Human Genetics 14

Overview

  • Schedule Reminders:

    • Quiz on Wednesday covering material up to today's lesson.

    • Next exam on Monday covering Chapters 3, 4, and 5.

Genetics Concepts

Categories of Inheritance

  • Some genetic traits may fit into multiple categories of inheritance (e.g., autosomal dominant or autosomal recessive).

  • Molecular Analysis is necessary to determine the type of inheritance, typically using:

    • Exome sequencing

    • Whole genome sequencing

Spontaneous Mutations

  • A spontaneous (de novo) mutation occurs in a child where no similar syndrome has been seen in the parents.

    • Termination: These mutations are not inherited but arise during processes like spermatogenesis or oogenesis.

    • Examples of spontaneous mutations include:

    • Child with different colored eyes due to a mutation occurring in a precursor cell.

    • Two parent carriers producing an affected child with autosomal recessive disorder.

Molecular Analysis of Pedigrees

-Step 1: Align DNA sequences.

  • Compare chromosome one from each parent and their affected child using bioinformatics software.

    • Step 2: Identify differences (or variants) in DNA sequences.

  • Definition of a variant: A difference in the DNA sequence between two individuals. In genetic analysis, these are termed variants instead of mutations to avoid negative connotations.

  • Varieties may include:

    • Pathogenic variants: Causes diseases.

    • Variants of unknown significance: Differences that are not yet understood scientifically.

Importance of Terminology

  • Using variant can connote neutrality whereas mutation is often viewed negatively.

Analysis of Pedigrees

  1. Unknown inheritance types can be identified through molecular analysis.

    • E.g., a pedigree analysis may show unaffected parents with affected children.

    • Outcomes:

      • If autosomal recessive: Both parents are carriers.

      • If a new de novo mutation: Child expresses a trait not present in either parent.

  2. Genetic examples of inheritance scenarios:

    • If a parent has a new mutation, potential children may inherit the gene or not:

      • Example notation: big A (dominant), little a (recessive) leading to various combinations of children's traits.

Moving Towards Advanced Concepts

Chapter 5 Introduction

  • This chapter will cover topics beyond Mendel's single trait findings, focusing on:

    • X-linkage

    • Complex traits

    • Continuous variability (e.g., height is determined by multiple genes and environmental factors).

Extensions to Mendel's Laws

  1. Complex traits: Most traits, unlike Mendel's findings, will show a bell curve due to the involvement of multiple genes.

    • E.g., human height involves numerous genes and environmental factors, contrasting Mendel’s binary trait study.

  2. Genetic Ratio Modifications:

    • Ratios may not conform exactly to Mendelian ratios but still follow some underlying rules.

    • Modified phenotypic ratios can occur when multiple alleles or lethal alleles come into play.

Lethal Alleles

  • Example: Achondroplasia (a form of dwarfism).

    • Genotype implications:

    • Big A little a (achondroplasia) versus big A big A (embryonic lethal).

    • When two carriers (big A little a) reproduce:

    • Punnett square yields:

      • 1/4 average height (wild type)

      • 2/4 dwarfism (achondroplasia)

      • 1/4 embryonic lethal

    • Phenotypic ratio modified to 1:2 (with living offspring) rather than expected 1:4 ratios.

Disease Examples

  • Cystic Fibrosis (CF):

    • Involves multiple alleles affecting the lung's CFTR protein and chloride movement.

    • Type 1 mutations lead to the absence of protein, while Type 2 causes misfolded proteins, and Type 3 mutations affect channel function.

    • With multiple alleles, genotype understanding is essential for treatment considerations.

    • New treatments aim to improve chloride ion movement rather than simply being classified as autosomal recessive.

Compound Heterozygotes

  • Individuals with two different mutations at the same gene locus can show variations in disease severity due to the specific functions of each allele.

Types of Dominance

Incomplete Dominance

  • Definition: The heterozygote expresses an intermediate phenotype.

    • Example: Familial Hypercholesterolemia.

    • Wild Type: Low cholesterol

    • Heterozygotes: Intermediate cholesterol levels

    • Homozygotes: Very high cholesterol levels.

Codominance

  • Defined as both alleles being simultaneously expressed without dominance.

    • Example: ABO Blood Groups where both A and B antigens may be present in an individual with AB blood type, while O has no antigens but produces antibodies against A and B.

Conclusion and Next Steps

  • In Genetics, knowledge of molecular functions, and allele interaction is paramount over traditional dominant/recessive classifications.

  • Importance of understanding various genetic conditions, their symptoms, and potential treatments is emphasized as we transition to discussing rejection in organ transplants and other complexities of genetic relationships in human health.