genetics exam 5

what is the most common type of cancer? list the other types as well.

*Carcinomas - epithelial tissue - most common type.* Sarcomas - connective tissue. Lymphomas - lymphatic tissue. Gliomas - glial cells (CNS). Leukemias - hematopoietic organs. o Tumor cells usually arise from a single ancestral cell = *monoclonal*

how would you describe the recurrence of rare diseases in an isolated population?

*Founder effect* - Accumulation of random genetic changes in an isolated population because the population is made up of descendants from a few parent colonizers -> rare diseases might manifest more b/c of skewed allele frequencies. o Ex: BRCA mutations in Ashkenazi Jewish population -> some genetic panels can look for specific mutations based on patient ethnicity. o 1/800 individuals has a BRCA1/2 mutation, but it is 1/40 in Ashkenazi Jews.

the body has many mechanisms to prevent the development of cancer. in order for tumorigenesis to occur, what protective factors must be bypassed?

*Genetic mutations in cell regulatory systems = primary basis of carcinogenesis.* Additional growth signals Resistance to signals that would normally inhibit growth Disabling of apoptosis (programmed cell death that would typically get triggered in abnormal cells) Nourishment for the growing mass -> angiogenesis (new vessel formation). *Malignant state*; tumor able to invade nearby tissues and metastasize (spread) to distant sites when it overcomes enough inhibitory signals (vs benign neoplasms, which cannot spread or metastasize).

what is Pharmacogenetics? what is Pharmacogenomics?

*Pharmacogenetics* - Study of genetic variants that modify human responses to pharmacological agents. - Pharmaceutical drugs -> get metabolized and transformed into a variety of products -> each human varies in how efficient and fast this process is. - aka Role of inheritance in individual variation in drug metabolism. - *Pharmacogenomics*: Assessment of how many genes act together simultaneously. - aka Study of how genes affect a person's response to drugs.

what is the cause of Chronic Myelogenous Leukemia (CML)? what abnormal protein activities may be observed?

*Philadelphia chromosome* = reciprocal translocation b/w long arms of csome 9 & 22. - Portion of chromosome 9 that's translocated -> contains *proto-oncogene abl* - abl gene is added to csome 22 at a location called *"breakpoint cluster" (bcr) = bcr/abl fusion gene.* o New protein has abnormal *tyrosine kinase activity* (normal Abl protein does not!) o Tyrosine kinase activates too many stem cells to develop into WBCs -> increased granulocytes or blasts (ignores normal signaling, pressures cells to replicate)

Li-Fraumeni syndrome is a condition associated with breast and ovarian cancer. What is the gene associated with this syndrome and what are the potential effects?

*associated with p53 : Germline mutation* on chromosome 17 -> premenopausal breast cancer w/ brain tumors, childhood sarcoma, leukemia, and adrenocortical carcinoma.

for quantitative traits such as height or blood pressure, we look to what type of measurement besides concordance for twins?

*intraclass correlation coefficient* is used. This statistic varies between −1.0 and +1.0 and measures the degree of homogeneity of a trait in a sample of individuals If a trait were determined entirely by genes, we would expect the correlation coefficient for MZ pairs to be 1.0 (i.e., each pair of twins would have exactly the same height). A correlation coefficient of 0.0 would mean that the similarity between MZ twins for the trait in question is no greater than chance.

what is the most common underlying cause of coronary heart disease?

- *atherosclerosis* other multiple risk factors: Smoking, obesity, hypertension, elevated cholesterol, and positive family history (one or more affected first-degree relatives). o If affected relative(s) = female -> higher risk because females are the less commonly affected sex (more disease-related genetic/environmental factors in the family).

what can concordance tell us about twins and genetics? what does discordant mean?

- Concordance between twins can help determine how much a trait is influenced by genes. o *If both twins share a trait = concordant* o *If the twins do not share a trait = discordant* o If a trait is determined completely by genes -> MZ twins always concordant (DZ twins concordant, but less often since only 50% of DNA shared, and twins might be opposite sexes). o Concordance rates for contagious diseases similar for MZ and DZ twins -> not influenced much by genes.

what are the group of liver enzymes important in drug metabolism? how does different expression affect drug metabolism?

