Non-Mendelian Genetics Notes

Non-Mendelian Genetics

Recessive Lethal Genes

  • The dominant yellow allele (Ay) of the Agouti gene in mice leads to a yellow coat but contains a recessive lethal mutation.
  • A cross between two heterozygous yellow mice (AyA) results in a 2:1 ratio of yellow to black offspring, instead of the expected 3:1 Mendelian ratio.
  • This is because the homozygous (AyAy) genotype is lethal, and these individuals do not survive.
  • Genotypes:
    • AA: Black
    • AAy: Yellow
    • AyAy: Lethal

Incomplete Dominance

  • The heterozygote displays an intermediate phenotype compared to the parental homozygotes.
  • Example: Flower color in snapdragons (Antirrhinum).
  • A cross between a red flower (CRCR) and a white flower (CWCW) results in pink flowers (CRCW) in the F1 generation.
  • The F2 generation shows a 1:2:1 ratio for red:pink:white flowers instead of the Mendelian 3:1.
  • Genotypes:
    • CRCR: Red
    • CRCW: Pink
    • CWCW: White

Co-dominance

  • Two alleles encode for different gene products, and both alleles are expressed in the heterozygote.
  • This results in a phenotype that shows both traits associated with each homozygote.
  • Example: Coat color in cattle.
  • A cross between a red-coated cow (RR) and a white-coated cow (RWRW) results in roan-coated offspring (RRW) in the F1 generation.
  • The F2 generation shows a 1:2:1 ratio for red:roan:white coats, instead of the Mendelian 3:1.
  • Genotypes:
    • RR: Red
    • RRw: Roan
    • RwRw: White

Multiple Alleles

  • Mendel's laws apply to biallelic genes, but some genes have more than two alleles in a population.
  • An individual can only have two alleles, but there could be several possible allelic combinations in the population (e.g., A1A1, A1A2, A2A3).
  • Example: Human ABO blood groups.

ABO Blood System

  • The ABO blood system is determined by three alleles: IA, IB, and i.
  • IA and IB are co-dominant, and i is recessive.
  • This results in six possible genotypes and four phenotypes (blood types).
  • Phenotypes and corresponding genotypes:
    • O: ii
    • A: IAIA or IAi
    • B: IBIB or IBi
    • AB: IAIB

Deviations from Mendelian Ratios

  • Phenotype ratios from heterozygous crosses for the ABO blood system can deviate from the expected 3:1.
  • Examples:
    • AB x AB (IAIB x IAIB) yields a 1:1:2 ratio of A:B:AB
    • A x B (IAi x IBi) yields a 1:1:1:1 ratio of A:B:AB:O
    • A x AB (IAi x IAIB) yields a 2:1:1 ratio of A:AB:B

Influencing Inheritance

  • Inheritance can be affected by intra-locus (allele interaction) and inter-locus (gene interaction) actions.
  • Intra-locus interactions include:
    • Complete dominance (haplo-sufficiency)
    • Incomplete dominance
    • Co-dominance
  • Inter-locus interactions include:
    • Genes acting on different pathways
    • Genes acting on the same pathway (epistasis), which modifies Mendelian ratios

Dihybrid Cross

  • A cross involving two genes with two alleles each.
  • Parents: RRYY x rryy
  • F1 generation: All RrYy
  • F2 generation: Resulting from a cross of RrYy x RrYy, the phenotypic ratio is 9:3:3:1.
  • Punnett square:


\begin{array}{c|cccc}
& RY & rY & Ry & ry \
\hline
RY & RRYY & RrYY & RRyY & RrYy \
rY & RrYY & rrYY & RrYy & rryY \
Ry & RRyY & RrYy & RRyy & Rryy \
ry & RrYy & rryY & Rryy & rryy
\end{array}

Two Genes, One Trait

  • When two unlinked genes demonstrate complete dominance and act independently (in different pathways), expect a 9:3:3:1 ratio.
  • Example: Skin color in corn snakes, where one gene determines orange pigment and the other determines black pigment.
  • This is analogous to co-dominance but involves two genes.

Epistasis

  • Epistasis: Interaction between two genes where alleles at one gene (epistatic) mask the phenotypic expression of alleles at another gene (hypostatic).
  • This results in fewer phenotypic classes than expected.
  • The ratios indicate how gene loci interact.
  • Example: AABBCC = pink, AABBcc = blank, aaBBcc = blank, etc.

