HMB265: General & Human Genetics - Lecture Notes

Genetic Predictions and Counselling

• Genetic Counselling Sessions Involve:

  • Gathering a comprehensive family history.

  • Constructing a pedigree chart to visualize inheritance patterns.

  • Providing detailed information on specific genetic disorders, their modes of inheritance, and available tests.

  • Identifying family members at risk.

  • Arranging necessary genetic testing and discussing the results thoroughly.

  • Connecting individuals to support groups and appropriate services.

  • Ensuring follow-up contact for ongoing support and information.

Issues Associated with Genetic Screening

• Justification: Why should genetic screening be performed at all?

• Test Accuracy: When is a genetic test sufficiently accurate and comprehensive to be used as a basis for broad screening?

• Mandatory vs. Optional: Once an accurate and reasonably priced test is available, should screening be mandated or remain optional?

• Target Population: If a screening program is established, who should be included in the testing?

• Data Access and Privacy: Should private companies and insurance providers have access to employee and client genetic test results?

• Education: What kind of education and information needs to be provided to individuals regarding their test results?

Extensions of Mendelian Genetics (Part 1)

Challenging Mendel's Laws: "Wrinkles"

While Mendel's laws provide a foundational understanding of inheritance, certain genetic phenomena introduce complexities:

• Incomplete Dominance: Neither allele is fully dominant, leading to an intermediate phenotype in heterozygotes.

• Codominance: Both alleles are expressed equally and distinctly in heterozygotes.

• Multiple Alleles: A gene can have more than two alleles within a population.

• Pleiotropy: A single gene affects multiple, seemingly unrelated phenotypic traits.

• Variable Expressivity: The degree or intensity of a phenotype varies among individuals with the same genotype.

• Incomplete Penetrance: Not all individuals carrying a particular genotype express the associated phenotype.

• Environmental Influence: Environmental factors can significantly impact gene expression and phenotypic outcome.

Dominance is Not Always Complete

Crosses between true-breeding strains can produce hybrids ($F_1$) with phenotypes differing from both parents.

Incomplete Dominance

• Definition: $F_1$ hybrids express an intermediate phenotype, meaning neither allele is completely dominant or recessive. The heterozygote's phenotype is distinct and often a blend of the two homozygous phenotypes.

• Phenotypic and Genotypic Ratios: The phenotypic ratios are identical to the genotypic ratios.

• Example: Flower Color

  • Parental (P) Cross: $A^1A^1$ (red) $\times$ $A^2A^2$ (white)

  • $F_1$ Generation: All $A^1A^2$ (pink) – an intermediate phenotype.

  • $F_1$ Self-Cross: $A^1A^2$ $\times$ $A^1A^2$

  • $F_2$ Generation Ratios:

  • Genotypic: $1 A^1A^1 : 2 A^1A^2 : 1 A^2A^2$

  • Phenotypic: $1$ Red $: 2$ Pink $: 1$ White (same as genotypic ratio).

• Loss-of-Function Mutations and Haploinsufficiency: In some cases, one wild-type allele is not enough to produce the full wild-type phenotype, leading to incomplete dominance. For example, if a threshold of enzyme activity is required for a phenotype, a heterozygote with only one functional allele might not reach this threshold (e.g., $R^+R^0$ where $R^+$ produces less pigment than $R^+R^+$).

• Example: Familial Hypercholesterolemia (FH)

  • Heterozygotes have a distinct phenotype that is intermediate between the two homozygous phenotypes, demonstrating incomplete dominance.

Codominance

• Definition: $F_1$ hybrids express the phenotype of both parents equally and distinctly. Both alleles contribute to the phenotype without blending.

• Phenotypic and Genotypic Ratios: The phenotypic ratios are identical to the genotypic ratios.

• Example: Roan Cattle Coat Colour

  • Parental (P) Cross: $C^SC^S$ (spotted red) $\times$ $C^DC^D$ (dotted white)

  • $F_1$ Generation: All $C^SC^D$ (roan—spotted and dotted regions present).

  • $F_1$ Self-Cross: $C^SC^D$ $\times$ $C^SC^D$

  • $F_2$ Generation Ratios:

  • Genotypic: $1 C^SC^S : 2 C^SC^D : 1 C^DC^D$

  • Phenotypic: $1$ Spotted $: 2$ Roan $: 1$ Dotted (same as genotypic ratio).

A Gene Can Have More Than Two Alleles (Multiple Alleles)

• Definition: Genes may possess multiple alleles (more than two forms) within a population, although any single individual carries only two of these alternative alleles.

• Dominance Relations: Dominance or recessiveness is specific to a pair of alleles, meaning one allele might be dominant to a second but recessive or codominant to a third.

• Example: ABO Blood Group System (Human)

  • Gene: $I$ (for isoagglutinogen, coding for glycosyltransferase).

  • Alleles: $I^A, I^B, i$ (three alleles).

  • Genotypes: There are 6 possible genotypes:

  • $I^AI^A$ (Type A)

  • $I^Bi$ (Type B)

  • $I^AI^B$ (Type AB)

  • $I^Ai$ (Type A)

  • $I^BI^B$ (Type B)

  • $ii$ (Type O)

  • Dominance Relationships:

  • $I^A$ is completely dominant to $i$.

  • $I^B$ is completely dominant to $i$.

  • $I^A$ and $I^B$ are codominant to each other (both expressed in heterozygotes).

  • Phenotypes: These 6 genotypes result in 4 phenotypes: Type A, Type B, Type AB, and Type O.

  • Molecular Basis: The ABO gene encodes a cell surface protein, glycosyltransferase, which adds specific sugars to red blood cell surfaces to create A and B antigens.

  • Blood Transfusion Compatibility:

  • Type AB individuals are universal recipients because they have both A and B antigens and produce no antibodies against A or B.

  • Type O individuals are universal donors because they have neither A nor B antigens and do not trigger an immune response in recipients with A or B antibodies.

  • Type A individuals can receive A or O blood types.

  • Type B individuals can receive B or O blood types.