- Cytochrome P450 family (CYP) o Patient phenotypes based on variations in CYP gene = Poor, normal, and ultra-rapid metabolizers. Poor metabolizers -> process drugs much slower than expected = increased drug levels in blood stream = increased risk of toxicity and side effects, even at standard dose. Ultra-rapid metabolizers standard dose can be ineffective b/c drug metabolized too fast -> higher dosage is needed.

what are the major phenotypic features of hereditary breast and ovarian cancer syndrome?

- Early age of cancer onset (usually before 50 YO) - Family history of both breast and ovarian cancer - Increased risk of bilateral cancers (both breasts, both ovaries) - Increased risk of getting both breast and ovarian cancer in the same person **Other clues might include: Autosomal dominant inheritance, family history of male breast cancer, Ashkenazi Jewish ancestry.

why is genetic prediction of Serious Adverse Drug Responses important?

- For every person, respond to chemicals (natural or synthetic) is partially determined by DNA polymorphisms in genes that control drug metabolism/transformation pathways and the target tissue. - Serious adverse drug reactions: Genetic profile (summary of person's risk alleles) could help predict how likely they are to respond to a drug vs get a bad reaction -> if you use a drug in a person who is unlikely to respond, then they are more likely to get an SADR.

Neural tube defects (NTDs) are birth defects including anencephaly (major part of brain/skull/scalp absent), spina bifida (incomplete closing of bone and membranes around spinal cord), and encephalocele (sac-like protrusions of brain/membranes through unfused portion of skull). whst are the associated risks?

- Frequency: 1/1000 in newborns - *Detected by alpha-fetoprotein (AFP) elevation (maternal serum or amniotic fluid)* - Multifactorial disease: o Recurrence risk for siblings of affected individual = 2-5% -> if a woman has a baby with one NTD, the risk for subsequent NTDs can increase. o Folic acid supplementation in maternal diet -> reduces risk of NTDs (important non-genetic factor causing disease to cluster in family + some genetic variation in folic acid response).

in the study of how genes affect a person's response to drugs (Pharmacogenomics), how can we develop effective and safe medications? How can we choose the best dosing for an individual's genetic make-up?

- How can we develop effective and safe medications? - Maximize therapeutic effects, minimize adverse effects! - How can we choose the best dosing for an individual's genetic make-up? Based on genetics, not trial-and-error! - What is the genetic explanation for why there's so much variability in drug responses between individuals?

what is the role of - N-acetyltransferase in drug metabolism?

- N-acetyltransferase: Liver enzyme that activates some drugs and deactivates others -> some patients acetylate faster than others = fast acetylators deactivate some drugs too fast, while slow acetylators can get increased risk of toxicity.

why are recurrence risks for multifactorial diseases more complicated than single-gene disorders? what type of risk is evaluated instead?

- Number of genes contributing to disease often unknown (parental alleles difficult to determine) + widely variable influence from environment. - *Empirical risks*: Risks based on data observation -> analysis of large families where one child (proband) has already manifested the disease. - Unlike single-gene diseases, recurrence risk for multifactorial disease can change significantly between different populations b/c allele frequencies and environmental factors vary a lot between cultures, etc.

who is commonly affected by CML? what are the symptoms?

- Occurs more frequently in men than women, median age: 55 YO. - Symptoms and findings: Fatigue, night sweats, fever, splenomegaly, elevated WBC count -> sometimes no symptoms.

what are the challenges associated with viral vectors for therapy?

- Only some of the target cells will successfully incorporate the normal gene -> desired protein might be expressed at subtherapeutic levels (though transient expression might be good enough in some situations). - Central nervous system disorders = difficult targets! - Viral vectors might be able to recover ability to cause disease once inside patient. - Immune system issues: o Vector might stimulate immune system -> reduces therapy effectiveness. o Difficult to repeat gene therapy with the same vector. - Difficult to precisely regulate the gene activity (ex: thalassemia = # of globin chain genes must be balanced correctly!)

what category of disorders tend to aggregate in families and reflects that some of the same genes that influence susceptibility?

