genetics review learning objectives

7/29/2019 genetics review learning objectives

1/6

Lecutre 1: Chromosomal Abnormalities1. Describe the molecular components of human chromosomes.2. Explain the mechanistic basis for congenital (condition present at birth) chromosomal abnormalities.3. Name human diseases caused by chromosomal abnormalities and their karyotypes.4. Define the terms provided in the "Basic Terminology" section of the notes.

Lecture 2: Gene Functions1. Describe the basic transcription machinery, the basic structure of genes (including promoters) and

transcription units, and the basic mechanism of transcription in eukaryotes.2. Discuss the roles of transcriptional activator proteins, enhancer elements, coactivators, andchromatin in regulation of eukaryotic transcription.

3. 3. Describe the cellular response (or signal transduction) pathway used by steroid hormones and listthe major hormones which interact with members of the nuclear receptor family.

4. Explain why agonists promote gene activation by steroid receptors, but antagonists inhibit steroidreceptor function.

5. Discuss the roles of steroid receptors and their agonists/antagonists in the etiology and/or treatmentof breast cancer.

Lecture 3: Gene Expression1. Understand and be able to state the basic steps of mRNA processing2. Understand how RNA processing can help regulate gene expression and stimulate biological

diversity3. Be able to explain how mistakes in RNA processing could lead to human disease

Lecture 4:1. Be able to describe the principle of mRNA translation and explain the degeneracy of the genetic

code2. Understand and be able to summarize the general steps of translation3. Be able to explain how aberrant translation can play a role in human disease: * splicing

mutations/frameshift changes4. The role of nonsense-mediated mRNA decay * aminoglycoside antibiotics/deafness

Lecture 5: DNA Replication1. Identify therapeutic agents that affect DNA replication and the basis for their activity2. Describe how defects n DNA repair and replication lead to common and rare diseases

3. Name diseases whose pathogenesis (cellular events and reactions and other pathologicmechanisms occurring in the development of disease) is related to inherited or acquired defects inDNA repair and replication

4. Define the terms provided in this handout

Lecture 6/7: Mendelian Genetics1. Interpret pedigree information and recognize Mendelian inheritance patterns2. Explain Hardy-Weinberg equilibrium and apply it to solving problems relevant to genetic counseling3. Define the terms provided in these handouts and recognize their clinical correlates4. Illustrate general principles of Mendelian inheritance based on attributes of human disorders

Lecture 8: Human Genome Projects1. Cite the relative abundance of the different classes of sequences in the human genome discusses in

this lecture

2. Explain basis for the observed differences in the genetic variation in different human populations3. Recall the relative abundance of different classes of medically important sequence variants in a

healthy persons genome4. Define haplotypes and discuss their application in Genome Wide Association Studies5. Explain the complex disease: common variant hypothesis and the results of GWAS studies relevant

to the hypothesis

Lecture 9: Epigenetics1. Explain the term epigenetics and how it differs from genetics


2/6

Epigenetics: mitotically or meiotically heritable alterations in phenotype that are not based on DNAsequence (for example DNA methylation and histone modification). Passes on what TYPE of cell adaughter cell should become. Epigenetics are similar (in one cell type) from person to person)powerful force in determining phenotypes and human disease.Mechanisms: DNA methylations, histone modifications, chromatic structure and nucleosomalpositioning , non-coding RNAs, TF regulatory networks

2. Explain the concepts of epigenetic writers, readers, erasers, remodelers, and insulatorsWriters: establish epigenetic mark

Readers: interpret epigenetic markErasers: remove epigenetic markRemodelers: shift nucleosomes aboutInsulators: separate epigenetic domains

3. Define and give specific examples of the role of epigenetics in Mendelian disordersInherited defects in epigenetic regulators:

-ICF (Immunodeficiency, centromeric instability, facial anomalies syndrome: mutation inDNMT3B (DNA methylation writer)

-Rett syndrome mutation in MECP2 (DNA methylation reader)-Kabuki Syndrome (MLL2 histone methylation writer)

Monoallelic Gene Expression and Genomic imprinting only one of two homologous alleles areexpressed (ex: X- inactivation, genomic imprinting)Uniparental disomy 2 copies of a chromosome from one parent and none from other

