Exam 1 Genetics Thread Flashcards
“n”
Designation
The number of chromosomes in a cell.
Diploid = 2n
Haploid = n
“N”
Designation
The amount of DNA in a haploid genome.
3x109 base pairs
Bivalent
Sister chromatids attached at the centromere.
Cell Cycle
Stages
- Interphase
- Prophase
- Prometaphase
- Metaphase
- Anaphase
- Telophase and cytokinesis
Interphase
- G1: makes proteins needed for replication
- S: DNA replication
- G2: grows, makes microtubules
Prophase
- Chromosomes condense and coil
- Becomes visible by LM
- Centrioles migrate to opposite poles
- Centrosomes start to form mitotic spindle
Prometaphase
Nuclear membrane disappears
Metaphase
- Mitotic spindles attach to centromere @ kinetocore
- Chromosomes align on metaphase plate
- Continues to condense
- Most karyotyping taken here
Anaphase
Sister chromatids split at centromere and separate.
Guided by spindle fibers and centrioles.
Telophase
Chromosomes have migrated to opposite ends of the cell.
Nuclear envelops begins to reform.
Cytokinesis forms two daughter cells.
Cell Cycle
Checkpoints
- Exists throughout interphase and M-phase.
- Ensures steps occured correctly.
- Apoptosis can be a normal process here.
Mitotic Spindle
Drugs
Halts cell cycle in metaphase.
- Vincristine (Oncovin)
- Binds tubulin dimer preventing microtubule assembly
- Paclitaxel (Taxol)
- Prevents depolymerization of microtubules
Meiosis
Characteristics
Reductive division
- Produces haploid gametes
- 1 n chromosomes
- 1 N base pairs
- Meiosis I ⇒ seperates homologous chromosomes
- Promotes genetic variation
- Independent assortment
- Recombination
Tetrads
2 homologous chromosomes = 4 sister chromatids
Meiosis I seperates homologous chromosomes
4N ⇒ 2N
Meiosis II seperates sister chromatids
2N ⇒ N
Synapsis
“Crossing-over”
- Occurs during prophase I
- Chiasmata: site where crossing over occurs
- # formed depends on chromosome size
Equatorial Divisions
Cell division where the number of chromosomes remains the same.
i.e. Mitosis and Meiosis II
Anaphase Lag
Delayed chromosome movment during anaphse of mitosis or meiosis.
- Lagging chromosome not incoorporated into new nucleus
- Can occur with chromosomes or chromatid
- Failure to connect to spindle apparatus
- Moves too slow
- Normal cell forms 1 normal karyotype and 1 monosomy
- Trisomy cell forms 1 trisomy karyotype and 1 “normal” karyotype ⇒ trisomy rescue
Uniparental Disomy
When both copies of a chromosome are inherited from one parent.
Usually results from anaphase lag then aneuploidy correction.
Non-disjunction
Failure of one or more chromosomes/chromatids to separate appropriately during mitosis or meiosis.
- Meiosis ⇒ aneuploidy of all cells
- Meiosis I ⇒ 2 cells w/ extra chromosomes, 2 cells w/ no chromosomes
- Meiosis II ⇒ 1 cell w/ extra, 1 cell with none, and 2 normal cells
- Mitosis ⇒ mosaicism
Mosaicism
Definition
Single individual with two or more genetically different cell types.
Euploidy
Normal chromosome number.
46 chromosomes
Trisomy
47 chromosomes
Usually incompatible with life ⇒ spontaneous abortion
Except trisomy 21, 13, 18, XXX, XXY, XYY
Monosomy
45 chromosomes
Usually incompatible with life except for Turner’s syndrome (45,X)
Spermatogenesis
Steps
Type A spermatogonia ⇒ mitosis ⇒ some type A spermatogonia & some type B spermatogonia
Type B spermatogonium ⇒ mitosis ⇒ primary spermatocytes (diploid, 2N)
Primary spermatocyte ⇒ meiosis I ⇒ secondary spermatocytes (diploid, 2N)
Secondary spermatocyte ⇒ meiosis II ⇒ spermatids
Spermatids ⇒ spermiogenesis ⇒ spermatozoa
Spermiogenesis
Radical morphological change of spermatids into mature spermatozoa.
