Exam 2: Genetics Flashcards

Question

Prenatal Testing Flow Chart

Answer 1

A change in the DNA of the cells that form gametes. Perpetuated from one generation to the next. Responsible for inherited diseases.

Answer 2

A change in the DNA of body cells. Doesn't affect germ cells. Does not affect future generations.

Answer 3

* **Point mutations** ⇒ SNP * **Errors in replication and repair** * Indel (insertion/deletion) variations * Copy number variations (CNV) * Satellite ⇒ 20-100K+ BP * Minisatellite ⇒ 10-20K BP * Microsatellite ⇒ 2-100 BP

Answer 4

* **Errors introduced during normal DNA replication** * ~ 1 mutation for every 2 cell divisions * Mutation rate at given locus varies * Mutational hot spots * **Base changes induced by endogenous or exogenous mutagens**

Answer 5

An agent that increases the spontaneous mutation rate by causing changes in DNA. Ex. hydrolytic and oxidative damage, chemicals, UV or ionizing radiation

Answer 6

Based on effect on DNA sequence OR the encoded protein. * **Classified by effect on DNA** * Insertions * Deletions * Substitutions * Inversions ⇒ 180° rotation of DNA segment * Translocations * Chromosomal rearrangements * **Classified by effect on the gene or protein's function** * Transcription * Translation * Protein function

Answer 7

* **∆ in promotor** ⇒ ∆ in mRNA expression * decrease or "prevent" expression * complete or partial * **heterochronic expression** ⇒ wrong time * **ectopic expression** ⇒ wrong place * **∆ in mRNA** ⇒ impacts RNA processing and half-life * RNA splicing mutations * interfere with transcription/translation * alter RNA stability * **∆ in protein coding regions** ⇒ ∆ translation and protein function * missense * nonsense * frameshift

Answer 8

A point mutation in DNA alters the codon ⇒ replacement of one AA by another Conservative ⇒ no significant change in function

Answer 9

Mutation causes codon to go from coding for AA to a stop codon. Leads to truncated protein. Ex. nonsense mutation in NF1 gene in neurofibromatosis

Answer 10

Caused by deletions and insertions not in a multiple of 3. Alters the reading frame of all downstream codons. Usually leads to a stop codon and truncation of the protein. Examples: ABO alleles ⇒ 1 bp deletion ⇒ changes A to O Tay-Sachs ⇒ 4 bp insertion

Answer 11

∆F508 3 BP deletion Lost residue prevents normal folding ⇒ retrograde destruction. Clinical picture is the same as the "null" allele phenotype.

Answer 12

* Promoter mutation ⇒ inc or dec RNA polymerase affinity * ↓ mRNA production ⇒ ↓ [protein] * Mutations in transcription factors or enhancer sequences * ∆ expression pattern of the gene

Answer 13

RNA processing mutations * **RNA integrity/function** * cap sites * polyadenylation sites * **RNA splicing** * ∆ in consensus sequences * splice donor or splice acceptor site * interfere with or abolish splicing * activation of cryptic sites * create new alternative donor or acceptor site * Ex. Tay-Sachs * mutation in donor site of Hexosaminidase A gene * translation into the intro often resulting in termination at stop codon

Answer 14

**B^o allele** from nonsense and frameshift mutations have no function. **_Creation of a cryptic splice site_** G→A of first intron creates abnormal splice acceptor site 90% of mRNA made using incorrect splice site 10% made with correct splice site **"Leaky" mutation results in B⁺ allele**

Answer 15

Base substitutions outside of coding sequences can interfere with transcription/translation. * Mutation in 5' UTR of factor IX gene * Results in 1/3 the normal amount of clotting activity

Answer 16

* Dynamic mutations * expansion of a segment of DNA containing a repeat nucleotide sequence * shows amplification * can be in coding sequence or 5' and 3' UTR

Answer 17

* deletion or duplication of hightly similar or identical DNA sequences * usually a multigene family with members in a tandem head-to-tail organization * members of the family misalign during sister chromosome pairing during meiosis * causes unequal crossing over ⇒ gene loss or duplication

Answer 18

Complete/partial gene deletion: * **Silent carrier** (_alpha-thalassemia minima_) ⇒ aa/a- * small amount of abnormal Hb detected in peripheral blood * possible mild hypochromia and microcytosis * no anemia and/or clinical manifestations * **Alpha-thalassemia trait** (_alpha-thalassemia minor_) ⇒ aa/-- or a-/a- * mild anemia * RBC hypochromic and microcytic * clinical sx usually absent * detected by Hgb electrophoresis and microscopic exam of peripheral RBCs * important to know phenotype because can have offspring with a-/-- or --/-- * **Hemoglobin H disease** (_alpha-thalassemia intermedia_) ⇒ a-/-- * moderate to severe anemia * elevated reticulocyte count * HbH inclusion bodies * Most live normal life * 25% need transfusion at some point * **Hemoglobin Bart syndrome** (_alpha-thalassemia major_) ⇒ --/-- * profound anemia * **hydrops fetalis** ⇒ abnormal accumulation of fluid in two or more fetal compartments * often leads to intrauterine death or death shortly after birth * increased complications of pregnancy for mother

Answer 19

Gene duplication: * 70% with type I CMT have 1.5 x 10⁶ duplication ⇒ **3 copies of PMP22 gene instead of 2** * **increased gene dosage** ⇒ demyelination ⇒ progressive atrophy of distal limb muscles

