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510_Module 5
Patterns of Inheritance, Imprinting, & Epigenetics
| Term | Definition |
|---|---|
| Allele | Alternate forms of gene characterized by differences in nucleic acid sequence |
| Locus | The site that a gene occupies on a chromosome |
| Hemizygous | Refers to a genetic condition in which only one copy of a particular gene or chromosome is present in an individual’s genome (Example: males are hemizygous for x linked genes because they only have 1 X) |
| Autosomal dominant inheritance | Trait appears in every generation. Only one copy of the disease-causing allele is needed for trait. Affected individuals transmit mutation to 1/2 their offspring M & F equally likely to have/transmit trait. Unaffected individuals don't transmit mutation. |
| X-linked recessive inheritance | Hemizyg M affected; heterozyg F unaffected F may be affected due to skewed XCI, homozyg. abnl allele, 45,X Nl.carrier mom transmits to 1/2 sons & 1/2 girls Affected M =all carrier girls,0% affected sons Unaffected M don't transmit |
| Autosomal recessive inheritance | Trait usually appears among sibs, not parents, offspring, other relatives. 2 disease-causing alleles req'd Carrier parents, (heterozygotes), ~¼ affected, ½ carriers, ¼ unaffected/non-carriers Unaffected child =2/3 chance a carrier M:F = 1:1 |
| Variable expressivity | A spectrum of phenotypic presentation within the same genetic condition. This can be a range in severity or differing symptoms from person to person (or both – even within the same family). Example- Osteogenesis Imperfecta |
| Pleiotrophy | A single genetic change influences multiple, seemingly unrelated phenotypes (Example- Phenylketonuria (PKU)). |
| Difference between polygenic and multifactorial conditions | Polygenic diseases: Combined effects of variants in several genes. Multifactorial (or complex) diseases: multiple gene variants and environmental factors interact. |
| Counseling considerations for multifactorial inheritance | # genetic loci involved usually not known Particular alleles at each relevant loci in parents are usually not known The effect of the factors, i.e. protective or deleterious, and how they interact, is undefined Environmental effects are often unknown |
| Real vs. Artificial association | Real - True disease susceptibility - variant affects gene funx. Linkage disequilibrium - not variant looking at, but next to the one involved Artificial - cases & control differ in more ways than whether or not they have disease |
| What is polygenic risk score? | Provides quant metric of person's inher risk based on cumulative impact of many common polymorphisms Weights generally assigned to each variant based on strength of assoc w/ disease risk Individuals scored combining effect size for risk genotype |
| X-Linked Dominant w/ Male Sparing | Manifest only in carrier females because hemizygous males are largely spared the consequences of the variant they carry. (Example: female-limited, X-linked epilepsy and cognitive impairment) |
| What is the recurrence risk for two heterozygous parents with an autosomal dominant condition? | 25% affected, 50% heterozygous affected, 25% unaffected |
| What is incomplete penetrance? | When individuals with a pathogenic genotype do not always show the phenotype. |
| Give an example of incomplete penetrance. | BRCA1/BRCA2 mutations—some carriers do not develop cancer. Aniridia HD (age related reduced penetrance) |
| What is variable expressivity? | The severity or specific features of a condition vary between individuals with the same genotype. |
| What is the difference between homozygous and heterozygous autosomal dominant disease? | Homozygotes often have more severe phenotypes or may be lethal (e.g., achondroplasia) |
| Recurrence risk for autosomal recessive when both parents are carriers? | 25% affected, 50% carrier, 25% unaffected |
| Common examples of autosomal recessive disorders? | Cystic fibrosis, sickle cell disease, Tay-Sachs. |
| Define consanguinity and its effect on inheritance. | Union between biologically related individuals increases the chance of recessive conditions. |
| Example of X-linked recessive disorder? | Duchenne muscular dystrophy. |
| What is X-linked dominant inheritance? | Both males and females can be affected by one mutant allele on the X chromosome. |
| Example of X-linked dominant disorder? | Rett syndrome. |
| What is mitochondrial inheritance? | Mutations in mtDNA transmitted only through the mother. |
| Key concept of heteroplasmy in mitochondrial disease? | Mixed population of normal and mutant mtDNA, affecting disease severity. |
| What is anticipation in inheritance? | Successive generations show earlier onset or increased severity, often due to repeat expansions. |
| Example of anticipation disorder? | Huntington disease, Fragile X. |
| What is mosaicism? | Presence of two or more genetically distinct cell populations in an individual. |
| Example of somatic mosaicism in disease? | Segmental neurofibromatosis. |
| Define epigenetics. | Heritable changes in gene expression not caused by changes in DNA sequence. |
| Major epigenetic mechanisms? | DNA methylation, histone modification, chromatin remodeling, noncoding RNAs. |
| What enzyme catalyzes DNA methylation? | DNA methyltransferase (DNMT). |
| What is the typical effect of promoter DNA methylation? | Gene silencing. |
| How does histone acetylation affect transcription? | Acetylation relaxes chromatin, increasing transcription. |
| What are imprinted genes? | Genes expressed from only one parental allele due to epigenetic silencing of the other. |
| Example of imprinting disorder? | Prader-Willi syndrome (paternal deletion/imprinting defect). |
| Contrast Prader-Willi vs Angelman syndrome. | Both involve 15q11-q13; paternal loss → PWS, maternal loss → Angelman. |
