Genetics Test II Questions

Explain how Targeted Gene Therapy can help reduce oncogenesis.

by binding fusion proteins If we can find the oncogenic protein that a fused gene makes, we can target specifically target it and hopefully reduce the oncogenic effects.

What are some easy ways to diagnose a Pedigree of Mitchondrial Inheritance?

-Males and Females equally affected -Only affected females can pass the trait on

An expectant mother recently had an ultrasound that showed that her two previous embryos had fused into one. What are some of the phenotypes we could expect to observe in this offspring?

-Multiple blood types -Cells with different genomes -Male/female gynandromorphy The fusion of two embryos can result in Chimerism. Chimeric individuals are rare and differ from mosaics because they can have two entirely different genomes present in different cells of the body.

In 1990, Bert Vogelstein and his Vogelgram showed that ______.

Cancer development is a progression of individual mutations Early mutations are generally seen in repair pathways, resulting in a mutator phenotype. The next main progression is the acquisition of an oncogenic mutation that promotes uncontrolled growth. The final step is a loss of tumor-suppressors, mainly p53.

There are three categories of Tumor suppressor genes. p53 and pRB are Gate Keepers, inhibiting cell proliferation and promoting apoptosis in cells with DNA damage. What are the other two classes?

Caretakers and Landscapers Caretakers, like BRAC1/2, assist in DNA repair. It is easy to see how mutations in BRAC1/2 lead to increased incidence of breast cancer. Landscapers, like APC, maintain the microenvironment around the tumor, preventing the cell from overgrowing into their neighbors.

A child is born with a defect in the CFTR gene that normally leads to Cystic Fibrosis but doesn't have all the full disease phenotype of Cystic Fibrosis. How is this possible?

Decreased activation of CFTR Modifier genes. Modifier genes alter the phenotype of a gene at another location. A defective CFTR can lead to activation of modifier genes that lead to the typical phenotype for a Cystic Fibrosis patient.

How is it that there could be more hemizygous individuals than triple-copy variant individuals?

Deletions are three times more likely to occur than duplications.

Genetic testing of a fetus reveals mosaicism in a large portion of their cells. Based on this information, we can infer that a mutation took place _____.

Early in embryogenesis. A mutated somatic cell will create clonal descendants of itself. The earlier on in development that this occurs, the more descendants there will be. ex: Imagine if that mutation occurred one step earlier in the picture. Half of all cells would be mutated.

An 8 year old male undergoes a colonoscopy after repeated bloody stools. Examination finds > 100 polyps in his colon. Excessive polyp growth at a young age is indicative of ____.

Familial Adenomatous Polyposis (FAP) FAP is caused by loss of the APC allele, the second hit results in total loss of both APC alleles. If untreated, 7% of patients will have colorectal cancer by 21, 87% by 45, and 93% by 50. Treatment is regular colonoscopy or prophylactic colectomy.

Examination of an 18-month old male reveals jaundice and pale skin due to severe anemia and a swollen abdomen, signs of Major Beta-Thalassemia (Cooley's Anemia). The father states that he was completely healthy as a newborn and started developing symptoms in the past couple of weeks. What is the reason for the delayed progression of this disease?

HbGamma acts as a beta precursor until after the fetus is born, then HbBeta undergoes expression. Delayed expression of mutant HbBeta is the reason that symptoms of B-Thal emerge late in the first year of life.

A chimeric man in presents in clinic for a checkup. He casually states that he and his wife are trying to have children. He and his wife are the picture of health and have limited family history of genetic disease. Is it safe to assume that their children will be free from disease?

No, because chimeric individuals can possess dominant disease alleles and not express the disease phenotype. Chimeric and mosaic individuals can pass on a lethal genetic trait to their children without showing signs of possessing the disease. This can be shown in a Pedigree through the "random" occurrence of an Autosomal Dominant Disease from two unaffected individuals.

A 5 year old in for a checkup has moderate intellectual impairment, temper outbursts, and exhibits hyperphagia. What are three possible chromosomal events that could lead to this condition?

Paternal Deletion of 15q13, Maternal Uniparental Disomy, or a Paternal Imprinting Defect. These are symptoms of Prader-Willi Syndrome. PWS occurs when there is lack of correct gene dosage on the paternal side of 15q13.

Individuals exhibiting the phenotype consistent with Neurofibromatosis are said to be around 50-80% of individuals that actually have the genotype for the disease. In this instance, we can say that Neurofibromatosis has a _____ of 50-80%.

Penetrance. Penetrance refers to the proportion of people that express the phenotype of the disease related to the total number of people that have the disease genotype.

Explain how it is possible that parents with Sensorineural Deafness can have children with a "normal" hearing phenotype.

Sensorineural Deafness is genetically heterogenous. Genetic heterogeneity is when mutations in different genes cause the same disease. SD is autosomal recessive, so it is possible that an aaBB and an AAbb parent can have children that are all AaBb, resulting in no disease phenotype.

An embryo recently underwent genetic testing that revealed the presence of cells with XO chromosomes and cells with XY chromosomes. This individual has ____ as a result of _____.

Sexual (Germline) Mosaicism as a result of a nondisjunction event early in development

An embryo recently underwent genetic testing that revealed the presence of cells with XX chromosomes and cells with XY chromosomes. This individual has ____ as a result of _____.

