Patterns of Inheritance and Genetic Disorders

Patterns of Inheritance and Genetic Pedigrees

• Dihybrid Cross Analysis (Tsuang, et al., 2000)

  • The transcript illustrates a dihybrid cross of organisms with the genotype $BrbrVgvg \times BrbrVgvg$.

  • Parents (P Generation) gametes for both individuals are: $BrVg$, $brVg$, $Brvg$, and $brvg$.

  • The resulting 4x4 Punnett square produces the following combinations:

    • Row 1: $BrBrVgVg$, $BrbrVgVg$, $BrBrVgvg$, $BrbrVgvg$

    • Row 2: $BrbrVgVg$, $brbrVgVg$, $BrbrVgvg$, $brbrVgvg$

    • Row 3: $BrBrVgvg$, $BrbrVgvg$, $BrBrvgvg$, $Brbrvgvg$

    • Row 4: $BrbrVgvg$, $brbrVgvg$, $Brbrvgvg$, $brbrvgvg$

• Sample Pedigree Case Study (Schizophrenia Spectrum)

  • Inheritance patterns are often tracked using pedigrees. Notable conditions mentioned in the context of the Tsuang et al. (2000) study include:

    • Schizophrenia

    • Schizoaffective, depressed

    • Schizotypal personality disorder

    • Other mental disorders

Classical Mendelian Genetics: Monohybrid and Dihybrid Crosses

• Monohybrid Cross (Tobacco Plant Leaf Color)

  • P Generation: Cross a homozygous green leaf plant ($GG$) with a gold leaf plant ($gg$).

  • P Genotypes: $GG$ and $gg$.

  • F1 Genotypes: All offspring are $Gg$.

  • F1 Phenotypes: $100\%$ green leaf plants.

  • F2 Generation (Crossing two F1 offspring):

    • Cross: $Gg \times Gg$

    • F2 Genotypes: $GG$, $Gg$, and $gg$ in a $1:2:1$ ratio.

    • F2 Phenotypes: Green leaf and gold leaf in a $3:1$ ratio.

• Dihybrid Cross (Collie Traits)

  • Traits examined: Coat color (Black $B$ is dominant over tan $b$) and tail shape (Straight $T$ is dominant over curly $t$).

  • P Generation: Homozygous black, straight tail ($BBTT$) crossed with a tan, curly tail ($bbtt$).

  • P Genotypes: $BBTT$ and $bbtt$.

  • F1 Generation:

    • F1 Genotypes: All offspring are $BbTt$.

    • F1 Phenotypes: $100\%$ Black, straight tail.

  • F2 Generation (Crossing two F1 offspring):

    • Cross: $BbTt \times BbTt$

    • F2 Genotypes: Multiple combinations result in a phenotypic ratio of $9:3:3:1$.

    • F2 Phenotypes:

      • 9 Black, straight tail

      • 3 Black, curly tail

      • 3 Tan, straight tail

      • 1 Tan, curly tail

• Tongue Curling Logic Problem

  • Ability to curl tongue is dominant ($T$).

  • Observations: You, your Dad, and your Sister can curl tongues. Your Brother and your Mom cannot.

  • Genotype Deduction:

    • Mom and Brother are recessive: $tt$.

    • Because the Mom can only provide a $t$ allele, the Dad must be a carrier of the recessive allele to have produced a brother with the genotype $tt$.

    • Dad's Genotype: $Tt$ (Heterozygous).

Variations on Mendelian Inheritance

• Incomplete Dominance

  • The phenotype of the heterozygote is intermediate (an appearance between the two dominant homozygous phenotypes).

  • Example: Snapdragon Flowers:

    • P Generation: Red ($RR$) crossed with White ($rr$).

    • F1 Generation: All Pink ($Rr$).

    • F2 Generation: Crossing $Rr \times Rr$ yields a phenotypic ratio of $1$ Red ($RR$) : $2$ Pink ($Rr$) : $1$ White ($rr$).

