Basic Genetics & Mutational Mechanisms Flashcards
Mendel’s First Law
The Law of Segregation: During meiosis, each allele of a single gene separates into different gametes
Mendel’s Second Law
The Law of Independent Assortment: At meiosis, the segregation of each pair of alleles is independent
Exception: genes linked on the same chromosome
Co-dominant traits
Both traits (alleles) are expressed in the heterozygous state
Semi-dominant or Incompletely Dominant
Heterozygous phenotype is intermediate between the two homozygous phenotypes
4 main categories of Mendelian Inheritance
Autosomal Dominant
Autosomal Recessive
Sex-Linked Dominant
Sex-Linked Recessive
Metabolic Disorders are frequently (pattern of inheritance)…
Autosomal Recessive; typically due to loss of function of an important enzyme
Penetrance
The fraction of individuals with a trait (genotype) who show manifestations of the disease
100% penetrance: all persons carrying a mutation demonstrate the trait
Expressivity
The degree to which a trait is expressed in an individual; a measure of severity
Pleiotropy
Multiple phenotypic effects (a syndrome) due to mutation in a single gene
Polymorphism
A locus for which at least two relatively common alleles exist within a population
Crossing over/meiotic recombination
Exchange of homologous segments of DNA between non-sister chromatids of a pair of homologous chromosomes; during Meiosis I
Acrocentric chromsomes
13, 14, 15, 21, 22; centromeres are located near the end of the chromosome; contain distinctive masses of chromatin (satellites) attached to their short arms by narrow stalks (secondary constrictions); stalks contain repetitive DNA sequences that code for rRNA
Metacentric chromosomes
The centromere is located in the middle of the chromosome
Submetacentric
The centromere is slightly removed from the center of the chromosome
Most common mechanism of imprinting
Allele-specific methylation of CpG dinucleotides in the promoter regions of imprinted genes, established and maintained in one of the two germ lines
Imprinting Centers
Non-coding DNA sequences that recruit DNA methyltransferase complexes that methylate CpG islands located near the IC on the same chromosome; this is where erasure & resetting of imprinting occurs
Chromosomal Microarray (CMA)
Flourescently labeled sample DNA and control DNA are mixed and hybridized to an array; visualization of the array gives information about the spots/color intensities for each probe
Advantages: allows investigation of the whole genome simultaneously and frequently reveals duplications or deletions that cannot be seen by standard cyteogenic techniques
Limitations: detects gains and losses ONLY (cannot detect balanced rearrangements); cannot detect specific mutations or SNPs
Heritability
The proportion of total variance in a trait that is due to variation in genes
Haplotype
A combination of alleles at different loci on a chromosome that are often inherited together and contribute to a trait or disease status
Ex. of incomplete penetrance
Type I Diabetes; 20% of the population carries one of two highest risk haplotypes, but incidence in the general population is only 0.4%
Allelic Heterogeneity
Two kinds:
- Different alleles in the same gene resulting in the same trait
- Different alleles in the same gene resulting in different traits
Ex: Many mutations in the CFTR gene (alleles) lead to CF; different ‘classes’ of alleles lead to different presentation of disease
Locus Heterogeneity
Variants in different genes result in similar clinical presentation
Ex: Early onset Alzheimer’s results from mutations in three separate genes on three different chromosome, which are all involved in the same physiological pathway
Phenocopy
An environmentally caused phenotype that mimics the genetic version of the trait
Ex: Thalidomide-induced limb malformation vs. genetically induced
Characteristics of Complex Traits
Incomplete Penetrance
Variable Expressivity
Heterogeneity - allele & locus
Presence of phenocopies
Lambda S (relative risk)
Risk of disease in siblings of affected / risk of disease in general population
Odds Ratio (OR)
Risk of disease given a particular gene variant / Risk of disease not given a particular gene variant
Compound heterozygote
An individual who carries two different mutant alleles of the same gene
Ex: HbS/HbC
4 mutational mechanisms
Loss of function of the protein
Gain of function of the protein
Acquisition of a novel property by the protein
Perturbed expression of a gene at the wrong time (heterochronic expression) or in the wrong place (ectopic expression)
Replicative Segregation
During cell division, the multiple copies of mtDNA in each of the mitochondria in a cell replicate and sort randomly among the newly synthesized mitochondria, which are distributed randomly between the two daughter cells
Homoplasmy & Heteroplasmy
Refers to the proportion of mutant and wild-type mitochondrial DNA passed on to a daughter cell during replicative segregation; a daughter cell that receives a pure population of wild type mtDNA is homoplasmic, whereas a daughter cell that receives a mixture of wild type and mutant mtDNA is heteroplasmic
Loss of Function Mutations - 5 Examples
Duchenne Muscular Dystrophy - DMD gene, dystrophin
alpha thalassemia - alpha thalassemia gene, a-globin
Turner syndrome - loss of X chromosome
HNPP - PMP-22 gene, peripheral myelin protein
OI Type I - COL1A1 gene, COL1A1 type collagen
Gain of Function Mutations - 4 Examples
Hb Kempsey - B-globin gene, missense
Achondroplasia - FGFR3 gene, fibroblast growth factor receptor
Alzheimer Disease in Trisomy 21 - APP gene, amyloid precursor protein
Charcot-Marie-Tooth - PMP22 gene, peripheral myelin protein
Novel Property mutations - Examples
Sickle Cell Disease - b-globin gene/protein, missense
Huntington disease: CAG repeats/polyglutamine tracts lead to novel toxicity of protein
