Genetics and Hemoglobin Quiz

Molecular, Biochemical, and Cellular Basis of Genomic Disease

• The lecture covers the molecular, biochemical, and cellular underpinnings of genomic diseases.

Objectives of This Lecture

• Illustrate the fundamental mechanism behind genetic variation.
• Explain different types of mutations.
• Describe the effect of mutations on protein function.
• Describe protein classification based on expression patterns and tissue specificity.
• Understand genetic and phenotypic heterogeneity.
• Describe the relationships between protein expression sites and diseases.
• Describe diseases discussed in the lecture.

Genetic Variation Among Humans

• Substantial variations exist among humans (e.g., skin color, height, hair color, susceptibility).
• Mutation: any change in DNA sequence.
• Mutations in humans often cause genetic disease, typically affecting single genes and not microscopically apparent.
• Mutations can occur in coding or regulatory DNA sequences.
• Germline cells transmit mutations to the next generation, somatic cells do not.
• Allele: alternative forms/versions of a gene.
• Locus: a gene's location on a chromosome.
• Polymorphism: existence of multiple alleles for a gene in a population.

Molecular Basis of a Disease

• Molecular disease: disease traced back to a single molecular factor (e.g., protein, polypeptide).
• Mutation (inherited or acquired) is the primary cause of molecular disease
• Understanding molecular pathology is critical for treating genetic diseases and understanding normal functions.
• Biochemical genetics studies relationships between genes and observable traits (phenotypes) at the protein production, function, biochemistry, and metabolism (e.g., turnover) levels.

Types of Mutations

• Base-pair substitutions (point mutations): Single base changes.
• Base-pair deletions or insertions: Removal or addition of base pairs in DNA.
• Splice-site mutations: Affect the splicing process.
• Gene duplications/deletions: Changes in gene number.
• Promoter mutations: Affect gene expression.
• Mobile element insertion: Movement of DNA segments.
• Expanded repeats: Repetition of DNA sequences.

Dominant Alleles and Recessive Alleles

• Alleles determine traits.
• Dominant alleles express their trait even with one copy.
• Recessive alleles only express their trait with two copies.

Dominant Alleles and Recessive Alleles

• A depiction of how offspring inherit traits based on dominant and recessive alleles is illustrated
• Relationships between the genotype and phenotype are explained with diagrams

Linked Loci

• Loci on the same chromosome tend to be inherited together
• Physical distance between linked loci influences the frequency of recombination.
• Recombination frequency is used to map the relative locations of genes on chromosomes.

Red Blood Cells: Structure and Function

• Red blood cells (erythrocytes) are biconcave discs without a nucleus.
• They contain hemoglobin.
• Each red blood cell contains millions of hemoglobin units.
• Hemoglobin consists of 2 alpha and 2 beta units.
• Each heme unit contains iron for oxygen bonding.

Sickle Cell Disease

• a subunit encoded by HBA on chromosome 16.
• ẞ subunit encoded by HBB gene on chromosome 11.
• Sickle cell disease is an autosomal recessive disorder of hemoglobin.
• A missense mutation substitutes valine for glutamic acid at amino acid 6 of the β-globin gene.
• This mutation reduces the solubility of deoxygenated hemoglobin, causing the cells to sickle.

Importance of understanding disease at molecular level

• The transition from fetal to adult hemoglobin illustrates the importance of understanding disease at the molecular level.
• Genetic editing using CRISPR-Cas9 can target disease-causing mutations to cure the disease.

Genotype vs Phenotype

• A link exists between the genotype and phenotype.
• Large numbers of genes and phenotypes are linked.
• Over 7000 phenotypes and nearly 4000 genes are associated.

Effect of Mutation on Protein Function

• Mutations can affect protein function in 4 ways:
• Loss-of-function.
• Gain-of-function.
• Novel properties.
• Misexpression.

Loss-of-Function Mutations

• Alterations in a gene's sequence can lead to loss-of-function.
• Examples include nonsense mutations, missense mutations impacting protein stability, and decreased protein abundance.
• Disease severity often correlates with the degree of lost function.

Loss of Protein Function Mutations (Thalassemia)

• Thalassemia results from reduced or absent globin production.
• Alpha thalassemia involves deficiencies in alpha globin chains, resulting in excess beta chains.
• Beta thalassemia involves deficiencies in beta globin chains, resulting in excess alpha chains.
• Both forms lead to premature erythrocyte destruction and anemia.

Gain-of-Function Mutations

• Mutations can enhance normal functions of a protein or create novel ones.
• Examples include increased protein production or altered protein activity.

Novel Property Mutations (e.g., Sickle Cell Disease)

• Changes in amino acid residues can generate novel protein properties without altering normal functions.
• This involves mutations altering the biochemical properties of the protein, and creating new qualities that cause disease.

Mutations Associated with Heterochronic or Ectopic Gene Expression

• Mutations in regulatory regions cause abnormal gene expression inappropriate times or locations.
• This can lead to diseases like malignancy, or hereditary persistence of fetal hemoglobin due to mutations in the regulatory elements.

Ways for Mutations to Disrupt the Synthesis or Function of a Normal Protein

• Mutations can disrupt protein production and function at various steps, such as transcription, translation, folding, post-translational modification, assembly, subcellular localization, and cofactor binding.

Classification of Proteins

• Proteins are classified based on expression patterns;
• Housekeeping proteins: expressed in all cells; fundamental.
• Tissue-specific proteins: expressed in specific cells; unique functions.

Relationship Between Site of Protein Expression and Disease

• Mutations in tissue-specific proteins can cause diseases restricted to those tissues.
• Disease can also occur in other tissues, that do not express the defective protein.

Relationship Between Site of Protein Expression and Disease (Cont'd)

• Mutations in housekeeping proteins rarely cause severe, widespread diseases.
• Genetic redundancy or protein abundance can mitigate the impact of mutations in certain cases.

Genetic Heterogeneity vs. Pleiotropy

• Genetic heterogeneity: Different mutations can lead to the same phenotype.
• Pleiotropy: A single gene mutation can cause multiple phenotypes.

Protein Abnormalities and Genetic Diseases

• Mutations in functional classes of proteins lead to genetic disorders.
• These mutations affect various cellular components affecting their function.

How to classify mutations that disrupt cell and organ functions

• A classification system for mutations is needed, that describes and explains how different types of mutations can disrupt cell and organ function.