Mendelian Inheritance Variations

Complications of Mendelian Inheritance

• Clear dominant/recessive relationships are not always observed
• Pedigrees do not follow Mendelian inheritance rules
• X-linked diseases exemplify this
• Phenotypes are often influenced by two or more genes
• Polygenic traits are an example
• Phenotypes result from genetics and the environment

Types of Dominance

• dominance is observed in the phenotype of a heterozygote
• Complete dominance means the heterozygote has the same phenotype as the homozygote
• Incomplete/Partial dominance causes the heterozygote to show an intermediate phenotype
• Co-dominance causes the heterozygote to express both phenotypes

Incomplete Dominance

• Snapdragon petal color and horse coat color dilution genes exemplify incomplete dominance
• Chestnut horses have CC genes
• Palamino horses have CCrC genes
• Cremello horses have CCrCCr genes

Co-Dominant Inheritance

• ABO blood grouping exemplifies co-dominance
• There are three alleles: A, B, and O
• A and B show codominance
• The O allele is recessive to both A and B
• There are 6 possible genotypes: AA, AO, AB, BB, BO, 00
• There are four phenotypes: A, B, AB, and O

Incomplete Penetrance

• Reduced or variable penetrance occurs when dominant alleles sometimes skip a generation
• The individual has the mutant gene but does not express the disease phenotype
• BRCA1 and BRCA2 mutations in breast or ovarian cancer exemplify incomplete penetrance

Incomplete Penetrance & X-Linked Recessive (XLR)

• Both incomplete penetrance and XLR can skip generations in pedigrees
• XLR predominantly affects males and skips exclusively through females
• Incomplete penetrance is defined as affected/skipping

Age-Dependant Penetrance

• Late manifestation is another term
• Genetic diseases may not be expressed at birth; the age of onset may be later in life
• Gene mutations influence the age of onset
• Symptoms in later generations appear at progressively younger ages, known as anticipation
• CAG impacts Huntington's disease

Variable Expressivity

• A dominant and fully penetrant mutant allele causes a disease
• severity and expression will vary considerably
• Neurofibromatosis type 1 gives rise to Cafe-au-lait spots and dermal neurofibromas

Incomplete Penetrance vs Variable Expressivity

• Highlights the difference between penetrance and expressivity

Loss-of-Function Mutations

• Loss-of-function mutations are often seen as recessive diseases, but can also be dominant disorders
• Haploinsufficiency indicates 50% of the gene’s protein product is insufficient for normal function
• Dominant Negative Mutations occur when an abnormal protein product interferes with the normal protein product

Haploinsufficiency

• Involves having only one functional copy of a gene due to a mutation in the other copy
• A single functional copy is unable to produce enough gene product to display a normal phenotype
• Disease phenotype is due to the absence of the second functional allele, NOT the presence of the abnormal allele
• A loss of function effect occurs

Dominant Negative Mutation

• Mutated protein antagonizes the normal protein
• The functional protein often exists as a dimer or tetramer
• Leads to inactive function i.e a loss of function
• Disease phenotype exists because of the presence of the abnormal allele

Receptor Tyrosine Kinases

• Receptor tyrosine kinases are monomeric cell surface receptors
• When a ligand binds to their extracellular domain, receptor dimers form
• Dimerization activates the receptor by autophosphorylation of its intracellular domain
• Active function allows other proteins to bind to the intracellular domain

Epistasis

• The mutation of one gene interferes with or masks the phenotypic expression of another gene
• Modifier genes are the cause
• Widow’s peak and baldness exemplify it
• In humans, a widow’s peak is dominant (HH or Hh) to a straight hairline (hh)
• The gene for complete baldness is recessive (bb)
• Complete baldness suppresses the Widow’s peak

Pleiotropy

• A pleotropic gene influences multiple, apparently unrelated, phenotypic traits
• Marfan syndrome exemplifies this
• A mutation in the FBN1 gene encodes fibrillin, a protein important in connective tissue
• Impacts the skeleton, heart, blood vessels, eyes, lungs, and skin

Genetic Heterogeneity

• A single phenotype results from a multiple number of mutations in the same gene (allelic) or different genes (locus)
• Allelic Heterogeneity is an example with different mutations within a single gene that can cause the same phenotypic expression
• Cystic fibrosis exemplifies this with >1,000 known CFTR mutant alleles
• Locus Heterogeneity indicates disease caused by a mutation in one of many unrelated genes
• Retinitis pigmentosa exemplifies this with >38 genes; AD, AR, XL

Mosaicism & Chimerism

• Individuals who have more than one genetically distinct cell population
• Mosaicism occurs when genetically different cells arise from a single zygote: X chromosome inactivation in females and Mosaic Down syndrome (46,XX/47,XX+21)
• Chimeria occurs when genetically different cells arise from more than one zygote: Fusion of twin embryos, Maternal-foetal trafficking, Organ or stem-cell transplants

Genomic Imprinting

• An epigenetic process causes some genes to be expressed based on the paternal or maternal allele
• A sex-specific mark is required for normal embryonic development
• Non-expressed alleles are transcriptionally silenced by methylation and histone modification
• Genomic imprinting occurs prior to or during gametogenesis
• Different regions are marked dependant on sperm-forming or egg-forming tissues
• Silenced alleles are also imprinted
• Allele expression is determined in a parent-of-origin-specific manner
• Only the maternally inherited allele is ever expressed, or vice versa

Gene/Environment Interactions

• Phenotypes are often the result of both genetics and the environment
• Temperature effects on Siamese cat fur color and heat-shock proteins exemplify this
• Nutritional effects such as Phenylketonuria and Lactose intolerance also exemplify this

Polygenic & Multifactorial Diseases

• Many genes & environmental factors interact
• Most cancers, heart disease, diabetes, obesity, migraine, hypertension, Alzheimer, suicide, schizophrenia, bipolar disorder, alcoholism, osteoporosis, asthma, and arthritis exemplify this
• Complicates through by: Epistasis, incomplete penetrance, variable expressivity, pleiotropy

Mitochondrial Inheritance

• Mitochondria contain DNA (circular, 16.5kb, 37 genes)
• 13 of these genes encode for oxidative phosphylation
• Mitochondria are inherited maternally
• Paternal mitochondria (from sperm) are lost during fertilization

Role of the Mitochondrion

• Critical role in ATP production (for energy)
• The number of mitochondria in each cell varies (200-5,000 per cell)
• Cells that require more energy (muscle, heart, brain) have more mitochondria
• Affected females transmit the disease to all their children
• Affected males do not transmit the disease to their children

Heteroplasmy

• Cell contains mitochondria with both normal & mutant mtDNA
• Some cells may receive more or less defective mitochondria via chance
• Mitochondrial disease severity is highly variable
• Degree of heteroplasmy changes across affected organ types