Week 2 - Deeper Dive Into Genetics

Note For Week 1 Mendel's Peas, Pedigrees, and Mitosis/Meiosis Review BIO 1090 Notes

What do Recessive Mutations Involve?

• Often involve loss of gene function

• Null/Amorphic Alleles = Complete loss of function

  • I. A nonfunctional protein is produced OR

  • II. No protein is produced

• Hypomorphic Alleles = Partial loss of function

  • I. A poorly functioning protein is produced OR

  • II. Reduced amounts of a normally functioning protein is produced

What do Dominant Mutations often Involve?

• Gain/Change of Gene Function

• Dominant Hypermorphic Alleles = Too much normal function

  • Negative phenotypic consequences due to the over-production of a normal protein OR

  • Negative phenotypic consequences due to the production of a protein with increased activity levels

• Neomorphic Alleles = New function

  • Negative phenotypic consequences due to the presence of an altered protein that has a new function

  • Negative phenotypic consequences when the altered protein interferes with the wildtype protein (Dominant-negative allele)

The Three Different Kinds of Dominance

• Complete dominance and complete recessiveness are extremes of a range.

• Phenotype: BB=Bb is different from bb

• Complete Dominance: Heterozygotes appear similar to one of the homozygotes; used to define a dominant allele and a recessive allele

  • Dominant allele (W) encodes a functional protein and the one
    allele of the heterozygote is sufficient to produce the same
    phenotype as the two functional alleles of the WW homozygote.

  • White phenotype results from the absence of functional product in
    ww homozygote

• Incomplete dominance: BB, Bb and bb all differ phenotypically; Bb is intermediate between homozygous phenotypes ex. Flower colour (red, white, pink)

• Codominance: BB, Bb and bb all differ phenotypically, but Bb exhibits phenotypes of both homozygotes. ex. Blood type

Incomplete Dominance

• Heterozygote has an intermediate phenotype to either homozygote

• One allele is insufficient to produce the same phenotype as the two alleles of either homozygote, so the phenotype lies between

• As long as the heterozygote’s phenotype can be differentiated from those of the two homozygous and falls between them, dominance is incomplete

• Monohybrid crosses produce a 1:2:1 ratio of phenotypes in F2, so that
  each genotype has a distinct phenotype

Co-Dominance

• The phenotype of the heterozygote is not intermediate between the phenotypes of homozygotes; rather the heterozygote simultaneously expresses the phenotypes of both homozygotes.

• Phenotypes of both alleles appear in the heterozygote

• Each allele is expressed in the heterozygote, such as the antigens of the IA and IB alleles.

• IA Encodes A Transferase Which Adds Acetylgalactosamine

• IB Encodes A Transferase Which Adds Galactose

• Both enzymes are made, so the red blood cells have both A and B antigens. That's why Iᴬ and Iᴮ are codominant—neither one masks the other.

• i Encodes A Non-functional Transferase (Nothing…Loss of Function Allele!)

Can only two ever alleles exist at a particular loci?

• Some genes have many alleles.

• Some of these alleles are common; others are rare.

• Some alleles are associated with certain breeds or varieties of plants and animals.

• Frequency of a particular allele varies from population to population

Dominance Series/Allelic Series

• One allele can dominate another depending on which two are paired.

• In order of dominance;

• C → full function → normal/dark pigmentation
  cᶜʰᵈ → reduced/altered function (hypomorphic) → chinchilla
  cʰ → reduced/temperature-sensitive function (hypomorphic) → Himalayan pattern
  c → null allele → completely nonfunctional → no pigment-producing function from that allele → albino

• So, for example, C/cʰ looks wild-type because C dominates cʰ. And cʰ/c looks Himalayan because cʰ dominates the null c allele.

How do wild-type, null (amorphic), and hypomorphic alleles affect protein function and phenotype?

• Wild-type (a⁺): produces a fully functional polypeptide → normal/wild-type phenotype.

• Null/amorphic (a): complete loss-of-function → produces no functional polypeptide → can cause a severe mutant phenotype when homozygous.

• Hypomorphic (aʰ): partial loss-of-function → produces a partially functional protein (or reduced amount of functional protein) → usually causes a milder mutant phenotype than a null allele.

• In a⁺/a or a⁺/aʰ heterozygotes, the wild-type allele can produce enough functional protein for a normal phenotype (haplosufficiency), so these mutations are often recessive

How does a dominant-negative mutation differ from recessive loss-of-function mutations?

