Flashcards in Genetics Deck (174):
What is an allele?
A certain version of a gene
Define Mendel's Law of Segregation
Alleles segregate (at meiosis) into the gametes
Define Mendel's Law of Independent Assortment
The segregation of each pair of alleles is independent
The DNA sequence (alleles) at a particular locus
Define homozygous genotype
2 identical alleles at a given locus
Define heterozygous genotype
2 different alleles at a given locus
Define hemizygous genotype
Refers mostly to males (XY), who have just a single copy of each X-chromosomal gene
The observed/measured trait
A phenotype that is expressed (observed) in the heterozygous state
A phenotype that is expressed only in homozygotes or hemizygotes
When the heterozygous phenotype is intermediate between the two homozygous phenotypes
Some with a mutation can still be unaffected; ex. 80% penetrance indicates that 80% with the mutation are affected; Used with dominant and recessive mutations
Severity of phenotype in those who Are affected
Genes that have multiple effects in body; polysystemic versus monosystemic
What are three threats to Mendelian inheritance?
Penetrance, expressivity, & pleiotropy
Define environmental factors
Factors that are not genetic that affect the expression of Mendelian diseases
Define modifier genes
Genetic factors that influence a phenotype
Define stochastic effects
Stochastic (random) effects can influence the expression of phenotypes
Same phenotype as a genetic condition due to non-genetic factors
The affected member through whom a family with a genetic disorder is brought to attention
The person who brings the family to attention (affected or unaffected)
Segment of DNA occupying a particular position/location on a chromosome
Define compound heterozygote
Two recessive mutant alleles, but they're different
What is the difference between autosomal and sex-linked?
Autosomal affects males and females equally. Sex-linked means the mutation is on X chromosome
Define allelic heterogeneity
A single disorder, trait, or pattern of traits caused by different mutations within a gene
Define locus heterogeneity
A single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci
Define phenotypic heterogeneity
When different mutations in same gene cause different phenotypes
What are "threats" to Mendelian genetics?
Factors or characteristics of mutations that discourage phenotypes from following Mendelian rules or expectations.
What is the Mendel's First Law of Inheritance?
The Principle of Segregation: A gene pair separates, sending one allele to one gamete and the other to another gamete
What is Mendel's Second Law of Inheritance?
The Principle of Independent Assortment: Genes for different traits assort independently of one another in the formation of gametes
How many pairs of chromosomes make up the human genome?
23 pairs (one of which is a sex pair of chromosomes)
What is one chromosome made up of?
One single continuous double-helixed DNA strand
What is a typical gene? A retroposed genes?
A typical gene is intron-containing, while a retroposed gene is intronless
About what is the size range of chromosomes?
~50,000,000 bp - 250,000,0000 bp
What is a genetic map vs. a physical map in genomics?
Both maps are a collection of genetic markers and gene loci, but genetic map distances are based on the genetic linkage information measured in Centi-Morgans, while physical maps use actual physical distances measured in base pairs.
What is the Human Genome Sequence a record of?
Human evolutionary history
What is the average propensity of single nucleotide polymorphisms (SNP) in humans?
1 SNP every 1000 bp between any two randomly chose unrelated human genomes
What are the three gene-poor human chromosomes?
13, 18, 21 (viable)
Why are chromosomal banding patterns possible?
There is clustering (non-random distribution) of GC-rich and AT-rich regions
What are the two methods for sequencing the human genome?
1. Make clone libraries of genome, map them out, then sequence overlapping clones
2. Shotgun sequencing: break apart entire genome, sequence, then assemble it
Does genome sequencing sequence euchromatic or heterochromatic regions?
Euchromatic regions (accessible - heterochromatic regions usually just contain copies of genes)
What are DNA tandem repeats? aka "satellite DNAs"
Short sequences of DNA (2-5bps) that are repeated numerous times in a head-tail manner. Used as the basis for cytogenetic banding. Hotspots for human-specific evolutionary changes.
What are DNA alpha-satellite repeats?
A 171 bp repeat unit found near centromeric regions of all human chromosomes; may be important to chromosome segregation in mitosis & meiosis
What is non-allelic homologous recombination (NAHR)?
NAHR is a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles.
What is retrotransposition?
The insertion of DNA sequences mediated by an RNA intermediate. In humans, carried out through reverse-transcriptase.
How do we measure changing number of copies?
Array CGH (comparative genomic hybridization)
What is a 'gene family' composed of?
