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139 Cards in this Set

  • Front
  • Back
A sequence of nucleotides located in a particular position on a particular chromosome that encodes a specific functional product (a protein or RNA molecule).


A sequence of nucleotides that encodes a functional product.
“The chromosome characteristics of a cell or cell line” and is usually represented as an array of metaphase chromosomes (eg. 46 XX).

(1) Grow cells in vitro
(2) Stimulate lymphocyes with a MITOGEN
(3) After 3 days add cochicine (cells accumulate in metaphase)
(4) Lyse cell (hypotonic solution)
(5) Makes slides
(6) Stain with Giemsa reagent (g-banding)
A particular place on a particular chromosome.
One of the alternative versions of a DNA sequence at a given locus.
A locus that has two or more alleles in a population where the heterozygosity is at least 2% (Alleles with lower frequencies may be called "rare variants").

A mutation that has no apparent effect on the phenotype
(1) Genetic constitution of an individual.
(2) Specific alleles present at specific loci.
The characteristics of an individual
A specific phenotype.
The proportion of individuals of a specific genotype who exhibit a specific phenotype (it is all-or-none). The mutation is penetrant if ANY sign or symptom of the trait is present.

(1) Often age-specific
(2) May be modified by other genetic factors or the environment
(3) Can be different in males & females
(4) Trait may appear to 'skip' a generation
A person that carries two copies of the same allele at a give locus.
A person that carries two different alleles at a given locus
Only one copy of a locus is present
The first person in a family to seek medical genetic intervention
Autosomal dominant inheritance:
Pedigree characteristics?
When the trait (disorder) is expressed in the heterozygote (Dd) of an autosome.

(1) Each affected individual can be traced to an affected parent
(2) Males & females same chance of inheriting the mutation regardless of which parent is affected
(3) Equally transmitted by men & women
(4) Each child of an affected parent has a 50% chance of inheriting the mutation
(5) Unaffected persons do not transmit the trait
Autosomal recessive inheritance:
Pedigree characteristics?
When the trait is expressed only in the homozygote (dd) of an autosome.

(1) Both males & females are affected
(2) A mutant allele must be inherited from each parent, who are both carriers
(3) Carriers usually have no symptoms
(4) Usually no family history when first affected child is born (recurrence risk is then 1 in 4.
(5) Typically seen in only one sibship of a family (not in parents, offspring or other relatives, "horizontal" inheritance pattern)
(6) Increased consanguinity in the pedigree, especially if the condition is rare
Autosomal inheritance
Involves genes on the autosomes (chromosomes 1-22).
Sex-linked inheritance
Involves genes on the X chromosome or, very rarely, the Y chromosome.
Variable expression
Many diseases can exhibit a range of different signs & symptoms, not all of these will be observed in every individual.
Gain-of-function mutation
Mutant protein has increased function
Mutation results in up-regulation of transcription
Mutant protein has a novel function
Caused by a loss of function mutation
One copy of the wild-type gene is not enough for normal function
Dominant-negative mutation
Loss of function mutation
Mutant protein interferes with the action of the normal protein (e.g. by dimerization)
Genetic heterogeneity or locus heterogeneity
Mutations in different genes can cause the same disease
Allelic heterogeneity or clinical hetorogeneity
Different mutations in a single gene can cause different diseases (very uncommon)

The terms on the other side of the card are sometimes used to mean something other than the definition above.
Blood relationship because of common ancestry. (As close as or closer than 2nd cousins)
All the mitochondria have the same genotype (somewhat unusual).
There is a mixture of genotype in the mitochondrial population.
Genomic imprinting
Can result in different clinical features, depending on whether a mutation is inherited from the father or from the mother. One of the genes is at a specific loci (in either the father or mother) is imprinted & therefor not expressed.
Hardy-Weinberg Principle
The frequency of an allele or a genotype in a population is constant from one generation to the next under the following conditions:

(1) The population is large
(2) Mating is random
(3) Alleles cannot be lost or gained through out- or in- migrations
(4) No new mutations
(5) Allele frequency is not changed by selective pressure or discrimination
Abnormal NUMBER of chromosomes
e.g. Triploidy (in humans chromosome # must be a multiple of 23)
Trisomy 21
Down syndrome
Trisomy 13
Patau syndrome
Trisomy 18
Edwards syndrome
Monosomy X
Turner syndrome
47, XXY
Klinefelter syndrome
The transfer of genetic material from one chromosome to another.
Reciprocal translocation
When a break occurs in each of two chromosomes with the segments being exchanged to from two new derivative chromosomes.
Robertsonian translocation
A particular type of reciprocal translocation in which the break-points are located at, or close to, the centromeres of two acrocentric chromosomes.