-Angelman syndrome- 2 paternal copes if UBE3A mental retardation

-Prader-Willi Syndrome 2 maternal copies-Bechwith- Wiedmann Syndrome 2 paternal of IGF2

4. Define and give specific examples of the role of epigenetics in cancerSystemic silencing or predisposition to silencing of MSH2 DNA repair gene predispose to colorectalcancerEpigenetic silencing of tumor suppressor genes found in many types of cancer

5. Be aware of ongoing research of the role of epigenetics in other common diseases

Lecture 10:Mitochondiral

Lecture 11: Gene Therapy1. Understand why gene therapy can be called DNA as a drug2. Describe basic principles of retroviral vectors

3. Explain why HSC are a good target for certain gene therapies4. Understand that gene therapy can be more than just a treatment for genetic diseases, but also

infectious disease (HIV) and cancer5. Describe challenges facing this field of medicine

Lecture 12: Forensic Uses of DNA1. Discuss common forensic DNA techniques including short tandem repeats, mitochondrial DNA, Y-

chromosomes STRs, restriction length polymorphisma. Short tandem repeats DNA region with short repeat units of 2-6 bp.

i. Steps:1. Extract DNA2. Quantify3. Amplify using PCR with florescent proteins

4. Capillary Electrophoresis of sample recording using argon laser5. If math present, calculate probability of math occurring by chanceii. Number of repeats at each loci vary In people (receive one copy from mom and one

from dad), many different allelesiii. FBI uses 13 STR core as a standard panel

1. 12 autosomal, 1 on either x or y chromosome ( amelogenin)b. Mitochondrial DNA

i. The DNA found in mitochondria the energy-producing organelles of cells is oftenanalyzed to trace evolutionary pathways. Mitochondrial DNA (mtDNA) has a high"substitution" or mutation rate, compared with other sites in our genome.

ii. mtDNA is transmitted only from mother to child, and can be inherited intact overthousands of generations.


3/6

1. Mutations in the mtDNA sequence can be used to reconstruct the maternallineage of populations. assed through the egg of the mother at fertilization.egg has about 50,000 mitochondria whereas the sperm have just a few, andthose that do enter the egg are actually destroyed, so mitochondria and theirDNA are inherited exclusively from the mother.

iii. Typing results are expressed as differences from a standard sequence (theAnderson sequence)

iv. Highly degraded samples contain more mtDNA than nuclear DNA

v. mtDNA more variable than nuclear DA so exclusions mayvi. The entire mtDNA genome is inherited as a single locus, so it varies less betweenindividual

c. Y chromosomes STRsi. The Y chromosome is passed only from father to son, and can be used to trace the

evolutionary histories of men. The Y chromosome is more than 50 million DNA basepairs long and has 220 genes.

ii. Mutations at particular locations on the Y chromosome can be used to reconstructthe paternal lineage of populations.

iii. Used in sexual assault cases, or in paternity cases where alleged father is notavailable

iv. Can type a male relative who is paternally related to the alleged fatherd. Restriction length polymorphism

i. Steps:

1. Digest DNA with restriction enzymes2. Separate fragments by length using electrophoresis3. Transfer DNA to a membrane (Southern blot)4. Hybridize membrane to a labeled DNA probe

ii. Technique is obsolete because it is very time consuming and requires a lot ofsample

2. Explain calculations based on Hardy-Weinberg Equilibriuma. Assumptions for a population to be in Hardy-Weinberg equilibrium

i. Population is infinitely largeii. Mating is randomiii. Population is free from effects of migrationiv. There is no natural selection

v. No mutations occurb. For a population in equilibrium with two genes occurring at frequencies p and q

i. Probability of a homozygote is p2 or q2ii. Probability of a heterozygote is 2pqiii. When you have multiple alleles, you multiply the probabilitiesiv.

