Amazing Glossary at GeneReviews NCBI bookshelf {here}
Animations: genetics, more genetics, biochemistry
Basic Definitions
- Locus = the physical location of a gene on a chromosome
- Gene
= a specific sequence of DNA that codes for a specific protein (or part
of a protein) with a specific function. There can be many versions of a
gene
- Allele = one version of a gene at a particular location (locus) on the chromosome
- Genotype = the set of alleles a particular individual has
- Polymorphism = variation in the size or sequence of DNA in a particular gene
- Phenotype = the presentation (i.e. observable physical or biochemical change) that occurs when a gene is expressed
- Genome = the complete DNA sequence of an individual
- Chromosome =
Chromosome Structure
- Chromatin
- Heterochromatin
- Euchromatin
- DNA methylation
- Histone methylation
- Histone acetylation
Dominance
- Complete Dominance = If one allele (the dominant allele) is present, the phenotype will be expressed
- e.g. albinism. Both AA
and Aa will have normal phenotype (i.e. normal pigment) because only one
copy of the dominant A allele is needed for enough of the enzyme
Tyrosinase to be produced. Tyrosinase catalyzes the rate limiting step
in the production of the pigment melanin from tyrosine. If aa genotype,
no tyrosinase is produced and thus no melanin i.e. albinism.
- Codominance = both alleles contribute to the phenotype of the heterozygote
- IA allele --> type A
polysaccharide, and IB allele --> type B polysaccharide, and i -->
no polysaccharide. So, if IAIB both type A and type B polysaccharides
are produced and if ii no polysaccharides are produced.
- Children of IAi and IBi parents will have an equal chance of being AB, B, A, or O blood type.
- Link to interactive activity (McGrawhill) blood groups
- e.g. alpha-1 antitrypsin deficiency (AATD)
- due to mutation in SERPINA1 gene which
causes formation of a non-functional protein or no protein at all.
Without alpha-1 antitrypsin (AAT) to protect against elastase, elastase
destroys alveoli leading to emphysema.
- If a person gets 1 normal allele and 1
mutated allele, they can still produce enough AAT to protect against
elastase especially if they don't smoke. Those with both alleles mutated
have no funtional AAT produced and have the severe condition.
- M allele --> normal levels of AAT. PiMM = normal
- Z and S allele --> deficient in AAT. PiZZ = disease, PiSS = disease
- Heterozygote --> heterozygote & carrier. PiMZ and PiMS = carriers
- Links: genome.gov and nlm.nih.gov
- Incomplete dominance (Overdominance) = the phenotype of the
heterozygote is different than both of the homozygote parents. The
heterozygotes generally have an advantage over the homozygotes
- e.g. Sickle cell anemia.
- HbAHbA = normal adult hemoglobin
- HbSHbS = sick cell anemia/ disease
- HbAHbS = sickle cell trait (milder form, where sickling of RBCs only occurs when oxygen content of blood is low)
- Link to interactive activity (McGrawHill) sickle cell anemia
- Link to animation activity (pearson highder ed) codominance & incomplete dominance
Penetrance
- Penetrance = number of people with presenting with the genetic condition (regardless of severity) divided by the number of people with the genetic mutation. i.e. Nclinical / Nmutation
- Complete penetrance = everyone who has the mutation presents with the clinical condition. i.e. Nclinical = Nmutation
- Incomplete (aka Reduced) penetrance = some people with the mutation do not develop the genetic condition. i.e. Nmutation > Nclinical
- e.g. not everyone with BRCA1 and BRCA2 gene mutations will develop breast cancer
- reduced penetrance often occurs in familial cancer syndromes, and is due to a combination of genetic, environmental, and lifestyle factors.
- Lifetime penetrance = the probability that an effected person will develop the condition over their lifetime
- Penetrance & time-scale: Sometimes, the development of a genetic disease varies with age, such that the penetrance changes as the person ages.
- e.g. Huntington's disease: earlier onset in each generation (called "Anticipation")
- mutation in HTT gene causes disease, the mutation leads to the formation of trinucleotide repeats (CAG). CAG repeats are normally present in people but only occur 10 to 35 times. With the HTT mutation, they occur more often, and the long protein product is cut into many fragments which are toxic to neurons.