(1) The p arms are lost
(2) Inconsequential in itself
(3) Balanced
(4) rRNA genes lost on the p arms are not of any consequence because there are many copies of them

Most frequently down syndrome due to translocations is a Robertsonion translocation between chromosomes 14 & 21.
Chromosome in which the two arms are identical.
Paracentric inversion
Translocation between two chromosomes that does NOT involve the centromere.
Pericentric inversion
Translocation between two chromosomes that DOES involve the centromere
A permanent heritable change, in the DNA sequence.

Affects the phenotype, usually in a harmful way.
Point mutation
Exchange of a single nucleotide for another.
Insertion or deletion of one or more bases.
Silent mutation
A mutation that has no effect.
Acrocentric chromosome
Chromosome with centromere located terminally.
Metacentric chromosome
Chromosome with centromere located centrally.
Submetacentric chromosome
Chromosome with centromere in an intermediate position.
p arm
The short or "petite" arm of the chromosome.
q arm
The long arm of the chromosome.
RFLPs (Restriction fragment length polymorphisms)
-Cause a gain or loss of a restriction site.
-Bi-allelic: two alleles per locus (therefor low heterozygosity (maximum 0.5))
VNTRs (Variable number tandem repeats)
-Repeat elements usually tens-hundreds of bp
-Multiple alleles high heterozygosity
-The original DNA "fingerprint"
-Usually detected using southern blotting
STRs (Short tandem repeats)
-Variation in the number of repeats
-Multiple alleles, highly polymorphic (up to 90% of people heterozygous)
-Di,tri, or -tetra nucleotide repeats.
-Current DNA "fingerprint"
-Detected using PCR???? northern blot????
SNPs (Single nucleotide polymorphism)
-Most common type of polymorphism
-Usually only 2 alleles per locus (heterozygosity << 0.5)
-Detected by sequencing, PRC with allele-specific primers, microarry technology
Involving one gene.
Involving many genes.
Missense mutation
Changes a codon to produce a different amino acid
Changes a codon to a STOP codon.
Splice-site mutation
Removes a splice site or creates a new one (splicing is the process by which introns are removed)
Nuclear Genome:
How many base pairs?
How many autosomes?
What are the sex chromosomes?
How many protein coding genes?
Base pairs: 3 billion
Autosomes: 22 distinct chromosomes (arranged in pairs for a total of 44)
Sex chromosomes: X(2 in F & 1 in M), Y (1, only in males)
Protein coding genes: 21,000 (Exons are only about 1.5% of our DNA)
Humans also have thousands of 'non-coding' RNA genes (we have little idea about the function of most of them)
Mitochondrial genome?
How many base pairs?
How many genes?
Base pairs: Circular 16569
Genes: 37
2 rRNA
22 tRNA
13 polypeptides
Earlier age of onset, more severe phenotype in succeeding generations
Association study
A study that measures the occurrence of a specific genetic variant in affected patients and in an unaffected control group.
Linkage analysis
Involves comparing the segregation of polymorphic loci WITHIN individual families. Loci which are close together (linked) on a chromosome will be co-inherited during meiosis. This can help narrow down the location of the gene to a candidate region.

It loses power when a mutations has low penetrance.
Linkage disequilibrium
The co-occurrence of specific alleles at two loci in the genome at a higher frequency in a population than would be predicted by random chance
Normal genes that we all have that promote cell division (stimulatory).