Answer 20

**Reciprocal translocation** (9;22 - Philadelphia Chromosome) **Chimeric protein** formed from ***Bcr*** gene and ***c-Abl*** gene Aberrant expression of Abl and altered intracellular localization

Answer 21

The result of non-wild type gene products having less or no function. * Recessive traits * Heterozygotes ⇒ no discernible abnormal phenotype * Wild-type allele can mask effects of abnormal allele * Dominant traits * Heterozygotes ⇒ has a discernible abnormal phenotype * Called haploinsufficiency * Normal phenotype requires protein product of both alleles * Reduction of 50% of gene function ⇒ abnormal phenotype

Answer 22

**A mutation whose gene products adversely affects the normal, wild-type gene product within the same cell.** * Usually occurs when abnormal product can still interact with the same elements as the wild-type. * Usually with multimeric proteins. * Usually have dominant phenotypes.

Answer 23

**Mutation that alters the biochemical pathways by increasing one or more of the normal functions of the gene product.** * Usually have dominant phenotypes * Can be due to enhancing one function or increasing production/half-life of the gene product * Dec. degradation * Inc. catalytic activity * Inc. copy number of gene

Answer 24

Mutation that confers a new property on the gene product, without necessarily altering the normal function. Can occur with AD or AR diseases.

Answer 25

**Mutations that alter regulatory regions causing gene to be inappropriately expressed.** Expression at the wrong place ⇒ **ectopic mutation** Expression at the wrong time ⇒ **heterochronic mutation**

Answer 26

**Germ-line inheritance of a non-functional + somatic mutation of the only functional copy in 1 cell.** "Two-Hit" mechanism Explains why individuals can inherit diseases in an autosomal dominant manner despite needing the loss of both alleles. Ex. neurofibromatosis and BRCA-1 or -2

Answer 27

**Lack of LDL receptors** AD Displays **haploinsufficiency** * hh ⇒ normal [LDL receptors] ⇒ normal phenotype * Hh ⇒ 1/2 [LDL receptors] ⇒ atherosclerosis in 30's and 40's * HH ⇒ no LDL receptors ⇒ atherosclerois very early, heart attack in teens to 20's, Xanthomas

Answer 28

Mutation in gene for one of the two α₁-chains of collagen. Autosomal Dominant * **Type I** * **null mutation** in one of the α₁ genes * nonsense, frameshift * abnormal protein unable to combine with α₂ * 50% normal procollagen made * **haplosinsufficiency** * **Type II** * **missense mutation** in one of the α₁ genes * slightly abnormal protein still able to interact with α₂ * make only 25% of normal protein * **dominant-negative effect** * **all de novo mutations** because disease is lethal in infants

Answer 29

**Duplication** of PMP22 gene on chromosome 17. Autosomal dominant **Gain-of-function mutation** of peripheral myelin protein Progressive demyelination of peripheral nerves ⇒ peripheral muscle weakness and atrophy

Answer 30

**Point mutation** in FGFR3 gene ⇒ ligand independent activation Autosomal dominant **Gain-of-function mutation** of FGFR3 Inhibits chondrocyte proliferation within growth plate.

Answer 31

**Trinucleotide expansion** in HTT gene Autosomal dominant **Novel property mutation** Shows genetic **anticipation** \>36 copies ⇒ Huntingtin protein aggregation ⇒ nuclear inclusions in neurons ⇒ neuronal atrophy and death ⇒ uncontrolled movements, emotional disturbance, loss of cognition, death

Answer 32

**Translocation** of BCR from chromosome 9 to 22 **Chimeric BCR/ABL** Philadelphia chromosome Autosomal dominant **Heterochronic & ectopic gene expression** **Gain-of-function mutation** **Novel property mutation**

Answer 33

**Missense mutation** in β-hemoglobin gene Autosomal recessive **Novel property mutation** Aggregation of globin in deoxygenated state ⇒ sickle shaped RBCs

Answer 34

The process of identifying disease-associated/causing genes.

Answer 35

Loci are physically connect to one another along the chromosome. Independent assortment does not apply.

Answer 36

The actual combination of the individual alleles on the chromosome. Alleles are often inherited together. Haplotype arrangements designated: A1 B2 / A2 B2

Answer 37

**Uses the rate of recombination between two linked loci to estimate the distance between them.** Used to **ID disease-causing genes** and to **track single gene disorders within a family**. * Two genes are close together on a chromsome ⇒ usually inherited together, unless a recombination event separates them * Odds of a recombination event between two linked genes are inversely proportional to the distance between them * Measured using **centiMorgans (cM)** * **1 cM ⇒ distance where two loci recombine 1% of the time** * 1 cM equivalent to ~ 1 million base pairs * Crossing over more frequent with oogenesis

Answer 38

Logarithm of the odds score. **Tool used to analyze the probability of co-segretation and linkage.** Recorded as log₁₀. Strong evidence **for** linkage ⇒ **Lod score +3** ⇒ 1000:1 odds for linkage Strong evidence **against** linkage ⇒ **Lod score -2** ⇒ 100:1 odds against linkage

Answer 39

**DNA marker located near the disease-causing gene.** Allows tracking of the disease-causing allele through families. * **RFLPs** (restriction fragment length polymorphisms) * **SNPs** (single nucleotide polymorphisms) * **VNTR** (variable number tandem repeats)

Answer 40

1. Know the disease and its inheritance pattern 2. Use informative marker(s) near the disease-causing gene that allows tracking 3. **Determine the linkage phase for the disease** * Which marker is associated with the disease-causing allele

Answer 41

* Functional cloning * Candidate gene cloning * Positional gene cloning * Positional-candidate gene cloning

Answer 42

Limited to diseases where a biochemical defect can be determine and the protein isolated. **Limitation ⇒ need to know deficient protein or enzyme to identify the gene.**

Answer 43

**Begins with an educated guess of which genes are involved.** Look for mutations that are associated with the disease. **Limitation ⇒ need to know the normal mechanism and all of the genes in the pathway.** Compare gene sequences or gene expression patterns between affected and unaffected individuals.