- Psychiatric disorders - schizo - bipolar disorder - autism all have high heritability in twin studies *Familial aggregation and familial co-occurrence observed for many psychological disorders -> brain-expressed genes that encode neurotransmitters/receptors/etc. seem to be implicated*

what is the difference between Multifactorial versus Single-Gene Inheritance? what is a major gene?

- Single-gene diseases w/ locus heterogeneity can look like multifactorial diseases. o Single-gene diseases w/ locus heterogeneity: Only requires one mutation. - But the location of that one mutation can vary (multiple susceptible loci). - Ex: Some people have a mutation in locus A, while others have a mutation in locus B. o Multifactorial disease: Simultaneous involvement of multiple genes and environmental factors *Major gene*: The one locus that mostly controls a trait (usually + minor multifactorial component).

what is Thiopurine methyltransferase (TPMT used for?

- Thiopurine methyltransferase (TPMT): Metabolizes some immunosuppressant drugs -> each copy of TPMT gene produces some TPMT enzyme. o Three possible activity levels: Deficient, intermediate, and normal. o TMPT deficient patients = with standard dose, severe hematopoietic toxicity (need 1/10 dose).

what are some drug metabolizing issues that can arise due to problems with - UDP-glucuronosyltransferase?

- UDP-glucuronosyltransferase: Metabolize of a chemotherapeutic drug -> variation in gene = varying ability to break down the major active metabolites = increased blood concentrations = increased risk of side-effects.

what are some general uses of gene therapy?

1) Exchanging an abnormal gene for its normal counterpart (homologous recombination) 2) Repairing an abnormal gene and restoring its normal function (selective reverse mutation) 3) Alter the regulation of a particular gene (turn it off more or on more)

what are the major classes of cancer genes?

1) Tumor suppressors - normally inhibit cellular proliferation. regulates cell cycle 2) Oncogenes - normally activate cellular proliferation 3) DNA repair genes - prevent mutations from accumulating

what is the cause of maturity onset diabetes of the young?

1-5% of all diabetes cases, onset before age 25. Autosomal dominant: Mutations in glucokinase gene (50%) or any of the transcription factors involved in pancreatic development/insulin regulation.

what are the genetic and risk factors associated with colorectal cancer?

1/20 Americans will develop colorectal cancer, and 1/3 of those will die from it. Tends to cluster in families -> risk for someone with an affected first-degree relative = 2-3 times higher than general population. Can also be due to mutations in *APC tumor suppressor gene or DNA mismatch-repair genes (HNPCC)*; rarely: Peutz-Jeghers syndrome (STK11 tumor suppressor gene). Most cases are not inherited in Mendelian fashion, but due to interaction between inherited and somatic mutations + environmental factors. Environmental risks: Lack of physical activity, high fat/low fiber diet.

what are the different forms of cardiomyopathy and the cause?

Abnormal heart muscles = inadequate cardiac function -> heart failure. *Hypertrophic form*: o Thickening of the left ventricle -> half of cases are familial (autosomal dominant). o Most commonly affected genes = beta-myosin heavy genes, myosin-binding protein C genes, and troponin T genes. *Dilated form*: o Increased size of the ventricles = impaired contraction -> 1/3 of cases familial (autosomal dominant, X-linked, or mitochondrial inheritance). o Genes usually encode cytoskeletal proteins.

what is the two-hit model of carcinogenesis?

At least 2 mutations required to create a cancer, ex: *familial retinoblastoma*. - 1st hit: Mutation altering retinoblastoma gene -> in germline, then the child would be born with the 1st hit (inherited mutant allele = *constitutional mutation* -> a mutation present in all cells of the body) = predisposition to cancer. 2nd hit: Requires an additional unspecific genetic event occurring in the already-altered cell - this could be why only some people with the inherited retinoblastoma gene mutation actually develop cancer. *Both mutations in retinoblastoma are loss-of-function* -> a cell with only one mutated retinoblastoma gene (RB1) cannot become a tumor - normal allele prevents tumor formation. For someone who did not inherit the "first hit", it's much harder to get the cancer because both hits have to occur somatically in the fetus - highly improbable, & unlikely to develop more than one tumor.

a patient is found to have breast cancer. what genotypic modification is causing her disease?