(1) Growth factors or their receptors
(2) Transcription factors
Tumor suppressor genes
They provide negative regulation of cell division & may interact with proto-oncogenes.
'Mutator' Genes (caretaker genes)
Genes involved in:
DNA replication
Recombination machinery
Chromosome segregation
DNA repair
Cell cycle control
p53 gene
Triggers apoptosis if there is genome damage
Programmed cell death with dozens of genes involved
Amsterdam criteria for the disease HNPCC
(1) At least 3 affected relatives (related to each other by first-degree relationships), one a first-degree relative of the other two
(2) At least two successive generations affected
(3) Cancer diagnosed before the age of 50 in at least one relative
Modifier genes
Genes that affect the occurrence or severity of a Mendelian disorder
Qualitative traits
Traits that exist or don't exist (e.g. Cleft palate, cancer)
Quantitative traits
Traits that can be measured on a scale of severity (e.g. BMI, hypertension)
Concordant pair
A pair of family members with the same disease
Discordant pair
One affected and one unaffected family member
λs (relative risk for siblings)
(prevalence of the disease in the sibling of an affected person) / (prevalence of the disease in the general population)
Genetic correlation comparison
The tendency for the values of a specific quantitative trait to be more similar among relatives than among the general population
Liability threshold model
When the liability factors as a whole exceed a certain threshold, a person will present with the disease
Association study: Indirect association
The locus identified by the association study is near the locus that contributes to the trait and therefor always tends to segregate with it. This allows for narrowing of the region in the genome to find the particular locus.
Association study: Direct association
The locus identified by the association study is an actual locus that contributes to the trait.
Criteria for Effective Newborn Screening Programs
(1) Treatment is available
(2) Early treatment reduces or eliminates the severity of the illness
(3) Routine physical exam will not reveal the disorder (a specific test is required)
(4) A lab test is available that is very sensitive (no false negatives) & reasonable specific (few false positives)
(5) Screening is cost effective
(6) The infrastructure is in place to manage positive screening results
Coefficient of correlation (R)
The measure applied to compare a pair of measurements in quantitative traits.
Ethics of screening
(1) Screening should be offered rather than imposed
(2) Informed consent should be obtained
(3) Screening results should be kept confidential
(4) Discrimination based on screening results should be prevented
Nondirective counseling
(1) Patients & families are given information about the various testing & management options
(2) They are NOT told which option is "the best" nor in theory to offer the counselor's opinion
(3) They are provided with resources and support in order to help make the best decision for themselves and their familes
Three cardinal ethical principles:
(1) Beneficence: Doing good for the patient
(2) Autonomy: Individual's right to control their medical care and be free of coercion
(3) Justice: Ensuring that all individuals are treated equally & fairly
Reference sequence (Human genome project)
(1) Covers about 99% of the gene-containing regions
(2) Sequence error of <1 in 10,000 bases
(3) Remaining gaps cannot be reliably resolved with current technology

INDIVIDUAL human genomes may differ significantly from the reference
The entire complement of proteins expressed in any given cell at any given time

There are more proteins than genes because of:
(1) Alternative splicing of transcripts
(2) Post-translational modification
(3) Multimeric proteins
The entire complement of mRNA expressed in any given cell at any given time
All the genome variants found in human populations (SNP's, repeat sequences, structural variants, etc.)
(1) The Human Epigenome Project (HEP)
(2) Identify genome-wide DNA methylation patterns of all human genes in all major tissues
Pharmacogenetics (Pharmacogenomics)
The significance of genetic variation in the response to drugs
Northern blot
RNA electrophoresis & detection
Southern blot
DNA electrophoresis & detection
Western blot
Protein separation by electrophoresis in 2 dimensions by size & isoelectric point
Oncogenic mutations
Lead to a gain of function mutation
(1) Gene amplification
(2) Mutation in regulatory region of gene
(3) Chromosomal translocation next to or more active promoter/enhancer
(4) Mutation in coding region of proto-oncogene
A gene that contributes to the production of a cancer. Oncogenes are generally mutated forms of normal cellular genes (proto-oncogenes).
The Central Dogma
DNA -> transcription -> mRNA -> translation -> Protein
How do the base sequences of humans compare to each other?

How about the genome structure?
Between humans base Sequence 99.9% identical.
Between humans & chimps base sequence 99.9% identical.

BUT the genome STRUCTURE is less similar than base sequence in both cases.
Chromosome structure?
Between cell division & initiation of DNA synthesis, during which time the cell ENLARGES.

One DNA molecule with centromere & is not condensed.
Chromosome structure?
Non-dividing cell.

One DNA molecule with centromere & is not condensed.
Between the end of DNA synthesis & mitosis.
S phase
DNA synthesis occurs, chromosomes replicated.

