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71 Cards in this Set
- Front
- Back
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Gene
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hereditary factor that interact with the environment to determine the trait
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Alleles
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alternative forms of a gene occupying a given chromosomal locus
There may be multiple normal and abnormal alleles of any particular gene |
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Locus
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a specific location of a gene on a chromosome. Since human chromosomes are paired, every person has two alleles at each locus
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Genotype
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genetic constitution, representing allelic makeup of an individual
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Phenotype
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end results of genetic and environmental factors giving the clinical picture or the observed expression of the gene
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Homozygote
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a person with two identical alleles at a single locus
Alleles may be either normal or abnormal |
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Heterozygote
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a person with two different alleles at a single locus
Usually one normal one mutant allele A person is called a carrier |
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Compound heterozygote
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an individual with two different mutant alleles at one locus
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double heterozygote
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an individual with two mutant alleles, each at a different locus
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Autosomal
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autosomes (nonsex chromosomes)
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Synteny
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when two loci are on the same chromosome
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Linkage
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occurence of two or more genetic loci in such close physical proximity on chromosome that they are more likely to segregate together during meiosis
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Penetrance
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phenotype expression of the mutant gene (all or nothing phenomenon)
% of persons with a mutant allele who are affected |
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Expressivity
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the degree of (continuous) expression of particular allele in a person
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Pleiotropy
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the production of multiple phenotypes by a single gene or gene pair
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Phenocopy
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is mimic of a phenotype produced by specific genotype (may be caused by environmental factors)
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Genetic heterogeneity
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different mutations at the same locus or different loci result in similar clinical phenotype
-CF- |
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Sex influenced
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severity of the disease depending on the sex of the person carrying a mutant gene(s)
Hemochromatosis (AR) in males CAH (AR) in females |
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Autosomal recessive inheritance
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The trait spread horizontally
There is no sex predilection If the trait is rare, parental consanguinity is increased |
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Autosomal dominant inheritance
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Transmission of the trait is from generation to generation (without skipping)
Except for new mutation every affected child will have an affected parent The two sexes are affected in equal numbers |
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X-linked inheritance (recessive)
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The trait is transmitted by normal heterozygous mothers :
Hemizygous affected males have normal sons and daughters. All daughters of affected father are obligatory carriers |
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X-linked inheritance (dominant)
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There is no male-male transmission
All female offspring of affected males will be affected |
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Germinal mosaicism
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The presence of two gametes carrying normal and mutant alleles
May change recurrence risk for the offspring |
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Mitochondrial inheritance
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Types of mutations: point /deletions
Predominantly maternal inheritance |
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heteroplasmy
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presence of normal and mutant DNA in the same cell
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homoplasmy
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presence of only normal or only mutant DNA in the same cell
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Uniparental disomy
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The presence in the diploidal cell line of a both chromosomes of a given pair from only one parent
Possible consequences: - imprinting of sigle genes or chromosome region - homozygosity for mutant allele |
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Genomic imprinting
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Differential expression of a gene depending on whether it was inherited from the mather or the father epigenetic control of gene expression
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Genomic imprinting/UPD & microdeletion syndromes
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Prader- Willi syndrome (Del 15q11-q13) -70% pat
Angelman syndrome (Del 15q11-q13) -70% mat |
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Genetic linkage
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Refers to loci not to alleles
The phase of the linkage Family studies are necessary Measurements of the linkage chromosomal distance recombination fraction = cM lod score coupling = cis repulsion = trans |
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Linkage: measurements
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The recombination fraction between two loci is the probability of the occurence of crossing over between loci
LOD score |
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Conventional chromosomal banding
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g-banding (trisomy 13)
c-banding |
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FISH
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micro-deletions
duplications aneuploidies translocations gene fusion |
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Numerical abnormalities
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Polyploidy (3n,4n,5n)
Aneuploidy (2n-1,2n+1,2n+2) |
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Structural abnormalities
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Terminal Deletion
Interstitial Deletion Inversion Duplication Isochromosome (iso-q,iso-p) Ring Chromosome Robertsonian translocation Reciprocal translocation |
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Complex inheritance
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Does not follow simple Mendelian pattern
