Genetics Lecture 2 PDF

Genetics Zainab waleed aziz Lecture II Summary of the previous lecture: ✓ All Human diseases in general, can be classified into three categories (genetically determined, or completely environmentally determined or both genetics and environment share in their developmen...

Genetics Zainab waleed aziz Lecture II Summary of the previous lecture: ✓ All Human diseases in general, can be classified into three categories (genetically determined, or completely environmentally determined or both genetics and environment share in their development) ✓ Not all congenital diseases are genetic & not all genetic diseases are congenital. ✓ Euploid is any exact multiple of the haploid number of chromosome (xn). While polyploid is 3n (triploid=69) & 4n (tetraploid=92) & generally results in a spontaneous abortion. And aneuploid is any number that is not an exact multiple of n ✓ Deletion, isochromosome and inversion types of structural chromosomal abnormalities B. Defects of Single Gene with Large Effect (Unifactorial or Mendelian Disorders) Over 5000 Mendelian disorders known. Account for 1% of adult hospital admissions and 6-8% of pediatric admissions. Most common genetic abnormality. Caused by single-gene mutation. Mutation Defined as a permanent change in the DNA sequence. Such a change occurs in a gene or in a chromosome. Types of mutations: 1. Chromosome mutation – structural changes within the chromosome – translocations, deletions – loss or gain of whole chromosomes: monosomy and trisomy 2. Gene mutation – alterations at the level of the gene. Germ cell mutations can be inherited and cause inherited diseases. Somatic cell mutations do not cause hereditary diseases but can lead to cancers and some congenital malformations. Gene Mutation: Mutations occur at the level of individual genes. They involve changes in the nucleotide sequence of a gene. 1. Point Mutations: A mutation involves substituting one base with another in a DNA sequence a. Missense Mutation: Changes one base pair, leading to the substitution of one amino acid for another in the protein sequence. i. Conservative Substituted amino acid is biochemically similar to the original. Typically has little impact on protein function. ii. Non conservative Missense Mutation: Substitutes the normal amino acid with a biochemically different one. Can significantly affect protein function.  Sickle cell anemia Mutation of β-globin gene b. Nonsense Mutation: When the base sequence change gives rise to a stop codon rather than a codon specifying an amino acid. Leads to premature termination of gene translation, results in the premature termination of protein synthesis. Example: β0-thalassemia: Point mutation affects glutamine codon (CAG), creating a stop codon (UAG). Results in a severe form of anemia due to a deficiency of β-globin chains. c. Silent Mutation: Alters a single base pair but does not change the amino acid coded for. Often occurs in non-coding or redundant regions of the gene and does not affect protein function. 2. Frame shift Mutation: Involves the insertion or deletion of one or more nucleotides that shift the reading frame of the gene for process of translation, leading to an entirely different protein sequence downstream of the mutation. Typically results in non-functional proteins. 3. Trinucleotide repeats mutation (Expansion Mutations): Characterized by amplification of a sequence of three nucleotides (trinucleotide repeat). Such type of mutation leads to amplification of a sequence of 3 nucleotides as in fragile X chromosome syndrome in which there is a 250 or more repeat of CGG within a gene called familial mental retardation 1 (FMR1).  Types of Mutations https://app.lecturio.com/#/article/3813 Transmission Patterns of Single-Gene Disorders Mutations involving single genes follow one of three patterns of inheritance: 1. autosomal dominant 2. autosomal recessive 3. X-linked. A single-gene mutation may lead to multiple phenotypic effects Phenotype means the clinical expression. Could be physiological (height, color) or pathological (DM, HT). A phenotype results from the expression of the genetic code (genotype), as well as the influence of environmental factors and the interactions between the two. All Mendelian disorders are the result of mutations in single genes that have large effects. 80% to 85% of these mutations are familial. 1. Autosomal Dominant Disorders: Characteristics: Allelic Mutation: Manifests when one allele at a specific gene locus is mutated. Parents Usually Affected: Typically, at least one parent is affected. Siblings at Risk: Siblings have a 50% chance (1 in 2) of inheriting the trait (recurrence risk). New Mutations: Some affected individuals do not have affected parents due to new mutations. Incomplete Penetrance: Clinical features can be modified, and some individuals inherit the mutant gene but remain phenotypically normal. An example: Hereditary breast and ovarian cancer caused by BRCA1 and BRCA2 variants. While the lifetime risk of cancer is increased by having one of these variants, not everyone with a pathogenic BRCA variant will develop cancer in their lifetime. Variable Expressivity: The mutant gene is expressed differently among individuals carrying it; variable expressivity is common. Late Onset: Onset of symptoms often occurs in adulthood. Heterozygous Manifestation: Disorders are primarily manifested in the heterozygous state. Equal Gender Effect: Both males and females are affected equally, and both can pass on the disorder. 2. Autosomal Recessive: Characteristics: Allelic Mutation: Manifests only when both alleles at a specific gene locus are mutated. Parents Not Usually Affected: Parents of affected individuals are typically not affected themselves (carriers). Siblings at Risk: Siblings have a 25% chance (1 in 4) of inheriting the trait (recurrence risk). Consanguinity: In cases where the mutant gene is rare in the population, affected individuals (proband) may be the result of a consanguineous marriage. Contrasting with Autosomal Dominant Disorders: Uniform Expression: Expression of the disorder tends to be more uniform compared to dominant diseases. Complete Penetrance: High likelihood of complete penetrance, meaning most individuals with the gene mutation will express the disorder. Early Onset: Onset of symptoms is often early in life. Rare New Mutations: New mutations are rare and seldom detected. Enzyme-Encoding Genes: Many mutated genes in autosomal recessive disorders encode enzymes. Inborn Errors of Metabolism: Autosomal recessive disorders encompass most inborn errors of metabolism. 3. X-Linked Disorders: Characteristics: No Father-Son Transmission: Absence of transmission from fathers to sons. Obligate Carriers: All daughters of affected males are obligate carriers. Hemizygous Males: Dominant and recessive terms apply only to females; males are hemizygous. Predominantly Recessive: The majority of X-linked disorders are recessive. Rare X-Linked Dominant Disorders: Examples include vitamin D-resistant rickets, Alport's syndrome, Goltz syndrome, and X-linked dominant porphyria. Features of X-Linked Disorders: Sex Distribution: Females are carriers, and males are typically affected. Maternal Transmission: Carrier females transmit the disorder to their sons, who have a 50% chance of being affected. No Paternal Transmission to Sons: Affected males cannot transmit the disease to their sons, but all their daughters are carriers. Rare Expression in Heterozygous Females: Heterozygous females rarely express the disease when there is: – Random inactivation of the other X-chromosome. – Father is affected & mother is a carrier. – Female has one affected X-chromosome as in Turner syndrome.