Genetics unit 2 Flashcards
pedigree
ancestry
Gene
a name given to some stretches of deoxyribonucleic acids (DNA) and ribonucleic acids (RNA) that code for a polypeptide or for an RNA chain that has a function in the organism
allele
a version of a gene. Allele’s are different forms of the same gene/genetic locus
Mendel’s Law of segregation
The Law of Segregation states that every individual possesses a pair of alleles (assuming diploidy) for any particular trait and that each parent passes a randomly selected copy (allele) of only one of these to its offspring.
gamete
cell that fuses with another during fertilization
Mendel’s Law of Independent Assortment
separate genes for separate traits are passed independently of one another from parents to offspring
Genotype
A particular DNA sequence (allele’s at a locus). Refers to homologous alleles
-can be homozygous, heterozygous, or hemizygous
Phenotype
Observed/measured/expressed trait
Hemizygous
Having only one chromosome in a diploid cell.
ex; In males (XY) that have just one copy of the genes on X chromosome or just one copy of the genes on the Y chromosome.
Penetrance
On/Off (if you have mutation are you affected/not)
Can have complete/incomplete penetrance
If have genotype but no phenotypical expression -> incomplete penetrance.
expressivity
severety of onset
age of onset
“like a dimmer control on a light”
Pleiotropy
complexity of gene (one organ or many)… “One Gene contributes to multiple phenotypic effects”
polysystemic -> systemic affects multiple
monosystemic -> affects only 1 system
Chediak-Higashi Syndrome
- Autosomal recessive:
- chromosome 1
lysosomal trafficking defect
Pleiotropy: light hair, albinism pigmentation, neuropathy, parkinsonism
- Variable expressivity
- Penetrance: In white cells of most, not all pts.
Semi-Dominant/ incomplete dominance
When the heterozygous phenotype is intermediate between the two homozygous phenotypes
Karyotyping and karyotype
Process of staining chromosomes in metaphase.
-stained, ordered, numbered BY- morphology, size, arm-length ratio, banding pattern
- > diagnostic for some diseases (sex chromosome and trisomies)
- > can be performed on many different tissues
A karyotype (Greek karyon = kernel, seed or nucleus) is the number and appearance of chromosomes in the nucleus of a eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.
ex: the display of 23 paired and stained chromosomes
Non-allelic homologous recombination (NAHR)
Aberrent recombination because of misalignment of homologs at repetitive DNA sequences -> deletion and duplication.
This is during Meiosis (obviously since we’re talking about recombination). There are still seperate chromosomes, they now have slightly more or less DNA. This also can happen in DNA repair
“Tandem repeats/ satellite DNA”
Just means that there are independent sections of repeating sequences.
- used in cytogenic banding
- Specifict Pentanucleotide sequence 1, 9, 16, Y (hotspots for human specific evolutionary changes) found in heterochromatic regions
- “Alpha-Satelite” (171bp repeat unit) found near centromeric region. Speculated to be involved in mitosis/meiosis
cytogenic banding
used to make karyotype stains
Dispersed repetitive DNA elements
These families can move around genome
-Alu Family = (SINE’s)- short interspersed repetitive elements about 300 bp, with 500,000 copies in genome.
-L1 Family = (Lines)-> long interspersed repetitive elements about 6kb length with 100,000 copies
-L1 & Alu speculated to have medical relevance
-Retrotransposition may cause insertional inactivation of genes
RNA->cDNA -> inserts itself
-Repeats may facilitate aberrant recombination
events between different copies of dispersed repeats leading to diseases…
- Non-allelic homologous recombination (NAHR)
CNV (copy number variation)
- A variation in number of copies of a certain section of DNA.
- SIZE: 200 bp – 2 Mb
- measured by array comparitive genomic hybridization (array cpg)
- primary type of structural variation
For example, the chromosome that normally has sections in order as A-B-C-D might instead have sections A-B-C-C-D (a duplication of “C”) or A-B-D (a deletion of “C”).
DUF1220
DUF1220 domains are approximately 65 amino acids in length and are located primarily on chromosome 1 in region 1q21.
