Mendelian Inheritance and Monogenic Diseases

Mendelian Inheritance

• Mendelian Genetics: Principles established by Gregor Mendel regarding the transmission of traits.

  • Monohybrid Crosses: Demonstrates Mendel's First Law.

  • Dihybrid Crosses: Demonstrates Mendel's Second Law.

  • Meiosis and Mendel's Laws: Explanation of how meiosis relates to these laws.

• Human Genetics: Focus on monogenic diseases.

  • Autosomal Recessive Diseases: Genetic disorders requiring two copies of an abnormal gene for expression.

  • Autosomal Dominant Diseases: Genetic disorders requiring only one copy of an abnormal gene for expression.

• Chromosomal Theory of Inheritance: Explains sex-linked inheritance.

  • X-linked Recessive Diseases: Conditions related to the X chromosome where the mutated gene is recessive.

  • X-linked Dominant Diseases: Conditions related to the X chromosome where the mutated gene is dominant.

  • Holandric Inheritance (Y-linked): Traits inherited via the Y chromosome.

• Analysis of Pedigree Trees: Method to study inheritance patterns in families.

• Modes of Monogenic Inheritance: Summarizing different inheritance patterns.

Mendel's Experiments

• Laws/Principles of Mendel: Describe how traits are passed from one generation to the next in diploid species ($2n$) with sexual reproduction.

• Gregor J. Mendel (1822-1884):

  • Conducted hybridization experiments on plants in 1866 at the Monastery of Saint Thomas in Brno, Czech Republic.

• Concept of a Gene: Mendel's work introduced the concept of genes.

Mendel’s Traits

• Pea Plant (Pisum sativum) Characteristics: Short life cycle, many seeds, easy and economical to grow, requires little space, wide variety, and capable of both self-fertilization (natural) and cross-fertilization (artificial), allowing controlled crosses.

• Qualitative Traits: Each trait has two variants or forms of expression.

Mendel’s Traits (cont.)

• Plant Selection: Mendel used plants that differed in only one trait, ensuring two pure lines for each trait.

• Pure Line Definition: A population of plants whose offspring, obtained through self-fertilization or cross-fertilization, remain homogeneous for a specific trait across generations.

Monohybrid Crosses

• Mendel focused on plants differing in one character (monohybrid crosses).

• Parental generation (P) produced F1 generation, which then produced F2 generation.

• Observed ratios in F2 generation consistently approached 3:1 (dominant:recessive).

• Examples: Seed texture (smooth vs. wrinkled), seed color (yellow vs. green), flower color (purple vs. white), pod texture (smooth vs. constricted), pod color (green vs. yellow), flower position (axial vs. terminal), stem length (tall vs. dwarf).

Monohybrid Crosses (cont.)

• Observed phenotypic ratio of 3:1 in F2 generation.

• Genotypic ratio within the 3:1 phenotypic ratio is 1:2:1.

• Test of progeny revealed the underlying genotypic ratios.

• F3 generation results further supported Mendel's conclusions.

Explanation of Monohybrid Crosses

• Particulate Inheritance: Hereditary factors (genes) exist as discrete particles.

• Alleles: Each F1 plant has two factors (alleles) for each trait: dominant and recessive.

• Segregation: The two factors for each trait segregate equally into sex cells.

• Gametes: Each gamete contains only one factor from each pair.

• Random Union of Gametes: Gametes from each parent unite randomly during fertilization.

• Using Punnett squares, if $A$ is smooth and $a$ is wrinkled, the resulting phenotypic ratio is 3:1.

Mendel’s First Law

• Paired Factors: Each cell contains a pair of discrete hereditary factors for each trait.

• Equal Probability: During gamete formation, each gamete receives only one factor from each pair, with equal probability.

• Law of Segregation: The two alleles of a gene segregate equally among gametes.

Test of Mendel's First Law

• Test Cross or Backcross: Crossing an individual of unknown genotype with a homozygous recessive individual.

• Phenotypic Proportions: Resulting phenotypic proportions for monohybrid crosses are 1:1.

Modern Genetic Terminology

• Gene: A segment of DNA on a chromosome that influences a specific trait.

• Allele: A variant of a gene that arises through mutation during evolution; each individual has two alleles per gene (paternal and maternal).

• Genotype: The genetic constitution of an organism.

  • Homozygous: An individual with two identical alleles for a gene.

    • Dominant: Homozygous for the allele that determines the dominant phenotype (AA).

    • Recessive: Homozygous for the allele that determines the recessive phenotype (aa).

  • Heterozygous: An individual with two different alleles for a gene (Aa).

• Phenotype: The observable form of a trait, generally resulting from the interaction between the genotype and the environment.

Dihybrid Crosses

• Mendel crossed plants differing in two traits, such as seed color and texture.

