Non-Mendelian Inheritance

Complications of Mendelian Inheritance

• Clear-cut dominant/recessive relationships are not always observed.
• Pedigrees do not always follow Mendelian inheritance rules.
• X-linked diseases are an example of non-Mendelian inheritance patterns.
• More than one gene often influences a single phenotype.
• Polygenic traits are when multiple genes influence a single phenotype.
• Phenotypes often result from genetics and environmental interactions which affect gene expression.
• Multifactorial traits are when genetics and environmental factors influence a phenotype.

Types of Dominance

• Dominance is seen in the phenotype of a heterozygote
• Complete dominance is when the heterozygote has the same phenotype as the homozygote.
• Incomplete/Partial dominance is when the heterozygote shows an intermediate phenotype.
• Co-dominance is when the heterozygote expresses both phenotypes.
• Snapdragons petal color is an example of incomplete dominance.
• Color dilution gene in horses is an example of incomplete dominance.
• Chestnut horses have the genotype (CC).
• Palamino horses have the genotype (CCrC).
• Cremello horses have the genotype (CCrCCr).
• ABO blood grouping is an example of co-dominance inheritance.
• ABO blood grouping has three alleles: A, B, and O.
• A and B alleles show codominance.
• The O allele is recessive to both A & B.
• There are 6 genotypes: AA, AO, AB, BB, BO, OO.
• There are 4 phenotypes: A, B, AB, O.

Penetrance

• Penetrance is when apparently dominant alleles sometimes skip a generation.
• This is also known as reduced or variable penetrance.
• The Individual has the mutant gene but does not express the disease phenotype.
• BRCA1 and BRCA2 mutations (breast or ovarian cancer) are examples of this;
• Both incomplete penetrance and X-linked recessive (XLR) inheritance patterns present pedigrees that skip generations.
• XLR predominantly affects males and skips exclusively through females.
• Incomplete penetrance is when the disease is affected/skipping.
• Age-dependent penetrance is also referred to as 'late manifestation'.
• Not all genetic diseases are expressed at birth, the age of onset may be later in life.
• Gene mutations can influence the age of onset.
• Symptoms in later generations are often more severe and appear at progressively younger ages, known as anticipation.
• Huntington disease are examples of age-dependent penetrance.

Expressivity

• Variable expressivity is when a dominant and fully penetrant mutant allele causes a disease in all individuals although the severity and expression vary considerably.
• Neurofibromatosis type 1 which causes Cafe-au-lait spots and dermal neurofibromas

Penetrance vs Expressivity

• Incomplete penetrance means that not all individuals with the genotype express the phenotype,.
• Variable expressivity means that the phenotype varies among individuals with the same genotype which can also include some penetrance.

Loss of Mutations

• Loss-of-function mutations are most often seen as recessive diseases, but can be seen in dominant disorders.
• Haploinsufficiency is when 50% of the gene’s protein product is insufficient for normal function.
• Dominant Negative Mutations is when an abnormal protein product interferes with the normal protein product.
• Haploinsufficiency has only one functional copy of a gene is present, and the other copy is mutated.
• Since the Single functional copy is unable to produce enough gene product (i.e. protein) to display the normal phenotype, incomplete dominance occurs.
• Disease phenotype is due to the absence of the second functional allele NOT the presence of the abnormal allele, therefore, loss of function.
• With Dominant Negative Mutation only one functional copy of a gene is present, the other copy is mutated.
• Mutated protein antagonizes the normal protein and results in inactive function.
• Disease phenotype is due to the presence of the abnormal allele, not the absence of the second normal allele.
• Receptor Tyrosine Kinases are monomeric cell surface receptors.
• When a ligand binds to their extracellular domain receptor dimers form.
• Dimerization causes receptor activation by autophosphorylation of the intracellular domain;

Genetic Modifiers

• Epistasis is when the mutation of one gene interferes or masks the phenotypic expression of another gene, also known as modifier genes.
• Widow's peak & baldness are examples of epistasis.
• In humans, a widow's peak is dominant (HH or Hh) to a straight hairline (hh).
• The gene for complete baldness is recessive (bb).
• With complete baldness (bb), it does not matter if there is a widow's peak (H) or (hh).
• Pleiotropy is when a pleotropic gene influences multiple (apparently unrelated) phenotypic traits.
• Marfan syndrome is an example of Pleiotropy that is caused by a mutation in the FBN1 gene which encodes fibrillin, a protein important in connective tissue.
• Impacts the skeleton, heart, blood vessels, eyes, lungs, and skin

Genetic Variance

• Genetic heterogeneity is when a single phenotype may be caused by any one of a multiple number of mutations in the same gene (allelic) or different genes (locus)
• In allelic heterogeneity different mutations within a single gene (multiple alleles) can cause the same phenotypic expression.
• An example of this is cystic fibrosis with greater than 1,000 known CFTR mutant alleles
• Locus heterogeneity is when a disease is caused by a mutation in one of many unrelated genes.
• An example of such is retinitis pigmentosa with greater than 38 genes; AD, AR, XL
• Mosaicism and Chimerism pertains to individuals who have more than one genetically-distinct population of cells
• Mosaic are genetically different cells that all arise from a single zygote.
  • An example of this would be X chromosome inactivation in females or Mosaic Down syndrome (46,XX/47,XX+21)
• Chimeria are genetically different cells that arise from more than one zygote.
  • An example of this would be fusion of twin embryos, maternal-foetal trafficking or organ or stem-cell transplants.
• Females are Genetic Mosaics with respect to genes on X Chr, because of X-Chromosome inactivation.
• Genomic Imprinting is an epigenetic process by which some genes are expressed based on the paternal or maternal allele
  • This Leaves a sex-specific mark that is required for normal embryonic development
  • The Non-expressed allele is transcriptionally silenced by methylation and histone modification
  • Thought to occur either prior to- or during gametogenesis where Different regions are marked dependant on sperm-forming or egg-forming tissues
• Silenced alleles are said to be imprinted
• Which allele is expressed is determined in a parent-of-origin-specific manner and only the maternally inherited allele is ever expressed, or vice versa
• Prader-Willi Syndrome and Angelman Syndrome
• Gene/Environment Interactions result when Phenotypes are often the result of both genetics & the environment within which genes are expressed
  • Temperature effects like Siamese cat fur color or Heat-shock proteins
  • Nutritional effects like Phenylketonuria or Lactose intolerance
• Polygenic & Multifactorial Diseases involves the interaction of many genes & environmental factors.
  • Examples of this include, cancers, heart disease, diabetes, obesity, migraine,hypertension, Alzheimer, suicide, schizophrenia, bipolar disorder,alcoholism, osteoporosis, asthma, arthritis, etc.

Mitochondrial Inheritance

• Mitochondria contain DNA
• DNA is circular, 16.5kb, 37 genes
• 13 of these genes involved in oxidative phosphylation
• Mitochondria are inherited maternally because Paternal mitochondria (from sperm) lost during fertilization
• Mitochondria has a Critical role in ATP production (for energy)
• Number of mitochondria in each cell varies (200-5,000 per cell)
• Cells that require more energy (muscle, heart, brain) have more mitochondria
• Some Characteristics of Mitochondrial Inheritance indicates that Affected females transmit the disease to ALL their children whilst Affected males DO NOT transmit the disease to their children
• Heteroplasmy is when a cell contains mitochondria with both normal & mutant mtDNA, and by chance some cells may receive more or less defective mitochondria
• With Heteroplasmy, Mitochondrial disease severity is highly variable and the degree of heteroplasmy can also vary from affected organ to organ