Answer 44

**Look for disease-causing genes/alleles by identifying areas in the genome that appear to be linked to a specific trait or disease.** Uses linkage mapping. DNA from families with affected members ⇒ track thousands of markers ⇒ **ID chromosomal regions that cosegregate with disease/trait via LOD score** ⇒ ID region chromosome ⇒ look for recombination events ⇒ **DNA sequence analyzed and sequenced** **Strength** ⇒ track phenotypic trait without knowing the cause underlying the trait. No biochemical or functional info about the gene needed. **Weakness** ⇒ works well on high-penetrance, single gene traits and diseases. Need pedigrees of related individuals and a phenotype that is present in some but not all family members.

Answer 45

* Use the same technique as positional gene cloning * Track markers in families with affected people * Enter chromosomal region into DNA database * ID potential genes of interest * ID genes in that area and extrapolate which genes are likely responsible * Once potential gene identified and cDNA identified, sequence both affected and unaffected members for differences

Answer 46

Compare DNA from people with the disease and similar people without the disease. Used for low penetrant genes responsible for multifactorial disorders. * Do not require large pedigrees * Search subject's genomes for **markers that occur more frequently in people with disease** than without * SNP or other variations * Uses **microarrays or SNP chips** * Variations are said to be "**associated**" with the diease * may not directly cause the disease * might be marking the nearby causal variant * need more research to confirm role of variant

Answer 47

Uses microarray analysis. Track expression of new and unidentified genes in different tissues. Commonly used with high-speed sequencing. Look at differentially expressed genes to understand role in normal function and pathogenesis.

Answer 48

Once one or more potential genes identified, need to determine if gene is involved in disease development: 1. **ID if gene expressed in an expected tissue pattern** * **assess mRNA exression pattern** * northern blot * PCR of cDNA * high-throughput RNA sequencing * **assess protein expression** * western blot * immunofluorescence * biochemical assay 2. **ID mutations in patients but not unaffected family members** 3. **Dissecting role of gene in normal function** 4. **Determine how different mutations affect gene function and cause disease** * evaluation of patients with the disease * creating genetically modified animals

Answer 49

* ID all genes in human DNA * Determine sequences that make up human DNA * Improve tools for data storage and analysis * Transfer related tech to private sector * Address ethical, legal, and social issues

Answer 50

The study of the **complete set of chromosomal and extra-chromosomal DNA/RNA** of an organism, cell, organelle, or virus.

Answer 51

The study of **total messenger RNA expressed** in a cell or tissue at a **given point in time**.

Answer 52

The systematic study of **all proteins present** in a genome, cell, tissue, or organism.

Answer 53

The study of the **unique chemical fingerprints of** **specific cellular processes** through the **quantification of small-molecule metabolite profiles** (ex. NADH, ATP) in a given tissue or cell type of an organism.

Answer 54

The simultaneous **measurement of thousands of molecular components** (transcripts, proteins, metabolites) and the **integration of that data with clinical end points**, in a biologically relavant manner. Model can be applied to disease.

Answer 55

* Genotyping * Determine disease susceptibility * Measure efficacy of treatment * Forensic analysis * Genetic linkage analysis

Answer 56

**Application of information technology to molecular biology.** Databases, algorithms, and stat tools ⇒ manage, analyze, and interpret biological data

Answer 57

Genetic Information Nondiscrimination Act * **Prohibits use of genetic information in:** * health insurance * employment decisions * **Does not prevent discrimination if:** * individual has signs or symptoms * individual receives a diagnosis of a genetic disease * **Does not apply to:** * life insurance * disability insurance * long-term care insurance * Patients can sometimes ask to not include genetic testing info in medical record

Answer 58

Specific **endonucleases** that recognize certain **recognition sequences** and **cut the sugar-phosphate backbone of DNA**. Sequences are typically **palindromic**.

Answer 59

Alterations in the digestion pattern of homologous genomic DNA by a specific restriction enzyme caused by polymorphisms.

Answer 60

Detect specific sequences in genomic **DNA**. 1. DNA digested with a restriction enzyme 2. Seperated via gel electrophoresis 3. DNA transferred onto blotting membrane 4. Probe labeled and allowed to hybridize with DNA

Answer 61

* Detect significant changes in DNA * translocations * insertions/deletions * Analysis of RFLP

Answer 62

Analyzes **RNA**. 1. RNA extracted 2. Seperate by gel electrophoresis * Oligo (dT)-coated beads often used to seperate out mRNA via poly(A) tails 3. Gel contents transferred to a blotting sheet 4. Labeled probes used to visualize bound targets

Answer 63

* Examine specific gene expression levels * different tissues * developmental stages * response to drugs * under pathological conditions * Measure the actual size of mRNAs * look for splice variants or aberrant splicing patterns

Answer 64

Analysis of **proteins**. * Protein samples obtained * Seperated via gel electrophoresis * Transferred to blotting sheets * Proteins visualized with labeled antibodies.

