Genetics Exam 3

A man begins to show symptoms of Alzheimer's Disease in his early 40s and by his mid-40s he cannot perform tasks such as brushing his teeth. He has one biological son. What is the chance that his son will develop AD, too? 0% 100% 25% 50%

50%

A DTC service, such as 23andme, indicates that Jane has a SNP that is a genetic risk factor for hypothyroidism. The SNP has an odds ratio (OR) of 1.5. The average population risk of developing hypothyroidism is 4%. Based on this information, what is Jane's overall risk of hypothyroidism? 4% 1.5% 5.5% 6%

6%

Jane's mother had Familial Adenomatosis Polyposis (FAP), a colon cancer syndrome caused by mutations in the APC gene. Jane has been diagnosed with colon cancer and analysis of the cancer cells indicates that they have the mutated APC gene. Jane's colon cancer is most likely: a result of Jane's smoking habit a result of a sporadic mutation in APC a result of a germline mutation in APC the result of a mutation in the APC gene that is only present in the colon cells

a result of a germline mutation in APC

Recognize the technical challenges and ethical concerns of gene therapy

1. Delivering healthy genes to correct cells (getting it where it needs to go) 2. Controlling gene expression (controlling when it should be turned on and off) A major challenge is getting the gene into the cells. There are physical and chemical methods, but the most common uses biological approaches. This takes advantage of a natural factor that is extremely good at infecting human cells - viruses. viral vectors posed a serious threats to gene therapy. They can trigger the immune system, and can also integrate into chromosomes and activate proto-oncogenes. These two issues caused a series of tragic setbacks and a suspension in many gene therapy trials. Gene therapy has resumed only just recently. Gene therapy is getting safer. There are new delivery methods, such as safer viral vectors.

A GWAS on Barrett's Esophagus (BE) reports a risk factor with an OR of 2.5. What does this mean? An individual who inherits that risk factor has a 2.5 increased risk of developing BE than someone without the risk factor if you inherit that risk factor, you have a 2.5 % chance of developing BE 2.5% of the population has BE If one inherits the risk factor, he/she will develop BE in 2.5 years

An individual who inherits that risk factor has a 2.5 increased risk of developing BE than someone without the risk factor

Which of the following circumstances describe a genetic screen as opposed to a genetic test? Select ALL that apply. An individual has symptoms that are consistent with a rare genetic disease and needs confirmation An individual is a newborn and her blood is being analyzed for inborn errors of metabolism An individual whose mother has a BRCA 1 mutation wishes to determine her own BRCA 1 status. An individual is of Ashkenazi Jewish descent and is being evaluated as a carrier for several genetic diseases prevalent to individuals with this background

B and D

If you plot out the BMIs (body mass index) of a population of individuals, we would expect to get a bell-shaped curve. Based on this distribution alone, what do we know about the genetics of body mass index? BMI is controlled by a single gene BMI is controlled by the action of more than one gene, each with an equal contribution BMI is not under genetic control BMI is controlled by the contribution of more than one gene, each with varying degrees of impact

BMI is controlled by the contribution of more than one gene, each with varying degrees of impact

Studying the microbiome includes the analysis of: all parts of the human genome that encode protein human DNA in microorganisms DNA from microorganisms in the human body genes that contribute to or control metabolism

C

Jane needs an antidepressant. Prior to prescribing a specific antidepressant and dosage, her medical team first determines Jane's genotype for a gene involved in antidepressant metabolism. This is an example of: Select ALL that apply. pharmacokinetics recombinant DNA technology pharmacogenetics precision medicine

C and D

Recognize role of cell cycle control in maintaining the balance between proliferation and differentiation

Cancer cells are defined as disorganized tissue growth, or neoplastic - an abnormal proliferating mass. It has lost its nice organized structure. There is a net increase in number of dividing cells. Tumors lose the balance between cell proliferation and cell differentiation. As cells differentiate, they begin as stem cells that become more highly specialized into their fully differentiated self through division. Cancer cells travel down a pathway of unrestricted cell division. Cancer cells are dedifferentiated and are less specialized than their normal counterparts (they actually resemble immature stem cells). They lose their function and travel down a path of unrestricted cancer cell division. What happens when cells lose control of the cell cycle and ignore the checkpoints? Cancer. Cancer cells escape the controls of the normal cell cycle. Cancer cells divide rapidly, often in the absence of growth factors. They do not need growth factors to replicate. In cancer, they do not need these growth factors. Growth is not inhibited by other cells, and tumors form (benign remaining in the original site and malignant metastasizing). Cancer can result from mutations in genes that play a role in controlling cell division.

Recognize how comparative genomics identifies biologically important regions of the genome

Comparative genetics is a field that studies the genomes among different species and searches for similarities and differences in the genome. Genomic regions with a higher percent of identity regions are called conserved regions and are thought to be biologically important because the more conserved a species is, the more important they are to the biology and vitality of the organism and species itself. For example, in a honeybee colony all bees are 100% genetically identical, yet they vary in their functioning roles. Epigenetics causes this role variation because of how the genes are turned on or off in t more important they are to the biology and vitality of the organism and species itself. For example, in a honeybee colony all bees are 100% genetically identical, yet they vary in their functioning roles. Epigenetics causes this role variation because of how the genes are turned on or off in the bees.

Distinguish between DTC genome scans, exome and whole genome sequencing

DTC companies can provide a few different types of services for one to receive their genomic information using genome scans of a limited number of SNPs. The SNPs are ones that are associated with some known phenotype and are identified as a risk factor. There are multiple providers of this service, but they only provide insight into less than 1% of your genome. Exome sequencing provides 3% of your genome sequence. Genome sequencing services give you the entire genome sequence, but are considerably more expensive at this stage but price is declining rapidly. Currently, only one or two providers of this service exist. Right now, a company has broken the 1000$ barrier, offering whole genome sequencing for $999. Both genome scans and genome-sequencing services are paid for individually and can be obtained without any medical professional input. DTC providers are not regulated like providers of genetic tests - it is a little bit of a risk.