BRCA1 and BRCA2 tumor suppressor genes. normally regulate cell growth and cell death. Other functions: DNA repair, genomic stability, transcriptional regulation, cell cycle control. o Normal individual: Two BRCA1 genes (chromosome 17) and two BRCA2 genes (chromosome 13). *For cancer to develop: Both copies of the set must be mutated*

Blood in stool, unintentional weight loss, diarrhea not due to diet or other illness, chronic constipation, crampy abdominal pain, change in bowel habits, stool progressively gets decreases in size/caliber, frequent feeling of distention or bloating, vomiting, continual fatigue are all symptoms associated with what cancer?

Colorectal Cancer: - Can start as adenomatous polyps (little benign growths) that evolve into cancer. - Has both sporadic and familial patterns. - First degree relatives of affected individuals have a 2-4x fold lifetime risk of developing colon cancer.

what type of mutation is mostly considered multifactorial?

Congenital Malformations: By definition are present at birth, most considered to be multifactorial. - Seen in approximately 1/50 live births. - Specific genes and environmental factors identified for some, but most are largely unknown.

what is the most well-studied polymorphic drug-metabolizing liver enzyme in humans? (30+ medications metabolized by this enzyme; polymorphisms causes increased activation or inactivation of various drugs)

Cytochrome P450 2D6 - polymorphisms causes increased activation or inactivation of various drugs. Ex: If enzyme is not functional, some patients cannot activate codeine from the inactive prodrug = no pain relief.

an abundance of polyps found in the colon is most likely due to what mutations?

FAMILIAL ADENOMATOUS POLYPOSIS: Majority of cases are inherited - *APC (adenomatous polyposis coli) tumor suppressor gene* = increased risk of developing colonic adenomas, if mutated. Autosomal dominant condition caused by APC gene mutation (function: cell adhesion regulation and apoptosis) -> insertions, deletions, nonsense mutations leading to frameshifts.

what is one of the the most common autosomal dominant disorders that contributes to the cause of heart disease?

Familial hypercholesterolemia mechanism: *Endocytosis*: Cells take LDL-bound cholesterol into the cell via LDL receptors on cell surface. o Low number of functional LDL receptors = reduced cholesterol uptake = increased blood cholesterol. - Multiple classes of LDL receptor gene (LDLR) mutations identified. number of effective LDL receptors is really reduced!! - Other mutations possible: Apolipoprotein B gene, etc.

what changes occur to the BRCA genes in order for cancer to manifest?

For cancer to develop: Both copies of the set (BRCA1 and BRCA2) must be mutated. In hereditary cancer -> 1st mutated copy already inherited from parents (germline mutation), then a 2nd mutation occurs (ex: if 2nd mutation in ovary = ovarian cancer). If second mutation never acquired -> individual probably won't get cancer (might look like a "skipped" generation, but individual will still pass on 1st hit mutation). o *Other mutations also have to occur in addition for tumorigenesis - loss of both copies of either BRCA1 or BRCA2 is just the first step.*

what changes may be useful towards development of individualized drug therapy?

Genetic studies helpful for determining polymorphisms that: 1. Might contribute to disease susceptibility -> those gene products can make good targets for drugs. 2. Modify metabolism or response to drugs. - Many drug responses are determined by more complicated profiles = multiple polymorphisms at multiple loci. - Testing for these polymorphisms is important b/c it leads to better predictions for patient drug responses -> reduced risk of bad side-effects and better dosing.

what is the key risk factor for other disorders and causes around half of all cardiovascular mortality?

Hypertension - significant genetic contribution (family studies: 30-50%, twin studies: ~60%). Also a significant (~40%) environmental contribution -> sodium intake, physical activity, psychosocial stress, and obesity. Rarely caused by single-gene disorders (ex: Liddle syndrome -> ENaC channel affected).

what is the relationship between prevalence of disease in a population and the risk of the offspring?