Sexual (Germline) Mosaicism as a result of twin fusion.

A newborn fetus with X and Y chromosomes has observable gonadal dysgenesis resulting in ambiguous genitalia formation. Mapping of his sex chromosomes would most likely find a deletion where?

The SRY region of the Y chromosome. The SRY (Sex-determining Region of the Y chromosome) is responsible for normal development of testes. The SRY region is one of a few genes that are outside of the PAR, meaning that they are specific only to the Y chromosome.

You're tracking the levels of CDK/cyclin complexes and notice a spike in the G1/S cyclin. What is happening to the cell at this time?

The cell is encountering the G1 Checkpoint. Cyclin levels peak as the checkpoint is reached. At peak cyclin levels, they reach a threshold that activates autophosphorylation and, ultimately, degradation. You can see the specific cyclin complex peaks correlate with certain checkpoints.

Why could an embryo that has a potentially fatal mutation in some cells ultimately be okay?

The effects of somatic mosaicism depend on dosage. If the mutation occurs late enough in development, a small portion of the cells may only be affected which could limit their overall effect on the fetus.

How can we diagnose a Sexual Mosaic on a Pedigree?

The presence of a dominant disease in an affected child as a result of unaffected parents.

Two twin brother both have a genetic condition that causes abnormal fingernail growth. One brother is a smoker with a high stress job in New York City whose abnormal fingernail growth requires trimming 2 times a day. The other brother is a marathon runner who lives in a cabin in the woods whose abnormal fingernail growth requires trimming once a week. Different expression of the same phenotype due to environmental factors is an example of ______.

Variable Expressivity Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype. The expression of the phenotype may be modified by effects of aging, environmental factors, or other genetic loci.

How can translocation cause cancer?

gene fusion events causing fusion proteins If a gene is translocated to another chromosome and fuses with another gene, they can create a fused protein that promotes tumorigenesis. The ALK oncogene is very common.

We know that mitoDNA and nuDNA are different, but what about their RNA?

mitochondrial mRNA has no cap and a short polyA tail. mitochondrial mRNAs are polycistronic wherase nuclear mRNAs are monocistronic.

A patient has been diagnosed with Ewing's Sarcoma. Karyotyping will reveal what event?

t(11:22)

The notion that cancer acts like a recessive mutation is the basis of _____.

the Two-Hit Theory The Two-Hit theory states that cancer arises as a result of two mutations to a cell's DNA, typically one hereditary and one environmental event lead to carcinogenesis.

Explain the ways in which mitochondrial DNA is different than Nuclear DNA?

- Circular - only has 37 genes - Polycistronic transcripts - Different genetic code

What are some easy ways to diagnose a Y-Linked Disorder on a pedigree?

-Affected Father -Only Males get it from their father -Disease doesn't skip generations If any females have the trait then it cannot be Y-Linked.

What are some easy ways to diagnose an Autosomal Dominant Inheritance pattern on a Pedigree?

-Affected fathers pass down to sons and daughters -Trait doesn't skip a generation ****An affected father passing down to a son is a very key clue distinguishing Autosomal Dominant from X-Linked Dominant****

What are some easy ways to diagnose an Autosomal Recessive Inheritance pattern on a pedigree?

-Most affected children have unaffected parents -Two unaffected parents can have an affected child -Traits can skip a generation

What are some easy ways to diagnose an X-Linked Dominant Inheritance pattern on a Pedigree?

-The trait doesn't skip a generation -Affected males die in utero -Affects half of females

What are some easy ways to diagnose an X-Linked Recessive inheritance pattern on a Pedigree?

-Unaffected individuals pass the trait on to an affected individuals. -Affected mother passes the trait on to all of her sons

A man has with a mitochondrial disorder has children with a healthy female. What are the chances that their kids inherit the mitochondrial disorder?

0% chance. Since the mother has a "normal" mitochondrial genome, all of their children will inherit it.

A male has recently been diagnosed with X-linked acrogigantism, an X-linked dominant disorder. What were his chances of inheriting this disease if his father had also been diagnosed? What were his chances if his mother was diagnosed?

0% from his father. 50% from his mother. Males (XY) don't inherit any X chromosomes from their fathers. In an affected mother, the male can either get the disease allele or the wild type allele.

If a colorblind male mates with an unaffected female, what is the probability that they will have an affected child? What is the probability that they will have a carrier?

0% of the children will be affected. 100% of the daughters will be carriers. The father is automatically going to pass his diseased X allele to his daughters. If the mother is a carrier, then there is a 50% chance that the female will be affected.

Both mitochondrial and nuclear genomes contain sections that code for proteins, however protein coding DNA makes up a different portion of each genome. What proportion of the nuclear genome codes for proteins? What proportion of the mitochondrial genome codes for proteins?

1.5% of the human genome. 93% of the mitochondrial genome. The mitochondrial genome has around 17k base pairs comprising 37 genes, the majority of which code for proteins. The nuclear genome has 3.2 billion base pairs, 30,000 genes, with only 1.5% of those coding for proteins.

A female has been diagnosed with X -linked acrogigantism, an X linked dominant disorder. What were her chances of getting this disorder if her father also had this condition? What if she inherited it from her mother?