Identify ELSI issues stemming from personal genomics and DTC providers

DTC personal genome services can have a lot of ethical and legal gray areas associated. First off, whose DNA is being tested (you can figure out a way to get DNA from a spouse, parent, child without consent and claim it as your own)? Who owns the data and who can see the results? Can the company give the data to third parties, such as investigators? Some people have concerns whether this is this a luxury or expenditure? Or an exercise in vanity when so little utility can come from this new information? The service is not overseen by the medical professional, so who interprets (or over interpret) results? Personal genomics challenges us with many ELSI issues some are expected and others are unexpected. 1. D evelop policies for genetic discrimination 2. U ncover the relationship among genomics, race, ethnicity, and understand the consequences of that relationship -is there a biological definition of race? 3. W hat are the consequences of uncovering genomic contributions to traits and behaviors - such as intelligence, or addictions? There is a genetic role in these behaviors and environmental influence. How will we balance these and understanding their weight? 4. H ow to define ethical boundaries for the use of genomics? For example, in reproductive genetic testing sometimes embryos will be genetically tested if they have lethal alleles, but what if it used to assess athletic performance as well? Is this ethical?

Identify genomics-based approaches to researching and detecting cancer

Microarray expression reveal a pattern or profile of thousands of different genes and whether they are turned on or off in various conditions. This is commonly done in cancer, where gene expression profiles are compared to their cancer tissue. Each gene that is unusually expressed in cancer (either over or under expressed) is a potential target for telling us what particular gene is playing a role in cancer development and becomes a potential target for treatment. Cancer research and using genomics in the fight against cancer is a huge part of the cancer medicine initiate. Traditionally to treat cancer, there is surgery where cancerous tissue is removed and cut out of the body. There is also radiation and chemotherapy. These methods are still the "go-to" for cancer. They can attack/target cells that are rapidly dividing, but also means they can damage healthy cells, leading to all the devastating side effects. These treatments can be effective, but are blunt in their side effects. We can take what we know about genomics and create more targeted and personal treatments. One way is to use the phenotype to select a drug. One example of this is in women who have a particular kind of breast cancer and have positive estrogen receptors can take a drug that attaches to these receptors, inhibiting the cancer. Genotypes can also be used to select drugs. Women that express HER2-positive cancers are given a particular personalized drug for treatment. GWAS - genome wide association studies are one approach, such as the Cancer Genetic Markers of Susceptibility where the national cancer institute that is looking for risk factors which increase susceptibility to cancer. Large scale sequencing of cancer genomes, exome sequencing, and ctDNA are all other methods as well. cell-free tumor DNA (ctDNA). This is very similar to cell free DNA analysis used for prenatal testing. Little bits of DNA break off of tumor cells causing small pieces of tumor DNA to be present in bloodstream of patients. A blood draw can isolate DNA and identify it, therefore it is a noninvasive approach to sequencing tumor DNA from blood. The amount of ctDNA correlates with cancer stage - the less ctDNA found, the less severe the cancer; the more ctDNA found the more severe/progressed the cancer. The further along you are, the more ctDNA is found. It can be used for detection, staging, and treatment (how does a drug affect tumor). They look at ctDNA before and after treatment. This helps to indicate whether a patient's cancer is resistant to certain chemotherapy or other treatments. It has the nickname "liquid biopsy". It is estimated that alterations in 3-7 genes are necessary in the establishment of cancer. If you are born with an alteration in a key gene, then you are one step closer to tumor development. This multistep nature of cancer is a prominent theory in cancer biology - it guides a lot of cancer research! The karyotype of cancer cells looks sporadic. There are missing chromosomes and trisomy in other places. There are large-scale duplications, deletions, and rearrangements can be observed by karyotype. Inactivating telomerase is a significant area of research and was thought to be the magic bullet for the treatment of cancer several years ago.

Determine the appropriate genetic test or screen based on clinical information and distinguish the differences between them

Tests are ordered by a health profession because of a patient's history, symptoms, or circumstances (e.g age of parents) and are usually specific for a condition or set of conditions. They are considered targeted because there is a reason behind it. A screen, though, is not based on a specific medical reason other than that a member of a specific population. The best example of this is a newborn screening. All newborns are screened in general because they are a part of the newborn population. Prenatal testing: • • • • Sperm Selection - cell sorting used to increase the likelihood of having either son or daughter. Techniques sort sperm cells for those with or without Y-chromosomes. It is used to enrich the population and is used in in-vitro population. This is very valuable and important if X-linked disorder is present in family history. If you have an X-linked recessive disorder in the family, you can use this method to enrich/increase the likelihood of having a daughter because there is less of a chance for them developing the disorder. Preimplantation Genetic Diagnosis (PGD) - also used for in-vitro; when an embryo in the 8 cell stage, before implantation in uterus, one cell can be removed for genetic analysis. Researchers will determine if there is an inherited Mendelian disorder or genetic mutation. If it is considered to be genetically healthy, the embryo can be implanted into a women, but if there is disease present, it will not be implanted into a women. An embryo starting from the 7th cell stage at implantation can develop in a healthy way. NIPT, Maternal Serum Markers, Amniocentesis, CVS - testing a fetus for genetic disease. Non-invasive prenatal testing (cell-free fetal DNA), maternal serum markers, amniocentesis, CVS (chorionic villi sampling) are all ways to test a fetus for a genetic disease and are usually chromosomal abnormalities. Recent studies now indicate that cfDNA sequencing is better at detecting trisomies than amniocentesis and CVS. They are non-invasive. It is more accurate at detecting, but has a high false positive rate. It is used more as a prenatal screen currently. The recommendation is to continue using NIPT but follow up with diagnostic amniocentesis. Rescue Karyotyping - used to detect CNVs (copy number variants - too small to be detected by karyotypes, but bigger than single-based variations/SNPs) to assess risk for future pregnancies or to reveal aneuploidies. It can involve single to millions of nucleotides and vary from individual to individual. They contribute to genetic diversity and variation in the human population. They are associated with disorders, but what researchers are currently doing is taking tissue from woman after a miscarriage and can do rescue karyotyping to determine her risk of future pregnancies having disorders, or reveal any aneuploidies that are present that could have caused the miscarriage in the first place. They are useful for unexplained pregnancy losses. (1) Newborn Screening - The purpose of newborn screening is to identify newborns at high-risk for certain inherited diseases. These diseases (50 or so) of these conditions are "actionable" because the treatments and services can be provided to increase the quality of life. A heel stick is performed for blood, and the baby is analyzed for biochemicals, which are products of genes that may be missing in important metabolic pathways and DNA. (2) Newborn Genome Sequencing Ongoing pilot studies are occurring to determine feasibility of sequencing ENTIRE genome of newborns to replace newborn screening panels. A baby is born, with the heel stick, you can sequence the entire genome! Chromosome Microarray Analysis (CMA) detects copy number variants (CNVs) that are associated with autism, developmental delay, intellectual disability, behavioral problems, and other phenotypes. A patient's DNA can be collected and compared to the DNA on an array. If the child has too much of one section of a genome, or too little of a genome section. It detects the copy number variants that are too small to be karyotyped. Exome sequencing is sequencing just the coding regions of genes (just the exons of an individual. This can reveal rare mutations that cause disease. Dor Yeshorim: carrier tests for Jewish genetic diseases; preconception sickle cell disease: test athletes; carriers at risk for symptoms Comprehensive carrier testing: up to 500 tests for heterozygotes for single-gene diseases; preconception population carrier screen: tests for heterozygotes for diseases more prevalent in certain population groups ancestry testing: Y chromosomes and mitochondrial sequences point to geographic origin; DNA markers identify distant cousins forensic testing: copy numbers of short tandem repeats in crime scene or disaster evidence military: identify remains risk for depression, PTSD, rapid infection diagnosis susceptibility: BRCA cancer, AD pharmacogenetics: drug efficacy, adverse effects, and dose genome-wide association studies: identify genes contributing small degrees to a phenotype paternity: half of a child's genome form father's genome centenarians: identify gene variants that extremely old people share

