Mendelian Inheritance Patterns

• Mendelian Inheritance Patterns involves the study of how traits are passed down from parents to offspring

Gregor Mendel (1823-1884)

• Mendel proposed the theories of inheritance without knowledge of chromosomes or genes
• He developed the concept of dominant and recessive units
• Units exist in pairs and are now referred to as genes

Alleles & Zygocity

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

Dominant/Recessive Alleles

• Single gene example with the possibility of 2 alleles where allele 1 = A and allele 2 = a
• In a diploid cell, the possibilities are AA, Aa, aA, aa
• Dominant phenotype traits are expressed in both the homozygote (AA) and heterozygote (Aa)
• Recessive phenotype trait is only expressed in the homozygote (aa), referred to as Recessive homozygote

Monohybrid Cross

• Monohybrid cross details include possible phenotypes, genotypes, and resulting gamete formations and fertilizations
• The zygocity of resulting offspring can be heterozygous or homozygous

Mendel's First Three Principles

• Unit factors are inherited in pairs where genetic characters are controlled by unit factors existing in pairs in individual organisms
• Dominance/Recessive factors say that when two unlike unit factors responsible for a single character are present in a single individual, one unit factor is dominant to the other, which is said to be recessive
• The Law of Segregation states that during meiosis the 2 alleles for any given gene separate so that each ends up in different gametes.
  • Each gamete contains only one homologous chromosome & therefore only one allele for each gene.

Punnett Square

• In a Punnett Square, alleles of the parents are combined to show all possible genotypes of the offspring
• The resulting ratio is 1:2:1 for genotype and 3:1 for phenotype

Punnett Square Convention

• Female alleles are on the top
• Male alleles are on the left
• Dominant allele in upper case (D)
• Recessive allele in lower case (d)
• The Dominant allele is always written before the recessive (Dd)

Mendel's 4th Principle of Inheritance

• The Law of Independent Assortment states that during meiosis the 2 alleles for any given gene separate independently of other alleles for other genes
• Note this is not true if the 2 genes are found on the same chromosome

Chromosomal Theory of Inheritance

• Genes are a part of the chromosomes and are segregated during meiosis
• There is independent assortment of nonhomologous chromosomes

Independent Assortment & Gamete Diversity

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

Family Studies

• Family studies use pedigrees (family trees) to study modes of inheritance
• Pedigrees are used to look for the presence/absence of specific traits in each family member of each generation to determine to mode of inheritance and risk factors

General Modes of Inheritance

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

Autosomal Dominant (AD)

• Only requires one copy of mutant gene to show phenotype or disease symptoms
• There is a Gain-of-function
• Includes one affected parent or sporadic mutation
• Statistically 50% of offspring are affected exhibiting a Vertical pedigree pattern
• Less severe than recessive disorders, may show variable expressivity, shows anticipation of earlier age of onset with increased severity in successive generation

Autosomal Dominant Inheritance

• The disease allele is dominant and located on a non-sex chromosome which means that only one copy of the allele is needed to cause the disease
• Affected individuals typically have one affected parent; unaffected offspring of an affected parent are not carriers
• All offspring of two unaffected parents are also unaffected, if one parent is affected and the other is not, each child has a 50% chance of inheriting the disease

AD Pedigree

• Visual diagram of autosomal dominant pedigree

Autosomal Recessive (AR)

• Requires both copies of mutant gene to show phenotype or disease characteristics
• Includes Loss-of-function mutation
• Generally inherited from both parents who are usually unaffected carriers
• Statistically 25% of offspring affected exhibiting a Horizontal pedigree pattern
• Typically more severe than dominant disorders offering less variable expressivity with Clustering of phenotype among siblings

Autosomal Recessive Inheritance

• The disease allele is recessive and located on a non-sex chromosome, meaning two copies of the allele are needed to cause the disease
• If both parents are carriers (i.e., heterozygous) but unaffected, each child has a 25% chance of inheriting the disease, a 50% chance of being a carrier, and a 25% chance of being neither affected nor a carrier
• The trait may skip generations

Loss-of-Function Mutations

• A loss of function mutation diagram is presented for illustration

AR Pedigree

• A visual diagram of autosomal recessive pedigree

Sex-Linked Inheritance

• Refers to genes inherited on the X chromosome, showing NO male-to-male transmission
• X-Linked Dominant includes at least one parent affected where males & females are equally affected
  • Males display more severe forms and all females children of affected males are affected
• X-Linked Recessive skips generations and exhibits more affected males
  • 50% of sons of carrier females are affected

Hemizygocity

• Males are hemizygous for most X-linked genes
• Only a single X chromosome, where very few of the same genes are on the Y chromosome

X-Linked Dominant (Affected Father)

• All daughters have the disease and all sons do not have the disease
• 50% of the offspring may be affected

X-Linked Dominant (Affected Mother)

• 50% of daughters have the disease, 50% daughters do not have the disease
• 50% of sons have the disease, 50% of sons of do not have the disease

XLD Pedigrees

• Visual diagrams of X-Linked Dominant pedigree

X-Linked Recessive (Carrier Mother)

• 50% of daughters do not have the disease
• 50% of daughters are carriers
• 50% of sons do not have the disease
• 50% of sons have the disease

X-Linked Recessive (Affected Father)

• All daughters are carriers
• All sons do not have the disease

XLR Pedigree

• Visual diagram of X-Linked Recessive pedigree inheritance

Establishing Mode of Inheritance

• Autosomal Dominant: Males & females are affected in equal proportions, includes affected individuals in multiple generations, and transmission by individuals of both sexes
• Autosomal Recessive: Males & females are affected in equal proportions includes affected individuals usually in only one generation, and transmission by individuals of both sexes
• X-Linked Dominant: Affected individuals in multiple generations. No male to male transmission where all daughters from an affected father are also affected
• X-Linked Recessive: includes Only males usually affected, transmits through unaffected females, and affected males cannot transmit the disorder to their sons
• Y-Linked: Affected males only

Single Gene Disorders

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