• A dominant-negative allele (aᴰ) produces an altered protein that interferes with the functional protein produced by the wild-type allele.

• Therefore, an a⁺/aᴰ heterozygote can have a mutant phenotype because the normal allele cannot fully compensate.

• In contrast, recessive null (a) and hypomorphic (aʰ) proteins generally do not interfere with the wild-type protein, so a⁺/a and a⁺/aʰ can remain wild-type.

• Key idea: Null = no function | Hypomorphic = reduced function | Dominant-negative = interferes with WT function.

Key Points To Remember about Genetics

• Genes often have multiple alleles.

• Mutant alleles may be dominant, recessive, incompletely dominant, or codominant.

• Most genes encode polypeptides.

• In homozygous condition, recessive mutations often abolish or diminish polypeptide activity.

• Some dominant mutations produce a polypeptide that interferes with the activity of the polypeptide produced by the wild-type allele of a gene.

What are wild-type and loss-of-function alleles?

• Wild-type allele: generally produces a normal, functional protein/enyzme; “wild-type” can also describe the common phenotype/genotype in a natural population.

• Loss-of-function (LOF) allele: reduces/eliminates normal gene function because the protein is not produced, produced at lower levels, or is nonfunctional.

• LOF mutations are often recessive, but they can sometimes be dominant.

What are haplosufficiency and haploinsufficiency, and how do they affect dominance of loss-of-function mutations?

• Haplosufficient: one functional allele (~50% normal protein) is enough for a normal phenotype → LOF mutation is usually recessive.

  • Often the wildtype allele is dominant over the loss of function allele

  • Half as much protein is synthesized yet this is often sufficient to achieve the wildtype phenotype

• Haploinsufficient: one functional allele (~50% protein) is NOT enough for a normal phenotype → LOF mutation can be dominant.

  • In the heterozygote, half as much protein is synthesized and this is not sufficient for a normal phenotype

  • E.g Tailless Cats (Manx)

• Therefore, whether a LOF mutation is dominant or recessive depends on how much functional protein is required.

Why aren't dominant alleles always normal/wild-type alleles?

What are lethal alleles, and how do dominant vs. recessive lethal alleles differ?

• Lethal alleles are mutations that can cause death when present in certain genotypes, often because they affect an essential gene.

• Dominant lethal: lethal in heterozygotes and homozygotes (e.g., Bb and BB lethal; bb viable).

• Recessive lethal: lethal only when homozygous; heterozygotes survive (e.g., ts/ts lethal; TS/ts viable).

• Yellow mice example: Y is dominant for yellow coat colour but recessive for lethality:

  • YY = lethal

  • Yy = yellow and viable

  • yy = non-yellow and viable

• Therefore, Yy × Yy initially gives ¼ YY : ½ Yy : ¼ yy, but the YY offspring do not survive, leaving a 2 yellow : 1 non-yellow ratio.

• Key clue: a 2:1 ratio among surviving offspring often indicates a recessive lethal allele.

What are penetrance and expressivity?

• Penetrance: the percentage of individuals with a particular genotype who actually express the expected phenotype.

  • Example: If 38/42 people with a polydactyly allele show polydactyly → 90% penetrance.

• Expressivity: the degree/severity to which a phenotype is expressed in individuals who show it.

  • Example: One person with polydactyly may have a fully developed extra finger, while another may only have a small amount of extra tissue.

• Key difference:

  • Penetrance = WHETHER the phenotype appears.

  • Expressivity = HOW MUCH/HOW SEVERELY it appears.

• Remember: The determination of phenotypes is further complicated by the fact that the same genotype does not always produce the same phenotype.

What are complete/incomplete penetrance and variable expressivity, and what causes them?

• Penetrance = the proportion of individuals with a particular genotype who express the expected phenotype.

• Complete penetrance: 100% of individuals with the genotype show the phenotype.

• Incomplete penetrance: <100% show the phenotype; some have the genotype but do not express the trait.

  • Example: If only half of people with the polydactyly genotype have extra digits → 50% penetrance.

• Variable expressivity: individuals with the same genotype express the phenotype to different degrees/severities.

• Differences in penetrance/expressivity can result from other genes and environmental factors that modify or suppress gene expression.