If someone is born with a mutation in one allele of a tumor suppressor gene (tsg), why are they almost certain to develop cancer? Their DNA is more prone to mutations from radiation than most individuals Their cells will acquire the second hit to completely deactivate both tag genes Mutations in tumor suppressor genes are often dominant The inherited mutation will promote apoptosis

Their cells will acquire the second hit to completely deactivate both tsg genes

What role do/could viruses play in treating genetic disease? Viruses can "wake up" an immune system that has been ineffective at battling a disease. Some viruses have healing properties by repairing damaged tissues. Viruses can transport drugs specifically to their targets so as to avoid a systemic reaction to a medication. Viruses can deliver healthy genes by their ability to infect human cells and integrate into their DNA

Viruses can deliver healthy genes by their ability to infect human cells and integrate into their DNA

In Alzheimer's Disease, tangles are formed: When microtubules clump together When beta amyloid fragments clump together When tau no longer supports microtubules When ApoE4 is not exported from the cell

When tau no longer supports microtubules

What is a mechanism cancer cells use to evade destruction by the immune system? commit cell suicide signal VEGF to initiate blood vessel growth express a cell surface protein that suppresses the action of immune cells mimic immune cells

express a cell surface protein that suppresses the action of immune cells

Most DTC services such as 23andme can be classified as ___ and are ____ by a medical professional.

genome scans; not ordered

Jane's aunt has chronic kidney disease, a multifactorial trait. You explain to Jane that her empiric risk of developing chronic kidney disease is ___ than the general population risk of chronic kidney disease because she has an aunt with the disorder whom she shares ___ of her DNA.

higher; 25% of her gene

To identify biologically important regions in a genome, researchers search for genomic regions that are ____ among ___.

highly conserved; different species

A nasal spray for cystic fibrosis patients, which contains adenovirus particles carrying a normal human CFTR gene, is an example of ___ gene therapy that targets ___ .

in vivo; somatic cells

An individual who is classified as an Intermediate Metabolizer of Warfarin probably: is heterozygous for a Cyp gene is homozygous recessive for a loss of function Cyp allele has a duplication of a Cyp gene that leads to increased expression

is heterozygous for a Cyp gene

Identifying specific bacteria that are associated with diseases versus bacterial species associated with health will be complicated because: microbiomes vary from day to day bacteria in humans are too rare to detect microbiomes vary among different people and different tissues healthy individuals do not have microbiomes

microbiomes vary among different people and different tissues

Individuals who inherit two copies of the ApoE4 allele are ___ likely to develop ___ Alzheimer's Disease, which is a ___ .

more; late onset; multifactorial disorder

Mutations in ___ help cancer cells to evade ___.

p53; death

Please match the description to the genetic test/screen. analysis of an individual to determine if they have an allele associated with an increased risk of disease analysis of an individual to determine if they have an allele that causes a disease analysis of an individual to determine if they are a carrier for a panel of recessive diseases analysis of a whole genome of a newborn

predisposition test predictive test preconception comprehensive carrier test newborn genome sequencing

Jane has BRCA1 associated breast cancer. Her sister Jill is healthy, but wants to know if she has inherited the BRCA1 mutation that could make her more likely to develop breast cancer. Jill is a candidate for a ___. If Jill has inherited a BRCA1 mutation, she has ___ risk of developing breast cancer.

predisposition test; 50 - 85%

What is the significant difference between genome scans and genome sequencing? genome scans are only offered to certain populations of individuals, whereas sequencing is only done to confirm a diagnosis scans only provide information about exons, whereas sequencing provides information about the entire genome scans provide info on a limited number of SNPs, whereas seqencing provides the entire genome sequence genome scans are ordered and interpreted by a health care professional, whereas genome sequencing is not

scans provide info on a limited number of SNPs, whereas seqencing provides the entire genome sequence

Which of the following is a non-invasive approach to detect, stage and monitor treatment of cancer? exome sequencing GWAS pharmacotherapy sequence analysis of circulating tumor DNA

sequence analysis of circulating tumor DNA

A couple would like to have a baby, but they are concerned that the baby may inherit a very serious X-linked recessive condition that is present in the mother's family history. Which of the following tests may be appropriate for this couple? sperm selection maternal serum marker analysis rescue karyotyping predictive test

sperm selection

Recognize the key characteristics and mechanisms of the 10 hallmarks of the cancer development process

