Lecture 14: Non-Mendelian Inheritance

Non-Mendelian and Multifactorial Inheritance

• Factors influence the phenotypic expression of single-gene disorders
• Focus on Mosaicism, Incomplete Penetrance, Variable Expression, Genetic Heterogeneity, and Pleiotropy
• Polygenic and multifactorial inheritance are unique from one another
• Multifactorial inheritance of complex diseases, including Quantitative traits, Qualitative traits and Threshold
• Traditional ways to study multifactorial traits such as Family studies, Twin studies, Adoption studies, and Genome-wide association studies

Factors Influencing Phenotypic Expression in Single Gene Disease

• Non-Mendelian inheritance, traits do not segregate in accordance with Mendel's laws
• Mendelian genetics concerns single genes on chromosomes in the nucleus, for multiple allele traits, codominance, incomplete dominance, and polygenic traits
• Genes are typically expressed from both alleles in diploids, one from each parent
• Instances that deviate from the Mendelian inheritance patterns, such as X-inactivation and mitochondrial inheritance
• Factors influence phenotypic expression of single-gene disorders

Mosaicism

• Mosaicism has distinct cell lines in the same person
• Somatic mosaicism may occur in individuals with imprinting disruptions
• Asymmetry and obscuring genotype-phenotype correlations can result from mosaic distribution
• Chromosome nondisjunction is the principal cause of chromosomal aberration, leading to mosaicism
• Unusual events in cell division (mitosis) and gene mutation during development
• Chromosomal mutation during development; X-inactivation creates mosaicism

McCune-Albright Syndrome

• Mutation affects G-protein signaling
• Characterizations: unilateral café-au-lait spots, polyostotic fibrous dysplasia, precocious puberty, and multiple endocrine abnormalities
• Survivable in patients with mosaicism, lethal if mutation occurs before fertilization

Penetrance vs Expressivity-Definitions

• Penetrance shows the percentage of people who have the genotype and express phenotype
• Penetrance factors consist of Sex, age, environment, modifier genes, and heteroplasmy
• Complete penetrance is characterized as every individual with a mutation showing disorder symptoms
• Incomplete penetrance as individuals with disease genotype possibly not displaying disease phenotype
• Expressivity shows phenotypic variation between individuals with the same genotype
• Factors affecting expression of a genetic disease consist of age, diet, exercise, exposure to harmful chemicals, smoking, and UV light, etc
• Heteroplasmy results in variable expression in mitochondrially inherited disease
• Complete or 100% penetrance is rare
• Not all individuals with a mutant genotype show the mutant phenotype
• Expressivity refers to the intensity of the phenotype in an individual
• Variable Expressivity means one genotype produces a range of phenotypes
• 2 patients with Neurofibromatosis type I may have varying disease severity

Incomplete Penetrance Examples

• Does an individual with the genotype show ANY phenotype?
• Pathogenic variant in the BRCA1 or BRCA2 genes increase risk for specific cancers, but not all individuals with one of these genes develops cancer
• BRCA1 mutation carriers who never develop cancer demonstrate incomplete penetrance
• 4 features are present for Waardenburg syndrome, including premature graying, hearing loss, white forelock, and different colored eyes
• The family member has the same genotype but shows a different combination of symptoms
• Hemochromatosis occurs early for males (around 30 yo) and after menopause for females
• Hemochromatosis is a disorder with extra iron builds up, iron can damage many parts of the body
• Most patients develop serious problems through inherited genes for the disorder

Incomplete Penetrance/Variable Expressivity

• Neurofibromatosis type 1 (NF1) has around 50-80% penetrance and variable expressivity
• A parent may exhibit few café-au-lait spots and axillary freckling
• A child may exhibit many subcutaneous neurofibromas, café-au-lait spots, and an optic glioma
• Board exams cover generational skipping (incomplete penetrance) and varying severity (variable expressivity) through pedigree analysis

Genetic Heterogeneity

• Variable expression can result from allelic heterogeneity where different alleles or variants in the same gene can lead to the same phenotype
• Allelic heterogeneity means different mutations in the same gene cause similar phenotypes such as >2,000 CFTR mutations for cystic fibrosis
• Locus Heterogeneity means mutations in different genes cause similar phenotypes

• over 50 genes for retinitis pigmentosa

• Some cystic fibrosis gene mutations can cause a complete absence of the chloride channel, while some cause a partially active one
• Subunits of procollagen triple helix are encoded by 2 genes located on chromosome 17 and 7
• Mutations in other genes like CRTAP and P3H1 also give rise to osteogenesis imperfecta
• Different alleles/genes cause the same phenotype, many disease-causing variants/gene
• Allelic heterogeneity can be classified as adaptive or disadaptive
• Hemophilia A involves Nonsense vs Missense mutation in factor VIII gene

Pleiotropy

• Single genes influence multiple phenotypic traits and affect multiple systems
• Marfan Syndrome is caused by mutations in the FBN-1 gene (fibrillin-1)
  • Cardiovascular: Aortic root aneurysm or dissection
  • Ocular: Ectopia lentis (abnormal lens position)
  • Skeletal: tall stature, long (arms, legs, fingers), arachnodactyly)
• Cystic Fibrosis is caused by a mutation in CFTR gene with severe damage to the respiratory system, digestive system, etc
• Genetic testing can be complex, seemingly unrelated symptoms may have a single genetic cause