Follows G1 (G1->S Phase: regulated by Rb) gene.
o Chromosomes start to condense and become visible in light microscope
o RNA synthesis STOPS
o Sister chromatids of each chromosome joined together at centromere
o Nuclear envelope begins to fragment
o Spindles begin to form
o Association of chromosomes with spindle fibers
o Nuclear envelope fragmented and chromosomes released into cytoplasm
o Chromosomes are completely condensed now and attach to spindle apparatus
o Chromatids attach to opposite poles
o Chromosomes align at “equator” of spindle
o Separation of sister chromatids
o the centromere splits
o sister chromatids are pulled to opposite poles
o spindle elongates
o Cytokinesis, re-formation of nuclei
o 46 chromosomes arrive at each pole
o New nuclear envelope forms around each set of chromosomes
o Chromosomes begin to decondense
o Cytoplasm separated (cytokinesis) – 2 daughter cells with 46 chromosomes each produced
o RNA synthesis resumes
What are the main achievements of meiosis?
(1) Recombination
(2) Independent assortment
of homologous chromosomes
Describe recombination
(1) Involves the exchange of genetic information between 2 homologous chromosomes
(2) Chiasmata are formed at the regions where information is being exchanged and are adherences that persist between homologous chromosomes (forming a tetrad) until anaphase I.
(3) There are usually between 1 & 3 chiasmata between homologous pairs of chromosomes
(4) Recombination does not occur at random throughout the chromosome, but rather there are specific "hot spots" where recombination is likely to occur, which average (-8Kb: range (1-120kb) & are inherited unchanged over hundreds of generations.
(5) "Hotspots" are very important in finding genes involved in multifactorial diseases
How many possible gametes are possible in humans through the process of independent assortment alone?
2^23 = 8.4 million.
Meiosis (gametogenesis) in males:
When does it start?
How many days does it take to produce a gamete?
How many gametes are produced in one meiotic cycle?
How many gametes per ejaculate?
Starts: Puberty
Time: 60-65 days
# gametes: 4
# gametes/ejaculate: 1-2million
Meiosis (gametogenesis) in males:
When does it start?
How many days does it take to produce a gamete?
How many gametes are produced in one meiotic cycle?
How many gametes per ovulation?
Starts: Early fetal life
Time: Between 10-50 years
Meiosis 1: Ends @ ovulation
Meiosis 2: Begins only after fertilization
# gametes: 1 (2 polar bodies)
# gametes/ovulation: 1
Mendelian Trait
(1) Heritable phenotypes, which are caused by mutations in only a single gene
(2) Other genetic variations, or the environment, have no effect or only a small effect
Segregation analysis
Involves the tracing the occurrence of the trait through a family tree
Conditions that favor it?
Recessive trait carrier (Aa) has a child with a person with the recessive trait (aa) so that the probability of a recurrence is 50% so the trait appears dominant.
(1) Common trait
(2) Consanguinity in parents
(3) Assortive mating
(4) Genetically isolated populations
Autosomal recessive mutations & their role in human disease
(1) Most are loss-of-function mutations
(2) Ne mutation rate is insignificant because most mutations in the population are unaffected heterozygotes
(3) Genes coding for enzymes are common targets
X-linked recessive inheritance:
Pedigree characteristics?
Females: 2 X chromosomes
Males: 1 X chromosome (need only one 'recessive' mutation to produce the recessive phenotype.

(1) Incidence is MUCH higher in males than females
(2) Trait is expressed in hemizygous males or homozygous females
(3) Heterozygous females are USUALLY unaffected (may express trait due to skewed X-inactivation)
(4) All daughters of affected males are carriers
(5) Sons of a carrier female have a 50% risk of being affected
(6) Typical pedigree shows only males affected with 'skipped' generations
Y-linked inheritance:
Pedigree characteristics?
(1) Very few genes involve genes on the Y-chromosome
(2) Male-to-male transmission only
(3) Contribute little to the overall burden of disease
(1) Occurs in females because only one copy of the X-chromosome in each cell is transcriptionally active (acts as a gene dosage compensation, the extra copy is inactivated by condensation of the chromatin)
(2) Inactivation probably occurs in the early embryo (32-64 cells)
(3) The copy of the cell that is inactivated is random (could be maternal or paternal copy in any given cell)
(4) All descendants of a cell have the same X-inactivation
(5) Can lead to mosiacism
X-linked dominant:
Pedigree characteristics?
Females: 2 X chromosomes
Males: 1 X chromosome