In general, if the prevalence of the disease in a population is "f" (values between 0-1), the risk for offspring/siblings of probands is ~the square root of "f". Recurrence risk for single-gene diseases is independent of population prevalence.

in the two-hit model for cancer development, how are heterozygotes at risk?

Inherited mutations are dominant at the organism (ex person) level (heterozygotes usually develop disease) but recessive at the cellular level (heterozygous cells do not form tumors) -> if you inherit the first hit (all cells heterozygous BUT NON-CANCEROUS to start), a sporadic somatic mutation in one of your cells will cause a tumor to form = *heterozygous individuals tend to form tumors* Incomplete penetrance can occur - individual with the inherited mutation never experiences the second hit.

what is the cause of type 1 DM? what are the associated genes?

Lymphocytic infiltration of the pancreas -> destruction of insulin-producing beta cells, autoantibodies against pancreatic cells/insulin/related enzymes -> *no production of insulin* Early onset (before age 40 usually). *Associated with HLA class II genes -> autoimmune disease* • HLA locus = 40-50% of genetic susceptibility to type 1 DM. • 95% of whites w/ type 1 DM -> HLA DR3/DR4 alleles (only 50% general population have these). • Additional genes: VNTR polymorphism (more repeat units might affect insulin gene transcription), CTLA4 and PTPN22 genes (inhibition/regulation of T cells).

many major types of cancer are a result of what conditions?

Many major types of cancer (breast, colon, prostate, ovarian) can *cluster in families due to shared genes and shared environments* in breast cancer - Several predisposing genes: BRCA1 and BRCA2 (DNA repair genes) are most important. Environmental factors: *Nulliparity* (never having had children), bearing first child after 30 YO, high-fat diet, alcohol use, and estrogen replacement therapy.

how do factors such as penetrance, modifiers and relative risks relate to each other?

PENETRANCE: Probability that an individual who is a carrier for a harmful mutation will develop disease. - Relative risk of developing major disorder = comparing the incidence of condition in carriers vs incidence of the condition in non-carriers. o Modifiers (like environmental factors or secondary genes) can also be affected by penetrance. o Relative risk would then = comparing incidence of condition (ex: cancer) in people with the modifier (ex: tobacco smokers) vs people without it (ex: non-smokers).

what are phenocopies?

Phenocopies: When people have a phenotype that is normally associated with a mutation in a certain gene, but they themselves do not have that disease-causing mutation. (Ex: Having breast cancer with no BRCA1 mutation.) phenocopies along with locus heterogeneity, (multiple genes interacting with each other, degrees of penetrance, age-dependent onset, etc.) make finding genes for multifactorial diseases difficult

what is the difference between polygenic and multifactorial traits? ex?

Polygenic ("many genes"): Traits in which variation is thought to be caused by the combined effects of multiple genes Multifactorial: When environmental factors are also believed to cause variation in the trait, which is usually the case. Many quantitative traits (ex: blood pressure, measured on a continuous numerical scale) are multifactorial. height = polygenic and multifactorial

why are polymorphisms important to consider in medicine and drug treatments?

Polymorphisms: Common genetic variations between individuals -> can cause an individual to respond to differently to a certain medicine = 95% of variability in some drugs' effects (although non-genetic factors like age, drug interactions, etc. also play a role).

what are the disadvantages of using modified retroviruses as vectors for gene therapy?

Potential to induce tumor formation (due to integration into gene-rich areas -> could accidentally activate proto-oncogenes). Can only be used in actively dividing cells -> cells like neurons not good targets (but this might actually be helpful if you want to target neoplastic cells in the brain, since those divide fast while neurons don't).

what are the genetic and risk factors associated with alzheimer's disease?