Composed of genes with high sequence similarity that may carry out similar but distinct functions.
How are gene families the major mechanism behind evolutionary change?
When a gene duplicates it frees up one copy to vary while the other can continue carrying out its critical function
For what percentage of genes do we not know specific molecular function?
What is the primary type of genome structural variation?
Copy number variations
What do duplications of the DUF1220 indicate?
Macrocephaly & autism
What do deletions of the DUF1220 indicate?
Microcephaly & schizophrenia
What is indicated by 'gene-rich' and 'gene-poor?'
A gene-rich region of DNA has multiple genes within in. A gene-poor region... self-explanatory.
What is the missing heritability problem?
Studies that look for genetic factors in complex diseases only truly discover a small percentage of factors. Many genetic contributions are yet to be discovered and sequenced.
Chromosomal abnormalities occuring during meiosis can result in what kinds of mutations?
germ line mutations
Chromosomal abnormalities occuring during mitosis can result in what kinds of mutations?
somatic mutations, germ line mutations - results in mosaicism
Cells with more than one chromosomal composition - not all cells are identical when they should be
What are the basic steps of meiosis and what is the haploid state at each step?
2N cell undergoes DNA replication -> 4N -> Homologs pair and separate -> 2N -> another round of segregation to result in 4 haploid (N) gamete cells
How are X and Y chromosomes paired up for meiosis when they are not identical homologs?
There are regions called pseudoautosomal regions that share homology so that they can be properly aligned.
Expression of genes from characteristics other than DNA sequences
What on the DNA can be methylated?
CpG sites; sites where a cytosine and guanine are separated by only one phosphate, cyosine is 5' to guanine; cytosine methylated at 5' position
Describe Waddington's Landscape as Epigenetic Visualization
A ball (ex. pleuripotent stem cell) sits at top of hill. It waits for signals so that it can decide which route to roll down for different gene expression.
Non-disjunction during Meiosis I results in what?
100% abnormal gametes
Non-disjunction during Meiosis II results in what?
50% abnormal gametes
How are chromosomes visualized? (striped)
Giemsa Staining; GC do not stain (Giemsa-light) and AT stain (Giemsa-dark)
What are the three chromosomal structural classifications?
Metacentric, submetacentric, acocentric
In what order are karyotypes listed?
Number of chromosomes; gender; findings
Two or more chromosome complements present within a single individual; commonly caused by nondisjunction in an early post-zygotic mitotic division
What is polyploid mosaicism?
What is aneuploid mosaicism?
What are the two types of stuctural chromosomal abnormalities and their subcategories?
-Marker (ring) chromosomes
What is reciprocal translocation?
Exchange of genetic material between two non-homologous chromosomes
What is a paracentric inversion?
An inversion excluding the centromere; occurs when one chromosome undergoes two DSBs of the backbone and the intervening sequence is inverted prior to the rejoining of the broken ends
What is a pericentric inversion?
An inversion including the centromere; occurs when one chromosome undergoes two DSBs of the backbone and the intervening sequence is inverted prior to the rejoining of the broken ends
How can inversions show no phenotype but produce abnormal gametes?
Although there is an inversion, all genetic material is still present. During the pairing of homologs in meiosis, a loop is introduced in the homolog containing the inversion
What is the risk that a carrier of a reciprocal translocation will produce offspring with balanced translocation?
Reciprocal chromosome translocation leads to what kind of leukemia?
Chronic Myelogenous Leukemia; 95% of patients with CML have the Philadelphia chromosome and an abnormal chromosome 9
What is a Robertsonian Translocation?
Fusion between centromeric regions of two acrocentric chromosomes, with deletion of both short arms.
A chromosome in which one arm is missing and the other arm is duplicated in a mirror-like fashion
What chromosome is involved in the most common isochromosome?
Long arm of X chromosome
What percentage of the viable offspring of a carrier of isochromosome 21 are abnormal?
How do aberrant recombination events lead to unbalanced chromosomal rearrangements?
Two chromosomes align slightly out of register with each other and one homolog contains a deletion while the other contains a duplication
What percentage of gametes in a Robertsonian translocation are normal?
Define contiguous syndrome
Abnormal phenotype caused by over-expression or loss of neighboring genes
Mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence, but by reversible post-translational modifications of histones or DNA methylation, for example
What is genetic imprinting?