(1) Very uncommon
(2) Pedigree 'looks' dominant
(3) Twice as many females affected as males
(4) Sons of affected males are all normal (No male-to-male transmission)
(5) Daughters of affected males are all affected
(6) Affected women often have milder & more variable phenotype than affected men due to mutant x chromosome inactivation in some cells
Mitochondrial inheritance:
Pedigree characteristics?
(1) Mitochondrial DNA (mtDNA) inherited from the mother only (sperm contributes no mitochondria to the zygote)
(2) Passed on to both sons & daughters
(3) Mitochondrial diseases are extremely varialbe in presentation (depends on the relative proportions of normal & mutant mtDNA in the cells making up the different tissues)
International System for Human Cytogenic Nomenclature (ISCN)
Regions, Bands & sub-bands
(1) Numbered consecutively from centromere to telomere
(2) Centromere is 10 (either p10 or q10)

e.g. 1p31.1
(1) Chromosome
(2) Short arm
(3) Region 3, band 1, sub-band
Products of conception
How common are chromosomal abnormalities in pregnancy?
(1) Chromosome abnormalities (>10% of all sperm & >25% of ova)
(2) 15%-20% of all recognized pregnancy end in spontaneous abortion
(3) Approximately 50% of all spontaneous abortions have a chromosome abnormality
(4) From conception onwards, the incidence of chromosome abnormalities falls rapidly
(5) By birth it has declined to a level of 0.5%-1%
(6) 5% in stillborn infants
FISH (Fluorescent in situ hybridization)
Stain chromosomes with 'probes'
(1) Specific single stranded DNA sequences (attached to a fluorescent dye)
(2) Choose the DNA sequence of interest
(3) Particularly useful in identifying micro deletion syndroms
Prenatal diagnosis
Usually >35 years: The risk of a fetus with a chromosome abnormality is about equal to the risk of miscarriage associated with amniocentesis

Risk of chromosome abnormality
Baseline: 3%
Age-related risk: 1/190 (0.5%)
Total risk: 0.5%+3% = 3.5%
Risk of miscarriage?
When is it done?
Risk of miscarriage: 1/200

Women over 35 (Risk of chromosome abnormality is 1/190 or more)
Taken typically 15th to 16th week LMP (Can be done earlier 10-14 weeks LMP ins some centers)
AFP (Alpha-feto protein)
Can be detected in amniotic fluid or maternal serum to assess whether a neural tube defect has occured
Folic acid & pregnancy
Folic acid supplements are given to women EARLY in pregnancy to reduce the risk of neural tube defects
When can chorionic villus sampling be done?
10-12 weeks LMP
Loss-of-function mutation
(1) More common than gain-of-function
(2) The result of gene product having reduced function

(3) Usually recessive but can be dominant when:
(a) Reduced dosage of normal gene product changes the phenotype (haplo-insufficiency)
(b) Altered protein blocks the action of the normal (wild-type) protein
Gain-of-function mutaion
(1) Less common than loss-of-function
(2) Productions gains a new & abnormal function
(3) Over-expression of the normal gene product
(4) Usually dominant
Overall mutation rate
10^-9 per bp per cell
(1) approx 6 mutations per diploid genome per division
(2) 10^15 divisions over life of an adult
(3) 25 million mutations per minute over th course of a lifetime
Ultraconserved elements
Elements in the human rat & mouse that are 100% identical.

481 were found with segments longer than 200bp w/ some >700bp
What types of mutations can't sequencing DNA find?
Big deletions or insertions.
Common DNA damage
(1) Hydrolysis of -A or -G from the deoxyribose (10,000 events/cell/day)
(2)If unrepaired can cause
(a) Base deletion
(b) Wrong base
(c) Strand nick

(2) Deamination
(a) C->U
(b) A->Hypoxanthine (pairs with C)

(3) Oxidative damage

(4) Pyrimidine dimers T-T, C-C, T-C
(a) Thymine dimers most common
(b) UV-induced
DNA repair mechanisms
(1) Base excision repair (Single nucleotide damaged by hydrolysis, methylation or oxidation)
(2) Nucleotide excision repair (2-30 bases e.g. pyrimidine dimers)
(3) MisMatch repair (repairs mispaired bases)
(4) Non-homologous end joining (double strand breaks)
(5) Recombinational repair (homologous recombination during meiosis of double strand breaks)
Direct mutation testing?
(1) Must know the specific mutation involved
(2) Design a test for each mutation
(3) Specialized techniques for large del/ins
(4) If specific mutation is not known, can sequence likely genes (Expensive)
Multiple, often seemingly unrelated physical effects caused by a single genotype