Progressive dementia and memory loss due to amyloid plaques/neurofibrillary tangles in the brain o Affected first-degree relative = doubled risk. o Most cases not due to single-gene mutation, but 10% follows autosomal dominant inheritance (likely the early-onset AD -> early-onset clusters more strongly in families). o Genetically heterogeneous -> *around half of early-onset cases related to genes affecting amyloid-beta deposition.* PS1/PS2 = very similar; cleavage of amyloid-beta precursor by gamma-secretase -> too much cleavage = accumulation and deposition in the brain. Late-age version: APOE (apolipoprotein E) locus

How does the retinoblastoma/RB1 gene act as a tumor suppressor and what can go wrong?

RB1-encoded protein = pRb = "cell cycle break." • Active when unphosphorylated - binds to E2F transcription complex to inactivate it -> halts progression into S phase. • Downregulated when phosphorylated by CDKs (kinases) before S phase of cell cycle -> allows cell to move forward in cell cycle b/c pRb is downregulated and cannot bind E2F. *Loss-of-function mutation in both copies of RB1* = permanent inactivation of pRb = no more breaks -> cell proceeds through cell cycle uncontrolled. • Other possible mutations: Deletions, hypermethylation (which would limit the gene's transcription). One functional copy of RB1 is enough to control cell growth at least sufficiently to prevent tumor growth. o Similarly, loss-of-function in other inhibitory factors can result in unregulated cell cycle progression -> *CDK inhibitors*

what do genetic studies reveal about strokes?

Strokes tend to cluster in families -> several single-gene disorders are associated and some inherited coagulation disorders. • Twin studies show concordance for MZ twins = 10% and DZ twins = 5% -> genetic influence! • Coagulation disorders -> increased risk.

what types of cells are usually targeted for gene therapy?

Theoretically both somatic and germline cells can be transformed, but historically most gene therapy has been directed at somatic cells. - Good candidates for targets: Long lifespan in the body, easily accessible; sometimes proliferating cells preferred b/c replicating DNA can be more readily targeted by vectors. Ex: Hepatocytes, skin fibroblasts, muscle cells. - Most current therapy: Replaces missing gene product by inserting normal gene (corrects loss-of-function mutations). Viruses as Gene Therapy Vectors - Has been used to treat severe combined immunodeficiency.

what are the types of alcoholism and inheritance patterns?

Type I: Later age of onset (25+), males and females, with greater psychological dependence on alcohol -> solitary, introverted drinkers -> less likely to cluster in families and has less severe course/more easily treated. Type II: Predominantly seen in males with onset before 25 YO -> involves persons who are more extroverted/thrill-seeking -> more difficult to treat and is more strongly clustered in families. o Likely involves key enzymes involved in alcohol metabolism -> better alcohol metabolism = higher susceptibility to alcoholism

what is warfarin used for? what enzyme is responsible for its metabolism?

Warfarin: Anticoagulant primarily metabolized by cytochrome CYP2C9 enzyme, mechanism of action = inhibition of vitamin K epoxide reductase complex subunit 1 (VKORC1) -> genetic variation in either gene = toxicity/efficacy variation. - INR (international normalized ratio) and prothrombin time = lab values used to measure how effective the warfarin dosage is. - *CYP2C9 variants -> take longer to achieve stable dosing compared to wild-type, higher risk of acute bleeding complications.*

how do cancer cells emerge from a population of normal cells?

by accumulating mutations in genes that govern growth and differentiation -> if a cell continues to grow instead of stopping growth to differentiate (as it normally should) Accumulation of changes -> progressively greater deregulation of growth in the cell lineage -> eventually the ancestral cell gives rise to descendants that are so unregulated they can multiply w/o restraints. Descendant cells can also eventually accumulate more changes -> ability to invade adjacent tissues = metastasis. *Multi-hit concept of carcinogenesis*: Multiple mutations = multiple changes required for progression from benign growth to malignant neoplasm.

what is heritability of multifactorial traits?

heritability is the percentage of population variation in a trait that is due to genes (statistically, it is the proportion of the total variance of a trait that is caused by genes)

what is liability distribution and threshold of liability? how do these factors influence disease development?

liability distribution - people on the low end of the distribution have little chance of developing the disease in question (i.e., they have few of the alleles or environmental factors that cause the disease). Those who are closer to the high end of the distribution have more of the disease-causing alleles and environmental factors and are more likely to develop the disease. For multifactorial diseases that are either present or absent, a *threshold of liability* must be crossed before the disease is expressed. *Below the threshold, the person appears unaffected; above it, he or she is affected by the disease.*

what is the cause of so much variation in height?