- Acrosome creation
- Shedding of cytoplasm
- Middle piece formation ⇒ lost of mitochondria
- Flagellum development
Primordial Follicles
1º oocyte (arrested in prophase I) housed in layer of flat epithelial cells.
Begin to mature into primary follicles at puberty.
Oogenesis
Overview
Primordial follicle ⇒ 1º follicle ⇒ 2º follicle ⇒ 3º follicle ⇒ graafian follicle.
Primary oocyte completes meiosis I three hours prior to ovulation producing a secondary oocyte (haploid, 2N DNA) + first polar body.
FSH surge triggers ovulation.
Secondary oocyte only completes meiosis II if fertilized by sperm.
Formation of
Primary Follicles
- Epithelial cells of primordial follicle become cuboidal ⇒ now considered a primary follicle
-
FSH stimulates 1º follicle to form more cuboidal cells
- Cells now called granulosa cells
- Provides nutritional and hormone support
- Cells now called granulosa cells
Formation of
Secondary Follicles
1º follicle ⇒ 2º follicle when:
- Zona pellucida forms around 1º oocyte
- Mucopolysaccharide layer
- Liquor folliculi accumulates
Primary oocyte and surrounding granulosa cells remain on one side of the follicle.
Secondary Follicle
Characteristics
- Sits on cushion of granulosa cells called cumulus oophorous.
- Provides nourishment and support
- Liquor folliculi continues to accumulates
- Becomes a 3º follicle when the follicular antrum becomes large and filled with fluid
Tertiary Follicle
Characteristics
- Outer thecal cells divide into two layers:
-
Theca interna
- procudes androgens that granulosa cells convert into estrogens
-
Theca externa
- Vascularized
- Provides nutritional support
-
Theca interna
- Continues to enlarge
- Usually only one 3º follicle will become a graafian follicle
Ovulation
3 hours prior to ovulation the 1º oocyte within the graafian follicle will complete meiosis I to form a 2º oocyte.
FSH surge triggers follicle rupture and ovulation.
Releases 2º oocyte, zona pellucida, and corona radiata.
Remaining granulosa cells become the corpus luteum.
Sertoli Cells
Provides protection and nutrition to the developing spermatozoa.
DNA Content
for
Spermatogenesis and Oogenesis
Single-gene
(Mendelian)
Disorders
Disease caused by pathogenic mutations in an individual allele or pair of alleles at a single genetic locus (1 gene).
Chromosomal disorders
Disease due to aberrations of one or more chromosomes.
Two main groups:
Those caused by abnormalities in the number of chromosomes.
Those caused by abnormalities in chromosome structure.
Multifactorial Diseases
Due to the interaction of multiple genes as well as environmental factors.
Do not follow a Mendelian pattern of inheritance.
Acquired Somatic Cell
Genetic Diseases
Results from mutations not present at the time of conception.
Pedigree Symbols
Genetic Relatedness
SNPs
Single nucleotide polymorphism
A single base pair change anywhere in the genome.
SSRs
Simple sequence repeat polymorphisms.
Stretches of DNA with di-, tri-, or tetranucleotide repeat sequences.
The actual number of repeats varies in individuals.
Tandem Repeats
Repeats of ten to hundreds of bases where the number of repeats varies between individuals.
Copy Number Variation
Different numbers of copies of specific DNA sequences.
Hemizygosity
A state where only a single allele exists at a given locus in an otherwise diploid cell.
Ex. normal males are hemizygous for all X chromosome alleles.
Law of Segregation
Parental genes are randomly seperated during meiosis so that each gamete contains only one gene of the pair.
