Week 8

Foundations of Modern Transmission Genetics

Mendels laws

laws of segregation

law of independent assortment

• True Breeding: Each strain Mendel used was true-breeding, meaning offspring in successive generations were identical in appearance to the parents (e.g., yellow-seeded plants produced only yellow-seeded offspring).

• Reciprocal Crosses: Mendel performed crosses where the expressions of traits in male and female parents were swapped. These yielded identical results, suggesting the inheritance of these traits was independent of which parent contributed which trait.

The Principle of Segregation

• Mendel’s Key Discovery: The $F_1$ progeny of a cross between different true-breeding plants did not breed true. When $F_1$ plants self-fertilized, the recessive trait reappeared in the $F_2$ generation.

• The $3:1$ Ratio: Mendel observed a consistent numerical proportion in the $F_2$ generation: approximately $3$ offspring with the dominant trait for every $1$ with the recessive trait.

• Mechanism of Segregation:

  • Cells (except gametes) contain two alleles of each gene.

  • Homozygous: Genotypes with two identical alleles (e.g., $AA$ or $aa$).

  • Heterozygous: Genotypes with two different alleles (e.g., $Aa$).

  • Principle of Segregation: During gamete formation, the two members of a gene pair separate equally into gametes. Half the gametes receive one allele, and half receive the other.

• Physical Basis in Meiosis: Segregation corresponds to the separation of homologous chromosomes during Anaphase I of meiosis.

Non-Mendelian Dominance and Probability

• Incomplete Dominance:

• The phenotype of the heterozygote is intermediate between the two homozygotes.

• heterozygous is a blend of the dominant and recessive phenotypes

• Codominance:

• Both alleles in a heterozygote are fully and detectably expressed.

• both traits are expressed equally in heterozygous

  • Example: ABO blood groups. Alleles $A$ and $B$ are codominant (genotype $AB$ has both modifications), while both are dominant to allele $O$.

  • Incomplete penetrance

• a situation where not all individuals with a particular genotype may not express the expected phenotype

• 100% penetrants (fully penetrant) everyone with a particular genotype WILL express the expected phenotype

Variable expressivity

• a condition where trait is always expressed in individuals with the appropriate genotype but to vary levels of severity

• Probability Rules:

  • Addition Rule: Used for mutually exclusive outcomes ("either/or"). The probability is the sum of individual probabilities. Example: Probability of $F_2$ being $AA$ or $Aa$ is $1/4 + 1/2 = 3/4$.

  • Multiplication Rule: Used for independent events occurring together ("and"). The probability is the product of individual probabilities. Example: Proportionality of four seeds in a pea pod where the first is green ($1/4$) and the next three are yellow ($3/4$) is $(1/4) \times (3/4) \times (3/4) \times (3/4) = 27/256$.

Independent Assortment

• The Principle of Independent Assortment: Segregation of one set of alleles is independent of the segregation of another set of alleles of a different gene pair.

• Dihybrid Cross: Mendel crossed a strain with yellow, wrinkled seeds with one having green, round seeds.

  • $F_1$: All yellow and round ($AaBb$).

  • $F_2$: Observed results for $639$ seeds: $367$ yellow/round, $122$ green/round, $113$ yellow/wrinkled, $37$ green/wrinkled.

  • Ratio: Approximately $9:3:3:1$.

Human Genetics and Pedigrees

• Pedigree: A diagram of family history used to summarize ancestral relationships.

• Dominant Traits (e.g., Brachydactyly):

  • Affected individuals appear in every generation.

  • Affected individuals typically have one affected parent (matings are usually $Aa \times aa$).

  • About $50$% of offspring from an affected parent are affected.

• Recessive Traits (e.g., Albinism):

  • Traits can skip generations.

  • Affected individuals can have unaffected parents (heterozygous carriers).

  • Increased frequency in matings between relatives (consanguinity), such as first cousins.

  • Mutation in OCA2 gene often involved in albinism.

• Incomplete Penetrance: Not all individuals with a specific genotype show the expected phenotype (e.g., type $2$ diabetes risk genes like TCF7L2).

• Variable Expressivity: The severity of a phenotype varies among individuals (e.g., alpha-$1$ antitrypsin (alpha-$1$AT) deficiency and emphysema).

• Multiple Alleles: A gene can have many different mutant and nonmutant forms within a population.

  • Example: Phenylketonuria (PKU) is caused by more than $400$ different mutant alleles of the phenylalanine hydroxylase gene.