DUF1220 is a protein domain of unknown function that shows a striking human lineage-specific (HLS) increase in copy number and may be important to human brain evolution. ->CNV’s
dosage may affect brain size (number of the copies)
1q21.1 duplication
Macrocephaly and autism
DUF1220 area
1q21.1 deletion
Microcephaly and schizophrenia
DUF1220 area
autism and schizophrenia correlation
proposed diametric opposites
What portion of Human Genome is transcribed (through all of life)
1.5% WHHHHAAAT!!!???!?!?!
chiasma (singular)
chiasmata (plural)
section of chromosome crossover in meiosis I
2-3 chiasmata per pair homologous chromosomes
->usually one on each side of centromere
homologues
2 autosomal chromosomes that have the same genes (with possibly/definitely slight differences)
sex chromosome crossover MALE
Cross-overs also occur within pseudoautosomal regions of sex chromosomes during male meiosis
Meiosis I nondisjunction (%abnormal gametes?)
100%
Meiosis II nondisjunction (% abnormal)
50% (because it’s just one cell -> 2), the other cell -> II is normal
G-banding or Giemsa banding
used in karyotyping
GC does not stain well (grey) AT does (black)
chromosome classification by centromere (constriction) position
Metacentric = centromere in middle Submetacentric = closer to one end Acrocentric = #5 in humans (13, 14, 15, 21 and 22), 1 side is repetitive satellite elements + a stalk of repetitive (hundreds of copies of ribosomal DNA in heterochromatic region). 14 is most common chromosome involved in robertsonian translocation.
See pg.62 T&T for satellite/stalk explanation.
Aneuploidy
Loss or gain of certain chromosome
ex; trisomy 21, monosomy X
also 13 and 18
monosomy die in all but monosomy X
Most common mechanism: meiotic chromosomal nondisjunction (in meiosis 1)
polyploidy
gain or loss of ALL chromosomes
i.e. triploidy (3N), tetraploidy (4N)
Not found very often (and usually fatal)
terminalization and aneuploidy
Loss of cohesin (as you age?) allows chiasmata (site of recombination) to move to “termanalize” move toward end of homologous pairs, then they seperate = precocious seperation = meiosis I nondisjunction
zygote
is the initial cell formed when two gamete cells are joined by means of sexual reproduction
epigenetics
the study of heritable changes in gene activity which are not caused by changes in the DNA sequence
Oncogene
A gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.
Allelic Heterogeneity
Different mutations in the same gene cause similar phenotype
Different mutations same gene = similar phenotypes
Different mutations at the same locus causes a similar phenotype. For example, β-thalassemia may be caused by several different mutations in the β-globin gene.
Phenotypic Heterogeneity
Different mutations in the same gene/locus cause different phenotypes.
Different mutations same gene = different phenotypes
heterogeneity
quality of being diverse and not comparable in kind
Locus/genetic heterogeneity
A mutation in more than one locus causing the same/similar clinical condition
Classic example: Early onset Alzheimer disease (AD)
-> Mutations in 3 different genes all result in identical clinical presentation of early-onset AD
Uniparental disomy
Heterodisomy: Meiosis I error -> usually benign (one allele from parental/maternal genes)
Isodisomy: Meiosis II error -> bc both are same parent -> could be recessive expression
Balanced Structural rearrangement
Inversion, reciprocal translocation, and Robertsonian translocation
Unbalanced Structural rearrangement
Deletion, Duplication, Ring Chromosome (arms have joined), Isochromosome (arms have duplicated)
Epigenetics
Definition: mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence
example: IMPRINTING!!!
Imprinting
Reversible, post-translational modifications of histones and DNA methylation (CpG) are examples of epigenetic mechanisms that alter chromatin structure, thereby affecting gene expression.
Imprinting Methylation
by MeCP (methyl CpG binding protein)
-> binds methylated CpG’s -> In complex with SWI/SNF and HDAC’s and HMT (histone methyl transferase)
compacts chromatin-»» silencing gene
SWI/SNF
possess a DNA-stimulated ATPase activity and can destabilise histone-DNA interactions in reconstituted nucleosomes in an ATP-dependent manner, though the exact nature of this structural change is unknown.
–> affect chromatin remodling by moving histones around
Imprinting distribution
Imprinted genes are usually clustered and account for about 1% of gene’s in genome
_____ enzyme recognizes hemimethylated DNA in Mitosis
maintenance methyltransferase
Chromosomal MicroArray (CMA)
1:Many 60 nucleotide sequences fixed.
2. DNA to study is added.
3. Gain/Loss/normal ration seen
Green = gain. Red = Loss. Yellow =normal ratio
Cannot detect SNP’s or balanced rearrangements. Poor at detecting mosaicism (15%).