3. Give case examples of forensic uses of DNAa. Identify unknown sample

i. Locard Principle: every contact leaves a traceb. Molecular autopsy: cause of death

i. Long QT syndrome in sudden cardiac death or unexplained drowningii. Cytochrome p450 mutations in drug toxicity,iii. Alpha-tropomyosin in hypertrophic cardiomyopathy

iv. hereditary thrombophilia (protein C deficiency) in pulmonary embolismc. Paternity testingd. Missing persons/mass disasterse. Military usesf. Convicted felon database

i. Data housed in CODIS (Combined DNA Index System) which is a standardizedsystem of 13 STR loci

g. Historical investigation

Lecture 13: Genomes and Medicine1. Discuss strengths and limitations of genetic testing in adults2. Describe the technological basis for non-invasive fetal genome sequencing


4/6

a. Non invasive fetal genome sequencing takes advange of the fact that 13% of ell free DNA inplasma of pregnant female is fetal in origin

b. DNA is sequenced and computational alanlzy required to discrimbate between thesequences derived from mother and fetus

c. False positives are common3. Cite genotype-specific therapies for Mendelian disorders

a. Missense Mutation therapy point mutation causing change in one amno acidi. CFTR G551d reaches cell surface but defective chloride transport

ii. Ivacaftor potentiates CFTR channel activity by binding to proteinb. Nonsene Mutations convert codon to a premature stop codon, which causes nonsensemediated decay

i. CF and Duchenne Muscular Dystropy (DMD)ii. Nonsense suppressor therapies: drugs that promote the read through of stop

codonsiii. PTC124 binds ribosome to promote read through and prevent NMD

Only increases read through by a little bitc. Frameshift mutation therapies: insertion or deletion of base pairs, to shift reading frame and

eventually produce a premature stop codoni. Duchenne Muscular dystrophy (DMD) X linked recessive disorder that results in

progressive weakening and loss of muscle funticon Caused by mutations in DMD gene (dystrophin) DMD exons are deleted

or duplicated (huge protein)

Dystrophin: stabilizes and links the muscle fiber cytoskeleton the membraneand renders muscles fibers more resistance to mechanical strength

ii. Exon skipping terapy chemically modified antisense oligonucleotide (AO) binds toand masks specific splice junctions

Goal is to alter splicing so that mutant exons are removed whilepersevering the correct open reading frame

Produces truncated but partially functional proteind. Chronic myelogenous leukemia (CML) therapies

i. Philadelphia chromosome present in cancer cells reciprocal translocation betweenchromosomes 9 and 22

ii. Produces a bcr-abl fusion gene that produces unregulated tyrosine kinase leadsto CML

iii. Imatinib blocks the tyrosine kinase activity of bcr-abl and results in decreased

cancer growthiv.

4. Recognize and recall examples of pharmacogenomic applications in cancer therapiesa. Pharmacogenomics studies how all of the genes (the genome) can influence responses to

drug. Pharmacogenomics is the study of how genes affect a persons response to drugs.This relatively new field combines pharmacology (the science of drugs) and genomics (thestudy of genes and their functions) to develop effective, safe medications and doses that willbe tailored to a persons genetic makeup.

b. Pharmacokinetic effects - the movement and change of drugs in the body over a period oftime. Genetic variation in processes involved in the absorption, distribution, metabolism, orelimination of a drug can result in changes in drug availability. genetic polymorphisms lead tovariations in the levels or concentrations of drugs or their metabolites at the site of action.

i. Ex . Colorectal cancer: Treated with Irinotecan (topoisomerase inhibitor)

ii. UGT1A1 processes active metabolites of irinotecaniii. seven TA dinucleotide repeats instead of six repeats in the promoter region ofUGT1A1 less UGT1Ai enzyme produced lower enzyme activity decreasedrate of drug metabolism (more active metabolite floating around) more toxicity

iv. Rate of toxic effects associated with irinotecan (diarrhea and myelosuppression) isincreased in patients with seven TA dinucleotide repeats

c. Phmacodynamics and Drug Response, the study of the biochemical and physiologicaleffects of drugs and the mechanisms of their actions. Genetic variation in drug targets cancause measurable differences in the response of an organism to a drug. Data in thiscategory document that the biological or physiological response to a drug varies, and thatthis variation can be associated with the variation of one or more genes. This variation isoften measured at the whole-organism level.