Law of Independent Assortment
Genes for different traits independently seperate from one another during meiosis, giving traits an equal opportunity of occuring together.
Law of Dominance
An organism with alternate forms of a gene wil express the form that is dominant.
Autosomal Dominant
Characteristics
- Assume that affected individuals are heterozygous unless there is other information
- Both a verticle and horizontal pattern of inheritance.
- ♂ and ♀ equal in frequency and severity
- Males can transmit disease
- Offspring of affected individual with 50% chance of inheriting disease
Autosomal Recessive
Characteristics
- ♂ and ♀ equal in frequency and severity
- Pedigree
- Rare trait ⇒ single sibship (horizontal pattern in 1 family)
- Common trait ⇒ scattered families with the trait
- Risk of disease increases with consanguinity
Compound Heterozygote
An individual with 2 different mutated alleles at a given locus.
Obligate Carrier
An individual who by pedigree analysis must carry a gene but otherwise has a normal phenotype.
X-chromosome Inactivation
Dosage compensation for two X-chromosomes in females through transcriptional silencing via non-coding RNA.
- XIST (X-inactive specific transcript) gene expressed by the X chromosome that is undergoing silencing.
- ncRNA produced coats the chromosome that made it.
- Recruits silencing protein complexes.
- Results in DNA methylation and histone hypoacetylation.
- Condensation into a Barr body
XIST only expressed in cells containing 2 or more X chromosomes.
X inactivation is random except for placental cells which undergo imprinted inactivation of the paternal X chromosome.
Results in mosaicism of cells in females.
X-Linked Recessive
Characteristics
-
No male to male transmission
- Affected males with normal sons and carrier daughters
- Mother of sporadic affected male can:
- Be heterozygous
- Have mosaic gametes
- Affected male + heterozygous female could look like autosomal dominant on pedigree
- 1/2 ♂ affected ⇒ likes like ♂ to ♂ transmissions
- 1/2 ♀ affected as severely as hemizygous ♂
X-linked Dominant
Characteristics
- Females affected twice as often as males
- Males often more severely affected than females
- Affected females ⇒ 1/2 of ♂ and 1/2 of ♀
- If the disorder is lethal in utero in hemizygous males
- only see affected females
- affected females have fewer sons than daughters
- affected females have more spontanous abortions
Y-linked Inheritance
Characteristics
- Only males affected
- Only male to male transmission
Male Sex
Determination
- SRY gene codes for sex-determining region Y protein
- Transcription factor causes fetus to develop as a male
- SRY mutations gives rise to XY females with gonadal dysgenesis
- Translocation of SRY gene from Y to X chromosome results in 46,XX testicular disorder of sex development
- Present in phenotypic females who lack functional androgen receptors
Mitochondrial Inheritance
Characteristics
- Maternally inherited
- No male to male transmission
- Carrier will have both normal and defective mtDNA ⇒ heteroplasmy
- Ratio of defective/normal mtDNA in ova will affect inheritance, severity, and onset ⇒ threshold effect
- Mitochondrial donation ⇒ “three-parent” inheritance
- Female pronuclei of a person with known mitochondrial disease inserted into cell with normal mitochondria
Heteroplasmy
A mixture of two or more mitochondrial genotypes within a cell or individual.
Ratio of normal vs altered mtDNA can influence the severity and timing of disease onset ⇒ threshold effect
New Mutations
Sudden appearance of an autosomal dominant or X-linked recessive trait assumed to be a sporadic case caused by a new mutation.
Ex. 1/3 of new cases of Duchene muscular dystrophy (DMD) represent a new mutation.
- De novo mutation in offspring ⇒ nearly zero chance of recurrence
- De novo mutation in parent ⇒ recurrence risk varies and can approach 50%
Mixed Mosaicism
Mutation occurs very early in pre-embryo or embryo before seperation of germline cells from somatic cells.
Can be present in the germ and/or somatic cells.