Genes that are inherited in a transcriptionally active state from one parent and a transcriptionally inactive state from the other parent
About what percent of genes in the human genome are thought to be imprinted?
At what point are DNA methylation marks established?
In the gamete
Why does DNA methylation have to be reversed and reset?
So that during gametogenesis, the sex-appropriate marker can be placed
What are four characteristics of epigenetics?
1. Different gene expression patter/phenotype with an identical genome
2. Inheitance through cell division, even through generations
3. Like a switch: on/off
4. Erase-able (inter-convertible) - therapeutic potential
Describe Waddington's Landscape as epigenetic visualization
A ball sits at top of hill (pleuripotent stem cell). It can roll down the hill through multiple divets and paths. Hills represent the "activation energy" to go down that pathway. The ball waits for cues to differentiate into different types of cells.
Where can DNA methylation occur?
Only on cytosines of CpG; where C is just 5' to G
Do epigenetic mechanisms and inheritance occur inside or outside nucleus?
What gene can lead to cancer when aberrantly methylated with 5meC?
Tumor Suppressor Gene (TSG)
What constitutes a genetic test?
1. Analyzing an individual's genetic material to determine predisposition to a particular health
condition or to confirm a diagnosis of genetic disease.
2. Examining a sample of blood or other body fluid or tissue for biochemical, chromosomal, or genetic
markers that indicate the presence or absence of genetic disease.
What are 'informative' and 'non-informative' genetic test results?
Informative test results are when the results actually determine disease presence/absence and identification. Non-informative implies that more information is needed.
Explain how allelic heterogeneity can affect the sensitivity of genetic tests.
Explain how genetic heterogeneity can affect the sensitivity of genetic tests.
What is the basic approach of chromosomal analysis?
What is the basic approach of fluorescent in-situ hybridization (FISH)?
What is the basic approach of microarray analysis?
What is the basic approach of DNA sequencing?
What are the advantages of chromosomal analysis?
What are the advantages of fluorescent in-situ hybridization (FISH)?
What are the advantages of microarray analysis?
What are the advantages of DNA sequencing?
What are the limitations of chromosomal analysis?
What are the limitations of fluorescent in-situ hybridization (FISH)?
What are the limitations of microarray analysis?
What are the limitations of DNA sequencing?
What is the chance that an unaffected sibling is a carrier of an autosomal recessive allele?
In the p/q equation, what determines frequency of mutant allele?
In the p/q equation, what determines frequency of carriers of a mutant allele?
In the p/q equation, what determines frequency of an autosomal recessive disease (prevalence)?
Define allelic heterogeneity
Presence of multiple common mutant alleles of the same gene in a population
Define compound heterozygote
An individual who carries two different mutant alleles of the same gene (different alleles regardless)
Define incomplete dominance
When homozygotes are affected more severely than heterozygotes
Define slipped mispairing
Mispairing of bases in regions of repetitive DNA replication coupled with inadequate DNA repair systems
How do you calculate risk of disease in relatives in diseases of multifactorial inheritance?
gamma(s) = risk of disease in siblings of affected / risk of disease in general population
Define allelic heterogeneity
Different alleles in the same gene result in same trait, or different trait
Define locus heterogeneity
Variants in different genes result in very similar clinical presentations
Environmentally caused phenotype that mimics the genetic version of the trait
Define sexual dimorphism
The phenotypic differences between males & females
How does the female body choose which X chromosome to inactivated?
Random process; the inactive X chromosome expresses the XIST gene
What is nonrandom X chromosome inactivation?
Occurs when there is a structurally abnormal X chromosme; more of the normal Xs are turned on
What is skewed X inactivation?
When there is an imbalance in a good/bad X chromosome that's inactivated.
What does gonad determination depend on?
What is the "default" state: female or male?
What determines secondary sex characteristics?
In the embryology of reproductive organs, what occurs in the 5th week?
Coelomic epithelium becomes genital ridge
In the embryology of reproductive organs, what occurs in the 6th week?
Primordial germ cells migrate to the dorsal mesentary of the hindgut adn enter undifferentiated gonad; epithelial cells of gonadal ridge proliferate and form primitive sex cords
In the embryology of reproductive organs, what occurs in the 7th week in males?
The genital ridge is differentiated into Sertoli and Leydig cells
In the embryology of reproductive organs, what occurs in the 8th week in males?
Leydig cells begin producing testosterone and Sertoli cells produce AMH; primitive sex cords differentiate into testis cords & rete testis
In the embryology of reproductive organs, what occurs in the 7th-8th weeks in females?