Answer 65

* Confirmatory diagnosis of diseases * HIV infection * Bovine spongiform encephalopathy * Lyme disease * Protein analysis

Answer 66

* Four deoxy nucleotides and small amount of single dideoxy nucleotide used * Chain elongation continues until dideoxy nucleotide incorporated * Obtain DNA chains of differing lengths * DNA chains seperated by size using electrophoresis * Sequence is determined by reading gel from smallest to largest

Answer 67

* Single reaction with all four dideoxy nucleotides * Each ddNTP has a **different fluorescent group attached** * Reaction allowed to run to completion * Mixture seperated by **capillary electrophoresis** * Labeled chains detected by **fluorometer** * Read colors as they pass through the detector

Answer 68

DNA bases identified as small fragments that are synthesized off of a template. * DNA degraded into small fragments * Adaptor molecules added to each end of fragments * DNA amplified with PCR and gel purified * DNA library placed into flow cell * Attach to flow cell via adaptor molecules * Radiolabeled nucleotides allowed to hydridize with DNA fragments * Flow cell visualized and clusters analyzed * Data interpreted with bioinformations to determine sequence

Answer 69

Determines the complete DNA sequences of an organism's genome. Includes nuclear and mitochondrial DNA.

Answer 70

Sequencing all of the **protein-coding regions** in a genome. ~ 1.5% of genome encodes for exons. Less expensive and quicker. Misses changes in the non-coding regions.

Answer 71

Uses **oligonucleotide primers** that flank target DNA region. Three step cycle: 1. **Denaturation** * Reaction heated to melt dsDNA in ssDNA 2. **Annealing** * Reaction cooled to allow primers to bind to DNA 3. **Elongation** * DNA synthesis using primers to start replication * Uses thermostable DNA polymerases

Answer 72

Detection and quantification of mRNA in a sample. 1. Use **reverse transcriptase** and primer to anneal and extend mRNA 2. Transcribes a complimentary strand of DNA (**cDNA**) 3. PCR used to amplify targer sequences in cDNA

Answer 73

PCR-based technique. Used to detect SNPs, short deletions or insertions. Need to know the exact mutation and where to look. 1. PCR amplifies DNA containing site of interest 2. DNA spotted many times onto solid matrix * Sometimes beads used 3. Hybridized with ASO probes * Short probes of 15-20 BP * Sensitive to even single-base pair mismatches 4. Matrix analyzed

Answer 74

Primers flank the unstable region containing trinucleotide repeat. DNA amplified using PCR. DNA seperated by size via gel electrophoresis. Correlate size to phenotype/risk.

Answer 75

* **Microsatellites and simple sequence repeats** * number of copies highly variable * highly polymorphic between homologous chromosome and between individuals * **Primers used that flank regions** * **PCR ⇒** **gel electrophoresis** * Used for: * genetic mapping * linkage analysis * trace inheritance patterns * ID uniparental disomy * ID specific individuals through DNA fingerprinting

Answer 76

**Simultaneous amplification of multiple exons in a single PCR.** Used to detect the loss of one or more exons in the gene of interest. Does not pick up missense, nonsense, or frameshift mutations. **Always start with the affected individual.** * **Primer pairs** used ⇒ covers different regions of the gene * Produce PCR products of differing sizes * **Lack of a particular PCR product** usually means **significant structural changes** in DNA

Answer 77

1. Gene expression profiling 2. Chromosomal microarray analysis (CMA) 3. Single nucleotide polymorphism (SNP) analysis 4. Antibody microarray 5. Microbial pathogen detection 6. Alternative splice site detection

Answer 78

Expression of multiple genes simultaneously monitored. Steps: 1. **Create/obtain DNA microarray** * Contains multiple **ssDNA sequences** from **coding strand** of multiple genes 2. **Isolate and purify mRNA** from multiple samples * One usually serves as a control for comparison 3. **Reverse transcribe, PCR, and label** each mRNA with a different color 4. **Cohybridize** equal amounts of cDNAs on array 5. **Scan array and quantitate signal** to relative amount of cDNA binding 6. **Interpretation**

Answer 79

* Identifies **duplicated or deleted chromosomal material and copy number variants** (CNVs). * microdeletions & microduplications * abnormal chromosome numbers * trisomy & monosomy * unbalanced rearrangements * translocations * excessive homozygosity * triploidy * Does not detect: * point mutations * very small duplications/deletions within a single gene * trinucleotide repeats * balanced chromosomal rearrangements * balanced translocations * inversions

Answer 80

1. Create/obtain DNA microarray * multiple ssDNA sequences from various regions throughout genome 2. Isolate multiple DNA samples * Sample of interest and control 3. Amplify with PCR 4. Label each sample 5. Cohybridize with DNA 6. Scan microarray and quantitate signal for relative [cDNA] 7. Interpretation

Answer 81

Autonomously replicating extrachromosomal piece of DNA found in bacteria. Common vector.

Answer 82

A molecular technique used to make specific, targeted changes in DNA sequence.

Answer 83

(r-DNA produced medical proteins) **Proteins made through biological processes inside host cells.** Most common systems involve bacterial hosts or eukaryotic cell lines. Undergo 3 basic steps: 1. Transfecting the gene of interest into host cells 2. Expressing large quantities of the product 3. Harvesting/purifying the product

Answer 84

Preferred for **non-glycosylated, non-post-translationally modified recombinant proteins**. Typically uses a **plasmid** vector. Ex. human insulin Generics called **biosimilars**.