100% from her father. 50% from her mother. X-linked dominant disorders only need one dominant allele in the genotype for the disease phenotype to occur. Since females (XX) always inherit one X from their father, an affected father will always pass the disease onto them. An affected mother can pass either the disease allele OR the normal allele to the daughter.

If two parents are heterozygous carriers of the Pompe Disease allele, what is the risk that one of their children will develop Pompe disease?

25% Pompe disease is an autosomal recessive condition in which both recessive alleles must be present in the genotype for disease phenotype.

The gene for color blindness is located on the X chromosome. What is the probability that a carrier mother and an unaffected father have an affected child? What is the probability that they have a carrier child?

50% chance that a male is colorblind. 50% chance that a daughter is a carrier. If the mother is a carrier, she has one normal and one "disease" allele. Since males (XY) only inherit their X chromosome from their mother, they have a 50% chance of getting the disease allele. Females (XX) get one X from their father and one X from their mother, so there is a 50% chance that one is a carrier.

If a man has Lynch Syndrome, what are the chances that his child will develop Colorectal Cancer?

50% chance that the child will inherit the mutation; 90% chance of developing cancer if inherited.

____% of people with mutated BRCA1 and ___% of people with mutated BRCA2 will develop breast cancer, however they only account for ___% of total breast cancer cases.

60% of BRCA1, 40% of BRCA2, 5% of total breast cancer cases.

A patient comes into clinic with slightly yellow skin tone and sclera. You suspect Gilbert Disease. Upon genetic testing, what would prove you right?

7 TA repeats in the TATA box of the UGT1A1 gene. Gilbert Disease is characterized by the buildup of bilirubin due to slow metabolism of bilirubin. If an individual has 7 dinucleotide TA repeats on both chromosomes at the UGT1A1 gene, they will have Gilbert disease.

An individual with Huntington's disease volunteers for fragment analysis. What difference could we expect to observe between his fragment analysis and someone with a "normal" phenotype?

A CAG peak shifted to the right for the HTT gene. In fragment analysis, the number of Trinucleotide repeats on a gene are shown by the peak. The more repeats, the further right the peak.

A 12 year old boy is admitted to the hospital with pain in his periphery and chronic low oxygen saturation. A blood smear is performed and shows that some of his red blood cells are sickle-shaped due to malformation of hemoglobin. What class of disease does he have?

A structural hemoglobinopathy. Hemoglobinopathies are genetic diseases of hemoglobin. Structural abnormalities are caused by mutations in the coding sequence that leads to a malformed Hb structure. In this case, the boy has HbS or sickle cell disease.

A 53 year old man has a colonoscopy wherein a polyp is discovered. A mutation in _____ causes excessive ______ buildup which leads to polyps.

APC proteins; B catenin APC proteins are landscaper TSGs. They lead to degradation of the gene promoter B-catenin. If APCs can't form complexes with B-catenin, B-catenin builds up and continuously stimulates cell growth. This leads to polyp formation.

You observe variegation in the eye color of a fly where some splotches are red and some are white. You know that if the pigment gene is inactive, then the cell will be white. If the pigment gene is active, then the cell will be red. Other than PEV, what could cause activation and deactivation of these genes?

Acetylation and Methylation of the histone tails around the gene DNA is wrapped in histone proteins that form a nucleosome. These histones have tails that can be altered to loosen or tighten the coiling. Acetylation loosens the coiling (euchromatin) allowing transcription factors to bind to the DNA. Methylation tightens the coiling (heterochromatin) which doesn't allow TFs to bind.

A cell is preparing for mitosis and is stopped at the G1 checkpoint. What general conditions must be satisfied before the cell can proceed through this checkpoint?

Adequate nutrition and space to divide At the G1 checkpoint, the cell asks "Do I have enough nutrition to keep growing?" and "Is there enough space to grow?", if both of these conditions are met, the cell will proceed into S phase.

A woman has a low level of heteroplasmy in a pre-oocyte. This pre-oocyte undergoes meiosis and a dizygotic fertilization occurs where two separate sperm cells fertilize two mature oocytes. Although they are twins, one of her children is born with a mitochondrial disease while one does not have the disease. Explain how this could occur?

Although her pre-oocyte had a low level of heteroplasmy, a large amount of mutant mitochondria went into one oocyte and a small amount went into the other during meiosis. This is called the sampling effect, similar to the founder effect. In the original population (pre-oocyte) there was a small proportion of mutant mtDNA. During meiosis, one of the cells randomly received a large portion of the mutant DNA and replicated it.

We want to uncoil a bunch of facultative heterochromatin for a very specific process, what would a writer, reader, and eraser do to histone tails in this process?

An eraser would demethylate histones, a writer might add acetylation, and a reader would assist in changing the state of the chromatin. Facultative heterochromatin makes up regions of the chromosome that are usually heterochromatin, but can be uncoiled for coding purposes. Erasers remove histone modifications, so we would want to remove methylations that increase coiling. Writers add modifications, so we would want to add acetylation to loosen the conformation. Readers interact with these modifications to either add more mods or change the state. For any histone, there are multiple writers and erasers that are highly regulated.

A 24 year old male presents in clinic with symptoms indicative of Huntington's disease. He states that his father had Huntingtons that developed when he was in his 60s. What processes lead to him developing symptoms earlier and seemingly only from his father?