• F1 generation showed all dominant traits (e.g., yellow and smooth seeds).

• F2 generation exhibited a phenotypic ratio of 9:3:3:1.

• Observed phenotypic ratios: 315 yellow smooth, 101 yellow wrinkled, 108 green smooth, 32 green wrinkled.

• Ratios approximate 3:1 for individual traits, resulting in a combined ratio of $(3:1) Imes (3:1) = (9:3:3:1)$.

Explanation of Dihybrid Crosses

• Independent Segregation: The segregation of factors determining one trait is independent of the segregation of factors determining another trait.

• Genotypes in F2: Includes $A<em>B</em>$, $aaB<em>$, $A</em>bb$, and $aabb$, representing different combinations of alleles.

• Phenotypes in F2: 9/16 yellow smooth, 3/16 green smooth, 3/16 yellow wrinkled, and 1/16 green wrinkled.

• Mendel's Second Law (Law of Independent Assortment): The alleles of one gene assort independently of the alleles of another gene.

Test of Mendel's Second Law

• Test Cross or Retrocross: Crossing F1 dihybrid (e.g., smooth, yellow) with homozygous recessive parent (e.g., wrinkled, green).

• Expected Ratio: If genes assort independently, the expected phenotypic ratio in the progeny is 1:1:1:1.

Mitosis and Meiosis

• Mitosis: Cell division resulting in two identical daughter cells.

• Meiosis: Cell division resulting in four genetically different daughter cells with half the number of chromosomes as the parent cell.

Comparison of Mitosis and Meiosis

• Mitosis:

  • Occurs in somatic cells.

  • One cell division results in two daughter cells.

  • Chromosome number remains the same ($2n$).

  • One S phase per cell division.

  • No pairing of homologous chromosomes.

  • No crossing over.

  • Centromeres divide in anaphase.

  • DNA content per nucleus: 4n -> 2n.

  • Conservative process: daughter cells have identical genotypes to parental cell.

• Meiosis:

  • Occurs in cells during sexual cycle.

  • Two cell divisions result in four daughter cells.

  • Chromosome number is halved (n).

  • One S phase for two cell divisions.

  • Synapsis of homologous chromosomes in prophase I.

  • At least one crossover per pair of homologs.

  • Centromeres do not divide in anaphase I, but do in anaphase II.

  • DNA content per nucleus: 4n -> n.

  • Generates variation among products of meiosis.

Meiosis and Mendel's First Law

• Principles of Inheritance: Two alleles per gene, equal segregation of alleles in heterozygotes during gamete formation (3:1, 1:1 ratios).

• Segregation Explanation: The principle of equal segregation is due to the separation of homologous chromosomes during anaphase I of meiosis.

Meiosis and Mendel's Second Law

• Independent Segregation: Independent segregation of alleles for each gene (9:3:3:1, 1:1:1:1 ratios).

• Explanation: The principle of independent segregation results from the independent assortment of chromosomes during anaphase I of meiosis.

Human Genetics: Genetic Disorders

• Genetic Diseases: More than 9,000 genetic diseases known with over 16,000 genes identified.

• Monogenic Diseases: Caused by a mutation in a single gene, often referred to as 'rare' diseases (affecting 5% of births).

  • Inheritance Patterns: Autosomal recessive (AR), autosomal dominant (AD), X-linked recessive (XR), X-linked dominant (XD), and holandric.

• Types of Hereditary Human Diseases: Monogenic, mitochondrial, chromosomal, and multifactorial.

• Incidence Rates: Vary for different types of genetic disorders.

  • Most syndromes are monogenic.

Human Genetics

• Study Limitations: Reliance on existing families, small family sizes, and long generation times.

• Pedigree Analysis: Used to analyze inheritance patterns and provide genetic counseling.

• Important Considerations: Family size, reliable family records, and minimizing subjectivity.

Autosomal Recessive Diseases

• Characteristics:

  • Typically, both parents are carriers (Aa) -> 1/4 offspring affected (aa).

  • Affected individuals (aa) are generally rare and often result from consanguineous pairings.

  • Unaffected individuals outside the family are usually AA.

Autosomal Recessive Diseases (Examples)

• Phenylketonuria (PKU): Deficiency in phenylalanine hydroxylase (PAH) gene.

• Sickle Cell Anemia: Mutation in the HBB gene, affecting the beta subunit of hemoglobin.

• Albinism: Deficiency in tyrosinase (OCA1 gene).

• Cystic Fibrosis: Defect in the CFTR gene, affecting chloride ion transport.

• Newborn Screening: Guthrie card used for early detection and intervention.

Autosomal Dominant Diseases

• Characteristics:

  • Affected individuals (Aa) typically have at least one affected parent (Aa).

  • The disease appears in every generation.

  • Heterozygotes (Aa) are more common than homozygotes (AA).