Answer 85

Recombinant protein production and purification from eukaryotic cells significantly more difficult and more expensive. Ex. erythropoietin (EPO)

Answer 86

* **Transgene injected into pronucleus of embryo** * Shortly after fertilization * Before fusion of male and female pronuclei * Transgene **randomly integrated** into genome * Genetic changes occur in a random manner * Creates a **transgenic animal** (usu mouse) * Mouse **mated with other mice** to create a transgenic line of **"genetically identical" animals**

Answer 87

* **Pluripotent embryonic stem cells (ES)** modified in tissue culture * Via **homologous recombination** into site of interest * Modified ES ce**lls injected into an early embryo** ⇒ **chimeric embryo** * Embryo implanted into uterus of female mouse and allowed to develop into mouse pups * Some tissues derived from modified ES cells ⇒ **chimeric animal** * If changed gene is **in the germ-line**, it will **propogate** through generations * **Selective breeding** can result in animals homozygous for transgene

Answer 88

Gene modification resulted in the deletion or inactivation of the existing targeted gene.

Answer 89

Gene modification resulted in a modification of the gene tht changed the function of the gene/protein.

Answer 90

Adding, disrupting, or changing the sequence of specific genes through use of the **CRISPR/Cas9-mediated system**. Uses Cas9 protein and guide RNA. Genome can be cut at any desired location. Precise point mutations can be made.

Answer 91

The replacement of a defective or diseased cell population by transplantation of normal cells from an unaffected donor. Includes solid organ, bone marrow, and embryonic stem cells.

Answer 92

**The transfer of genetic material into the patient's cells to treat disease.** Process known as **transfection**. Can be broken down into type of tissues impacted and how procedure is done. Several approaches are being tested: 1. Replacing a mutated gene with a normal one 2. Inactivating the abnormal gene 3. Introducing a new gene

Answer 93

**Modifies the genes in the somatic cells of a single individual.** Not passed on to future generations. Currently practiced.

Answer 94

**The permanent modification of genes found in germ cells.** * Techniques like transgenics, knockout, and knock-ins * Would be transmitted to future generations * If done during preimplantation dx or IVF ⇒ impacts all cells of embryo * Currently ethically unacceptable * Some mitochondrial-replacement techniques are used

Answer 95

**Transfer of the gene outside of the body.** * **Process:** * Cells removed from the patient * Cells transduced in vitro with vector carrying therapeutic gene * Cells returned to the patient * **Advantages:** * can control which cells are altered * high transduction efficiency * **Disadvantages:** * difficulty in removing enough cells * hard to re-engraft cells back in * usually limited to hematopoietic stem cells and cancer * **Examples:** * Familial hypercholesterolemia ⇒ liver cells * SCID ⇒ bone marrow cells * Cancer ⇒ transfecting tumor cells and CAR modification of T cells

Answer 96

Transfer of the gene within the individual to cells inside the body. * **Advantages:** * can access virtually any site * **Disadvantages:** * difficult to control dosage * difficulty delivering enough therapeutic vector to target tissue without toxicity to other tissues * risk of dissemination of vector throughout the body * risk of germline contamination * **Examples:** * Angiogenin gene * Dystrophin gene * Inborn errors of metabolism * Hemophilia B * Lipoprotein lipase deficiency

Answer 97

1. Safe and efficient transfer of the gene 2. High-level appropriately regulated stable gene expression

Answer 98

1. **Safe and extended delivery of DNA** * Transfection often very **inefficient** * Transfection **difficult with large pieces** of DNA * Many vectors **toxic** to host cells and induce **immune responses** * May vectors **do not integrate DNA** into host cells * Retroviral vectors do promote random integration but has risks * **loss of function** of critical genes * protooncogene ⇒ oncogene ⇒ **cancer** 2. **Promoting appropriate expression of inserted genes** * difficult to transfer entire human genes * size * **impact of location on transcription** * usually use transgene

Answer 99

A method to deliver target DNA into cells.

Answer 100

* _Types:_ * **Naked DNA** * **DNA coated gold particles** * **Liposomes** * DNA enclosed by vesicles * _Benefits:_ * **Minimal immunogenicity** * Does not require specific receptors * _Can deliver large DNA sequences_ * _Disadvantages:_ * **Low efficiency of transfection** * **Transient expression of DNA**

Answer 101

Virus enters cells ⇒ genome reverse transcribed ⇒ enters nucleus of **dividing cells only.** Viral DNA **randomly integrates** into the host genome. * _Benefits:_ * **High efficiency** * **Integration into host DNA** * **long term expression** * **expression in daughter cells after mitosis** * _Disadvantages:_ * **Random integration into host genome** * may disrupt cellular genes ⇒ **insertional mutagenesis** * associated powerful regulatory elements may **alter expression of endogenous genes** * Very limited DNA size that can be carried

Answer 102

* _Process:_ * Binds to receptor and internalized in endosome * Viral expression from **episomal (extrachromosomal) elements** * Replication blocked in "gutless" adenovirus * Some **specificity** with insertion point (chromosome 19) * _Benefits:_ * **Infects both dividing and nondividing cells** * _Disadvantages:_ * **Transient expression** * No integration * High doses often **toxic and significantly immunogenic**