1. uncontrollable growth: grow even in absence of growth signals. go right through the checkpoints. can make their own external growth factors and stimulate their division without activating an external signal. Ras photo-oncogene turns on a signal telling cell to divide and becomes locked in a proactive state, constantly transmitting a signal if it has a dominant mutation. 2. evading growth suppressors: mutations in pRB prevent it from inhibiting the growth cycle, loss of function. takes two mutant Rbs to knock out its function. mutations in TSGs like Rb, are recessive because it takes two copies to knock out its function. However, the cancer risk itself acts like a dominant trait. If you inherit one recessive allele of a TSG, then you are very likely to acquire the second mutation (90% likely) in your cells and you have a very high risk of developing cancer. Although you may only inherit one recessive allele, it acts like a dominant trait. 3. evading cell death: eve apoptosis by dialing p53, which is considered the gatekeeper for apoptosis, triggering it in response to DNA damage and other signals. 4. obtaining nutrients: angiogenesis. Tumors send out proteins called vascular endothelial growth factor to stimulate the growth of nearby endothelial blood vessels. 5. becoming immortal: as cells age and undergo divisions, the telomeres shorten. cancer cells find ways to activate telomerase, an enzyme that lengthens the telomere DNA and protects ends of chromosome form erosion. 6. invasion and metastasis: Cancer cells can overcome inhibitory signals and invade other tissues and migrate to distant sites in the body. This process is called metastasis. Cancer cells must activate the expression of many different genes to drill through the basement layer of tissue, enter the blood stream, exit the blood stream, and then reinvade a distant site. Few cancer cells survive this process, but it only takes a few cells to be successful. 7. Escaping Immune Destruction: Cancer cells do not display normal cell proteins on their surface (low immunogenicity). They are very abnormal looking. The immune system is constantly monitoring the body for irregular cells. However, to survive, cancer cells must escape detection by the immune system. Cancer cells devise clever strategies to evade the immune system (pictured right). As previously discussed, they do not display surface molecules (proteins). They have also developed ways to swallow the cell-surface antigens (molecules) to reduce changes of being recognized (antigenic modulation). Some cancer cells have figured out a way to activate surface certain proteins that suppress or deactivate helper T-cells, in turn suppressing the immune system (tumor induced immune suppression). Some cancer cells cover themselves in cell surface proteins called PDL-1 or PDL-2. When these cell surface proteins interact with cell surface receptors that extend off the T-cells, it causes activity of the T-cell to be suppressed and the cancer cell then continues to proliferate. 8. Reprogramming Metabolism: Cancer cells need a lot of fuel and have high energy demands because they are growing and proliferating so fast. They reprogram the energy pathways themselves in cells to ones that facilitate synthesis of new organelles and new amino acids necessary for cell reproduction. 9. Promoting Genomic Instability: The genomes of cancer cells differ from the genomes of normal cells. Cancer cell genes acquire mutations - they accumulate mutations over time!! They have gene deletions and gene duplications - all of this adds up to an unstable genome. 10. Tumor-Promoting Inflammation: Immune cells infiltrate tumors and result in inflammation. However, this inflammatory response can actually enhance cancer development and promote tumor growth. Immune cells can release growth factors, factors that help cancer cells to avoid death and proliferate and increase blood supply through angiogenesis. Inflammatory cells also release chemicals called reactive oxygen species that can cause mutations in nearby cancer cells and thereby enable the cancer to become even more aggressive. Even though cancer can stimulate the immune system response, if it happens to encounter it, cancer cells can manipulate immune functions to work in their favor, turning against the body and helping cancer to overtake it.

Please match the description of cancer cell activity with its hallmark. hijacking energy pathways in cell to synthesize more organelles drilling through tissue to enter bloodstream expressing telomerase knocking out all activity of a tumor suppressor gene

1. reprogramming metabolism 2. invasion and metastasis 3. becoming immortal 4. evading growth suppressors

Recognize the role of a genetic counselor and identify the primary reasons for visiting one

A genetic counselor is a health care professional who helps patients and families interpret and make decisions about genetic tests. This requires a Master's Degree, therefore it is an M.S. level position and there is a shortage. Genetic counseling addresses medical, psychological, sociological, cultural, and ethical issues so a genetic counselor must have medical, scientific, and strong communication skills. In a genetic counseling session, the genetic counselor will take the family history, construct a family pedigree, provide information on specific disorders, modes of inheritance, and tests to identify at-risk family members, arrange for testing and discuss any available results, provide links for support groups and other appropriate services, and provide follow-up contact. The two main reasons, though, why a family seeks genetic counseling: (1) Prenatal genetic counseling - counselor presents empiric and family-based risks, explains tests and helps to weight the risks vs. benefits of testing (amniocentesis vs. cfDNA). (2) Family history of inherited diseases - (typically include the rarer, Mendelian, or single gene disorders) counselors explain the mode of inheritance, risk of having an affected child, and predictive tests for the adult onset disorders.

Which of the following might a genetic counselor do as part of her job? Select ALL that apply. explain the inheritance of a specific genetic disorder in a family require a patient to take a genetic test evaluate risks of recurrence of a genetic disorder advise on genetic testing options take a DNA sample from a patient and family members

A, C, D

What is the major advantage of the CRISPR/CAS system as a gene therapy strategy? It can replace all of the disease causing SNPs of a multifactorial disorder in a single treatment It uses a safer virus based delivery mechanism It is ideal to treat diseases of unknown cause It can edit out and replace a specific mutation

It can edit out and replace a specific mutation

Recognize specific biological processes involved in Alzheimer's Disease

AD is an example of a Mendelian disease and a multifactorial genetic disease (complex disease). The causes of AD are a combination of genetics and lifestyle risk factors. In AD, the nerve cells die in areas for memory. Nerve cell connections are disrupted. As more brain cells die, the brain shrinks and memory is lost. During her autopsy, Dr. Alzheimer discovered abnormal structures that he described clumps in the brain (plaques) and tangled nerve bundles (tangles). These structures were later identified as the two hallmarks of AD - plaques and tangles. Beta amyloid plaques are abnormal structures. AD features a destruction of amyloid precursor proteins (APPs) protruding from a neuron. In cells you have proteins that protrude from the surface of the neuron. Normally enzymes cleave up these amyloid proteins, but in AD, they incorrectly cut up them up into pieces; one piece is called beta amyloid protein. These beta amyloid proteins clump together, forming plaques. Plaques form in areas that encode memories and are used in the decision process. The other hallmark is the tangles of neurons. Within a neuron, microtubules provide support and structure for the neuron. The protein, tau, supports and stabilizes these microtubules. In AD, tau proteins tangle together and result in a loss of microtubule stability. The microtubules disintegrate and eventually, the neuron dies.