Same sex DNA as control
You add c DNA fragments from across the whole HUMAN GENOME.
JUST DETECTS GAINS/LOSSES
Methylation of DNA ONLY occurs at what sequence
on Cytosine of CpG
Does not affect base paring of 5-meC with G.
Contributes to gene silencing by solidifying the repressed state
Hardy-Weinberg assumes
Random Mating of Large population
No selection
No Mutation
No Migration/Drift
multifactorial inheritance + disease examples
Genetics + environment = disease
Some cancers - Schizophrenia Type 1 diabetes - Cleft lip/palate Type 2 diabetes - Hypertension Alzheimer disease - Rheumatoid arthritis Inflammatory bowel disease - Asthma
Phenocopy
Environmentally caused phenotype that mimics the genetic version of the trait.
-Environment MOSTLY responsible
- ex: Thalidomide-induced limb malformation vs. genetically-induced.
- ex: DM II (healthy person w/DM II vs overweight/poor habits person)
Odds Ratio (OR) =
Risk of disease having a given gene variant /
Risk of disease not having a given gene variant
Linkage disequilibrium:
non-random association of genes at two or more loci, that descend from single, ancestral chromosomes… It means that different genes aare inherited together more often than can be expected by chance.
Microsatellites
also known as Simple Sequence Repeats (SSRs) or Short Tandem Repeats (STRs)
or
STRPs (Short Tandem Repeat Polymorphisms)
repeating sequences of 2-6 base pairs of DNA.[1] It is a type of (VNTR). They are used as molecular markers in genetics, for kinship, population and other studies. They can also be used for studies of gene duplication or deletion, marker assisted selection, and fingerprinting.
DNA Human Variation
Minisatellites, Microsatellites, SNP’s, CNV’s.
Others: chromosomal or larger scale variations, rearrangements, translocations, etc
Variations can be silent (majority) or have a functional effect.
Gene family
Gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions
Gene families arise through gene duplication, a major mechanism underlying evolutionary change
Minisatellites
tandemly repeated 10-100 bp blocks of DNA VNTR (variable number of tandem repeats)
Barr body
Heterochromatic mass present for inactive X chromosomes. (only 1 per inactive X)
XIST gene
transcriptionally active on INACTIVATED X chromosomes, necessary for inactivation.
Produces non-coding RNA that associates closely with Barr body (initiates modification -> methylation and histone modification).
Side note: 10-15% inactive X chromosome is still expressed.
SRY gene
It’s presence (on short arm of Y chromosome) leads to development of testes.
SRY (sex reversal Y) codes a TF binding protein (family of HMG (high mobility group) box family which binds to DNA, inducing differentiation of cells derived from the genital ridges into testes. (It opens the DNA to transcription)
In the absence of SRY, undifferentiated gonadal tissue -> Ovaries.
WT gene
directs differentiation of the mesonephros (middle temporary kidney) and genital ridge, events that precede gonadal development. ( helps differentiate cells into undifferentiated gonads)
BUT
If gene mutated -> development of ovaries/gonadal dysgenesis despite Y chromosome presence.
Sertoli cells
NON-GERM cells within testes. produce peptide hormone (all of these are the same, just different names): Mullerian Inhibitory Factor (MIF) Antimullerian Hormone (AMH) Mullerian Inhibitory Substance (MIS)
MIF prevents formation of mullerian duct derivatives (fallopian tubes, uterus, cervix, and upper portions of the vagina). Mullerian duct also called paramesonephric duct.
see slide 22
Leydig cells
NON-GERM cells within testes-
produce testosterone in response to stimulation by the pituitary.
Testosterone promotes -> Development of Wolffian (mesonephric) duct into the epididymal duct and ductus deferens. And other secondary male characteristics. such as descent of testes
Sex reversal
Gonadal sex is opposite of what is predicted from karyotype (genetic sex).
Mutations on Loci on chromosomes 9 (SF1),11(WT) and 17(SOX9), (and X really DAX1)) can lead to sex reversal (development of female gonadal/genital sex) in the presence of SRY expression.
examples:
MALE: SRY gene translocated onto an autosome in XX genotype.
FEMALE: Deletion of SRY gene (or) duplication of DAX1 gene
Intersex (True hermaphrodite)
Both ovarian and testicular tissue are present. Clinical cases are generally found to be mosaic for expression of genes involved in
determination of gonadal sex. XX, XY chromosomal mosaicism is most common.