5/6

i. Ex: Non-small cell lung cancer: EGF normally binds EGFR to promote cell growth,but mutations causes out of control growth

ii. Treat with Gefitinib which is a kinase inhibitor blocks kinase activity of EGFR effectively shuts down the cancers ability ot replicate quickly

iii. Nonsmall-cell lung cancer tumors with activating mutations in the EGFR tyrosinekinase domain are more sensitive to Gefitinib treatment. These are somaticmutations acquired during tumorigenesis

iv. tumor genome plays a critical role in the response to gefitinib since the sensitivity of

nonsmall-cell lung cancer to this drug is enhanced by activating mutations in thekinase domain of the gene encoding epidermal growth factor receptorv. TumorEGFRencoding activating mutations within the kinase domain results in

enhanced tumor sensitivity to Gefitinib

5. Describe drug rescue and drug repurposing efforts for rare disordersa. NCATS initiative: find novel drug therapies for rare diseasesb. Drug rescue: involves small molecules and biologics whose development was abandoned

before the could be approved by FDAi. rescuing a drug that wasnt deemed effective for its intended purpose but was

deemed safe for human usec. Drug repurposing: involves small molecules and biological approved to treat a disease or

condition to see if the are safe and effect ive for treatingother diseasei. repurposing a drug that is already used in practice but it is hoped that it can be used

to treat another disease as well

Lecture 14: Genetics Counseling1. Define genetic counseling and integration into different clinical settings

a. The process of helping people understand and adapt to the medical, psychological andfamilial implications of the genetic contributions to disease

b. Goal: to promote informed choices and adaptation to the risk or conditionc. Integration in medicine

i. Family Planning/Prenatal: risk for genetic diseaseii. Pediatric: failure to thrive, developmental delaysiii. Adult: predisposition to adult onset

2. Describe three psychosocial considerations relevant to genetic testing and diseasea. Prenatal and preconception testing

i. Chronic sorrow refers to the difficulty resolving the sense of loss that comes fromthe birth of a child with a syndrome or congenital defect. Also, can refer to the lossassociated with terminating a pregnancy.

b. Pediatrici. Impact on child

1. Self-image2. stigmatization

ii. Impact on parents1. Shame and guilt2. Interpersonal relationship strain

iii. Impact on siblings1. Deprivation of paternal attention2. Fear and embarrassment

c. Adulti. Impact on patient1. Fear of disease development2. Image of self

ii. Impact on family1. Survivor guilt - refers to the guilt experienced by an individual who tests

NEGATIVE for a known family mutatio2. Unified-divided front against disease

iii. Availability of treatmentiv. Insurabilityv. Reproductive issues and family planning

3. Define ELSI and GINA


6/6

a. ELSI Ethical, Legal, and Social Implications arising from the Human Genome Project -Major point: privacy and confidentiality

i. Fairness in the use of genetic information by insurers, employers, courts, schools,adoption agencies, and the military, among others.

ii. 2. Privacy and confidentiality of genetic information.iii. Psychological impact and stigmatization due to an individual's genetic differences.iv. Reproductive issues including adequate informed consent for complex and

potentially controversial procedures, use of genetic information in reproductive

decision making, and reproductive rights.v. Clinical issues including the education of doctors and other health service providers,patients, and the general public in genetic capabilities, scientific limitations, andsocial risks; and implementation of standards and quality- control measures intesting procedures.

vi. Uncertainties associated with gene tests for susceptibilities and complex conditions(e.g., heart disease) linked to multiple genes and gene-environment interactions

vii. Conceptual and philosophical implications regarding human responsibility, free willvs. genetic determinism, and concepts of health and disease.

viii. Health and environmental issues concerning genetically modified foods (GM) andmicrobes.

ix. Commercialization of products including property rights (patents, copyrights, andtrade secrets) and accessibility of data and materials.

b. GINA Genetic Nondiscrimination Information Act, passed in 2008

i. Genetic discrimination refers to concerns about being treated differently by anemployer or insurer because an individual has a genetic condition or are at risk ofhaving an inherited disorder.

ii. GINA Does:1. Prohibits the use of genetic info to determine eligibility or to adjust

premiums/contributions2. Prohibits employers from firing, refusing to hire, or from other workplace

discriminations based on genetic infoiii. GINA Does Not:

1. Mandate coverage for any particular test or treatment2. Prohibit medical underwriting based on current health status3. Cover life, disability, or long-term care insurance4. Apply to members of the military

4. Discuss one pro and one con to the clinical integration of next generation sequencinga. Personalizedrisk assessmentb. Creates potential to address riskc. For some, less anxiety and stressd. Possibility to alert and involve other at-risk family memberse.

Lecture 15: Newborn Screening

Lecture 16: Problem Sovling

genetics review learning objectives

Documents