Recognize what can be revealed in a whole genome sequence and limits of the interpretation

Analysis would reveal: mutations in known genes (carrier status), gene variants that affect drug responses, gene variants associated with multifactorial diseases and traits (risk factors), novel mutations, and copy number variants. It will determine the likelihood of their future children being afflicted by disease(s). Genetic risk of multifactorial disease can influence lifestyle choices now (diet, exercise, smoking). If you learn you are at higher risk for heart disease or diabetes, this can influence your lifestyle decisions now (e.g. diet, exercise, smoking, etc.). It can provide predictive genetic information, such as the allele for late onset Alzheimer's or breast cancer. One valuable aspect to having your genome sequenced is that it can provide a resource for future genetic discoveries. This means that anytime you hear about another genetic result that has identified a risk factor in a disease, you can look at your status every time a risk factor is identified to see whether or not you are at risk;will determine the likelihood of their future children being afflicted by disease(s). Genetic risk of multifactorial disease can influence lifestyle choices now (diet, exercise, smoking). If you learn you are at higher risk for heart disease or diabetes, this can influence your lifestyle decisions now (e.g. diet, exercise, smoking, etc.). It can provide predictive genetic information, such as the allele for late onset Alzheimer's or breast cancer. One valuable aspect to having your genome sequenced is that it can provide a resource for future genetic discoveries. This means that anytime you hear about another genetic result that has identified a risk factor in a disease, you can look at your status every time a risk factor is identified to see whether or not you are at risk;

Calculate the odds ratio of a phenotype based on a DTC result

DTC services multiply the OR of the SNP that you have with the average population risk to calculate your overall risk for the disease.

Distinguish the characteristics and genetic mechanisms of early and late onset AD

Early onset is Mendelian and late onset is complex. Early onset AD: starts at ages 4-=60 and runs in families. It is autosomal dominant and acts like a classic Mendelian disease (Familial Alzheimer's Disease). A parent who has early onset AD has a 50% chance of passing the trait to their child. In early onset AD, the APP is cut into primarily beta amyloid peptides, which then form plaques. This happens because mutations in the APP mask the normal cleavage sites. In healthy individuals, APP is typically cleaved once by one type of enzyme and then again by gamma-secretase. This cuts the peptide/chain of amino acids into two and doesn't form plaques. With early onset-AD, the mutations mask the correct cleavage site and it is cleaved at a different site than normal, resulting in the beta amyloid chunks. These accumulate into plaques. Mutations result in a gain of function (monkey wrench) and there is abnormal protein interfering with normal functioning (plaques). Late onset AD: the result of a combination of genetic, environmental, and lifestyle factors. ApoE4 is estimated to account for half of the genetic risk for LOAD. About 25% of the population is heterozygous for the ApoE4 allele and is 4x more likely to develop LOAD. About 2% of the population is homozygous for the ApoE4 allele and is 10x more likely to develop AD. Recent research by the Mayo Clinic indicates that tau is the major driver of AD, not amyloid and that the focus should be on tau for therapeutics and prevention. The shift is now toward Tau and not plaques in the cause for AD.

Distinguish between empiric risk, incidence, and prevalence

Empiric risk: a statistic based on the incidence in a specific population. increases with the severity of the disorder, the number of affected family members, and how closely a person is related to an affected individual. the more relatedness or higher degree of relationship, the higher the percentage of genes shared (coefficient of relatedness); 1st degree is sibling or parent to child (50%), 2nd degree is uncle/aunt/niece/nephew or grandparents (25%), and 3rd degree is cousin (12.5%). incidence (e.g. number of new cases of a disorder diagnosed per year): a rate that a certain event occurs in a population. Population can be defined broadly (e.g. number of cases of asthma diagnosed in 2015 in the U.S.) of narrowly (number of new cases of asthma diagnosed in 13-15 y.o. boys of Jewish decent in the U.S.). used in empiric risk. prevalence: the proportion of individuals in a population that has a particular disorder at a specific time-period. (e.g. the number of individuals in the united states who have asthma). Diabetes is a prominent disease in the US - broad. In the year 2010, for individuals over the age of 20, the incidence of diabetes was every 6/1000 people (0.6% of the population) - narrow.

Which technique has the most potential to identify the specific mutation that causes a genetic disease? GWAS Coefficient of relatedness testing Empiric Risk estimation Exome Sequencing

Exome Sequencing

Identify the process of GWAS and exome sequencing and recognize advantages and limitations of their use

GWAS: a method to map genes that contribute to multifactorial disorders by using genetic variation in the human genome to find regions associated with phenotypes. common disease, common variant. use by analyzing individuals with and without the disease of interest at large number of genetic markers throughout the genome and identify patterns that differ between the two groups. SNPs are most common markers. A SNP may be: (1) a cause of a disease or (2) may be linked to another SNP in a gene that contributes to the disease (this is most often the case). What a genome-wide association study does is takes a large population of people and divides them into people with disorders, trying to match them up according to various factors, such as age and gender and other differences as much as possible. It then takes the patient DNA, analyzing for any SNAP pattern, looking for patterns more frequent in individuals with disease versus those without disease. They compare the SNP patterns of the two groups, looking for situations that help identify patterns in disease. The OR indicates an increased risk of having disease if you have one of the risk factors. OR is usually very low (less than 2.0). Therefore, if you carry a SNP associated with a disease (risk factor with odds ratio of 2) you are two times more likely to develop that disease as compared to someone who doesn't have that SNP. Limitations of GWAS: (1) Reveal associations but not causes; after all the work, they cannot pinpoint the actual cause of the disease. (2) Small impact of each risk factor - each risk factor has a very small impact and may not even be the risk factor for the disease. (3) Risk of false positive result - maybe it's not the risk factor/SNP shared or contributing to the development, but an environmental exposure? Exome sequencing: the idea that you sequence or analyze the 3% of the genome that is protein coding (just the exons of every gene). You compare the exome sequence to the human reference sequence and to other exomes to find variants that cause disease. Limitations: What about other types of variants that can affect phenotype, such as altering gene expression? It won't catch SNPs in promoters, splice sites, etc. Exome sequencing won't be helpful for phenotypes caused by epigenetic alterations, expression differences, and may miss copy number variants that are contributing more and more to what we know about genetic variation and what we know about human genetic disease. Exome sequencing may miss CNVs.

