Inheritance and Genetic Variation

Mendelian Inheritance

• Mendel's Laws explain the inheritance of monogenic conditions.
• More complex patterns of inheritance are extensions to Mendel's Laws.
• Genetic variation arises from single nucleotide variants and chromosomal variants, impacting protein synthesis and function.

Darwin's Theory of Natural Selection

• Natural variation exists within a population.
• Individuals with advantageous traits have a fitness advantage.
• Giraffes with longer necks can reach more leaves and survive better.
• They pass the long neck trait to their offspring.
• Giraffes with shorter necks have less chance of survival and don't pass on their shorter neck trait.
• Over time, evolution selects for longer necks.

Important Questions

• Where does variation within a species come from?
• How is variation passed on from parent to offspring?

Gregor Mendel and Mendelian Inheritance

• Mendel was a priest in Brno (Czech Republic) who studied biology, physics, and mathematics.
• He spent seven years crossing plants and studying the outcomes on seeds and plants.
• He recorded the outcome for over 20,000 progeny.
• He applied mathematical knowledge to his results, proposing new ideas about inheritance.
• This was all done before the discovery of DNA, genes, and chromosomes.
• His work was initially ignored but later recognized after the discovery of chromosomes.

Mendel's Experimental Design

Advantages of Pea Plants

• Variability in easily scorable characters.
• Large family sizes.
• Short generation times.
• Easy and inexpensive to grow.

Controlled Mating

• Pea plants have both male (stamen) and female (pistil) sex organs.
• Normally, they self-fertilize.
• Stamens can be removed to prevent self-fertilization.
• Pollen from different plants can be used to fertilize the plant.

Seven Characteristics Studied

• Plant height.
• Pod shape and color.
• Seed shape and color.
• Flower position and color.

Definitions

• Character: An observable physical feature (e.g., seed shape).
• Trait: A particular form of a character (e.g., round vs. wrinkled seeds).

Generations

• Parental generation.
• First filial generation (F1).
• Second filial generation (F2).
• These terms are still used today in genetics (e.g., mouse genetics).

Monohybrid Crosses

Analyzing a Single Character

• Example: Seed shape (round vs. wrinkled).
• Cross-hybridization of plants with round and wrinkled seeds.
• F1 generation: All seeds were round.
• F2 generation: Three-quarters of seeds were round, and one-quarter were wrinkled.

Dominant and Recessive Traits

• Dominant trait: Appears in the F1 generation and is more abundant in the F2 generation (e.g., round allele).
• Recessive trait: Less common (e.g., wrinkled allele).

First Law of Mendelian Inheritance: Law of Segregation

Genes and Alleles

• Genes can exist as variants (alleles).
• Individuals have two copies of each gene in their genome.
• Alleles: Differences between the same gene.
• Example: Round seeds (R) and wrinkled seeds (r).

Law of Segregation

• When an individual produces gametes (eggs or sperm), the two copies of a gene separate.
• Half the gametes receive one copy, and half receive the other.
• Meiosis splits the gene copies into separate gametes.
• Homozygous: Both alleles are the same (e.g., RR or rr).
• Heterozygous: Alleles are different (e.g., Rr).

Gamete Formation

• Homozygous for round seed gene: All gametes get the round seed gene.
• Homozygous for wrinkled seed gene: All gametes get the wrinkled seed gene.
• Heterozygous: Half the gametes get the round allele, and half get the wrinkled allele.

Fertilized Egg

• A gene from the female and a gene from the male come together.
• Inheritance depends on the alleles carried by the parents.

Crossing Homozygous Plants

• Parental generation: Homozygous for round (RR) and wrinkled (rr) seeds.
• F1 generation: All seeds are heterozygous (Rr).
• F2 generation: Self-fertilization of F1 plants.

Possible Outcomes

• Inherit both round alleles (RR): Round seed.
• Inherit the wrinkled allele from father and the round allele from mother (Rr): Heterozygous, round seed.
• Inherit the round allele from father and the wrinkled allele from mother (Rr): Heterozygous, round seed.
• Inherit both wrinkled alleles (rr): Wrinkled seed.
• Three-quarters of seeds will inherit the round allele, while a quarter will inherit both wrinkled alleles.