Anticipation and Parental Bias Anticipation is where each generation either has more severe symptoms or a younger age of onset. In Huntington's disease, this is due to a generational increase in the amount of tandem repeats. 60 or more causes juvenile onset where 40 or more causes adult onset. The fact that he inherited an increase of these tandem repeats from his father is called Parental bias.

You've just read a paper that states there is an increased risk of hypertension, a polygenic disorder, in people of West-African descent. You set out on a quest to find the "hypertension" gene by studying the haplotypes of the entire population of West-African descendants and cross-reference it against people from the population that have hypertension. What method of quantitative analysis did you just use?

Association Mapping Association mapping allows us to look at the genetic information of the population as a whole by locating specific haplotypes. The assumption is that the "gene" is located within the haplotype and looks to see variations in the number of haplotypes between affected and unaffected individuals.

A patient that has excessive bleeding or café au lait lesions could have inherited a disease through which inheritance pattern?

Autisomal Dominant Inheritance Pattern These two symptoms are characteristic of Von Willenbrand Disease and Neurofibromatosis, two diseases in which presence of the Dominant gene in the genotype leads to diseased phenotype.

Explain how backwards slipped strand mispairing can lead to Huntington's disease.

Backwards slipped strand repair results in an extra repeated trinucleotide (CAG). Enough CAG repeats codes for a large enough portion of Glutamine that it causes misfolding and aggregation. This can happen in the HTT gene that eventually leads to Huntington's.

Genetic testing on a 3 year old male reveals no presence of transcription factors on both copies of chromosome 11 in somatic Bone-Marrow cells. What condition could be reasonably diagnosed? What symptoms would we expect to see?

Beta Thalassemia Major. The child would have severe anemia, signs of jaundice, and would need to be transfusion dependent for the rest of his life. If there is no expression of HbB, the child has two B0 alleles. B0 is the allele that results in no expression of B genes. B+ is reduced expression, BE is a structural variant. Presence of any of these alleles in a genotype can lead to either minor or intermediate B-Thal. Presence of two B0's leads to Major B-Thal.

How does mutation of the tumor suppressor genes and oncogenes disprove the Two-Hit Theory?

Both mutations are needed for tumor suppressors to inactivate, oncogenes must be activated. At least three hits to cause cancer

A newborn presents significantly larger than its age with an enlarged tongue. What can be said of the imprinting pattern in its chromosomes?

Both the maternal and paternal chromosomes are imprinted at the same location. These symtpoms indicate Beckwith-Weidemann Syndrome which is a result of overexpression of IGF2 growth factor. Imprinting the H19 gene causes the IGF2 gene to become active. Normal phenotypes have one parental imprint and one normal imprint. Children with BWS have two imprints, leading to an overproduction of growth factor.

Throughout normal fetal development, hemoglobin genes are expressed in chronological order. If researchers wanted to study Hb gene of the alpha and beta chains, where in the genome would they look?

Chromosome 11 (beta) and Chromsome 16 (alpha) Hemoglobin genes are expressed in different tissues at different stages throughout development. HbA is produced on chromosome 16 essentially right away. On Chromosome 11, HbGamma is produced largely until birth, then HbB production ramps up.

In mitosis the cell is stopped at the M checkpoint. What general conditions must be satisfied before the cell can proceed through this checkpoint?

Chromosomes are ready for equal segregation into two new cells The M checkpoint takes place during metaphase. At this point, the cell asks itself "Has mitosis proceeded appropriately?", if the answer up to that point is yes, the cell will enter anaphase, telophase, and finally cytokinesis.

Cystic Fibrosis is considered to be a heterogeneic disease. Mutations in different genes can cause dysfunction that ultimately lead to different disease phenotypes. These different phenotypes can be split up into different classes. If the CFTR protein is created and reaches the cell surface, but doesn't function properly, a person has ____ Cystic Fibrosis.

Class III Class I leads to no function CFTR created and Class V leads to insufficient CFTR protein. Refer to the picture for the rest of the classes.

You suspect 22q11.2 duplication syndrome in a patient. What test can you order to confirm this?

Comparative Genome Hybridization arrayCGH allows us to observe increases and decreases in copy number by hybridization intensity and number of genotypes. This technology can be used to find insertions and deletions that are just a few genes in size.

What is NuMT?

Copies of the mitochondrial genome inside of the nuclear genome There are several full copies of the mitochondrial genome present inside of the nucleus of every cell. This allows the cell to produce many mitochondria at once during replication.

You're working in a lab trying to isolate the two proteins that are present in the interphase checkpoints (G1 and G2). What do you expect to see in a normal cell at these checkpoints?

Degradation of pRB and p53 pRB is present at the G1-S checkpoint. When everything is signaled to proceed, the CDK/cyclin complex phosphorylates pRB which degrades it. Degradation releases transcription factors that stimulate S-phase genes. p53, on the other hand, is a transcription factor that synthesizes inhibitors that block cell entry into mitosis. When the cell is ready to proceed, p53 is degraded and the inhibitors no longer bind and the cell can enter mitosis. p53 is mutated in about half of all cancers.

Explain how targeted gene therapy may work for one individual with Osteogenesis Imperfecta but not another.

Different classes of Osteogenesis Imperfecta are caused by mutations to different genes. Diseases like OI, Cystic Fibrosis, SCID, and Dyskeratosis Congenita display Genetic Heterogenosity. Genetic Heterogenosit is where mutations in two different diseases can produce the same disease.