  • Human Example: Hypercholesterolemia:

    • $HH$: Homozygous for ability to make LDL receptors (Normal phenotype).

    • $Hh$: Heterozygous (Mild disease; fewer LDL receptors).

    • $hh$: Homozygous for inability to make LDL receptors (Severe disease; no LDL receptors).

• Codominance

  • Both dominant alleles are expressed simultaneously.

  • Example: Blood Types (ABO System):

    • Blood types reflect specific antigens on the cell surface.

    • Type O: Genotype $ii$; Antibodies present: Anti-A and Anti-B.

    • Type A: Genotype $I^A I^A$ or $I^A i$; Antibody present: Anti-B.

    • Type B: Genotype $I^B I^B$ or $I^B i$; Antibody present: Anti-A.

    • Type AB: Genotype $I^A I^B$; Antibodies present: None.

Sex Chromosomes and Inheritance Systems

• Standard Systems

  • Humans/Mammals: $XX$ (female) and $XY$ (male).

  • X-O System (Grasshoppers): Female is $XX$; Male has only one X chromosome ($XO$ or $X$).

  • Z-W System (Birds, Fish, Butterflies): Female is $ZW$; Male is $ZZ$.

  • Chromosome Number (Bees/Ants): Sex is determined by whether the individual is haploid or diploid. Females are diploid ($32$ chromosomes); Males are haploid ($16$ chromosomes).

• X-Linked Genes

  • These are genes located specifically on the sex chromosomes. Because of the difference in chromosome size and content between X and Y, inheritance patterns differ for males and females.

  • Example: Fruit Fly Eye Color:

    • Red eyes ($R$) are dominant; White eyes ($r$) are recessive.

    • Inheritance occurs via the $XY$ system.

Human Genetic Disorders

• Overview

  • Over $1000$ human genetic disorders have been identified.

  • They can affect the $22$ pairs of autosomes or the sex chromosomes.

  • Disorders may be recessive (more common) or dominant.

• Recessive Genetic Diseases

  • Cystic Fibrosis:

    • Frequency: $1$ in $31$ Americans carry the disease allele ($1$ in $28$ Caucasians).

    • Historical Survival: In $1969$, the median age of survival was $14$ years. By $2002$, the median age of survival increased to $33.4$ years.

  • Sickle Cell Anemia:

    • Affects millions globally, common in families from sub-Saharan Africa, South America, Cuba, Central America, Saudi Arabia, India, and Mediterranean countries (Turkey, Greece, Italy).

    • Statistics in the US: Affects approximately $72,000$ people. Occurs in $1$ in every $600$ African-American births and $1$ in every $1,000-1,400$ Hispanic-American births.

    • Traits: About $2$ million Americans carry the sickle cell trait ($1$ in $12$ African Americans).

    • Symptoms: Anemia and pain (crises) resulting from blocked blood and oxygen due to sickle-shaped cells. Pain can be Acute (sudden, hours to days), Chronic ($3-6$ months or longer), or Mixed.

• Dominant Genetic Diseases

  • Huntington's Disease (HD):

    • Pathology: Genetically programmed degeneration of brain cells (neurons) in specific brain areas. Causes uncontrolled movements, loss of intellectual faculties, and emotional disturbances.

    • Inheritance: Dominant inheritance; it does not skip generations. If a person carries the gene, they will develop the disease if they live long enough and can pass it on to offspring.

    • Population: Approximately $30,000$ Americans have HD; $150,000$ are at risk of inheriting it from a parent.

    • Characteristics: Slurred speech, unsteady gait, involuntary movements, personality changes, depression, impaired judgment, difficulty swallowing, and an "intoxicated appearance."

    • Prognosis/Treatment: Currently, there is no way to stop or reverse the course of HD. Medications can help control emotional and movement problems but often have side effects like fatigue, restlessness, or hyperexcitability. Physical activity is highly recommended for better outcomes.