- In each generation the length of the trinucleotide repeats in the HTT gene increases, so the grandson of someone affected will have a longer HTT gene, more CAG repeats, and thus an earlier onset of the disease.
- visit this site
- nlm.nih.gov
Anticipation
- Anticipation = individuals in successive generations will have...
- (a) an earlier onset of the condition e.g. child will develop the disease earlier than affected parent in Huntington's disease
- (b) a more severe form of the condition e.g. child will develop a more severe form of the disease than the parent AND develop it earlier in Myotonic dystrophy type 1 (DM1)
- DM type 1 is due to a mutation in DMPK which produces a CTG expansion in the 3' untranslated region (3'UTR) of messenger RNA (mRNA). This leads to abnormally long mRNA that accumulates and froms clumps in cells. With each successive generation, longer CTG repeats, and therefore longer mRNA.
Expressivity
- Variable expressivity = the phenotype (i.e. type and severity of the condition) varies among people with the same genotype
- e.g. Marfan's syndrome is due to a mutation of FBN1, but individuals with the mutation have varying severity
- e.g. Neurofibromatosis type 1 (NF1)
- variable expressivity is also due to a combination of genetic, environmental, and lifestyle factors
Links:
penetrance animation (
phgfoundation)
penetrance & expressivity explanation (
nih.gov)
Loss of Heterozygosity (LOH)
- Loss of heterozygosity (LOH) = when individuals that are heterozygous for a mutation (one normal allele, one mutated allele) lose their normal allele (normal allele is either deleted or becomes mutated)
- e.g. Retinoblastoma (RB) and the "Two Hit hypothesis"
- due to mutation of Rb1 gene which produces a protein called pRB which acts as a "tumor suppressor" i.e. it stops other proteins from triggering DNA replication. When non-functional or no pRB is produced, developing retinal cells replicate uncontrollably leading to cancer. If one normal allele is present, enough pRB is produced to prevent cancer, both alleles must be mutated/ deleted for cancer to occur (i.e. "two-hits"). This pattern is typical of tumor suppressor proteins.
- Sporadic mutation of Rb1 is responsible for 60% of RB cases, and inherited mutations are responsible for approx. 40%.
- Inherited Rb -> since one mutated Rb1 is already present, higher risk of sporadic mutation/deletion of remaining normal Rb1, meaning higher likelihood of multiple cancers and earlier onset
- Sporadic Rb -> since both Rb1 alleles are normal, low risk of both becoming mutated/deleted, and if it does occur, it will be at a later age, and usually only one or a few tumors
Dominant Negative Mutation
- Dominant Negative Mutation = when the product of the mutated allele is prevents the functioning of the product of the normal allele, i.e. the mutated allele is "dominant".
- e.g. Mutated allele produces transcription factor with an abnormal allosteric binding site, but a normal active binding site. So, the nonfunctional transcription factor takes up all the binding sites and prevents normal transcription factors from binding to DNA.
- e.g. Pachyonychia congenita
- mutated KR genes lead to the production of abnormal keratin proteins which disrupt the formation strong, stable keratin networks within cells
- link to ghr.nlm.nih site
- e.g. Marfan's Syndrome
- mutated FBN1 gene produces truncated fibrillin-1 protein. Normal fibrillin-1 proteins form microfibrils in the extracellular matrix. Defective fibrillin-1 proteins can disrupt the formation of microfibrils.
Recombination (Crossing Over)
- Homologous Recombination = exchange of alleles between two homologous (i.e. similar) chromosomes; occurs during prophase I of meiosis
Linkage Analysis
- Linkage = the tendency for alleles close together in a chromosome to be inherited together
- Halotype = a set of alleles on a chromosome that tend to be inherited together
- Halotype analysis = genetic testing done to identify a set of closely linked alleles
- Linkage Equilibrium = alleles at different loci (locations) will undergo independent assortment i.e. their inheritance is random and not dependent on their location
- Linkage Disequilibrium = when alleles do not undergo independent assortment. If both alleles are on the same chromosome, they will be segregated together during meiosis, and unless homologous recombination occurs they will be inherited together. The closer two alleles are on a chromosome the less likely homologous recombination will affect them.
- Interference = a homologous recombination (cross-over) in one region decreases the probability of a recombination in a region next to it. Therefore, a "double-crossover" is very unlikely.