How do imprinted methylation patterns affect the next generation?

During production of sperm and eggs certain genes are methylated and some are not. This means some inherited genes from dad are turned off and some from mom are turned off. Once fertilization occurs zygotes have sites where a gene will only be expressed by either the maternal or paternal chromosome depending on which one is imprinted.

A 42 year old patient has just been diagnosed with breast cancer. What, if any, indications could there be that she has a mutation in BRCA-1 and 2 genes indicating inherited breast cancer?

Early age of onset, multiple cases of cancer in the pedigree, male breast cancer in the pedigree, triple negative breast cancer in the pedigree, a member of the Ashkenazi jewish population BRCA1/2 should be suspected in individuals with any of the above following and many more. However hereditary breast cancer makes up 5% of total breast cancer cases. Nearly 95% of them are sporadic tumors.

A patient has recently been diagnosed with Burkitt's Lymphoma. The presence of ______ in her medical history is a large part of the reason for developing Burkitts.

Epstein Barr Virus EBV is an oncovirus. Oncoviruses are retroviruses that contain oncogenes that embed into the genome upon reverse transcription. Oncogenes don't serve any purpose to the virus, but can cause the cell to divide irregularly and continue passing down the oncogene. Proto-oncogenes are homologous "normal" genes that can be mutated to become oncogenic.

Fresh blood has been found at the scene of a break-in where the burglar cut themselves on a window. The police have a suspect in custody. How can they be sure that their suspect is the burglar?

Fragment analysis of VNTR loci. Each person has a "DNA fingerprint" that is unique to their DNA only. DNA is analyzed for the number of VNTRs at 18 specific locations in the genome. By running a Fragment Analysis at all 18 locations and comparing them, we can see if the DNA are the same from the crime scene and in the suspect.

A patient has been diagnosed with Li-Fraumeni syndrome, what is the next step?

Genetic testing to determine if mutation is in p53 or CHEK2 p53 and CHEK2 are both gateway tumor suppressor genes. p53 is mutated in 70% of LFS cases. Genetic testing is important because LFS is a highly inherited disorder and it's important to monitor these genes in offspring.

Fetal genetic testing reveals a slight reduction of transcription factors on maternal chromosome 16, but the fetus seems completely healthy. Fetal O2 sat and paO2 are within normal limits and the fetus can be expected to grow into a happy, healthy human. How can this be?

Genotypes with one disease allele have a normal phenotype. There are two alpha genes on each C16, making 4 alpha genes between the two C16s. Presence of only 1 defective allele makes an asymptomatic carrier, which is what our patient would be. Presence of two or more results in microcytic and hemolytic anemia. All 4 defective alleles is incompatible with life.

A patient comes in for a regular checkup and during the social history states they have recently been traveling, skydiving, and plan to summit 5 Himalayan peaks within the next couple of years. This guy is clearly a risk-seeker and gravitates towards novel experiences. What could be different between his genome and the run-of-the-mill homebody?

He may have extra copies of the 48 bp repeat unit in the DRD4 receptor. The 48 unit repeat in the DRD4 receptor adds or subtracts a unit of the 16 amino acid repeat motif at the protein-interaction site of the dopamine receptor. More repeats means more dopamine can interact with the receptor, leading to a more intense dopamine rush. DRD4 is called the "novelty-seeking" gene.

The gene coding for proteins that comprise cones in the retina are present on the X chromosome. Males are _____ for this gene. Males with color-blindness are have _____ for the color-distinguishing trait.

Hemizygous. Haploinsufficiency. Hemizygous refers to having only one gene for a trait. Haploinsufficiency is the deleterious effect of not having two genes for a trait. In the case of colorblindness, a male who inherits a defective gene is hemizygous and haploinsufficient for the cone-producing proteins.

If a female was diagnosed with inherited RETT syndrome (X-linked dominant), which parent would she be more likely to inherit it from?

Her mother, because males with RETT syndrome die in utero. This is just an example of the fact that some X-linked diseases are only observed in females because they are fatal for males in Utero. In reality, the majority of individuals with RETT syndrome have spontaneous cases.

A pair of twins has undergone DNA fingerprinting through VNTRP detection that shows identical banding patterns. If concordance of a disease is high in these twins opposed to twins with different banding patterns, what does this tell us about the heritability value of this disease?

Heritability would be closer to 1 Identical banding shows us that these twins are monozygotic, meaning that they have identical genomes. Concordance is the condition wherein both twins have a disease. Heritability of 1 is a theoretical value stating that the phenotype is 100% determined by genetics. If twins with identical genomes are concordant, it points to a strong genetic component influencing the disease phenotype.

A cell is preparing to divide. In preparation, it creates multiple copies of the mitochondrial genome that create multiple mitochondria in order to meet the metabolic needs of the cell. A point mutation in one of the NuMT copies is transcribed while the other copies are identical to the mitochondria present in the cell. This cell would be considered _____ because it has more than one form of mtDNA in it.

Heteroplasmic Heteroplasmy refers to a cell that has more than one form of mtDNA present. Healthy cells can be heterplasmic; cell health depends on the amount of mutant genomes present.