Answer 103

Piece of DNA or gene that usually has been created in a lab and incorporated into an organism's genome through genetic engineering. **Promoter attached to the cDNA.** - Tissue specific promotors - Promotors with high activity - Drug sensitive promotors

Answer 104

1. Draw the pedigree 2. Determine the disease 3. Determine the inheritance pattern 4. Determine what information you need to calculate 5. Apply each of these to the HW equilibrium 6. Calculate answer

Answer 105

1. **Non-random mating** * Stratification * Assortive mating * Consanguinuity 2. **Selection** * Negative selection * loss of fitness * Heterozygote advantage 3. **Mutation** * Assumes no new mutations * Mutations occur at virtually all loci 4. **Small population size** * genetic drift * frequency of allele changes with generations * drifts p=1 or p=0 5. **Gene flow** * migration

Answer 106

Probability of inheriting two copies of the same allele from an ancestor that occurs on both sides of the pedigree.

Answer 107

"Genetic bottleneck" A small group breaks off from a larger population to form a new colony. Leads to reduced genetic variation. Non-random sample of genes ⇒ can significantly alter allelic frequency.

Answer 108

* _Inheritance & Pathogenesis:_ * **Autosomal dominant** * **Single gene mutation** * 80% de novo * Only in paternal germline * Constitutive activation of **FGFR3** ⇒ **dysplasia** of cartilage to bone in growth plate * Shows p**aternal age effect** * _Major Phenotypic Features:_ * **Rhizomelic** **short stature** * Megalencephaly * Spinal cord compression

Answer 109

* _Inheritance & Pathogenesis:_ * Chromosomal * Nondisjunction or anaphase lag in paternal gamete results in 2 copies of Y and one X * Paternal age effect * _Major Phenotypic Features:_ * Normal at birth * Subsequent tall stature * Cognitive development normal but educational difficulties * Radial-ulnar synostosis

Answer 110

* _Inheritance & Pathogenesis:_ * **Multifactorial** * Spontaneous chromosomal deletion * Uteroplacental insufficiency * Teratogens * _Major Phenotypic Features:_ * **Poor growth** * **Increased nuchal fold** * **Dysmorphic facies**

Answer 111

* _Inheritance & Pathogenesis:_ * **Autosomal dominant** * Chromosomal * Position-effect **translocation of Sonic Hedgehog** * Loss of SHH ⇒ abnormal embryological developmental patterning * _Major Phenotypic Features:_ * **Ventral forebrain maldevelopment** * **Facial dysmorphism** * **Developmental delay**

Answer 112

* _Inheritance & Pathogenesis:_ * **X-linked** * **Expansion of CGG repeat** in 5' UTR region of **FMR1** gene * \> 200 repeats ⇒ hypermethylation and supression * **Sex specific anticipation** * Only maternal transmission of premutation alleles * Paternal transmission can actually dec. repeats * FMRP protein chaperone some mRNAs for translation * _Major Phenotypic Features:_ * **Intellectual disability** * **Dysmorphic facies** * Male post-pubertal macroorchidism

Answer 113

* _Inheritance & Pathogenesis:_ * Multifactoria * Abnormal insulin secretion and insulin resistance * _Major Phenotypic Features:_ * Hyperglycemia * Relative insulin deficiency * Insulin resistance * Obesity * Acanthosis nigricans

Answer 114

* _Inheritance & Pathogenesis:_ * **Autosomal dominant** * **Single gene mutation** of CHD7 * Abnormal gene product affects chromatin structure and gene expression during development * Haploinsufficiency * _Major Phenotypic Features:_ * **C**oloboma of eye * **H**eart defects * **A**tresia of the choanae * **R**etardation of growth/development * **G**enital abnormalities * **E**ar anomalies * Facial palsy * Cleft lip * Tracheoesophageal fistula

Answer 115

(16p11.2 Deletion Syndrome) * _Inheritance & Pathogenesis:_ * **Autosomal dominant** or **De Novo** * **Contiguous gene deletion** on 16p11.2 * 25 genes in region * Pathogenesis unclear * Can show **copy number variant** * _Major Phenotypic Features:_ * **Varied intellectual disability** * **Impaired social and communication skills** to frank **autism** spectrum d/o * Minor dysmorphic features

Answer 116

* _Inheritance & Pathogenesis:_ * **Chromosomal** * **Complete or partial monoploidy X** * Non-disjunction or loss of function * Haploinsufficiency * _Major Phenotypic Features:_ * **Short stature** * **Ovarian dysgenesis** * **Sexual immaturity**

Answer 117

* _Inheritance & Pathogenesis:_ * **Autosomal recessive** * **Single gene mutation** * **Locus heterogeneity** * Abnormal α-globulin or β-globulin of Hb * Inadequate Hb production ⇒ hypochromia and microcytosis * Unbalanced globulin accumulation ⇒ hemolytic anemia, ineffective erythropoiesis * _Major Phenotypic Features:_ * **Hypochromic microcytic anemia** * **Hepatosplenomegaly** * Extramedullary hematopoiesis

Answer 118

* _Inheritance & Pathogenesis:_ * **Autosomal recessive** * **Single gene disorder** * Missense mutation in **hemoglobin β subunit gene** * Abnormal Hb w/ dec. solubility of deoxygenated Hb **⇒** polymers that distort RBCs * Heterozygote advantage for malaria * _Major Phenotypic Features:_ * A**nemia** * **Infarction** * **Asplenia**