- CentiMorgan (cM) = measures the distance between genes and the probability of recombination. e.g. 1 cM = 1% probability of recombination
- Map unit (mu) = 1 map unit = 1 cM
- Lod Score = a method of calculating linkage distances (i.e. distance between genes)
- Linkage Analysis (aka Indirect DNA analysis) = used to determine
the inheritance pattern of disease in a family. We look for known DNA
sequences (i.e. marker regions) that are "linked" with the disease gene.
The markers should be close to the mutated gene on the chromosome so
that they will have a high probability of being inherited together.
Mosaicism
- Mosaicism = when an individual has some cells with different alleles. e.g. some cells have normal allele and other cells have mutated allele
- Germline Mosaicism (formerly called Gonadal Mosaicism) = mutated allele is found in some of the germline cells, but not in other cells of the body (i.e. somatic cells).
- Somatic Mosaicism = mutated allele is found in some of the somatic cells, and it may also be found in some of the germline cells.
Heterogeneity
-
Locus Heterogeneity = when mutations in genes with different locations (loci) cause the same phenotype
- Allelic Heterogeneity = when different mutations in the same location (loci) cause the same phenotype
Heteroplasmy
- Heteroplasmy = when the mitochondria within a single cell are different.. some have normal alleles and some have mutant alleles
Uniparental disomy (UPD)
- Uniparental disomy (UPD) = when both copies of a chromosome are inherited from one ("uni") parent.
- Heterodisomy = uniparental disomy where both copies of the chromosome from the one parent are different (heterozygous)
- Isodisomy = uniparental disomy where both copies of the chromosome from the one parent are identical (homozygous)
Imprinting
- Imprinting = when inactivation of a gene occurs in one parental copy.
- Maternal Imprinting = maternal copy of gene is imprinted (i.e. inactivated)
- e.g. Prader-Willi Syndrome, maternal copy of gene is normally inactivated, so paternal copy is the only active copy. 70% of cases are due to deletion of paternal copy (so no functional gene copy), and 25% of cases are due to the patient inheriting both copies from their mother i.e. maternal uniparental disomy (so both are inactive).
- Paternal Imprinting = paternal copy of gene is imprinted (i.e. inactivated)
- e.g. Angelman Syndrome, is due to loss of activity of both copies of the UBE3A gene. In most of the body both copies are active, but in certain regions of the brain the paternal copy of gene is normally inactivated, so the maternal copy becomes essential. 70% of cases are due to deletion of the maternal copy (so no functional gene copy in certain brain regions), about 11% is due to mutation of the maternal copy, and less commonly cases may occur when a individual inherits both copies from their father (i.e. paternal uniparental disomy).
Hardy-Weinberg Equilibrium
- Hardy-Weinberg Equilibrium
Inheritance Patterns
- Autosomal Dominant = only one copy of the abnormal gene is required for the person to be affected. Because only one copy is needed, the disease is transmitted vertically (parent to child) and these diseases often "run in families". Autosomes are the 22 non-sex chromosomes, therefore, both males and females are affected equally.
- Mother (Aa) x Father (aa) = children (50% Aa, 50% aa) and heterozygotes (Aa) are affected because only one dominant allele is required for the affect to be observed.
- use a 4x4 square to get this ratio (see Punnett square image below)
- Autosomal Recessive = both copies of the abnormal gene are required fro the person to be affected. Autosomal, therefore, present equally in both males and females.
- X linked Dominant = Females need only one mutated X chromosome to be affected. Males always affected by X-linked mutations, since they only have one X chromosome.
- Mother (XX) x Father (XY) = sons (50% XY and affected), daughters (50% XX and affected). So, affected mothers will transmit their illness to 50% of daughters and 50% of sons.
- Mother (XX) x Father (XY) = sons do not inherit X from father, so not affected; daughters all get one X from father, therefore all are affected (XX).
- X linked Recessive = Females must have both X chromosomes mutated to be affected (XX). Males only require one X to be affected (XY).
- Mother (XX) x Father (XY) = sons (50% XY and affected), daughters (50% XX carriers)
- Mother (XX) x Father (XY) = sons do not inherit X from father, so not affected; daughters all get one X from father, therefore all are carriers (XX).