Epigenetics

• Focuses on changes caused by modifications of gene expression, not DNA sequence
• Epigenetic factors can alter gene expression and cause different disease profiles
• DNA methylation tags and activates or represses genes
• Histone Modification like Imprinting-base modification and Acetylation, methylation, phosphorylation, sumoylation, and ubiquitination can be inherited
• Epigenetic alterations are regulated by environmental factors and behavioral circumstances, such as the Degree of exposure to UV light in Xeroderma pigmentosum

Genomic Imprinting

• Core is Expression depends on the parental origin
• Silencing by DNA methylation impacts chromosomes 15q11-q13
• Prader-Willi and Angelman Syndromes stem from deletion, uniparental disomy or imprinting center defects
• First-line is methylation analysis
• An epigenetic modification of the genome where the allele from one of the parents are closed down and controlled by imprinting centers located at promoters
• Genetic imprinting leads to monoallelic expression
• turns off one copy of a gene depending of maternal or paternal
• There are two genome clusters in Chromosome 11 and 15 and only a small number of genes are active
• Homologous locus in the other parent is transcriptionally inactive
• Some loci only have the maternal or paternal loci active
• Maintained in all somatic cells of offspring
• Erased and re-established according to the individual’s sex during gametogenesis
• Imprinting involves cytosine methylation of an allele to imprint or inactivate the appropriate loci

Uniparental Disomy-UPD

• Receiving two copies of a specific chromosome from one parent
• Can lead to chromosomal aberrations and inheritance disorders
• UPD occurs with little impact since individual still has 2 gene copies, but can cause these disorders is inheriting two copies of an imprinted gene
• Trisomy rescue can result in UPD

Angelman (AMS) & Prader-Willi (PWS) Syndromes

• These are both genomic imprinting disorders
• Can arise via deletion, UPD, or imprinting issues
• Methylation analysis is first line
• Genetic Mechanism is Chromosome 15q11-q13
• PWS is Loss of paternally expressed genes, loss of maternally expressed for AMS

Anticipation

• Genetic disorder appears sooner and/or stronger in subsequence generations
• Typically due to expansion of CGG, CCG,CAG, and CTG triplets
• May be inherited through both autosomal dominant or recessive and by X-linked inheritance patterns
• Not necessarily 100% penetrant and Individuals in pedigree may inherit a repeat, and pass it to their children who would express the disease
• The disease appears earlier with greater severity than earlier generations

Triplet Repeat Disease

• Huntington's Disease involves CAG repeats, and Fragile X Syndrome involves CGG repeats.
• Huntington's has paternal anticipation
• Fragile X includes premutation carriers.
• Myotonic dystrophy involves CTG repeats and a severe congenital form has maternal transmission

New Mutation

• Disease caused by a new mutation transmitted from unaffected parent to affected offspring
• No family history is Pedigree's presentation
• Low recurrence risk for siblings, but equals the regular individual risk for any offspring
• Mutation manifests as a disease later in life

Overview: Polygenic and Multifactorial Inheritance

• Familial clustering deviates from Mendelian inheritance
• Most common congenital malformations can come from this
• Polygenic means multiple genes are at play, such as for hair and eye color
• Multifactorial includes environmental factors.
• Multiple genes and environmental factors influence traits, following normal distribution
• Two genes that are at play for human eye color are OCA2 and HERC2, with over 16 different genes at play

Multifactorial Inheritance

• Disorders or conditions due to single gene mutations are rare (monogenic)
• Traits that are purely polygenic are also rare
• Most are determined with environmental factors like diet or lifestyle through the DNA
• Conditions occur through combined threshold of DNA predispositions and environmental factors.

Threshold Model: Recurrence - Determination of Empiric Risk

• Multifactorial disorders follow a threshold model with individuals varying in genetic liability and condition developing with individual beyond threshold
• Based on observed recurrences in population studies such as 4% recurrence in siblings with neural tube defects
• Factors consist of number of affected relatives, the condition, sex, background, and modifiers.

Qualitative and Quantitative Traits

• Qualitative traits are phenotypes with discrete, easy measurements.
• Quantitative traits are measured over time, and caused by genetic and environmental factor effects
• Threshold Model means the disease is presented or absent
• This indicates the chance of developing pyloric stenosis.
• These are either expressed or absent, threshold of liability must be crossed before the disease is expressed.

Study Methods: Family Studies

• Relatives share more alleles than nonrelatives.
• Siblings share ~50% of their alleles on average
• Familial aggregation and correlation studies are used to study both genetic and environmental contributions.

Understanding Genetic and Environmental Influences Using Twins

• A Monoygotic twin set has 100% of the genes and home environment
• For Dizygotic (DZ) twin pairs, it is 50% genetic and 100% environmental
• We are a combination of the above.

Concordance Rate

• Twin studies that compares these rates between MZ and fraternal sets can suggest genetic cause
• Concordance rate if equal means the trait is strictly environmental, a higher one means a genetic component
• Data from MZ and DZs is used to show heritability, close to 1 is genes

Study Methods: Adoption Studies

• Separating genes from the environment through comparing those with genetic traits being raised under different factors
• • correlation in adopted children with biological parents shows behavior is genetic.

Genome-Wide Association Studies (GWAS)

• Compares common SNPs across genomes of individuals with and without diseases