• Key idea: Having a gene/genotype does not guarantee that its phenotype will appear or appear to the same degree.

What is variable expressivity, and what are some examples?

Variable expressivity = individuals with the same genotype can express the phenotype to different degrees or in different ways.

Examples:

• Split hand-foot syndrome (rare autosomal dominant disorder): severity/number of missing central digits can vary.

• Piebaldism (rare autosomal dominant disorder): amount and location of unpigmented skin/hair can vary due to absence of melanocytes in certain areas.

• Huntington disease (rare autosomal dominant disorder): age of onset and severity can vary among affected individuals.

Key idea: Expressivity asks “To what degree/how is the phenotype expressed?”, whereas penetrance asks “Is the phenotype expressed at all?”

What causes incomplete penetrance and variable expressivity, and what is the norm of reaction?

• Incomplete penetrance and variable expressivity can result from other genes and environmental factors that alter or suppress the effect of a particular gene.

• Factors that can affect phenotypic expression include:

  • Age

  • Sex

  • Temperature

  • Chemicals/environmental exposures

• These factors can determine whether a phenotype appears at all (penetrance) or how strongly it is expressed (expressivity).

• Norm of reaction: the range of phenotypes that a single genotype can produce under different environmental conditions.

Key idea:
Genotype + other genes + environment → phenotype.

How can temperature affect phenotype? Explain using Himalayan rabbits and Siamese cats.

Some alleles produce temperature-sensitive proteins, meaning the protein functions differently depending on temperature.

• Himalayan rabbits: the enzyme needed for dark pigment production is active at cooler temperatures but inactive at warmer temperatures.

  • Cooler extremities (ears, nose, feet, tail) → enzyme active → dark pigment

  • Warmer body core → enzyme inactive → little/no dark pigment → white fur

• Siamese cats: have a temperature-sensitive allele of the tyrosinase gene.

  • Cooler extremities → tyrosinase active → dark pigment

  • Warmer body regions → tyrosinase inactive → lighter fur

Key idea: The same genotype can produce different phenotypes depending on environmental conditions, such as temperature.

What is a phenocopy, and how can environmental factors produce one?

• A phenocopy is a phenotype caused by an environmental factor that mimics the phenotype normally caused by a genetic mutation.

• The individual does not need to have the mutation that normally produces the phenotype—the environment produces a similar effect.

• Example: exposure to thalidomide during fetal development can disrupt limb development, producing a phenotype similar to the genetic condition phocomelia.

• Key idea: Phenocopy = environment produces a phenotype that looks genetically caused.

How can controlling environmental factors influence the expression of a genetic condition?

Environmental factors can influence whether and how strongly a genetic phenotype is expressed.

• PKU: the genetic mutation is still present, but controlling phenylalanine intake can greatly reduce/prevent many of its harmful effects.

• More generally, environmental factors can modify:

  • Penetrance → whether the phenotype occurs.

  • Expressivity → how strongly/severely the phenotype occurs.

• Therefore, having a particular genotype does not always guarantee a particular phenotype because the environment can modify gene effects.

Key idea: The environment doesn't necessarily change the genotype—it can change how that genotype is expressed as a phenotype.

What is a genetic interaction, and what happens in a dihybrid cross with complete dominance at two interacting genes?

• A genetic interaction occurs when two or more genes contribute to the same phenotype because their gene products interact at the cellular/biochemical level.

• Mendelian segregation still occurs normally.

• For AaBb × AaBb, with complete dominance at both genes, offspring can be grouped as:

  • 9/16 A–B–

  • 3/16 A–bb

  • 3/16 aaB–

  • 1/16 aabb

• If each genotype category produces a distinct phenotype, the F2 phenotypic ratio is 9:3:3:1.

• Example: two genes can interact to produce four different coat colours.

Dominant Alleles in Cat Example

What is complementation, and how can a complementation test determine whether two mutations are in the same or different genes?

• Complementation occurs when two organisms with the same mutant phenotype have homozygous recessive mutations in different genes.

• When crossed, each parent supplies a functional allele of the gene that is mutated in the other parent, so the offspring has at least one functional copy of both genes and displays the wild-type phenotype.

• Example: cc AA × CC aa → Cc Aa (wild-type).

• Wild-type offspring → mutations are in DIFFERENT genes → complementation occurs.

• Mutant offspring → mutations are in the SAME gene → no complementation.