The presence of one BRCA1 gene mutation in an individual is said to be the disease genotype, yet presence of the disease genotype doesn't necessarily mean the phenotype will be expressed. This leads to an Autosomal Dominant trait showing pedigree traits of an Autosomal Recessive. What underlying factors lead to this anomaly?

Incomplete penetrance and different Age of Onset Presence of the disease genotype without the disease phenotype means that factors besides genetics are influencing expression of the disease.

Genetic testing is done on Stephen Hawking as a part of his post-mortem biopsy. What genetic abnormality would we expect to see in brain tissue cells?

Increased number of 6 base repeats in the C9orf72 Gene Frontotemporal Dementia and ALS are caused by an increase in this 6 base repeat.

Inversions as polymorphisms refers to the varying amount of inversions observable within the human population. How do we detect novel inversions? After that, how do we search for these inversions in other members of the population?

Inversions are detected by looking at fusion boundaries. Normal sequencing of a chromosome yields specific amounts of base pairs at specific spots. We can detect an inversion by changes in base-pair in the middle of a known base-pair sequence OR by deletion of a gene. Once the new base-pair is found, we can use FISH to find it in other individuals.

A child reports for a checkup and upon visual examination has a large forehead and large ears. His mom states that he is having trouble learning and isn't at the "same level" as all of the other kids in his grade. Genetic testing would reveal ______ on his _____ chromosome.

Large amounts of trinucleotide repeats on his X chromosome. Large forehead and ears paired with intellectual disability is indicative of Fragile X syndrome. Fragile X males have greater than 200 CGG repeats in the 5'UTR; normal X chromosomes have 6-53 repeats. Southern Blot must be performed to definitively diagnose FXS.

A 24 year old man is diagnosed with acute leukemia. He reveals that his brother died of soft-tissue sarcoma three years earlier and that his mother died of brain cancer at the age of 37. This patient's history indicates _____.

Li-Fraumeni Syndrome Li-Fraumeni Criteria should be suspected when pt has a tumor that belongs to the LFS tumor spectrum before age 46 and a second LFS tumor later OR if a 1st or 2nd degree relative has a LFS tumor before age 56 (except breast)

Genome sequencing of a man with a novel genetic disorder has tracked the change down to a one nucleotide difference between him a healthy counterpart. While it's still too early to tell, researchers believe that this variant can be the factor leading to negative phenotypes in his disease. What category would we place this variant in?

Likely Pathogenic Pathogenic variants have clinical evidence that an SNP will cause disease symptoms. Likely pathogenic variants haven't been studied extensively, but researchers believe they may cause disease. VOUS are completely unknown. Likely Benign variants are SNPs that are untested, but are unlikely to change a proteins behavior. Benign variants have clinical data showing there are no deleterious effects.

A 30 year old banker and mother of three is referred to a genetic counselor for strong family history of colorectal and uterine cancers. What syndrome should you test for?

Lynch Syndrome Lynch syndrome is the most common form of inherited colorectal cancers. The general population has a 6% risk of developing colorectal cancer while individuals with Lynch Syndrome have an 80% risk.

Since mitochondria have an entirely different genome than the rest of the cell, what does a pedigree of mitochondrial inheritance look like?

Males and Females inherit mitochondrial genomes through Females only.

During an eye exam, you notice abnormal, dark pigment deposits in the retina consistent with Retinitis Pigmentosa. What phenotypes could you expect to see in an individual with Retinitis Pigmentosa?

Malformed peripherin-ROM1 protein complexes. Retinitis Pigmentosa has a digenic inheritance. Digenic inheritance involves only two gene loci. ROM1 and Peripherin must form functional complexes for a normal phenotype to arise. RP can be caused by homozygous mutations in either loci, or a single allele mutation at both loci. One mutant allele at either loci results in normal phenotype.

HsInv0379 is an inversion that knocks out the transcription factor of its gene, resulting in a deleterious effect. Geographical tracking of the inversion reveals that it is prevalent in populations all over Southeast Asia. How is it possible that an inversion that deletes the function of a gene can still be held in a viable human genome?

Many inversions are benign or only slightly deleterious. Deleterious inversions, like the exon swap between chymotripsinogen genes on C16, aren't always incompatible with fitness. In the case of chymotripsinogen, there are at least 3 other genes to compensate if this inversion knocks out the gene.

A child has intellectual disability, ataxia, seizures, and an atypically happy disposition. What are three possible chromosomal events that could lead to this condition?

Maternal Deletion of 15q13, Paternal UPD, and a Maternal Imprinting Defect. This is Angelman Syndrome. Angelman occurs when there is lack of correct gene dosage on the maternal side of 15q13.

A gene is that is present in euchromatin has just been randomly silenced. None of the histones have been methylated, but there is a methylating protein nearby. If the methylating protein didn't act on the histone, how could it have silenced the gene.

Methylation of a CpG island CpG islands are regions near the promoter of genes that contain > 50% C-G dinucleotide repeats. These repeats can be methylated to turn off promotor regions of genes. DNA Methyltransferases are responsible for methylating CpG islands.

DNA is isolated from a eukaryotic cell and banded for a specific sequence of repetitive DNA. Satellite bands are isolated and placed through gel electrophoresis. What type of DNA would we expect to find at the bottom of the gel? What would we find at the top?

