cc/bb white
    • E gene is also epistatic to B: ee prevents deposition of pigment into hairs, even though the pigment is produced (eye color normal), so ee in dogs leads to yellow fur, regardless of B genotype
  • dominant epistasis produces a 12:3:1 ratio (the first two partial genotypes above have the same phenotype)
  • suppression - 13:3 ratio - recessive suppression of recessive mutation

Ratio
Partial Genotype
Phenotype
Ratio
9/16 pd+/-; su+/- wildtype 13:3 overall
3/16 pd+/-; su/su wildtype
3/16 pd/pd; su+/- purple
1/16 pd/dp; su/su wildtype
    • recessive suppressors cancel the effect of a recessive mutation
    • a dominant suppressor may also suppress a dominant phenotype. this produces a 13 mutant : 3 wildtype ratio, contrasting with the 13 wildtype : 3 mutant ratio of recessive suppressors

Interactions Between Genes in Different Pathways

  • results in a 9:3:3:1 ratio
  • nonparental phenotypes appear due to effects of superimposing the products of two biochemical pathways
  • cinnabar (or vermillion) and brown eye color interactions in Drosophila
    • cinnabar and brown are pigments produced in two different pathways, then superimposed to produce wildtype eye color
    • cn+ and bw+ are wildtype alleles that produce wildtype(red eyes),
    • cn = cinnabar eye color (lacks brown pigment), bw = brown eye color (lacks cinnabar pigment)
    • cn bw together = white eyes (lacks all pigment)
  • purple color in some flowers is produced by the same process - blue + red = purple
  • O/o gene (orange pigment) and B/b gene (black pigment) in snakes
    • the partial genotypes of the snakes below are O- B-    O- bb   oo B-  oo bb, respectively
     Camoflage Corn Snake      Orange Corn Snake      Black Corn Snake      i/F04-11d.jpg      
  • A gene (yellow band) and B gene (black/brown) in mammals
    • 9/16    A- B-   = agouti (black with yellow stripe)
    • 3/16   A- bb   = cinnamon (brown with yellow stripe)
    • 3/16   aa B-   = black (no yellow stripe)
    • 1/16   aa bb    = brown (no yellow stripe)

 

Mammalian Coat Color Genes - a summary of gene interactions in the production of a coat color phenotype (not all of these are present in all mammals)

  • A gene: yellow band present or absent
  • B gene: black vs brown pigment
  • C gene: whether or not pigment will be produced
  • D gene: modifier gene, incompletely dominant, DD = full expression
  • E gene: allows deposition of pigment into fur (ee = yellow fur)
  • S gene: S- produces piebald spotting, ss = no spots

 

A practice problem that involves gene interactions

Are multiple phenotypes due to multiple alleles or due to interactions between two genes? Sometimes it is hard to tell from ratios alone!

Example: Explain the basis for the results of the following crosses

  • blue x white = all blue F1, 101 blue + 33 white F2
  • blue x  pink = all blue F1, 192 blue + 63 pink F2
  • pink x  white = all blue F1, 272 blue + 121 white + 89 pink F2

Are these phenotypes due to different alleles of  the same gene or different genes?

Some hints:

  • check ratios - 3:1 or 1:2:1 = monohybrid cross, 4 phenotypes = dihybrid
  • some modified dihybrid ratios resemble monohybrid ratios
    • 13:3 (suppression) may resemble 3:1 (complete dominance)
    • 9:3:4 (recessive epistasis) may resemble 1:2:1(incomplete dominance)
  • check phenotypes of parents and F1 for consistency w/ monohybrid
    • in suppression, parents and F1 may all be one phenotype w/ some F2 an alternate phenotype
    • in recessive epistasis, F1 will not be intermediate to parents

 

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