more than 200 loci associated with human height, affirming that this is indeed a polygenic, multifactorial trait. The loci underlying variation in a quantitative trait such as height are termed *quantitative trait loci* individual genes underlying a multifactorial trait such as height follow the mendelian principles of segregation and independent assortment, just like any other genes. The only difference is that many of them act together to influence the trait.

as opposed to Familial adenomatous polyposis (FAP) , Hereditary nonpolyposis colorectal cancer (HNPCC) manifests as development of only a small number of polyps. what is the cause of this disease?

o Autosomal dominant condition -> cancer progression is rapid (compared to traditional polyps -> progression can take more than 10 years). o Caused by defect in one of several *DNA base-pair mismatch repair genes* -> MLH1, MSH2/6, PMS2 -> causes *microsatellite instability* (DNA abnormality where # of certain short, repeated sequences of DNA starts to increase; mutation rate goes up -> probably from DNA repair defects).

what types of cancer associated mutations occur in somatic cells and what type occurs in germline cells?

o Basic cause of cancer = damage to specific genes. - Usually accumulate in somatic cells over time until a cell has enough mutations for tumorigenesis. - Somatic mutations that cause cancer are not transmitted to future generations -> only germline mutations are. - *Cancer-predisposing mutations* can occur in germline cells -> these can be inherited = families with high incidence of specific cancers. - Ultimately, cancer risk = inherited factors + environmental factors.

why is Alzheimer disease difficult to analyze?

o Difficult to analyze -> genetic heterogeneity, diagnosis only made definitively by brain autopsy, and onset can be very late in life and can be disguised by other age-related causes of death.

why is the study of Pharmacogenetics important?

o Drugs get altered by enzymes during metabolism in body -> greater or lesser activity levels. o If a drug is metabolized too fast -> it doesn't stick around long enough to do what it needs to do! o Drugs are not "one size fits all" -> they work differently for everyone! Some people don't even respond!

how do inherited and sporadic cancers differ?

o Inherited form of cancer can be different than sporadic/non-inherited form - ex: inherited retinoblastoma is bilateral (both eyes), but sporadic usually affects only one eye (one tumor).

what are some difficulties associated with MZ twin studies?

o MZ twins are treated more similarly and more likely to seek the same environment = skews the data. o Uterine environments of MZ twins can vary in similarity - two amnions/two chorions, two amnions/one chorion, or one shared amnion/one shared chorion all possible. o *Somatic mutations can occur during mitotic divisions* in the embryos -> MZ twins *may not be exactly "identical."* o Methylation patterns (affects gene transcription) become more and more dissimilar b/w MZ twins as they age. o MZ twins can be raised separately to control for environmental bias -> if they are raised separately, any concordance b/w them should be primarily from genetic causes (not environmental).

the risks associated with multifactorial diseases increases if what conditions are present?

o More family members are effected ex. multiple siblings w same disease. o If disease has more severe expression: More severe expression = more disease alleles/more disease risk environmental factors -> "high" end of liability model -> higher risk for relatives. o If the affected proband is of the less commonly affected sex: Because if a person is from the less susceptible sex and they're *still affected*, they must have more risk factors -> higher risk for their relatives. o If someone is closely related to an affected person: Recurrence risk decreases rapidly for remotely related relatives since a remotely related relative not only has less genes in common with affected individual, they are also likely not to have the same environment.

what is the cause of the most common type of diabetes?

o Type 2 DM: More than 90% of all diabetes cases. Usually able to make some degree of endogenous insulin (unlike type 1 DM) until disease progresses too far -> problem is *insulin resistance.* No HLA/autoantibody associations -> usually *associated with obesity* *MZ twin concordance rates are much higher*than for type 1 DM (although both have genetic component). *Recurrence risk* for first-degree relatives of type 2 DM patients is also *higher* than for type 1 DM patients (ranging 15-40%).