Microsatellite DNA at the bottom. Satellite at the top. Microsatellite DNA consists of 1-6 bp repeats or short tandem repeats. Since these are smaller, they would be at the bottom of the electrophoresis gel. Satellite DNA has repeating units of 5-300 bp that tend to be heterochromatic. Centromeric DNA and Telomeric DNA are examples of Satellite DNA. Minisatellite DNA would be in the middle and are also referred to as VNTRs. recall the VNTRs were used to compare genomes of twins because they're the "DNA fingerprint"

Immunohistochemistry is one way to test for Lynch Syndrome, what is the other?

Microsattelite Instability Testing A peak shift in 2 or more loci shows High microsatellite instability. Luckily, MMR deficiency tumors are easy to kill with chemotherapy.

70% of Lynch Syndrome Families have germline mutations in ____ genes. How do we test for Lynch Syndrome?

Mismatch Repair Genes You test for Lynch Syndrome by taking a biopsy and of the tumor and using Immunohistochemistry to assess the activity of the four mismatch repair proteins.

If all cells (except for a few special ones) in the human body have a mitochondria, it would be safe to assume that all cells in every human body, male or female, have an inheritable mitochondrial genome. Why is it that mitochondria are only inherited through the female line?

Mitochondria in sperm cells only provide energy to their flagella for movement. When the head fuses, the mitochondria in the tail is left behind.

It is theorized that mitochondria in eukaryotic cells were once single-celled organisms that were engulfed by proto-eukaryotic cells. Mitochondria function was incorporated into the cell and eventually led to the symbiotic relationship that we see in all eukaryotic cells. Where do we see evidence of this symbiotic relationship today?

Mitochondrial-Nuclear Crosstalk There are ~1500 proteins encoded by nuclear DNA that assist mitochondrial function including ETC subunit assembly and matrix enzymes. At the same time, there are ~13 proteins encoded by Mitochondrial DNA that are integral to cellular survival (electron transport chain).

"Heart Disease" is a polygenic condition that has varying genetic as well as environmental factors. "Heart disease" is considered a _______ disease.

Multifactorial Polygenic traits that have an environmental modifier are multifactorial. Because of the environmental component, multifactorial diseases can occur in isolation and can be influenced by ethnic group.

How do we find mutations in tumor cells?

Next Generation Sequencing NGS maps tumor chromosomes and finds where the gene is mutated. A higher peak of mutation could indicate a driving mutations. Sequencing of Colorectal vs Breast cancer shows us that there are multiple ways that tumors can become cancerous. Since they are from different tissues, there may be different targeted ways to eradicate them.

Explain the imprinting pattern associated with Prader-Willi or Angelman syndrome.

On chromosome 15q11-13 there are identical genes on the maternal and paternal chromosomes that are each imprinted differently, giving a correct gene dosage of 1 of each gene. A normal phenotype has 1 dose of each gene. In the event of either uniparental disomy (2 of one gene, 0 of another) or a deletion (1 of one, 0 of another), Prader Willi or Angelman Syndrome will occur depending on loss of the paternal gene or maternal gene respectively.

A random sample of Americans yields a wide variety of skin pigmentation. Genetic evaluation shows that there isn't one specific gene leading to this phenomenon. This is because the skin pigmentation is a ______ trait.

Polygenic Polygenic traits are also called continuous or qualitative traits. These traits occur over a wide spectrum because they're influenced by the expression of multiple interplaying gene loci. Height is another polygenic trait. The opposite of polygenic is monogenic, meaning that there are usually two observable phenotypes that are influenced by one gene locus (widows peak).

There are many factors, both genetic and environmental, influencing cholesterol levels in the blood. High levels of cholesterol are considered disease-related level because they start to have negative effects on the body. For a polygenic trait like cholesterol levels, how do we set the "disease" phenotype?

Polygenic Thresholds Since quantitative polygenic traits exist on a spectrum, thresholds are set to qualify disease-related conditions. For cholesterol levels, any blood level > 240 mg/dL is considered "high" and can be related to many negative consequences.

You're tending your houseplants when you see two of the same species of plant that have been kept in the same conditions have differing heights. You extract the DNA and use chromosome banding while observing the phenotypes. You do this through multiple generations of directed mating until you have finally found the "height" gene locus. What method of quantitative analysis did you just use?

QTL Mapping QTL mapping is based on finding a linkage between phenotype and a genomic "signpost". In eukaryotic organisms, you study families with the disease and compare them to "normal" phenotypes, then use directed mating and chromosomal analysis to figure out the gene locus. It works best for short-generation organisms.

The ability to roll ones tongue is a discrete and easy to measure phenotype. It's characterized primarily by genetic influence and easily identifiable by simply observing someone perform the action. The ability to roll ones tongue is considered a _____ trait.

Qualitative (discontinuous) Qualitative traits are monogenic, easy to measure, aren't affected by the environment, and show Mendelian inheritance.

A 2 year old girl presents with progressive left esotropia. Ophalmologic exam reveals a tumor in the retina and DNA analysis shows a nonsense mutation in one allele of her RB1 Gene. What condition does this girl have?

Retinoblastoma. Retinoblastoma is caused by mutations in pRB, the gatekeeping tumor suppressor gene. Both alleles need to be mutated for malignancy. If found, other family members need to be tested to see if they have alleles. For some reason the tumor can't develop past age 7. 60% of cases are sporadic, 40% of cases are inherited.