In the absence of SRY & in presence of 2 X chromosomes, primitive sex cords dissociate into irregular clusters and go away; medullary cords regress and cortical cords are formed, which are destined to become follicular cells of the ovary.
What are the male genital ducts called? The female?
Male: Mesonephric (Wolffian)
Female: Paramesonephric (Mullerian)
What two genes are responsible for virilization and are on the Y chromosome?
SRY & SOX9 genes; produce AMH
What male gene is a chemotactic factor that causes tubules from mesonephric duct to penetrate gonadal ridge?
What male gene stimulates differntiation of the Sertoli & Leydig cells?
What do the mesonephric (Wolffian) ducts elongate to form?
Epididymis, seminal vesicles, vas deferens
What protein is responsible for differentiation of the ovary/
What gene is a nuclear hormone receptor up-regulated by WNT4 that functions to downregulate SOX9?
What gene is a coactivator of the WNT pathway in female development?
The paramesonephric (Mullerian) ducts form what?
Uterus, cervix, broad ligament, Fallopian tubes, upper 1/3 of vagina
At 3 weeks of embryonic development, what forms the genital tubercle and genital swellings?
Mesenchymal cells in the primitive streak
For finding disease genes, instead of sequencing entire genomes, how do we find genetic differences in individuals/families?
We genotype polymorphic DNA "markers" (any scoreable difference) at known genomic positions
What are three commonly used marker types when finding disease genes?
Microsatellites, single-nucleotide polymorphisms (SNPs), & copy-number variations (CNVs)
Recombination breaks macro-patterns of polymorphic genotypes on the same chromosome into haplotypes: genes too close together to be separated during recombination.
Define linkage disequilibrium
When marker alleles within haplotype blocks tend to be co-inherited because recombination within blocks is uncommon
What is candidate gene DNA sequencing?
Studies gene directly and depends on biological hypothesis and positional hypothesis/information
When is candidate gene DNA sequencing most useful?
Sometimes successful in Mendelian disorders, but in complex disorders it is most useful when candidates are positive from GWAS
Are most hypotheses from candidate gene DNA sequencing right or wrong?
What are candidate gene association studies?
Most common type of 'genetic study."
When are candidate gene association studies most useful?
Most powerful for common risk alleles with small to moderate effects.
How do fatal flaws lead to false-positives in candidate gene association studies?
The study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity
The genomic approach to pharmacogenetics, concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy
What are pharmacokinetics & pharmacodynamics?
Describes absorption, distribution, metabolism, and excretion of drugs. Pharmacodynamics describes the relationship between the concentration of a drug at its site of action and the observed biological effects.
Contrast Phase I and Phase II drug metabolism steps
In Phase I, a polar group is added (exposed) in order to solubilize. In Phase II, conjugation reaction (sugar/acetyl group) to detoxify.
Describe the central role of the CYP450 enzyme system in drug metabolism
Its gene products are active in liver and intestinal epithelium. Account for ~90% of phase I for common drugs.
What are the three main families of the CYP450 complex?
CYP1, CYP2, CYP3
What is the function of most CYPs?
Inactivate drugs. Rarely needed for activation.
Which CYP gene is needed to activate codeine into morphine?
What is the role of TPMT in terms of drug metabolization?
Just another way to metabolize
What is an important CYP3A substrate, inhibitors (2), and inducer?
CYP3A substrate: cyclosporine
Inhibitor: grapefruit juice & ketoconazole
What are two important substrates of CYP2D6? Three important inhibitors?
Substrates: Tricyclic antidepressants, codeine
Inhibitors: Fluoxetine, Quinidine, Paroxetine
What is an important substrate of CYP2C9?
What is an important substrate of the NAT gene?
Isoniazid for tuberculosis
What are two important substrates for TMPT?
6-mercaptopurine & 6-thioguanine; cannot give juvenile leukemia patients standard dose of these because it is fatal due to immunosuppression
What are two important substrates of G6PD? What is its mechanism?
Sulfonamide antibiotics & Dapsone. X-linked enzyme.
Those who are deficient in G6PD are susceptible to what after drug exposures?
If a patient has hemolytic anemia after a drug exposure, what are they most likely deficient in?
G6PD gene products
What is an important substrate of VKORC1 gene?
What is the medication Warfarin used for? What is its usual starting dose?
Blood thinner; 5mg