Inheritance of Monogenic Conditions

Monogenic Condition

• A disease caused by variants in a single gene.
• Disease-causing allele can be inherited in a dominant or recessive manner.

Dominant Inheritance

• One copy of the disease-causing allele results in the condition.

Recessive Inheritance

• Two copies of the disease-causing allele are needed to have the condition.

Pedigree Symbols

• Circles: Females.
• Squares: Males.
• White shapes: Individuals without the condition.
• Black shapes: Individuals with the condition.
• Hatched shapes: Carriers (one copy of the disease allele).

Example: Dominant Inheritance

• A parent without the disease allele and a parent with one copy of the disease allele (Aa).
• Fifty percent chance of passing the disease-causing allele to offspring.
• Offspring with the allele will have the condition.
• Example: Huntington's disease.

Example: Recessive Inheritance

• A parent with two non-disease-causing alleles and a parent with one copy of the disease allele.
• Carriers are non-symptomatic.
• Twenty-five percent chance that a child will inherit non disease causing allele.
• Fifty percent chance that a child will be a carrier.
• Twenty-five percent chance they will inherit two copies of the disease causing allele and therefore have the condition.
• Example: Child carrying the albinism gene will have albinism, the rest will not.

Second Law of Mendelian Inheritance: Law of Independent Assortment

Independent Assortment

• Copies of different genes assort independently.
• Determined by crossing peas different in more than one character.
• Example: Seed shape and seed color (round yellow vs. wrinkled green).
• Yellow is dominant to green, and round is dominant to wrinkled.

Results of Cross

• F1 generation: All seeds are yellow and round.
• F2 generation: All possible combinations are seen (round yellow, round green, wrinkled yellow, wrinkled green).
• Demonstrates that the yellow color gene and the round trait separate independently.

Exception to the Rule

• Genes on the same chromosome will be inherited together unless there's crossover during meiosis.

Extensions to Mendel's Laws

Complexities Beyond Two Alleles and Complete Dominance

• More than two alleles for a given gene.
• Dominance is not always an all-or-none phenomenon.
• Some genes can have multiple effects and phenotypes.
• Traits are determined by interactions between multiple genes and the environment.

Multiple Alleles

• Coat color in rabbits is determined by four alleles of the coat color gene.
• Alleles: dark gray, chinchilla, Himalayan, and albino.
• Hierarchy of dominance: dark gray > chinchilla > Himalayan > albino.
• Rabbits can only have two of these alleles.
• Temp-sensitive Allele: Himalayan allele in rabbits: pigment only at extremities (ears, mouth, paws).

Incomplete Dominance

• Heterozygotes display an intermediate phenotype.
• Example: Breeding of aubergines (eggplants): purple x white = violet.

Codominance

• Phenotypes for both alleles appear in the heterozygote.
• Example: ABO blood type in humans.
• Controlled by the ABO gene with three alleles (IA, IB, and I).
• Four possible blood types: A, B, AB, and O.
• A and B are completely dominant to O.
• A and B are codominant: If you inherit one copy of the A allele and one copy of the B allele, you will express both the A and the B antigens.
• Inheritance of ABO blood type involves multiple alleles, complete dominance, and codominance.

Pleiotropic Effects

• An allele can influence multiple traits (e.g., hormone levels or metabolic function).
• Example: Phenylketonuria (PKU) in humans.
• Caused by a variant in a gene for a liver enzyme that converts phenylalanine to tyrosine.
• Accumulation of phenylalanine impacts multiple aspects of development.
• Untreated PKU leads to intellectual disability, reduced hair and skin pigmentation.
• Newborn screening and dietary restriction can prevent symptoms.

Epistasis

• One gene is dependent on the action of another gene for its function to be seen.
• Also referred to as epistasis, which literally means to stand on.
• Example: Labrador coat color.
• Labradors can be black, chocolate (brown), or yellow.

Genes Involved

• B gene: Determines coat pigmentation color (black dominant over brown).
• E gene: Determines if pigment is deposited in the hair (allele that enables pigment deposition in hair being dominant over the allele which doesn't).
• If pigment can't be deposited in your hair, then the hair will be yellow irrespective of whether they are capable of making brown or black pigment.
• The E gene (pigment deposition) is epistatic to the B gene (pigment color).