Intersex (Pseudohermaphroditism)
Abnormal development of genital sex. External phenotype and, often, sex assignment at birth is at odds with genetic and gonadal sex.
Example: 1.female exposed to androgen in utero.
2. Male insensitivity to testosterone
DAX 1
gene needed for development of ovary. DAX 1 (2x X chromosomes) is needed for “perfect” development of ovaries.
(ovarian development is primarily a default setting)
If there is a duplication of DAX1 gene in XY individual -> ovarian development despite presence of SRY gene
Brain sexuality?
Nyep -> Dimorphic
Compound heterozygote
Also called “genetic compounds”
2 different mutant alleles
vs
simple heterozygous (1 wild type and 1 mutant allele)
Microcytosis
a condition in which red blood cells are unusually small as measured by their mean corpuscular volume
->microcytic anemia
MCV normal = 75-95fl
(deficiency = often iron or thalassemia problem)
hypochromia
anemic condition due to a deficiency of hemoglobin in the red blood cells. with insufficient color or pigmentation
Hemoglobin A2 components
Alpha2Delta2 = 4x tetramer (low in adult)**
vs
HbA = Alpha2Beta2 = 4x tetramer (high in adult)**
** given no hemoglobinopathies
alpha-alpha vs alpha-beta interaction
alpha-alpha = weak alpha-beta = strong interaction
Parental transmission bias
Trinucleotide expansion more prone to occur in gametogenesis of the male or the female
Pharmacokinetics:
the rate at which the body absorbs, transports, metabolizes, or excretes drugs or
their metabolites.
concerned with whether or how much drug reaches the
target(s)
Pharmacodynamics:
the response of the drug binding to its targets and downstream targets, such as
receptors, enzymes, or metabolic pathways
concerned with what happens when the drug successfully reaches its target
Phase I vs Phase II pharmacokinetics
Phase I (simplified): attach a polar group onto the compound to make it more soluble; usually a hydroxylation step
• Phase II (simplified): attach a sugar/acetyl group to detoxify the drug and make it easier to
excrete
cytochrome P450 (CYP450)
genes encode important enzymes that are very active in the liver and to a lesser extent in the epithelium of the small intestine.
->CYP450 enzymes metabolize a wide number of drugs.
->CYP families are involved in the Phase I
metabolism of ~90% of all commonly used
medications.
CYP3A4 itself takes part in the metabolism of
over 40% of all drugs used in clinical medicine
CYP family USUALLY inactivates drugs, but SOMETIMES activates them
ex CYP2D6 codeine -> morphine
clearance by CYP3
1 glass Grapefruit juice inhibits _____
CYP3A for 24-48hrs (intestinal inhibition)
So if taking Felodipine (antiHTN) with grapefruit juice-> CYP3A inhibition -> less clearance Felodipine -> increased drug in system -> hypotension
Renal transplant develops fungal infection
Reduce cyclosporin (an immunosuppressant) because ketocoazole (antifungal) -> inhibits CYP3A -> cyclosporin can become toxic bc of decreased clearance by CYP3A
Renal transplant with Tb exposure
Tx
Tb prophylaxis with Rifampicin -> Rifampicin is CYP3 INDUCER -> rapid metabolism by CYP3 -> need to increase cyclosporin dosage so it’s not cleared as fast.
Anchoring Effect
Entrenched/preexisting beliefs are hard to change
Adenoviruses
nonenveloped double stranded DNA virus
replacement of gene products
Enzyme replacement: Lysosomal storage diseases, alpha-1-antitrypsin
• Protein Replacement: Factor replacement in hemophilia
women aren’t good at…
men aren’t good at…
referring to genetics
women -> not good at sorting chromosomes
Men- > not good at sequencing (errors)
What inhibits CYP3A
Grapefruit Juice
Ketoconazole (for fungal infections)
- -> less clearance of cyclosporine (immunosuppressant)
- –> less clearance of Felodipine (antiHTN)
—>buildup of drugs occur increasing effects
What induces CYP3A
Rifampicin (RNA Pol inhbitor that prevents RNA elongation)
–> so increased clearance of cyclosporin in a renal transplant pt getting rifampicin —> must increase dosage of cyclosporin transiently while rifampicin is being administered.
Double Heterozygote
An individual who has two different gene mutations (i.e., is heterozygous) at two separate genetic loci