Utilize resources (including the Genetic Testing Registry, OMIM, GeneReviews, and Pubmed) to find information about genetic tests, diseases, phenotypes, and research articles. (Note: you learned about OMIM earlier this semester in a Discussion activity).

Genetic Testing Registry: If a patient needs to be tested for a genetic disorder after showing symptoms for a genetic disorder, this is a resource to find the certain tests that need to be done. It is very valuable. OMIM is Online Mendelian Inheritance in Man - the comprehensive resource for Mendelian disorders and over 12,000 genotype and phenotype relationships. Used by physicians, health professionals and genetics researchers Types of information you can learn form OMIM: 11 ▪ Genes associated with disease of interest (e.g. enter: cystic fibrosis) ▪ Information about a specific disease related gene or protein (e.g. enter: CFTR) ▪ Disease associated genes on a chromosome of interest (e.g. enter: Under Limits: check chromosome 10) PubMed Single Citation Matcher If you know an author, date, words in a title, or a journal, you can use Single Citation Matcher If you want to look up an article to simply learn more about it

Why are their warnings about genetic testing on medications containing Warfarin? Genetic variations may affect how a patient responds to Warfarin Warfarin can cause mutations in genes that lead to cancer Warfarin is a type of gene therapy Warfarin can block the expression of many genes

Genetic variations may affect how a patient responds to Warfarin

Two healthy individuals have a child who is born with a rare disorder caused by an autosomal dominant mutation. The medical team explains that the mutation in the child was spontaneous. However, the couple has a second child with the same rare mutation. What best explains this scenario? microbiome mosaicism germline mosaicism in one of the parents somatic mosaicism in both children two completely unrelated spontaneous mutation events

Germline

Distinguish between germline and sporadic cancer

Germline cancer is an inherited predisposition. In this type of cancer, every cell has a variant that increase susceptibility. The individuals are born with a cancer-predisposing allele (already born with a mutation). It includes childhood cancer (retinoblastoma). You have inherited a mutation in every one of your cells. It increases chances of developing cancer. Every cell has the mutation and genetic variant that increases their chances of cancer development. Sporadic cancer occurs when a somatic cell has acquired necessary mutations to induce tumorigenesis (this is what we mostly see). They acquire a mutation that is only observed in some of the cells. The individual will not pass on the risk for cancer to the next generation.

Distinguish the overall strategies and advantages of gene therapy approaches among both traditional and novel techniques (ex: genome editing and CAR)

Germline gene therapy alters the DNA of a gamete or fertilized egg so that ALL cells of the individual are changed. This is how transgenic organisms are made (e.g. GFP mice). The genes added are passed down to the next generation. Currently not done with humans. Somatic gene therapy addresses only the somatic cells that are not functioning properly (i.e. lung cells in CF patients). Any genes added are not passed down to the next generation. In ex vivo, cells are removed from the patient. The healthy, therapeutic version of the gene is added to the cell culture. The cells are then returned back to the patient in the body. In vivo, the healthy gene is administered directly to the cells in their in vivo state. Viral vectors are used in biological approaches. They help get healthy DNA back into the cells. Gene editing tools includes CRISPR - Cas9 System. This can make a double stranded break in the DNA and be target to know exactly where the change can be made. It has the ability to edit out and replace a specific mutation with a copy that is not mutated. Guide RNA matches the target sequencing using Cas9, which is an enzyme that cuts the DNA at a specific site. New corrected DNA is inserted in its place. This method is very promising because it can get around a lot of the challenges that normally inhibit gene therapy, such as how new DNA is delivered to the right cell and how it can be controlled when expressed. CRISPR stands for clustered regularly interspaced short palindromic repeats. It's a mechanism allowing cells to record, over time, the viruses they have been exposed to. And importantly, those bits of DNA are passed on to the cells' progeny, so cells are protected from viruses not only in one generation, but over many generations of cells. This allows the cells to keep a record of infection - the CRISPR locus is effectively a genetic vaccination card in cells. Once those bits of DNA have been inserted into the bacterial chromosome, the cell then makes a little copy of a molecule called RNA (pictured orange) that is an exact replicate of the viral DNA. RNA is a chemical cousin of DNA, and it allows interaction with DNA molecules that have a matching sequence. The little bits of RNA from the CRISPR locus associate, or bind, to protein called Cas9 (pictured white) and form a complex that functions like a sentinel in the cell. It searches through all of the DNA in the cell, to find sites that match the sequences in the bound RNAs. When those sites are found (the blue molecule is DNA) this complex associates with that DNA and allows the Cas9 cleaver to cut up the viral DNA. Chimeric Antigen Receptor - T-Mediated Gene Therapy This is a new method of how they are using gene therapy, cell therapy, immune therapy, all together to address cancer - shows a lot of promise, even with notorious cancers. What they do is extract T-cell from a patient, and in the lab they take them and integrate into the t-cell through a viral vector a way to get a new gene into the patient's own T-cells. This gene has been modified so that it expresses a chimeric antigen receptor on the surface of the T-cell. This type of receptor is like two different proteins in one (hence the name "chimeric"). When it expresses the receptor that scientists and researchers want it to, they take the t-cells back into the patient. The cancer patient now has t-cells expressing this new chimeric antigen receptor. Antigens react by fitting with another receptor molecule on another cell surface, triggering an immune response. These specific receptors are designed to be reactive to a certain protein expressed by a cancer cell, and ONLY by the cancer cells. This is genetically engineering a patient's own T-cells to become very highly specific to their cancer cells. This revs up their own immune system reactions and it is able to hone in like a laser on the cancer cells and attack, prompting the other actions of the immune response to fight against cancer.