| What is uniparental disomy (UPD)? | Both copies of a chromosome are inherited from one parent. |
| Example of disease from UPD? | Maternal UPD of chromosome 15 can cause Prader-Willi. |
| What is X-chromosome inactivation? | Random silencing of one X chromosome in female cells for dosage compensation. |
| What gene initiates X inactivation? | XIST gene |
| What is a CpG island? | Region rich in CpG dinucleotides near promoters, often methylated to silence genes. |
| Example of cancer linked to epigenetic silencing? | Hypermethylation of tumor suppressor genes (e.g., MLH1 in colorectal cancer). |
| Define epigenetic reprogramming. | Erasure and resetting of epigenetic marks during gametogenesis/early development. |
| How does environment affect epigenetics? | Nutrition, toxins, and stress can alter epigenetic marks. |
| Example of environmental epigenetic effect? | Dutch Hunger Winter → altered methylation linked to metabolic disease. |
| What is the role of miRNAs in epigenetics? | Post-transcriptional regulation by binding mRNAs to inhibit translation. |
| Example of therapy targeting epigenetics? | DNMT inhibitors (e.g., azacitidine for myelodysplastic syndrome). |
| Why is epigenetics reversible important clinically? | It allows therapeutic intervention through drugs modifying epigenetic marks. |
| What is the Hardy-Weinberg equilibrium (HWE) formula? | p^2+2pq+q^2=1. |
| What do p and q represent in HWE? | p = frequency of normal allele, q = frequency of mutant allele. |
| Assumptions of HWE? | Random mating, no mutation, no migration, no selection, large population. |
| What is genetic drift? | Random changes in allele frequency, strongest in small populations. |
| What is the founder effect? | Reduced genetic diversity and unique allele frequencies in a new isolated population derived from a small group. |
| Example of founder effect in humans? | Ashkenazi Jewish population and Tay-Sachs disease. |
| Define population stratification. | Subgroups in a population with different allele frequencies due to ancestry. |
| What is assortative mating? | Mating between individuals with similar phenotypes, affecting allele frequencies. |
| Define heritability. | Proportion of phenotypic variance explained by genetic variance. |
| What is the difference between broad vs narrow-sense heritability? | Broad includes all genetic variance; narrow includes only additive genetic variance. |
| What is a polygenic trait? | Trait influenced by many genes, each with small effect. |
| Example of polygenic trait? | Height, blood pressure. |
| What is multifactorial inheritance? | Trait influenced by both genetic and environmental factors. |
| What is the liability-threshold model? | Disease occurs when combined genetic/environmental liability exceeds a threshold. |
| Example of disease explained by threshold model? | Pyloric stenosis, congenital heart defects. |
| What is relative risk (λs)? | Ratio of risk for relatives compared to population risk. |
| Define linkage disequilibrium. | Non-random association of alleles at different loci. |
| What is a genome-wide association study (GWAS)? | A study scanning SNPs across genomes to find variants associated with disease. |
| Limitation of GWAS? | Often explains only a small proportion of heritability (“missing heritability”). |
| What is pharmacogenetics? | Study of how genetic variation influences individual drug response. |
| How many mitotic divisions ion the cells of the germline before meiosis in F vs M? | Females ~30; Males- hundreds |
| Parental transmission bias | When anticipation seems to occur only when the pathogenic allele is transmitted by an affected father/mother and not by an affected mother/father. |
| Loss of methylation at IC1 on the paternal allele results in silencing of IGF2; suppression of IGF2 results in reduced growth and causes | Russell-Silver syndrome (RSS) |
| Gain of methylation at IC1 on the maternal allele results in activation of IGF2, which promotes growth and causes: | Beckwith- Wiedemann syndrome (BWS) |
| Concordant | When twins have the same disease. |
| Discordant | when only one member of the pair of twins is affected and the other is not. |
| Gene | A segment of DNA that codes for a functional product. (CFTR, NF1, FMR1) |
| Allele | Alternate form of a gene characterized by differences in its nucleic acid sequence (Founder BRCA1 variants in Ashkenazi Jewish Population. (Exl Allele1: BRCA1 185delAG Allele 2: BRCA1 5382insC) |
| Locus Heterogeneity | Disease causing variants in different genes that cause the same disorder (Example- retinitis pigmentosa, 35+ genes) |
| Genotype | An individuals genetic constitution. This may refer to specific alleles at a single locus, chromosomal make-up, or the aggregation of MANY genetic factors. |
| Phenotype | The individuals observable or measurable features; either secondary soley to genotype OR a combination of environment and genotype |
| Homozygous | Having identical alleles at a locus (can be disease causing or non-disease causing alleles) |
| Heterozygous | Having different alleles at a locus (i.e. a carrier of a condition) |
| Hemizygous | Having only one copy of a gene (i.e. X-linked genes in 46, XY or 45,X individuals OR the remaining genetic material remaining in a location where there is a deletion. |
| Compound Heterozygous | Having two disease causing alleles at a locus, one on each chromosome. |
| Co-dominance | Having a heterozygous genotype, but expressing homozygous state of both alleles (i.e. ABO blood groups). |
| For an unaffected child, the risk of being a carrier is: | 2/3 |
| Allelic Heterogeneity | Different disease causing variant in the same gene causing the same condition (Example: founder BRCA1 variants in Ashkenazi Jewish Pop) |
| Phenotypic Heterogeneity | Different variants in the same gene can cause different phenotypes (Example- FGFR2 related conditions- Apert, Crouzon, and Pfeiffer) |
Created by:
hannahstevens