• Different genes → they complement. Same gene → they can't complement.

Complementation Example: Two Different Albinos

How can complementation occur in human pedigrees?

• A heterogeneous trait can be caused by recessive mutations in different genes.

• If two affected parents have mutations in different genes, they can produce unaffected offspring through complementation.

• Example: AA bb × aa BB → AaBb

• Each parent provides the functional allele missing from the other.

• AaBb has functional A and B alleles → wild-type phenotype.

• If both parents have mutations in the same gene, complementation does not occur and offspring remain affected.

Why can complementation produce a 9:7 F₂ phenotypic ratio?

For AaBb × AaBb, the normal dihybrid genotype classes are 9:3:3:1, but the wild-type phenotype requires at least one dominant/functional allele at BOTH genes.

• 9/16 A–B– → wild-type

• 3/16 A–bb → mutant

• 3/16 aaB– → mutant

• 1/16 aabb → mutant

The mutant categories combine:

3 + 3 + 1 = 7

Therefore, the F₂ phenotypic ratio is:

9 wild-type : 7 mutant

Key idea: Both genes must function for the wild-type phenotype.

What is epistasis, and what is the difference between an epistatic and hypostatic gene?

• Epistasis occurs when one gene masks the phenotypic expression of another gene at a different locus.

• Epistatic gene: does the masking.

• Hypostatic gene: is masked.

• Epistasis modifies the normal 9:3:3:1 dihybrid phenotypic ratio because different genotype classes can produce the same phenotype.

• Recessive epistasis: homozygous recessive genotype (aa) masks another gene → typically 9:3:4.

  • A/- b/b and a/a b/b have the same phenotype

• Dominant epistasis: at least one dominant allele (A–) masks another gene → typically 12:3:1.

  • A/- B/- and A/- b/b have the same phenotype

How does recessive epistasis produce a 9:3:4 ratio?

• In recessive epistasis, a homozygous recessive genotype at one locus masks the other gene.

• Mouse example:

  • A– C– → agouti = 9/16

  • aa C– → black = 3/16

  • A– cc → albino = 3/16

  • aa cc → albino = 1/16

• Because cc prevents pigment production, the A genotype doesn't matter when cc is present.

• The genotype at the A locus would have determined how the pigment is deposited: either black (a/a) or agouti (A/-)

• Therefore:

• 3/16 + 1/16 = 4/16 albino

• F₂ ratio = 9 agouti : 3 black : 4 albino

• Key idea: cc is epistatic because it masks A/a.

Recessive Epistasis Ratio

What is dominant epistasis and why does it produce a 12:3:1 F₂ phenotypic ratio?

• Dominant epistasis occurs when one dominant allele at one locus masks the expression of another gene.

• Cat example: W– masks the B/b locus, so any cat with WW or Ww is white, regardless of its B genotype.

• If the cat is ww, B/b can be expressed:

  • ww B– → black

  • ww bb → brown

• In a WwBb × WwBb cross:

  • 9/16 W–B– → white

  • 3/16 W–bb → white

  • 3/16 wwB– → black

  • 1/16 wwbb → brown

• The two white categories combine: 9 + 3 = 12

• F₂ phenotypic ratio = 12 white : 3 black : 1 brown (12:3:1)

• W is epistatic (does the masking); B is hypostatic (is masked).

Summary of F2 Ratios

What is pleiotropy, and how does it differ from epistasis?

• Pleiotropy occurs when one gene influences multiple distinct phenotypic traits.

• This can occur when the gene's product functions in multiple tissues or biological processes.

• Examples: sickle cell disease and cystic fibrosis, where a change in a single gene can have effects in multiple parts of the body.

• Pleiotropy: 1 gene → multiple phenotypic effects

• Epistasis: one gene masks/modifies the phenotypic effect of another gene

Some key points to remember

What is inbreeding depression and why can inbreeding cause it?

• Inbreeding increases homozygosity and decreases heterozygosity.

• This increases the chance that harmful recessive alleles become homozygous and are expressed.

• Expression of harmful recessive alleles can reduce fitness, growth, fertility, survival, or overall vigor.

• This reduction in biological performance is called inbreeding depression.

Inbreeding → ↑ homozygosity → ↑ expression of harmful recessive alleles → ↓ vigor/fitness

What is heterosis (hybrid vigor), and how is it related to inbreeding?