Determine the courses of action based on BRCA1/2 mutation testing results

If a patient is positive for a BRCA 1 or 2 mutations, it means that their lifetime risk for breast or ovarian cancer is much higher. With the mutation, the risk of breast cancer increases by 50 - 85%, and the risk of developing breast cancer a second time increases by 40 - 60%. The lifetime risk for developing ovarian cancer increases as well - mutations in BRCA 1 specifically increase risk by 40 - 60% and BRCA 2 mutations increase risk by 15 - 20%. Having a mutation in BRCA 1, the risk increases 46% for breast cancer, 12% for ovarian, and 5% for the development of both types. In BRCA 2, there is a 52% increased risk of breast cancer, 6% increased risk of ovarian, and 2% increased risk for the development of both. If a patient is positive for a mutation, the next step is to identify at risk relatives, and then provide increased surveillance of the patient, promote lifestyle changes, start chemoprevention, or perform prophylactic surgery. If a patient is negative for mutations in BRCA 1 or 2, there are different paths to take. If there are family members with the known mutation, the healthcare provider should emphasize the residual risk of sporadic cancer and encourage adherence to population screening guidelines. On the other hand, if the patient tested negative and does not have family members with a known BRCA 1 or 2 mutation, healthcare providers should emphasize potential risk of unidentified familial mutations (mutations that have not been discovered yet) and provide individualized risk management plans.

Which of the following refers to a scenario in which an individual has populations of cells that have a genome that is different from the genome in the majority of the individual's cells? microbiomes mosaicism metagenomics

Mosiacism

Distinguish characteristics of polygenic, multifactorial, and quantitative traits

Polygenic traits (e.g. eye color): result of the action of more than one gene. Very rare because they do not rely on anything else (e.g. environmental factors). Due to action of multiple genes, and nothing else. Multifactorial traits (e.g. chronic diseases): result of many genetic(s) AND environmental factors. Sometimes called complex traits. Can occur in isolation, affecting child of healthy parents (e.g. asthma); does not follow pattern of inheritance, but there can be a family history; environmental factors influence severity of phenotype and/or age of onset/efficacy of treatment (e.g. diet and exercise with diabetes); can occur more frequently in one gender, but is not sex-linked; can occur more frequently in a particular ethnic group; symptoms can be treated but root of cause may not be addressed because genetic contributors remain unknown. Genes increase risk o development. Quantitative traits (e.g. height, skin color--not race, cholesterol levels, fingerprints): result of many genes, and vary in phenotype- they are not either/or NOR affected/not affected; display continuous variation in population; can be classified into classes and the frequency of the classes can be calculated. Genes that contribute to these traits are quantitative trans loci; phenotypic variation distribution looks like a bell shaped curve; influenced by genes and environmental factors.

Classify the four broad types of medication responders according to their CYP genotype

Poor metabolizers (PM) of a drug may have inherited two loss-of-function alleles resulting in a phenotype for metabolism that is poor. An intermediate metabolizer may have inherited one loss of function and one wild-type allele (heterozygous). They still have one functioning allele - not functioning as good as they could, but they still have some functioning occurring. A person who has two wild-type alleles is likely a normal metabolizer (two completely functioning alleles). An ultra-rapid metabolizer (U-R M) occurs when there is a gain of function mutation (duplication, monkey wrench, etc.) that leads to more CYP activity than normal.

Identify the goals, advantages, clinical applications, and resources for precision medicine and pharmacogenetics

Precision (personalized) medicine is prevention and treatment that takes into account an individual's variability. It involves providing unique treatment and prevention strategies tailored to one's genome. It also requires many genomes to be analyzed first and requires health care professionals to be well educated In genomics. Pharmacogenetics can lead to selecting the best, most appropriate drugs for individual patients. Genetic testing (SNP testing) can test patients for: (1) Increased chance of suffering from an adverse reaction to a drug (2) Selecting a drug that is most likely to be effective based on genotype (3) Monitoring response to drug treatment (people with different genotypes have different responses to different drugs), and (4) Predicting the course of the illness (prognosis).

What is an advantage of precision medicine? Determining the cause of every disease experienced by an individual Identifying each patient's "super drug" - the one medication that will cure all Treatment plans tailored to a person's ethnicity Prescribing the best dosage of a drug based on a patient's genotype

Prescribing the best dosage of a drug based on a patient's genotype

Identify the main causes of cancer and the three types of target genes they affect.

Proto-oncogenes are genes that normally trigger cell division. When proto-oncogenes are activated at the wrong time and wrong place, they are considered oncogenes. An oncogene is a cancer-causing gene. Alterations in oncogenes are dominant and lead to a gain of function. This will result in a hyperactive growth-stimulating protein (monkey wrench), keeping it signaling constantly. Sometimes a proto-oncogene can, through mutations, cause multiple copies of the gene to be produced. This can result in a large excess of normal protein, increasing proliferation. Sometimes chromosomal translocations can occur and the proto-oncogene can find itself under the control of a new promoter, resulting in a normal protein structure but produced in excess. Because of this excess protein, it will act as a gain of function. Tumor suppressor genes (TSG) normally control or block cell division (in contrast to proto- oncogenes that trigger/promote division and proliferation). They function normally in healthy cells by breaking cell division. The proteins they encode normally help to prevent cancer from forming - which is why they are called tumor suppressor genes. If they are mutated, they lose their function (absent essentials) and cannot prevent cancer from occurring. Mutations to these genes are typically recessive. If one TSG loses its function and cannot prevent cancer, the other allele can still do its job, but not as well. If this isn't working, cell division is not controlled and leads to cancer. DNA repair genes normally function by repairing the spontaneous errors made during the DNA replication process. Remember that in DNA replication it is not a perfect process - mistakes can be made. Certain genes have function to repair these mistakes. If these genes, though, are altered and not doing their job, the mistakes in genes are acquired as they replicate in the daughter cell. The mutations accumulate and create an environment where more and more mutations are accumulating, making it harder to maintain a balance between cell proliferation and differentiation. Some of these mutations occur in proto-oncogenes or tumor suppressor genes. Thus, mutations in DNA repair genes leads to an accumulation of mutations and drastically increases the likelihood of cancer. Multiple genetic changes are necessary to develop cancer - it isn't just one mutation that causes cancer development. One mutation primes a cell, and usually a TSG has to be inactivated allowing a cell to grow into a benign tumor, where it then accumulates additional mutations that become more malignant. This is a stepwise process - cancer results from the gradual accumulation of mutations in somatic cells. This is why our risk for cancer increases overall as we age - we are accumulating mutations.