• Couple Characteristic: Aa x aa -> 1/2 Aa

Autosomal Dominant Diseases (Examples)

• Achondroplasia: Mutation in the FGFR3 gene affects FGF receptor type 3.

• Familial Breast Cancer: Mutation in the BRCA1 gene.

• Huntington's Disease: Mutation in the HTT gene affects the Huntingtin protein.

• Polydactyly: Mutation in the GLI3 gene affects the GLI3 protein.

Inheritance of Normal Traits

• Common Traits: Widow's peak, tongue rolling, chin dimples, free earlobes, eye color, and hitchhiker's thumb.

• Genotypes: Typically, $AA$ or $Aa$ for the presence of the trait, and $aa$ for the absence.

• Note: Unlike rare diseases, no prior assumptions can be made about the genotype.

Analysis of Pedigree Trees (Problems)

• Calculating probabilities in pedigree analysis.

• Key Concepts: Multiplying probabilities for successive events (AND) and adding probabilities for mutually exclusive events (OR).

Analysis of Pedigree Trees (Problem 3)

• Inheritance Pattern: Autosomal dominant (AD).

  • Reasons: Affected individuals have at least one affected parent, appears in all generations, and healthy parent x affected parent -> healthy and affected offspring.

• Genotypes: Affected individuals are Aa, healthy individuals are aa.

Analysis of Pedigree Trees (Problem 4)

• Inheritance Pattern: Autosomal recessive (AR).

  • Reasons: Healthy parents have affected children, skips generations, and healthy parent x affected parent -> all healthy offspring.

• Genotypes: Affected individuals are aa, healthy individuals can be AA or Aa depending on family history.

Chromosomal Theory of Inheritance

• Sutton and Boveri (1902): Genes are located on chromosomes;

• Parallelism: Parallelism between Mendel's hereditary factors and chromosome behavior during meiosis.

  • Pairing of homologous chromosomes in prophase I.

  • Segregation of factors during anaphase I.

  • Independent assortment of chromosomes.

Sex-Linked Genes

• Experiments: Morgan's work with Drosophila melanogaster (fruit flies) showing different results in reciprocal crosses.

• Conclusion: The gene determining eye color is located on a sex chromosome.

• Hemizygosity: Males are hemizygous for X-linked genes.

• Homozygosity/Heterozygosity: Females can be homozygous or heterozygous for X-linked genes.

Chromosomal Sex Determination

• Mechanisms: Different mechanisms exist across species.

  • Mammals/ Drosophila: XX (homogametic) for females, XY (heterogametic) for males.

  • Birds/Fish: ZZ (homogametic) for males, ZW (heterogametic) for females.

  • Orthoptera: X (heterogametic), XX (homogametic).

Sex-Linked Genes (cont.)

• Most sex-linked genes are on the X chromosome.

• SRY Gene: Determines sex.

  • XY + SRY -> male.

  • XX - SRY -> female.

X-Linked Recessive Diseases

• Characteristics:

  • Males are more frequently affected than females.

  • Affected individuals are rare and the disease can skip generations.

  • Affected males inherit the allele from their mothers.

• Couple Characteristic: Increased consanguinity increases incidence.

X-Linked Recessive Diseases (Examples)

• Hemophilia A: Deficiency in coagulation factor VIII (HEMA gene).

• Duchenne Muscular Dystrophy: Mutation in DMD gene, affecting dystrophin protein.

• Color Blindness: Deuteranopia and protanopia due to defects in OPN1LW and OPN1MW genes.

X-Linked Dominant Diseases

• Characteristics:

  • Affected females outnumber affected males.

  • Affected males transmit the disease to all daughters but no sons.

  • Affected females transmit the disease to 1/2 of their offspring.

X-Linked Dominant Diseases (Examples)

• Hypophosphatemic Rickets: Mutation in the PHEX gene affects the phosphate regulating endopeptidase.

• Hypertrichosis: Mutation in the CGH gene (protein unknown).

Holandric Inheritance (Y-Linked)

• Characteristics:

  • Only males are affected.

  • The condition appears in every generation.

  • Affected males transmit the condition to all their sons.

  • Related to maleness and infertility.

Analysis of Pedigree Trees (Problem 5)

• Rarer genetic disease.

• Inheritance Pattern:

  • Recessive.

  • Most likely linked to the X chromosome.

• Calculation of probabilities of having affected children.

Analysis of Pedigree Trees (Problem 6)

• Common hereditary trait.

• Inheritance Pattern:

  • Dominant.

  • Linked to the X chromosome.

• Calculating the probability of having an affected son.

Monogenic Diseases: Modes of Inheritance (Summary)

• Distinguishing between autosomal recessive (AR) and X-linked recessive (XR).

• Distinguishing between autosomal dominant (AD) and X-linked dominant (XD).