• Heterosis (hybrid vigor) occurs when hybrids produced by crossing genetically different lines show greater performance/vigor than the inbred parental lines.

• Different inbred lines are highly homozygous, often for different alleles.

• Crossing them produces offspring that are heterozygous at many loci.

• Functional alleles from one parent can mask harmful recessive alleles from the other.

• Therefore, hybrids may grow faster, survive better, or have greater yield than the inbred parental lines.

Different inbred lines → cross → ↑ heterozygosity → heterosis/hybrid vigor

What is the Hardy–Weinberg principle, and what assumptions must be met?

The Hardy–Weinberg principle states that allele and genotype frequencies remain stable across generations if a population is not evolving.

For Hardy–Weinberg equilibrium, the population must have:

• Large population size → minimizes random changes due to genetic drift

• Random mating

• No mutation

• No migration/gene flow

• No natural selection

If these assumptions are met:

• Allele frequencies do not change across generations.

• After one generation of random mating, genotype frequencies occur as:

  • p² = AA

  • 2pq = Aa

  • q² = aa

What is the difference between allele frequency and genotype frequency, and how are they calculated?

Genotype frequency = proportion of individuals with a particular genotype.

Example with 30 individuals:

• 7 CᴮCᴮ → 7/30 = 0.23

• 15 CᴮCᴳ → 15/30 = 0.50

• 8 CᴳCᴳ → 8/30 = 0.27

Allele frequency = proportion of all copies of the gene represented by a particular allele.

Because diploid individuals have 2 alleles each, 30 individuals have 60 total alleles.

For Cᴮ:

[(2 × # CᴮCᴮ) + (# CᴮCᴳ)] / total alleles

= [(2 × 7) + 15]/60
= 29/60
= 0.48

For Cᴳ:

= [(2 × 8) + 15]/60
= 31/60
= 0.52

Allele frequencies must add to 1.

What are the Hardy–Weinberg equations, and what do p, q, p², 2pq, and q² represent?

• Allele frequencies:

• p + q = 1

  • p = frequency of allele A

  • q = frequency of allele a

• Genotype frequencies:

• p² + 2pq + q² = 1

  • p² = frequency of AA

  • 2pq = frequency of Aa

  • q² = frequency of aa

• Why 2pq?
  A heterozygote can be produced in two ways:

• A from one parent + a from the other = pq
  a from one parent + A from the other = pq

• → pq + pq = 2pq

• Example: If p = 0.55 and q = 0.45:

  • AA = p² = 0.3025

  • Aa = 2pq = 0.495

  • aa = q² = 0.2025

• Key distinction:
  p and q = allele frequencies
  p², 2pq, q² = genotype frequencies

Recap: Hardy Weinberg Equations

How can the X and Y chromosomes pair during meiosis if they are not homologous?

• The X and Y chromosomes are mostly different and contain different genes.

• However, they share small homologous regions called pseudoautosomal regions (PARs).

• These matching regions allow the X and Y chromosomes to pair during meiosis in males.

What is dosage compensation and why is it necessary?

• Dosage compensation balances the expression of X-linked genes between individuals with different numbers of X chromosomes.

• XX individuals have two X chromosomes, while XY individuals have one X chromosome.

• Without compensation, XX individuals could have greater expression of many X-linked genes.

• In mammals, this is largely prevented through X-chromosome inactivation.

What is X-chromosome inactivation and what is a Barr body?

• In XX mammals, one X chromosome is largely inactivated in each cell.

• The X chosen for inactivation is generally random early in development.

• The inactive X becomes highly condensed and forms a Barr body.

• Once an X is inactivated, the same X generally remains inactive in descendant cells.

• This makes XX individuals mosaics for X-linked gene expression.

• Some genes can escape X-inactivation and remain expressed.

How does random X-inactivation cause mosaicism in females heterozygous for an X-linked gene?

• Early in development, one X chromosome is randomly inactivated in each XX cell and forms a Barr body.

• Some cells keep the maternal X active, while others keep the paternal X active.

• Once an X is inactivated, the same X generally remains inactive in that cell's descendants.

• Therefore, a heterozygous female can have groups of cells expressing different X-linked alleles, making her a mosaic.

• This random X-inactivation is described by the Lyon hypothesis.

• # of Barr bodies = # of X chromosomes − 1.

Calico Cat Example