In what circumstance might you consult the American College of Medical Genetics ACTion sheets? to diagnose a pediatric patient with unusual symptoms a newborn screens positive for an metabolic disorder to look up the latest research on non-invasive prenatal screening to find pharmacogenetic information

a newborn screens positive for an metabolic disorder

Distinguish among the different types and mechanisms of mosaicism and compare the phenomena to microchimerism

When individuals have small populations of cells originating from another zygote (individual) it is called a microchimerism. When one X-chromosome is entirely inactivated, it is an example of an epigenetic mechanism. It is possible for a child with a rare genetic syndrome to be born to parents who do not have the mutation. In the first child, it may be viewed as spontaneous mutation that occurred in somatic cells (this happens - not too unusual). Then, it has been recorded where a sibling may be born with the same genetic mutation. This causes researchers to go back to the parents' and look for this mutation to be present. Not all of the siblings may have the mutation, as only some sperm/oocytes have the mutation. This is because of germline mosaicism. There are two types of mosaicism: (1) Germline - mutation is confined to the germ cells (sperm or oocytes) and it can be passed down to offspring. This is suspected when a child is born with a rare Mendelian disorder not present in the parents, and a second sibling/child is born with the same development. (2) Somatic - normal and abnormal cell lines within the cells of the body can have a mutation. There is a patch of cells with all the subsequent divisions/generations of cells from the cell with the mutation will also have the mutation. In this case, mutation cannot be transmitted to offspring

Costello syndrome is a very rare genetic disease. A patient's symptoms are consistent with Costello syndrome, but a genetic test is needed for confirmation. Is there a genetic test available and where can it be done? Use online resources to answer this question. Yes ... Baylor Medical Genetics Laboratories yes ... CLIA yes... Florida Department of Health genetic test is not available for this condition

Yes ... Baylor Medical Genetics Laboratories

Loss of tumor suppression in a cell usually results from: translocation of an oncogene activation of a proto-oncogene by a virus a deletion or inactivation of both copies of a tumor suppressor gene a Copy Number Variant involving a tumor suppressor gene

a deletion or inactivation of both copies of a tumor suppressor gene

If you were to get your entire genome sequenced today, what could be revealed in the analysis? Check ALL that apply. carrier status for single gene disorders like cystic fibrosis copy number variations SNPs that affect how you metabolize Warfarin risk factors associated with some complex, multifactorial diseases

all

What factors should play a role when evaluating a 55 year old female patient's risk for the common, multifactorial disorder osteoporosis? Select ALL answers that apply. proportion of women in their fifties who are diagnosed with osteoporosis Coefficient of relatedness for affected family members lifestyle factors such as diet racial/ethnic background of individual

all are correct

What are some criticisms/ethical concerns of Direct to Consumer personal genome services? The results could be misinterpreted if a consumer does not understand risk The turn-around time is too slow. Results are not consistent between DTC providers. There is no way to verify the "owner" of the DNA sample

all except b

If a patient tests positive for a BRCA1/2 mutation. What are the courses of action to discuss? Please select ALL that apply. Increased surveillance chemoprevention prophylactic surgery adherance to general population screening guidelines

all except d

A karyotype of a tumor cell can indicate: Select ALL that apply. Whole Chromosome duplication trisomy dominant and recessive mutations Whole Chromosome loss Chromosome rearrangements

all except dominant and recessive mutations

Distinguish the processes by which the three gene target classes lead to cancer.

answered above

At a broad level, all cancers have a defect in: cell cycle control the cell's ability to extract energy from nutrients the formation of mitochondria DNA replication machinery

cell cycle control

Genome wide association studies (GWAS): are very effective at identifying disease causing mutations as long as the population is big enough use statistics to find SNPs that are more likely to be present in people with a particular disorder than in people without the disorder can uncover novel mutations that are at the root of Mendelian diseases

use statistics to find SNPs that are more likely to be present in people with a particular disorder than in people without the disorder

Identify the research approaches to study the role of the microbiome in human health

metagenomics. This is when you collect genetic material from a community of microorganisms and sequence the genetic material from another community of microorganisms to determine what bacteria are present based on their DNA. Sequencing can identify ALL members of the community and look up ALL genes present to uncover their role. Genes of identified microorganisms can be compared to already known genes of other organisms to discover what their role is, determine which species are present, and look at which proteins they produce to get a sense of how the community is functioning. Metagenomics can teach us many aspects about energy production, biofuel production, and human health that we don't already know. The microorganism communities associated with the human are called microbiome. They play a big role (especially in the gut) in many different diseases such as IBD, diabetes, and obesity. The microbiome is a new area that is being investigated by researchers. Microbiomes are a community of organisms residing in/on the human body. In our own bodies, microorganisms outnumber human cells 9:1. There are trillions of microorganisms associated with each person. These communities all throughout the body are distinct. For example: nasal communities are very different than the GI communities. Researchers are sequencing the entire microbiome of different regions to identify all members of the community and all the genes present to figure out their role and how they are involved in human health.

Please match the description of each genetic test/screen. analysis of a single cell of an embryo analysis of cell-free fetal DNA analysis of biochemicals and metabolites in infants analysis of just coding regions of a genome

preimplantation genetic diagnosis noninvasive prenatal testing newborn screening exam sequencing

The Florida Autism and Developmental Disabilities Monitoring Project studies Autism and related disorders in Florida. In 2008, in a single county in FL, Miami Dade, 7.2 out of every 1000 eight-year olds had Autism Spectrum Disorder. This is an example of: incidence prevalence empiric risk odds ratio

prevalence