Autosomal dominant

• trait is present in every generation

• affected children CANNOT be born to unaffected parents

• males and females appear to be equally likely to develop the trait

• Sex Chromosome Determination: Human females are $XX$ (homogametic) and males are $XY$ (heterogametimesc).

• Autosomes: Chromosomes that are not sex chromosomes.

• X Chromosome: ~$150$ Mb long, over $1,000$ genes.

• Y Chromosome: ~$50$ Mb long, ~$50$ protein-coding genes.

• Homology Regions: Small regions at the tips of the X and Y (totaling ~$3$ Mb) allow pairing and crossing over during meiosis I to ensure proper segregation.

• Sex Ratios:

  • Primary sex ratio: Ratio at conception ($1:1$ based on segregation).

  • Secondary sex ratio: Ratio at birth (slight excess of males, ~$105$ males to $100$ females in the U.S.).

X-Linked dominant

• trait will not skip generations

• affected fathers will ALWAYS have affected daughters, but affected mothers can have unaffected sons or daughter with equal likelihood

• affected fathers will NEVER pass the trait to their sons unless the mother is also affected

X-linked recessive

• affected children can be born to unaffected parents

• males appear to be affected in greater proportions compared to females

• affected mothers will ALWAYS have affected sons

• affected daughters CAN ONLY be born to affected fathers (mother could be heterozygous) but affected fathers can have unaffected daughters

The X and Y chromosomes

x Chromosomes

• very large, encoding 1000s of genes

• many not associated with sex characteristics

• necessary for life

Y chromosomes

• much shorter, only a few hundred genes

• many genes associated with male sex characteristics

• not essential for life

X-Linked Inheritance

• The X and Y chromosomes segregate radomly in meiosis so half gametes will contain each chromosome

• many genes on the X chromosomes DO NOT have a partner on the Y chromosome called the differential region on the X    

• Discovery: Thomas Hunt Morgan discovered X-linkage in 1910 through the white-eye mutation in Drosophila melanogaster.

• Crisscross Inheritance: Morgan found that a white-eyed male passed the trait to his second-generation grandsons through his daughters.

  • Males transmit the X chromosome only to daughters.

  • Males inherit the X chromosome only from mothers.

• Nondisjunction Evidence: Calvin B. Bridges provided the first evidence that genes are on chromosomes by observing "exceptional" offspring (white-eyed females and red-eyed males) resulting from chromosomes failing to separate normally in Anaphase I.

  • Exceptional females: $X^wX^wY$.

  • Exceptional sterile males: $X^+O$.

Y-Linked Inheritance and Ancestry

• SRY Gene: The "sex-determining region in the Y chromosome," which triggers male development.

• Y-Linked Traits: Rare, transmitted strictly from father to son (e.g., maleness and some types of reduced fertility).

• Tracing Ancestry: Since $94$% of the Y chromosome does not undergo recombination, it is inherited intact except for mutations.

• Haplotypes: Unique combinations of nucleotides along the Y chromosome. Differences in haplotypes allow researchers to trace paternal ancestry and migration patterns, identifying clusters in Africa, Southeast Asia/Australia, Europe/Western Asia, and the Americas.

Autosomal recessive

• trait CAN skip generations

• affected children can be born to unaffected parents

• males and females have an equal likelihood of developing trait

• Human X-Linked Traits:

  • Red-Green Color Blindness: Affects $1$ in $20$ males.

  • Hemophilia: Affects $1$ in $7,000$ males; famously present in descendants of Queen Victoria.

Genetic Linkage and Mapping

• Linkage: Genes close together on the same chromosome tend to be inherited together.

• Recombinants vs. Nonrecombinants:

  • Nonrecombinants: Offspring with the same allele combination as the parent.

  • Recombinants: Offspring with a different combination, resulting from crossing over during Prophase I.

• Recombination Frequency: The proportion of recombinant chromosomes among the total. It serves as a measure of genetic distance.

  • Formula: $\text{Recombination frequency} = \frac{\text{Number of recombinants}}{\text{Total progeny}} \times 100$

  • Limit: Ranges from $0$% (perfect linkage) to $50$% (independent assortment).

• Genetic Mapping: Constructed by Alfred H. Sturtevant using map units ($1$ map unit = $1$% recombination).

  • Example: Linkage between white ($w$) and crossveinless ($cv$) genes in fruit flies showed $12.2$% recombination, or $12.2$ map units.

Epistasis

• a situation where genes can modify the phenotype expression of other genes

• ratio of 9:3:4

• eg albino animals