Answer 119

* _Inheritance & Pathogenesis:_ * **Y-linked** * SRY mutation * **Chromosomal** * Translocation of SRY region on Y chromosome * Lack of functional SRY gene ⇒ 46,XY phenotypic female * _Major Phenotypic Features:_ * **Sterility** * Need two X chromosomes for oocyte maintenance * Lack of azoospermic factors ⇒ abnormal sperm * **Reduced secondary sex features** * Unambiguous **genitalia** **mismatched** to chromosomal sex

Answer 120

* _Inheritance & Pathogenesis:_ * **Autosomal dominant** * **Single gene mutation** * Genetic heterogeneity * 85% w/ ADPKD1 mutation * 15% w/ ADPKD2 mutation * Some with neither * Likely due to mislocalization of cell surface proteins * _Major Phenotypic Features:_ * **Renal and hepatic cysts** * **Progressive renal failure** * Intracranial saccular aneurysms * **Mitral valve prolapse**

Answer 121

* _Inheritance & Pathogenesis:_ * **Autosomal dominant** * **Single gene mutation** in LMNA gene * Abnormal lamin A ⇒ nuclear instability ⇒ premature cell death * _Major Phenotypic Features:_ * **Aged appearance** in childhood * **Failure to thrive** * Alopecia * **Facial dysmorphia** w/ beak nose * Indurated skin with dyspigmentation * Early cardiovascular disease / osteoporosis

Answer 122

* _Inheritance & Pathogenesis:_ * **Autosomal dominant** * **Single gene mutation in NF1** * Acts as a tumor suppressor gene * Results in abnormal cellular proliferation * Pleiotropy & variable expressivity * _Major Phenotypic Features:_ * **Café au lait spots** * **Lisch nodules** * Cutaneous and subcutaneous **neurofibromas** * Increased risk for malignancies and learning disabilities

Answer 123

* _Inheritance & Pathogenesis:_ * **Autosomal dominant** * **Expansion of CAG repeats** in HD gene * Mutant HD protein causes **progressive degeneration of neurons**, esp. in movement centers * Neuronal dysfunction and death * Sex-specific anticipation * _Major Phenotypic Features:_ * **Movement** abnormalities * Involuntary jerking or writhing movements (**chorea**) * **Cognitive** abnormalities * **Psychiatric** abnormalities

Answer 124

* _Inheritance & Pathogenesis:_ * **X-linked recessive** * **Single gene mutation** * Locus heterogeneity * Lack of Factor VIII or IX impairs clotting * _Major Phenotypic Features:_ * **Bleeding** * Hemarthroses * Hematomas

Answer 125

* _Inheritance & Pathogenesis:_ * **X-lined recessive** * **Single gene mutation** * Malfuntional G6PD ⇒ low [NADPH] ⇒ low [reduced glutathione] ⇒ **oxidative stress** ⇒ Heinz bodies ⇒ rigid **RBC's that hemolyze** * Heterozygote advantage against malaria * _Major Phenotypic Features:_ * **Hemolytic anemia** * **Neonatal jaundice**

Answer 126

**Trisomy 18** * _Inheritance & Pathogenesis:_ * **Chromosomal** * **Nondisjunction** or **anaphase lag** (Chromosome 18) * **Translocation types rare** * **Mosaicism** with milder phenotypes * _Major Phenotypic Features:_ * Growth retardation * **Polyhydramnios** * **Microcephaly** * Congenital malformations * **Clenched hand with overlapping fingers** * Hypotonia initially with hypertonia * Severe intellectual disability

Answer 127

* _Inheritance & Pathogenesis:_ * **Chromosomal** * **Abnormal chromosome # in multiples of 23** * Triploidy = 69 n * Tetraploidy = 92 n * Dispermy, Digyny, Diandry, Mosaicism * _Major Phenotypic Features:_ * **Intrauterine growth retardation** * Placental molar changes * Multiple congenital abnormalities * **Fetal mortality**

Answer 128

**XXY Males** * _Inheritance & Pathogenesis:_ * **Chromosomal** * Non-disjunction or anaphase lag in mom or dad * 2 copies of X chromosome and 1 Y * **Paternal age effect** * _Major Phenotypic Features:_ * Small testicles ⇒ **sterility** * Tall stature * **Gynecomastia** * Specific learning disability * Possible **behavioral and emotional problems**

Answer 129

* _Inheritance & Pathogenesis:_ * Chromosomal * **Nondisjunction or anaphase lag** (chromosome 21) * **Robertsonian translocation** (14q21q) or (21q21q) * _Major Phenotypic Features:_ * **Extra nuchal folds** * **Delayed development** * Small size * Hypotonia * Single palmar crease * Large/protruding tongue * Congenital heart disease

Answer 130

* _Inheritance & Pathogenesis:_ * **Chromosomal** * **Deletion (5p-)** * **Continuous gene syndrome** on the short arm of chromosome 5 * _Major Phenotypic Features:_ * **Cat-like cry** * **Severe intellectual disability** * **Microcephaly** * Low birth weight * Round face * Hypertelorism (wide set eyes) * Low set ears * Epicanthal folds

Answer 131

* _Inheritance & Pathogenesis:_ * **Autosomal recessive** * **Single gene mutation** * Deletion **SMN1 gene** (mostly * Degeneration and loss of anterior horn cells of spinal cord and brain stem * # of gene copies, # and type of mutations act together (epistasis) * _Major Phenotypic Features:_ * **Progressive weakness and muscle atrophy** * **Life expectancy \< 2 years**