The recurrence risk depends on: Degree of relationship with the proband Severity of the proband’s disease Number of affected individuals in the family Sex of the proband (more commonly affected) |
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Segregation analysis
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statistical comparison (binomial therom) of frequency and distribution of affected and unaffected individuals in families to determine the most likely mode of inheritance
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Association analysis
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statistical comparison to determine if a particular form of DNA polymorphism occurs more frequently in subjects with a phenotype of interest
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Linkage analysis
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analyze the distribution of loci within families to determine if a particular region of genome contains a gene related to the phenotype of interest
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Linkage mapping
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crossover frequency indicated the distance of separation on a chromosome
greater distance more frequency of crossing over, less likely to be linked LOD score |
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Recombinant frequency
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rearrangement of loci
equivalent to 'genetic map unit' 50% RF = not linked 0% RF = linked |
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Linkage disequilibrium
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synteny
study of population genetics for the non-random association of alleles at two or more loci, not necessarily on the same chromosome |
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LOD score
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logarithm of odds
3 LOD = linked -2 LOF = not linked |
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Non-disjunction
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failure to disjoin in mieosis I or II
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Molecular technique (FISH)
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in situ hybridization
cytogenetic technique which can be used to detect and localize the presence or absence of specific DNA sequences on chromosomes florescent probes with chromosomal similarity |
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Northern blot
Southern blot Western blot |
N - RNA
S - DNA W - protein |
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Polyploidy
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triploidy 3n
tetraploidy 4n |
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Aneuploidy
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non-disjunction during meiosis
trisomy 2n+1 monosomy 2n-1 |
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Examples of Aneuploidy
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13 (Patau)
18 (Edwards) 21 (Down) XXY (Klinefelter) X-monosomy (Turner) |
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Unbalanced structural mutations
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deletion - terminal/interstitial
duplication ring isochromosome (Turner) |
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Balanced structural mutations
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inversion
translocation |
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Inversions
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paracerntric (includes centromere)
pericentric (change in arm) |
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Translocations
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recipricol (exchange of material between nonhomologous chromosomes)
Robertsonian (long arms of two acrocentric chromosomes fuse at the centromere and the two short arms are lost) 13, 14, 15, 21, and 22 |
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Dynamic mutation
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unstable heritable element where the probability of mutation is a function of the number of copies of the mutation
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Examples of dynamic mutations
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Fra X
Huntington disease Dystrophia myotonica Ataxia Friedreicha |
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Gene mutations
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point mutation
frameshift mutation 'hotspot' |
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Point mutations
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missense (AA substitution)
nonsense (premature stop) silent/synonymous (no change) RNA processing/transcription |
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Frameshift mutations
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deletion
inversion insertion fusion |
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'Hotspot' mutations
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transition (T->C, A->G)
transversion (purine->pyrimidine) |
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Functional cloning
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Using information about the function of a known protein that could be involved in a genetic disease (limited approach)
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Positional cloning
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Using only information about the gene's approximate chromosomal location obtained from gene mapping
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Cystic fibrosis
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AR disorder pf epithelial ion transport
mutations in CFTR gene: cAMP regulated excretion of chloride and inhibition of sodium uptake "salty-baby syndrome" |
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Duchenne Muscular Dystrophy
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X-linked panethnic progressive myopathy
mutations in DMD gene that encodes dystrophin predominatly large deletions and large duplications |
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Fragile X Syndrome
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X-linked mental retardation disorder
mutations in FMR1 on Xq27.3 expansions of (CGC)n premutation -> full mutation |
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Huntington Disease
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AD panethnic progressive neurodegenerative disorder
mutations in HD gene expansion of polyglutamine-encoding CAG respeat sequence age of onset is proportional to number of HD repeats |
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Prader-Willi Syndrome
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panethnic developmental disorder, hypogonadism, obesity
loss of expression of genes on paternally derived 15q11-q13 (70%) maternal uniparental disomy (25%) genetic imprinting |
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Sickle Cell Anemia
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AR Beta-subunit missense mutation (Valine for Glutamine)
decreases solubility of deoxygenated hemoglobin anemia, failure to thrive, splenomegaly |
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Turner Syndrome
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female monosomy X
panethnic disorder complete or partial absence of second X chromosome in females 75% sperm lacking sex chromosome |
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Y chromosome differentiation
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ovarian pathway is followed unless TDF (testis-determining factor) is present
TDF Leydig cells, siminiferous tubules, testes, Sertoli cells, mesonephric ducts |
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X chromosome differentiation
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absence of TDF on SRY (sex-determining region on the Y)
ovaries, paramesonephric ducts |
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X chromosome inactivation
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formation of a Barr body
DNA methylation XITE, XIST, TSIX encoded XIST prevents expression of TSIX |
