Mendelian Inheritance Patterns

• Mendelian Inheritance Patterns are covered in this session.

Gregor Mendel (1823-1884)

• Mendel proposed the theories of inheritance without knowledge of chromosomes or genes.
• Mendel developed the concept of dominant and recessive units existing in pairs.
• Hereditary units are now called genes.

Alleles and Zygocity

• Genes have alternative forms called alleles that differ in sequence.
• Homologous chromosomes paired with identical alleles for a gene are homozygous.
• Homologous chromosomes paired with different alleles for a gene are heterozygous.

Dominant/Recessive Alleles

• A is allele 1 and a is allele 2 when taking a single gene with two possible alleles.
• A diploid cell has four possibilities which are AA, Aa, aA, aa.
• A trait expressed in both homozygotes (AA) and heterozygotes (Aa) is a dominant phenotype.
• A trait expressed only in the homozygote (aa) is a recessive phenotype.

Mendel's First Three Principles

• Inherited in pairs are Unit factors with genetic characters that are controlled by unit factors existing in pairs.
• 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 recessive.
• During meiosis the 2 alleles for any given gene separate to end up in different gametes in the law of segregation.
• Each gamete contains only one homologous Chr and one allele for each gene.

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).
• Dominant allele written before the recessive (Dd).

Mendel's 4th Principle: Law of Independent Assortment

• The 2 alleles for any given gene separate independently of other alleles during meiosis.
• This principle is not true if two genes are on the same chromosome (i.e. linked).

Chromosomal Theory of Inheritance

• Unit factors are in pairs during the first meiotic prophase.
• Segregation of unit factors occurs during gamete formation in the first meiotic anaphase.
• Independent assortment of segregating unit factors follows many meiotic events.

Independent Assortment & Gamete Diversity

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

Family Studies

• Controlled breeding experiments are unethical and not possible.
• Few offspring are available for study.
• Pedigrees (family trees) are traditionally used to study modes of inheritance.
• The presence/absence of traits are looked for in each family member of each generation.
• Pedigrees are used to understand mode of inheritance, risk factors, individual genotypes and genetic counselling.

Pedigree Conventions

• Pedigrees use specific symbols to denote male, female, affected individuals, carriers, etc, and portray relationships between family members.

General Modes of Inheritance

• The four modes of inheritance are: Autosomal Dominant, Autosomal Recessive, Sex-linked Dominant and Sex-linked Recessive.

Autosomal Dominant (AD)

• Only requires one copy of a mutant gene to show phenotype (disease symptoms).
• Gain-of-function mutations, one affected parent or sporadic mutation, and statistically 50% of offspring being affected are characteristics.
• Vertical pedigree pattern.
• Less severe than recessive disorders, may show variable expressivity, and may show 'anticipation', with an earlier age of onset and increased severity in successive generations, are also characteristics.

Gain-of-Function Mutations

• Gain-of-function mutations are mutations to a gene with a normal function, resulting in a new function.

Autosomal Recessive (AR)

• Requires both copies of a mutant gene to show phenotype (disease characteristics).
• Loss-of-function mutation, generally inherited from both parents who are usually unaffected carriers, statistically 25% of offspring being affected, and a horizontal pedigree pattern are all characteristics.
• Typically more severe than dominant disorders: less variable expressivity, clustering of phenotype among siblings, and parents & other ancestors usually not affected.

Loss-of-Function Mutations

• Loss-of-function mutations result in a gene product having less or no function.

Sex-Linked Inheritance

• Sex-Linked Inheritance genes are inherited on X chromosome.
• No male-to-male transmission shown in X-linked pedigrees.
• X-Linked Dominant means that at least one parent needs to be affected, with males and females being affected equally.
• Males display more severe forms and all female children of affected males are affected.
• X-Linked Recessive skips generations, with more affected males and statistically 50% of sons of carrier females being affected.

Hemizygocity

• For most X-linked genes, males are hemizygous.
• Single X Chr and very few of the same genes are on Y Chr.

Establishing Mode of Inheritance

• Autosomal Dominant has males & females affected in equal proportions.
• Affected individuals have transmission by individuals of both sexes in multiple generations.
• Autosomal Recessive also has males & females affected in equal proportions, however, affected individuals usually only show in a single generation, and has transmission by individuals of both sexes.
• X-Linked Dominant has affected individuals in multiple generations with no male-to-male transmission.
• X-Linked Dominant has all daughters from an affected father being also affected.
• X-Linked Recessive usually only has males affected, and is transmitted through unaffected females.
• Affected males cannot transmit the disorder to their sons.
• Y-Linked only has affected males, and affected males must transmit it to their sons.

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
• Y-Linked: Male infertility