Polygenic Traits

• Traits determined by multiple genes and the environment.
• Example: Height in humans.
• Single-gene traits display qualitative differences.
• Polygenic traits display a continuum.

Environmental Influence on Traits

• The environment can influence the penetrance of a trait.
• Penetrance: Probability that a specific genotype will lead to expression of the associated phenotype or trait.
• Example: Height of Dutch conscripts at age 20 (1860-1910).
• Significant increase in height correlates with changes in health care and wealth.
• Better living conditions, health care, and nutrition contribute to increased height.
• Interaction between genetics and environment (nutrition).

Terminology for Genetic Changes

Avoid Using the Term "Mutation"

• Carries negative connotations.
• Implies changes in our genome are detrimental, which is not always the case.
• Use the term "variants" instead.

How does Genetic Variation Arise

Arising Diversity

• No one (excluding identical twins) has the same genome.
• Basis of our individuality.
• Drives evolution.
• Arises through recombination during meiosis and accumulation of small changes.

Spontaneous Changes

• Chemical reactions that alter nucleotides.
• Byproducts of metabolism.
• Errors occurring during DNA replication.

Induced Changes

• DNA damaging agents (chemicals or UV radiation).
• Use of the term mutation may be appropriate here.
• Cells have mechanisms for repairing damaged DNA, but some changes persist.

Types of Variations

• Chromosomal variations.
• Single nucleotide variations.
• Impact on encoded protein and organism's phenotype and fitness.

Single Nucleotide Variations

SNVs

• Change in a nucleotide in the DNA.
• Genes can accumulate more than one change over time.

Transcription and Translation

• DNA is transcribed into mRNA, which is then translated into protein.
• mRNA is read as three nucleotide codons corresponding to particular amino acids (genetic code).
• There are 64 possible codons but only 20 different amino acids plus stop codons.
• Redundancy in the system.

Types of SNVs

Silent Variants

• Change in DNA does not impact the amino acid composition of the protein.
• Example: Position 12 in DNA with an A instead of a G; mRNA codon changes from CCU to CCA, both encoding for proline.

Missense Variants

• A nucleotide in the DNA results in a different amino acid being incorporated into the protein.
• Example: Position 14 in DNA with an A instead of a T; mRNA codon changes from GAU (aspartic acid) to GUU (valine).
• Impact on protein function can be variable.
• No impact if the substitution is in a non-critical region or the substituted amino acids are similar.
• Changing one amino acid can result in a nonfunctional protein (loss of function mutation or variant).
• Altered function of the protein (constitutively active) that can lead to cancer, or can also become dominant negative.

Nonsense Variants

• A nucleotide in the DNA creates a premature stop or termination codon.
• Example: Fifth nucleotide is a T instead of a C; mRNA codon changes from UGG (tryptophan) to UAG (stop codon).
• No functional protein is generated.
• Truncated proteins.

Insertion or Deletion

• Also known as frameshift variants.
• Addition or loss for nucleotide, which changes the DNA reading frame.
• Results in a completely different protein.

Chromosomal Variations

Types of Variations

• Number or structure of chromosomes is altered.
• Loss of an entire chromosome or rearranging of part of chromosomes.
• Results from double-strand breaks or crossing over in meiosis.
• Involve large segments of DNA that impact multiple genes.
• Usually have more severe consequences.

Impact on Development and Function

• Affect multiple tissues and organ systems.

Impact of DNA Variants and the Terminology

Categories of Variants

• Benign: No effect.
• Beneficial: Protective advantage (e.g., against disease).
• Pathogenic: Cause or increase the risk of a genetic condition.

Context-Dependent Impacts

• Some variants have different impacts depending on the genome of the individual or the environment.
  Example: Sickle cell anemia:
• Caused by a missense variant in the beta-globulin gene, which is inherited recessively.
• Homozygous individuals have sickle cell anemia, impacting the red blood cells' ability to carry oxygen (pathogenic variant).
• Heterozygous individuals are protected from malaria infection (beneficial).
• Higher incidence in regions with malaria.
• Problem occurs when two carriers have a child (25% chance of inheriting both copies of the sickle cell allele and having sickle cell anemia).