Detailed Notes on Genetic Inheritance

Genetic Inheritance

Allele

• A different form of a particular gene, positioned at the same relative location (locus) on homologous chromosomes.
• Homologous chromosomes contain the same genes but may contain different alleles.

Vocabulary

• Phenotype: The physical appearance of an organism for a trait (e.g., Tall).
• Genotype: The alleles an organism has in its genome (e.g., Tt).
• Homozygous: Organisms with identical alleles (e.g., TT or tt).
• Heterozygous: Organisms with different alleles in a pair (e.g., Tt).

Genes and Dominance

• P Generation: The original set of parents.
• F1 Generation: The first filial generation (offspring of the P generation).
• Alleles are passed from parent to offspring.
• Some alleles are dominant, and some are recessive.
• Dominant alleles typically make a working protein.
• Recessive alleles often do not make a protein or make a nonfunctional protein.

Testcross

• Determines if an individual with a dominant phenotype is a heterozygote or homozygote.

Mendel’s Second Law: Law of Independent Assortment

• Alleles of genes that govern two different characters segregate independently during gamete formation.
• This is due to independent assortment during meiosis.
• During meiosis I, tetrads can line up in two different ways before homologs separate.

Dihybrid Cross

• Involves two different alleles (e.g., Yellow-round seeds x green-wrinkled seeds: Y/Y, R/R x y/y, r/r).
• Seed color and seed shape genes are located on different chromosomes.

Mendelian Inheritance and Rules of Probability

• Rule of Multiplication: The probability that two events will occur simultaneously is the product of their individual probabilities.
• Probability that an egg from the F1 (Pp) will receive p = $1/2$
• Probability that a sperm from the F1 (Pp) will receive p = $1/2$
• Probability of offspring receiving two recessive alleles during fertilization: $1/2 \, x \, 1/2 = 1/4$

Incomplete Dominance

• Both genes affect the phenotype, resulting in an intermediate type.
• Heterozygote phenotype is different from either homozygote phenotype.
• Example: Pink snapdragons (CRCW). If you cross CRCW x CRCW, you get $1/4$ red flowered (CRCR), $1/4$ white flowered (CWCW), and $1/2$ pink flowered (CRCW).

Incomplete Dominance in Human Traits

• Sickle-cell disease: Homozygous recessive individuals have the disease, while heterozygotes have a milder sickle-cell trait.
• Tay-Sachs disease: Homozygotes have serious symptoms (inability to metabolize lipids, leading to neurological issues and early death). Heterozygotes have no symptoms but have detectable biochemical effects.

Codominance

• Both alleles for a trait are dominant, resulting in offspring with both phenotypes.
• Two alleles at a locus produce different and detectable gene products in the heterozygote.
• No dominance or recessiveness; no blended phenotype.
• Example: Blood type AB, where both A and B glycoproteins are produced.

Multiple Alleles

• Traits for which there are more than two alleles.
• Example: Blood type alleles A ($I^A$), B ($I^B$) (codominant), and O (i) (recessive), allowing for 6 possible genotypes:
  • $I^A I^A$, $I^A$ i (type A phenotype)
  • $I^B I^B$, $I^B$ i (type B phenotype)
  • $I^A I^B$ (type AB phenotype)
  • ii (type O phenotype)

Lethal Alleles

• Many gene products are essential for organism survival.
• Lethal alleles are lethal in the homozygous state and represent essential genes.
• Time of death depends on when the gene product is essential to development.
• Loss-of-function alleles can be recessive lethal.
• Heterozygotes may tolerate a non-functional mutant allele if the wild-type allele produces sufficient product.
• Recessive lethal alleles can still be dominant with respect to phenotype.

Lethal Dominant Mutations

• Both homozygous and heterozygous states are lethal.
• Generally rare.
• Example: Huntington's disease (humans), a nervous and motor system degeneration commonly exhibited after age forty.
• Afflicted persons are heterozygous (Hh).

Epistasis

• One gene affects the phenotypic expression of a second gene.
• Frequently occurs in pigmentation.
• One gene controls pigment production (on or off), while another controls the amount or color of the pigment.
• Example: Labrador coat color, where one gene (E/e) determines whether pigment is produced and another (B/b) determines the color of the pigment (black or brown).