A woman goes to a geneticist because her brother was just diagnosed with schizophrenia and she wants to know her risk of developing it. A pedigree is obtained and it is ascertained that she has a low relative risk ratio. What does this mean?

She has a low degree of familial aggregation for Schizophrenia. Familial aggregation is a measure of how many "bad genes" for a polygenic disorder are passed down from family member to family member. By calculating the prevalence of the disease in relatives and dividing it over the disease prevalence of the general population, we can get relative risk ratio. If her brother has children, they will have higher disease risk because, through familial aggregation, they have a high risk of receiving "bad genes" directly from their father.

An unbalanced Robertsonian translocation leads to a partial trisomy of the chromosome carrying the PMP22 gene. Explain the effects of this translocation.

The child will develop Charcot-Marie-Tooth Disease. 55% of all genetically diagnosed CMT cases are caused by a duplication of the Pmp22 gene. The negative effects of a partial trisomy or monosomy aren't due to the chromosomes themselves, but rather the amount of genes on those chromosome present in an individual.

How do epigenetics play a role in prostate cancer?

The degree of chromatin relaxation can allow for transcription of tumorigenic factors.

A cell is preparing for mitosis and is stopped at the G2 checkpoint. What general conditions must be satisfied before the cell can proceed through this checkpoint?

The genome must be properly duplicated and free of mutations At the G2 checkpoint, the cell asks "Did I replicate and repair correctly?" If these conditions are met, the cell will proceed into mitosis.

A woman has a low level of heteroplasmy in a pre-oocyte. This pre-oocyte undergoes meiosis and a dizygotic fertilization occurs where two separate sperm cells fertilize two mature oocytes. Why can one twin inherit a mitochondrial disease if both twins are inheriting heteroplasmic cells?

The negative effects of heteroplasmy are dosage-dependent. Each disease has its own "threshold" of mitochondrial mutants that cause the disease phenotype to arise. If the amount of mutants is under this threshold, the person will be healthy for the most part.

A patient comes into clinic for a regular checkup. Their medical history shows ADHD and they admit to cocaine and alcohol abuse. Their family history shows an increased risk ratio of Parkinson's disease. What could be different between his genome and another persons?

The number of 40 bp tandem repeats in the 3'UTR of the DAT1 mRNA. The Dat1 gene codes for a dopamine transporter. Studies have shown that the number of repeats of a 40bp unit in the 3'UTR have both behavioral and physiological effects.

You observe variegation in the eye color of a fly where some splotches are red and some are white. You know that if the pigment gene is inactive, then the cell will be white. If the pigment gene is active, then the cell will be red. Wild type eye color is red, what is one possible cause of eye-color variegation in this fly?

Translocation of the gene to a facultative heterochromatin region. In Position-Effect Variegation (PEV), the translocation of a coding gene from a euchromatin rich region to a heterochromatin rich region can lead to silencing of the gene. When the gene was in the euchromatin rich region, it was active, presenting red. Some cells had translocations that silenced the gene, so they turned white.

Alkaptinuria is one of many inherited diseases caused by the defect of a single gene. This inheritance pattern is an example of ____.

Unifactorial Inheritance A disease that's caused by a single gene results in the most simple pattern of inheritance because it is so easily trackable. There are more than 16,000 single-gene disorders that lead to Unifactorial Inheritance patterns.

Regions of Asia that have been historically vegetarian have been compared to regions that rely heavily on hunting and fishing for their source of protein. What changes could we expect to see in their genomes?

Vegetarian regions could expect to have more copies of the amylase gene. People from regions of the world that have a high-starch diet have more copies of the amylase gene than people with a low-starch diet. This is an example of Copy Number Variants throughout the human genome. The amount of copies of a gene can affect gene expression.

All women are mosaics. Why?

Women have 2 X chromosomes while men have 1. In order to compensate for gene dosage, 7-10 days after fertilization the X-ist gene is expressed activating lncRNA. Xist RNA recruits histone binding proteins that supercondense the chromosome shutting everything off except for the PAR. The X chromosome that gets shut off is completely random, resulting in some cells expressing a maternal X and some expressing a paternal X.

A 42 year old female has recently tested positive for breast cancer. Her family pedigree shows multiple generations with breast or ovarian cancer. Is it reasonable for her children to undergo genetic testing?

Yes, because the cancerous mutations are inherited. Early age of onset (<50), multiple generations having cancer, and a clustering of certain cancers are all indicators of Inherited cancer. Inherited cancer simply means that one or more mutations have been passed down, making the individual more likely to acquire further mutations.

Theoretically, if a nuclear mRNA made it into the mitochondria and was able to undergo translation, would the protein look any different?

Yes, the genetic code is different between the two genomes. In the mitochondrial genome, AUA codes for methionine not isoleucine, UGA encodes a tryptophan not a stop codon, and AGA and AGG are stop codons rather than arginine. This could lead to malformed proteins.

A patient has been diagnosed with CML leukemia. A karyotype of their genome would most likely show ______.

t(9:22) Translocation of a portion of the 22nd chromosome to the 9th is called the Philadelphia Chromosome. The Philadelphia Chromosome was the first discovery of a genetic mutation associated with cancer. This is caused by the fusion of two genes from the two different chromosomes.