Can result in phenotypic expression and/or transmission to offspring.
Somatic Mosaicism
Mutation effects somatic cells only.
Will affect the tissue(s) that arise from those cells.
Will have little effect onse the embryo has reached a certain size.
Will not be transmitted to offspring.
Germline Mosaicism
Mutation in germ line cell precursor persists in all the clonal descendant of that cell.
Individuals will have normal phenotype and normal DNA tests but likely to have multiple affected offspring.
Strongly suspected when phenotypically normal parents have two or more offspring with autosomal dominant disease.
Variation of age of onset
A static mutation could lead to a phenotype that could develop over a broad age range.
Anticipation
Phenotype becomes more severe from one generation to the next.
- Indications of anticipation:
- earlier age of onset with each generation
- increasing severity with each generation
- Usually due to dynamic mutations ⇒ expansion of trinucleotide repeats
- Threshold number of repeats must be reached for disease manifestation
Chromosome structure
Types of
Chromosome Shapes
Idiogram
The numbered banding pattern of a chromosome.
To identify a site on a chromosome, four items are required:
- Chromosome number
- Arm designation
- Region number
- Band number
G-Banding
Use cells in metaphase typically
Use cells in prometaphase for high resolution
Called a karyotype when chromomes put into an ordered arrangement.
- Use phytohemagglutinin (PHA) to include
- Use colchicine to stop cells in metaphase
FISH
(fluorescent in situ hybridization)
- Used to ID structurally abnormal chromosomes
- Can quantify a specific number of copies of a specific DNA segment
- Often used after chorionic villus sampling (CVS) or amniocentesis
- To determine the # of chromosomes 21, 13, 18, X, and Y
- Effective to ID microdeletions
- Need to know what you are looking for
Comparative Genomic Hybridization (CGH)
or
Chromosomal Microarray Analysis (CMA)
- Used as first-tier testing in patients who do not fit a specifically known syndrome
- Can identify copy number changes
- Detects unbalanced chromosomal changes (gains/losses)
- Does not detect balanced structural changes (translocations and inversions)
- Clinical interpretation can be complicated
Tranlocation
Definition
A piece of one chromosome becomes inappropriately attached to another.
The resulting chromosomes are called derivatives (der).
Reciprocal translocations
Involves breaks in two different chromosomes with mutual interchange and no apparent loss of chromosomal material.
If no critical material is lost, it is a balanced translocation.
Ex. Philadelphia chromosome and chronic myeloid leukemia (CML)
Robertsonian Translocations
The union of the long arms of two acrocentric chromosomes at the centromeres.
Loss of the repetitive copies of ribosomal RNA in short arms does not constitute a loss of critical DNA.
Are initially balanced.
May result in monosomy or trisomy following gametogenesis ⇒ form unbalanced gametes
Deletions
A piece of chromosome breaks off, does not reattach to any chromosome, and becomes lost in the cell.
A partial monosomy for the deleted region can result.
Clinical impact varied based on affected genes.
Two types:
Deletion ⇒ visible loss of chromosomal material that can be detected by traditional metaphase banding.
Microdeletion ⇒ loss of a smaller amount of chromosomal material only visible with high resolution banding or FISH. Associated syndromes referred to as continuous/contiguous gene syndromes.
Insertions
When a single chromosome breaks and a piece of that chromosome is reinserted elsewhere
Threshold of Liability
Model
The phenotype does not develop unless the individual crosses a threshold through the cumulative effects of genetic, environmental, and stochastic components.
Multifactorial Disease
Recurrence Risks
Empirical risks determined by direct observation of prevalence in the population.
Differ substantially from one population to another.
- Decreases rapidly in more remotely related relatives.
- If more than one close family member, recurrence risk higher in that family.
- If phenotype severe, recurrence risk higher.
- If trait more common in one sex, offspring of less freq. sex has a higher recurrence risk
- Recurrence risk for relatives of affected person increases as population risk decreases
