Unit II - Genetics Flashcards
(92 cards)
Acrocentric Chromosomes
Chromosomes whose centromeres are located near the end of the chromosome; stalks and satellites on the short arms contain repetitive DNA sequences that code for rRNA
Chromsomes 13, 14, 15, 21, and 22
Imprinting
Non-coding DNA sequences (imprinting centers) recruit DNA methyltransferase complexes that methylate CpG dinucleotides near the IC on that chromosome; imprinting is established and maintained in one of the two germ lines
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, which correspond to variation in degrees of expression
Advantages: allows investigation of the whole genome simultaneously, reveals duplications and deletions
Limitations: detects gains & losses ONLY, not balanced rearrangements or SNPs
Heritability
The proportion of total variance in a trait that is due to variation in genes
Allelic Heterogeneity
Different alleles in the same gene resulting in the same trait; OR, 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 3 separate genes, all of which contribute to accumulation of AB42
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)
Achondroplasia (FGFR3 gene)
Alzheimer Disease in Trisomy 21 (APP gene)
Charcot-Marie Tooth (PMP 22 gene)
Novel Property Mutations - 2 Examples
Sickle Cell Disease (B-globin)
Huntington Disease (CAG repeats/polyglutamine tracts lead to novel toxicity of protein)
Compound Heterozygote
An individual who carries two different mutant alleles of the same gene
Ex: HbS/HbC
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
Daughter cells may be homoplasmic (a daughter cell with a pure population of WT mtDNA) or heteroplasmic (a daughter cell with a mixture of WT and mutant mtDNA)
SINES & LINES
Short Interspersed Nuclear Elements (SINES) - Ex: Alu Family; ~300bp repeats, 10% of genome
Long Interspersed Nuclear Elements (LINES) - Ex: L1 family; ~6kb repeats, 20% of genome
Alpha satellite repeats
171 bp repeat unit found near centromeric region of all human chromosomes; likely important for chromosome segregation in mitosis and meiosis
Candidate gene association study
Markers within a candidate gene are identified and allele frequences are compared in cases vs. controls; association implies linkage disequilibrium with a causal mutation
Disadvantages: Cases & controls must be ethnically matched, population stratification may lead to false positives
Microsatellites & Short Tendem Repeat Polymorphisms (STRPs)
Repetitive DNA sequences 2-4 nucleotides long; short tandem repeat polymorphisms (STRPs) are different alleles that result from variation in the number of repeat units within a microsatellite region
Mini-satellites & Variable Number Tandem Repeats
Repetitive DNA sequences 10-100 nucleotides long; variable number tandem repeats (VNTRs) are different alleles that result from variation of the number of repeat units within a minisatellite region
Copy Number Polymorphisms (CNPs)
Recurring deletions or insertions of larger section of a chromosome, leading to gaps or duplications; may give rise to two discreet alleles (due to presence or absence of the chromosomal region) or to multiple alleles (due to variation in copy number of the chromosomal region)
Genome-Wide Association Studies (GWAS)
Same as candidate gene case-control association study but tests MANY markers across the genome searching for significantly different allele frequencies in cases vs. controls
Advantages: Can identify many genes, some new, that contribute to disease
Disadvantages: Requires a larger sample size (>1,000) to correct for multiple testing problem
Chromosomal Analysis
Detects gross anomalies in chromosome number as well as large structural rearrangements (deletions, insertions, etc.)
FISH
Flourescence In-situ hybridization; flourescently labeled, locus-specific probe can identify micro-deletions or multiple copies of loci of interest in patient DNA
Detects chromosomal microdeletion, microduplication, chromosomal rearrangements, and gene copy numbers of a known loci of interest
Single Nucleotide Polymorphism (SNPs)
A difference in a single DNA nucleotide base, within a particular gene, that gives rise to 2 discreet alleles; SNPs occur at a rate of ~ 1 per 1,000 nucleotides between any two individuals
Genetic Linkage Studies
Used to study genome segments that are disproportionately co-inherited along with disease to determine if the loci are linked; “multiplex” families with multiple cases of a disease are studied to determine the frequency of recombination events between two loci
Viral approaches to gene therapy
- Retroviral; can accomodate up to 8kb of DNA but requires target cell division for integration of recombinant DNA into host genome (i.e. limited use in non-dividing cells)
- Adenoviral: can accomodate up to 35kb and infect dividing or non-dividing cell but may lead to strong immune response
Non-viral approahces to gene therapy
- Naked DNA (i.e. cDNA with regulatory elements introduced in a plasmic)
- DNA packaged into liposomes
- Protein-DNA conjugates
- Artificial chromosomes