Pleiotropy

• One gene has effects on multiple phenotypes.
• Examples:
  • Cystic fibrosis
  • Porphyria variegata: inability to metabolize porphyrin, causing deep red urine and neurological symptoms.

Polygenic Inheritance

• Many genes are required to shape single complex phenotypes such as height.
• Results in a continuous variation of possibilities within a certain range.

Cytoplasmic Inheritance

• Mutant alleles in organelle DNA.
• Mendelian inheritance is not followed (no segregation by meiosis).
• Uniparental inheritance from the female.

Sex Linkage

• X,Y system used for sex determination in many animal and plant species.
• X is a large chromosome encoding many genes.
• Y is a small chromosome with few genes (not homologous to X but has a pairing region for synapsis).
• Males have a single copy of genes encoded by the X chromosome (hemizygous).
• These genes have unique inheritance/expression properties resulting from their “X-linkage”.

Human Sex Linkage

• Hemophilia: Disorder of the blood where clotting does not occur properly due to a faulty protein on the X chromosome (recessive).
• Colorblindness: Males only need one copy of the recessive allele to have the phenotype, making them more likely to inherit sex-linked traits.

Genetic Imprinting

• Genomic or parental imprinting: phenotypic expression depends upon the parental origin of the chromosome carrying the particular allele.
• Certain chromosomal regions are imprinted during gametogenesis.
• Methylation of CpG islands (5meC produced).
• Examples: Prader-Willi and Angelman syndromes, both loci in 15q1 region. One is maternally imprinted, and the other is paternally imprinted.
• Uniparental disomy.

Nondisjunction

• Chromosomes do not separate correctly in meiosis, resulting in too many or too few chromosomes in the offspring.
• Examples:
  • Down Syndrome (trisomy 21): extra 21st chromosome.
  • Turner Syndrome (X0): missing X chromosome.

Nature and Nurture: The Environmental Impact on Phenotype

• Phenotype depends on environment as well as genotype.
• The norm of reaction is the phenotypic range of a genotype influenced by the environment.
• Examples: Hydrangea flower color varies with soil acidity, temperature effects on evening primrose flower color, darker fur on cooler areas of Siamese cats and Himalayan rabbits.
• Temperature-sensitive mutations are expressed at lower temperatures.

Nutritional Effects

• Nutritional mutations prevent the synthesis of nutrient molecules (auxotrophs).
• Phenotype expression varies based on diet.
• Examples: Phenylketonuria (loss of enzyme to metabolize phenylalanine, requires a low-Phe diet), Galactosemia, and Lactose intolerance.

Delayed Onset of Phenotypic Expression

• Tay-Sachs disease: autosomal recessive, lipid metabolism issue, normal baby for a few months, dies by age 3.
• Lesch-Nyhan syndrome: X-linked recessive, purine salvage enzyme defect, normal for about 6 months, then…
• Duchenne muscular dystrophy: X-linked recessive, diagnosed at 3-5 years old.

Delayed Onset - Dominant

• Huntington's disease: Autosomal dominant, progressive cell death in the brain, onset commonly between ages 30-50.
• Genetic anticipation involves a progressively earlier age of onset and increased severity with each successive generation.
• Myotonic dystrophy: Autosomal Dominant, trinucleotide expansion, number of repeats increases with each generation.
• Fragile X and Huntington's disease also show a correlation between the number of repeats and severity.

Importance of Genetics

• The only way to understand hereditary diseases.
• Our genetic heritage determines susceptibility to multifactorial diseases.
• Critical to developing new disease treatments.

Importance of Recognizing Mendelian Disorders

• Establishment of definitive diagnosis.
• Recognition of other relatives with or at risk for the disease.
• More accurate prognosis.
• Anticipation/prevention of medical and emotional complications.
• More informed family planning.
• Distribution of Mendelian disorders: 68% Autosomal dominant, 26% Autosomal recessive, 6% X-linked recessive.

Clues That Suggest a Mendelian Disease

• Positive family history.
• Characteristic syndrome.
• Unusual syndrome (e.g., progressive neurologic deterioration, multiple organ system abnormalities).
• Common syndrome at an unusually early age.
• Lack of environmental or other primary cause of symptoms and signs.