Dominant Epistasis

  • Dominant allele at one locus masks the expression of alleles at a second locus.
  • Example: Fruit color in summer squash (Curcurbita).
  • W allele (dominant) masks the expression of Y/y alleles.
  • Cross: WWyy x wwYY
  • F1: All WwYy
  • F2 Phenotype Ratio: 12:3:1 (White:Yellow:Green)

Dominant Epistasis: Biochemical Pathway

  • Two-step biochemical pathway:
    • Gene W/w: masks Y/y gene. W_ inhibits Enzyme I, which converts a colorless pigment into a colored pigment.
    • Gene Y/y: Determines whether the colored pigment is yellow or green, but only if no W allele is present.
  • Phenotypes:
    • WY = White (9/16)
    • W_yy = White (3/16)
    • wwY_ = Yellow (3/16)
    • wwyy = Green (1/16)

Divergence from 9:3:3:1

  • Different types of epistasis can lead to various phenotypic ratios:
    • Dominant epistasis
    • Duplicate interaction
    • Recessive epistasis
    • Duplicate dominant epistasis
    • Duplicate recessive epistasis

Incomplete Penetrance & Variable Expressivity

  • Penetrance: Percentage of individuals with a particular genotype that express the associated phenotype.
  • Expressivity: Degree to which a given allele is expressed at the phenotypic level.
  • Example: All individuals carry a dominant allele (P_) to produce purple pigment but do not show the same intensity of purple color.

Continuous Traits

  • Discrete traits: Occur in distinct categories (e.g., cystic fibrosis, Huntington's disease) and follow Mendelian inheritance.
  • Continuous traits: Phenotypes vary along a continuum (e.g., hair color, eye color, skin color, height), and inheritance is polygenic.

Polygenic Traits

  • Inheritance can be very complex, involving multiple genes (polygenic inheritance).
  • Example: Human skin color, controlled by multiple genes with additive effects.
  • Individuals with AABBCC have very dark skin, while those with aabbcc have very light skin.

Polygenic Traits: Population Fraction

  • Skin color example, the fraction of the population can be represented from the combined allele effects.
  • \frac{1}{64} AABBCC (very dark)
  • \frac{1}{64} aabbcc (very light)
  • Human pigmentation is a polygenic trait shaped by gene-gene interactions.
  • Interactions between genes like HERC2, OCA2, and MC1R can influence human pigmentation phenotype.
  • Interactive effects between HERC2 and OCA2 may also be responsible for blue eye color determination.

Pleiotropic Effects

  • One gene affects multiple phenotypes.
  • Example: Marfan syndrome, caused by mutations in the fibrillin gene (connective tissue protein).
  • Fibrillin is widespread, causing problems in the eye, aorta, bones, etc.

Nature vs. Nurture

  • Phenotypic variation (VP) is the sum of genotypic variation (VG) and environmental variation (VE).
  • VP = VG + V_E

Nature vs. Nurture: Example

  • Capsaicinoids in chili peppers act as a deterrent against mammalian herbivores and fungal pathogens.
  • Genetics determines the range of capsaicinoid accumulation in different cultivars.
  • Environmental factors, such as drought and predation, increase capsaicinoid levels.

Nature vs. Nurture: Sexual Orientation

  • Sexual orientation is approximately 32% genetically heritable.
  • Other contributions include in utero and post-zygotic environment.

Detecting Genes in Complex Traits

  • Analysis methods include:
    • Family trees
    • Populations (Genome-wide association studies, GWAS)
    • Selected crosses (experimental models)
    • Model species
    • Knockout mutants
  • Sequencing methods include:
    • Targeted sequencing using PCR-based assays
    • Whole genome/exome re-sequencing
    • Whole genome profiling (Rad-Tag sequencing etc.)
  • Complex gene interactions (e.g., epistasis) complicate analysis.

Non-Mendel Summary

  • Variations from Mendelian inheritance patterns occur due to:
    • A trait may be lethal when homozygous.
    • More than one allele/genes may be responsible for a trait (incomplete dominance, co-dominance, epistasis, polygenic inheritance).
    • One gene may be responsible for more than one phenotype (pleiotropy).
    • Interaction with environmental factors.