Answer 132

* _Inheritance & Pathogenesis:_ * **Chromosomal** * **Microdeletion (chromosome 15)** * Absence of **_maternally_** derived chromosome ⇒ **uniparental disomy** * _Major Phenotypic Features:_ * **Severe intellectual disability** * Ataxic gait * Seizures * **Inappropriate laughter**

Answer 133

* _Inheritance & Pathogenesis:_ * **Matrilineal** * **Mitochondrial** * \>90% with point mutation in tRNA^lys gene * ↓ [tRNA^lys]_mito ⇒ ↓ translation and ↑ termination * Complexes I and IV of ETC most effected * _Major Phenotypic Features:_ * **Myopathy** * **Dementia** * **Myoclonic seizures** * Ataxia * Deafness

Answer 134

* _Inheritance & Pathogenesis:_ * **Chromosomal** * **Microdeletion (chromosome 15)** * Absence of **_paternally_** derived chromosome ⇒ **uniparental disomy** * _Major Phenotypic Features:_ * Infantile feeding difficulties * **Childhood hyperphagia and obesity** * **Hypotonia** * **Cognitive impairment** * Short stature * Dysmorphism

Answer 135

**Trisomy 13** * _Inheritance & Pathogenesis:_ * **Chromosomal** * **Nondisjunction** or **anaphase lag** (Chromosome 13) * **Robertsonian translocation** * _Major Phenotypic Features:_ * **Microcephaly** * Holoprosencephaly * **Cleft lip and cleft palate** * **Polydactyly** * Profound intellectual disability * Multiorgan abnormalities

Answer 136

* _Inheritance & Pathogenesis:_ * **Multifactorial** * Polygenic * Susceptibility vs protective alleles * Environmental trigger * **Autoimmune destruction of islet β cells of pancreas** ⇒ insulin deficiency ⇒ metabolic abnormalities * _Major Phenotypic Features:_ * **Hyperglycemia** * Polyuria, polydipsia, polyphagia * **Ketosis** * **Wasting**

Answer 137

* _Inheritance & Pathogenesis:_ * **Autosomal recessive** * **Single gene mutation** * Shows allelic & locus heterogeniety * Dysfunction of **CFTR anion channel** ⇒ malfunction of mucus producing organs * _Major Phenotypic Features:_ * **Progressive pulmonary disease** * **Exocrine pancreatic insufficiency** * Obstructive azoospermia ⇒ male infertility * Growth failure

Answer 138

* Multifactorial * 3 SNP variants in NOD2 gene increase likelihood * NO2 2 is a receptor that normally binds bacteria * Autoimmune * Sx: * episodic abdominal pain * hematochezia * ulcerations and fistulas

Answer 139

* Allelic heterogeneity * AD and AR versions * Frameshift mutation in GJB2 gene (2/3 of cases) ⇒ AR * Congenital deafness w/ AR * Progressive childhood deafness w/ AD

Answer 140

* X-linked recessive * Mutation within DMD gene * Large deletions or duplications * SNP's * High frequency of new mutations * Sx: * childhood onset muscle weakness * calf pseudohypertrophy * mild intellectual compromise * Growers maneuver * myopathy

Answer 141

* X-linked dominant * High level of variable expressivity * Some heterozygous females no sx * SNP in OTC gene * Error in urea cycle * build-up of AA catabolites * Arg becomes essential AA * Males with null mutation have neonatal onset * Sx: * hyperammonemia * floppy * lethargic * poorly controlled breathing and body temp * seizures * coma

Answer 142

* Multiple pathogenetic mechanisms * Chromosomal with imprinting * Autosomal dominant rare * Panethnic and sporadic * Imbalance of imprinted genes on 11p15 * Sx w/ prenatal onset * overgrowth * macroglossia * omphalocele * visceromegaly * embryonal tumors * renal abnormalities * adrenocortical cytomegaly * hypoglycemia

Answer 143

* Autosomal recessive * SNP in ACADM gene * Abnormal fatty acid oxidation * build up of FA metabolites * Loss-of-function mutation * Age of onset 3-24 months * Sx: * hypoketonic hypoglycemia * vomiting * lethargy * hepatic encephalopathy

Answer 144

* **Autosomal domiant** * **Trinucleotide repeat expansion in 3' UTR** * Locus heterogeniety * DMPK gene mutation ⇒ Type 1 * CNBP gene mutation ⇒ Type 2 * Gene expressed in heart, skeletal muscle, and brain * Novel property mutation * unstable region in mRNA clumps inside cells and intereferes with production of other proteins * Sx: 20-40 y/o at onset * Myotonia * Hypotonia * Typical pattern of muscle wasting * starts in jaw and neck muscles * Cataracts early * DM * Developmental delay

Answer 145

* **X-linked dominant** * **Loss of function in MECP2 gene** * codes nuclear protein that normally silences DNA * mutation results in inappropriate activation of target genes * **99% of presentations are de novo** * Sex dependent phenotype * Female prevalence * Neonatal to early childhood onset * **Acquired microcephaly** * **Decelerated head growth** * Neurodevelopmental regression * Repetitive hand movements

Answer 146

* Autosomal recessive * Most common lysosomal storage disease * GBA1 gene ⇒ beta-glucosidase * Childhood to early adulthood onset * hepatosplenomegaly * anemia * **thrombocytopenia** * Bone pain * Erlenmeyer flask deformity * short stature

Exam 2: Genetics Flashcards

(176 cards)