Mendelian Inheritance Patterns

• Mendelian Inheritance Patterns explores the principles of heredity through studying Gregor Mendel's work and related concepts.

Gregor Mendel (1823-1884)

• Gregor Mendel proposed the theories of inheritance without knowledge of chromosomes or genes.
• Mendel developed the concept of dominant and recessive hereditary units existing in pairs, which are now referred to as genes.

Alleles and Zygocity

• Genes can have alternative forms that differ in sequence, and are called alleles.
• Homologous chromosomes with identical alleles are referred to as homozygous.
• Homologous chromosomes with differing alleles for a given gene are heterozygous.

Dominant/Recessive Alleles

• A single gene is composed of 2 possible alleles: Allele 1 = A, and Allele 2 = a.
• In a diploid cell there is an AA, Aa, aA, and aa combination.
• The dominant phenotype is expressed in both the homozygote (AA) and heterozygote (Aa).
• The recessive phenotype is only expressed in the recessive homozygote (aa).

Monohybrid Cross

• Monohybrid cross illustrates the inheritance of traits stemming from one gene in tall and dwarf pea plants
• Gamete formation and fertilization are key processes showing how genotypes and phenotypes are determined.
• Zygocity is determined as being either heterozygous or homozygous, depending on the allele combination.

Mendel's First Three Principles

• Unit factors are inherited in pairs; genetic characters are controlled by unit factors in pairs in individual organisms.
• When two unlike unit factors for a single character are present in an individual, one unit factor is dominant to the other (recessive).
• During meiosis, the two alleles for any given gene separate so that each ends up in different gametes (Law of Segregation).
• Each gamete contains only one homologous chromosome, and therefore only one allele for each gene.

Punnett Square

• Punnett Squares show the probability of offspring genotypes and phenotypes from the parent generation.
• Punnett Squares show the genotypic ratio as 1:2:1.
• Punnett Squares show the phenotypic ratio as 3:1.

Punnett Square Convention

• On a Punnett Square, female alleles are mapped on the top.
• On a Punnett Square, male alleles are mapped on the left side.
• On a Punnett Square, dominant alleles are typed in uppercase letters (D).
• On a Punnett Square, recessive alleles are typed in lowercase letters (d).
• Dominant alleles are always written before recessive alleles when mapping genotypes (Dd).

Mendel’s 4th Principle of Inheritance

• During meiosis, the 2 alleles for any given gene separate independently of other alleles for other genes (Law of Independent Assortment).
• The law of independent assortment is invalid if the 2 genes are found on the same chromosome because there will be gene linkage.

Chromosomal Theory of Inheritance

• The Chromosomal Theory of Inheritance shows how the segregation of unit factors during gamete formation illustrates the law of segregation.
• The Chromosomal Theory of Inheritance describes how independent assortment of segregating unit factors illustrates the law of independent assortment.

Independent Assortment & Gamete Diversity

• There are >8.3 million (2 to the power of 23) unique ways to arrange the 23 pairs of chromosomes by independent assortment.

Family Studies and Pedigrees

• Controlled human breeding experiments are unethical, and also yield few offspring to study.
• Pedigrees (family trees) are used to study modes of inheritance through the presence/absence of specific traits in each family member.
• Pedigrees determine the mode of inheritance and risk factors.

Pedigree Conventions

• Pedigree Conventions show how families can be mapped to identify family members and modes of inheritance of traits.

General Modes of Inheritance

• Autosomal Dominant
• Autosomal Recessive
• Sex-linked Dominant
• Sex-linked Recessive

Autosomal Dominant (AD)

• Only one copy of a mutant gene is required to show disease symptoms/phenotype.
• AD traits have a gain-of-function.
• One affected parent or sporadic mutation results in statistically 50% of offspring being affected.
• AD traits follow a vertical pedigree pattern.
• AD disorders are generally less severe than recessive disorders.
• AD traits may show variable expressivity, but can show "anticipation" - earlier age of onset with increased severity in successive generation.

Gain-of-Function Mutations

• Gain-of-Function mutations result in an increase in activity of a gene product.

Autosomal Recessive (AR)

• Requires both copies of a mutant gene to show phenotype (disease characteristics).
• AR traits have a loss-of-function mutation.
• AR traits are generally inherited from both parents who are usually unaffected carriers.
• Statistically, 25% of offspring are affected in AR inheritance.
• AR traits have a horizontal pedigree pattern.
• AR disorders are generally more severe than dominant disorders, with less variable expressivity.
• There is clustering of phenotype among siblings in AR inheritance.

Loss-of-Function Mutations

• Loss-of-function mutations includes: point mutation, truncation, and deletion.

Sex-Linked Inheritance

• Sex-linked inheritance refers to genes inherited on the X chromosome.
• X-linked pedigrees show no male-to-male transmission.

X-Linked Dominant

• At least one parent is affected in X-linked dominant.
• Males and females are equally affected in X-linked dominant.
• Males display more severe forms in X-linked dominant.
• All female children of affected males are affected in X-linked dominant.

X-Linked Recessive

• Skips generations, more affected males in X-linked recessive.
• 50% of sons of carrier females are affected in X-linked recessive.

Hemizygocity

• Males are hemizygous for most X-linked genes because they have a single X chromosome.
• There are very few of the same genes on the Y chromosome.

X-Linked Dominant (Affected Father)

• In X-Linked Dominant (Affected Father), all daughters have the disease since he can only give a dominant X, while all sons do not have the disease.

X-Linked Dominant (Affected Mother)

• In X-Linked Dominant (Affected Mother), 50% daughters and sons have the disease - because mother is passing on either X or Y.

X-Linked Recessive (Carrier Mother)

• In X-Linked Recessive (Carrier Mother), 50% daughters are carriers, and 50% sons are affected by the disease.

X-Linked Recessive (Affected Father)

• In X-Linked Recessive (Affected Father), all daughters are carriers, and all sons do not have the disease.

Establishing Mode of Inheritance

• Autosomal Dominant: Males and females are affected in equal proportions, with affected individuals in multiple generations, and transmission by individuals of both sexes.
• Autosomal Recessive: Males and females are affected in equal proportions, with affected individuals usually only in a single generation, and horizontal transmission by individuals of both sexes.
• X-Linked Dominant: Affected individuals in multiple generations, with no male to male transmission, and all daughters from an affected father are also affected.
• X-Linked Recessive: Only males are usually affected, and can be transmitted through unaffected females, but affected males cannot transmit the disorder to their sons.
• Y-Linked: Only affected males.

Single Gene Disorders

• Autosomal Dominant: Achondroplasia, Brachydactyly, Huntington disease, Marfan syndrome, Neurofibromatosis, von Willebrand disease.
• Autosomal Recessive: Albinism, Cystic fibrosis, Phenylketonuria, Sickle cell anemia, Tay-Sachs, Thalassemia.
• X-Linked Dominant: Hypophosphatemia, Aicardi Syndrome, Chokenflok Syndrome, Rett Syndrome.
• X-Linked Recessive: Colour blindness, Duchenne muscular dystrophy, Fragile X, G6PD deficiency, Haemophilia, Lesch-Nyhan syndrome.