- Mitochondrial Inheritance = mitochondria are inherited from the mother, so all children of an affected mother will be affected to some degree. There is variable expression due to heteroplasmy (mitochondria in the cell have different alleles).
 |
| Punnett squares are a quick way to figure out the % of affected children. |
Inheritance diagram/ tree: circle = female, square = male, filled-in shapes = diseased/ affected individual. Animated tutorial on pedigree analysis here. Video on pedigree analysis with quiz from mit.open courseware here.
Trinucleotide Repeat Expansion
- trinucleotide repeat diseases occur when the number of repeats is greater than normal. These repeats expand during DNA replication and are larger and larger in each generation leading to anticipation.
- anticipation = in each successive generation, the disease severity increases and the age of onset decreases.
- Animation explaining trinucleotide repeats (after discussing general types of gene mutations) here.
- Examples of trinucleotide repeat diseases
- Fragile X syndrome - CGG repeat
- Huntington Disease - CAG repeat
- Myotonic dystrophy - CTG repeat
- Friedreich ataxia - GAA repeat
Autosomal Trisomy
Robertsonian Translocation
Nucleotides
- Purines
- Pyrimidines
- De Novo Synthesis of Nucleotides
- Salvage of Nucleotides
- Degradation of Nucleotides
Genetic Code
- Universal
- Redundant (Degenerate)
- Unambiguous
- Colinear
- Non-overlapping
- continuous (comma-less)
Reading Frames
Genetic Mutation
- Silent
- Missense
- Nonsense
- Frameshift
- Morphisms of mutations
- Amorphic
- Hypomorphic
- Hypermorphic
- Neomorphic
- Antimorphic
DNA replication
- Origin of Replication
- Replication fork
- Helicase
- SSBPs
- DNA topoisomerases
- Primases
- DNA polymerases
- DNA Ligase
- Teloisomerase
DNA repair
- Nucleotide Excision Repair
- Base Excision Repair
- Mismatch Repair
- Nonhomologous End Joining
Gene
- Promoter
- Enhancer
- Silencer
- Response Elements
- Introns
- Exons
- Related proteins
- Transcription factors
- Gene Expression modifications
- Transgenics
- Micro-injection
- Homologous Recombination
- Cre-Lox system
- RNA interference (RNAi) = when small RNAs (e.g. SiRNA, miRNA, piRNA) are used to direct gene silencing.
- SiRNA = small interfering RNA that is double stranded; may be injected into cell (= transfection) or made from longer double stranded RNA in the cell.
- miRNA = micro RNA that is double stranded; made in the nucleus and transported into the cytoplasm
- piRNA = PIWI interacting RNA
- RNAi process:
RNA
- RNA polymerase
- Ribosomal RNA (rRNA)
- Messenger RNA (mRNA)
- mRNA processing
- 5' Cap
- Poly A tail
- Splicing
- Quality Control
- Transfer RNA (tRNA)
- Structure
- tRNA function
- tRNA charging
- tRNA wobble
Proteins
Laboratory Techniques in Genetics
- Karyotyping - chromosomes are arrested in metaphase and analyzed for abnormalities in number or structure.
- karyotyping procedure animation from cengage.
- Microarrays - A microarray is made of microscopic droplets of single-stranded DNA arranged into rows and columns on a glass microscope slide. Once the human genome was sequenced, scientists wanted a way to analyze gene expression quickly. In microarray analysis, a computer database keep tracks of al the gene spots on the microarray. Each spot represents one gene. Microarrays are bought from biotechnology companies. Microarrays - Mcgrawhill animation and here. Great tutorial from Utah university here.
- Single Nucleotide Polymorphisms (SNPs, "snips") - A single nucleotide difference. These are the most common type of genetic variation between people, and most of the time they don't cause disease. When the change does cause disease, it can be used to track inheritance in families.
- Copy Number Variations (CNVs) - normally two copies of a gene are inherited, one from each parent. When there is a change in the number of copies of a gene inherited e.g. extra gene copy or missing gene copy, this is called a copy number variation.
- Blotting Techniques -
- Southern Blot
- Northern Blot
- Western Blot
- Southwestern Blot
- FISH (Fluorescent ImmunoSorbant Hybirdization) -
- cDNA libraries & Cloning
- Polymerase Chain Reaction
- ELISA (Enzyme Linked ImmunoSorbant Assay)
