Problems Section 1 1. Chromosomal disorders do not manifest disease until late in life. A. True B. False 2.

Genetic counselors currently do the majority of genetic counseling for patients A. true B. false 6 mercaptopurine has !een used successfullly to treat acute lymphocytic leu"emia and inflammatory diseases# li"e Crohn$s syndrome. %o&e'er# 1 in 3(( indi'iduals ha'e a to)ic reaction. There has !een signficant discussion a!out getting the F*A to re+uire appropriate la!eling. ,hy is thatA. 6 mercaptopurine ta"en &ith certain foods is to)ic B. .ndi'iduals &ith sic"le cell anemia cannot ta"e 6 mercaptopurine C. /atients &ith homo0ygous mutations in the T/1T gene ha'e a to)ic reaction to 6 mercaptopurine A patient is found to ha'e a mutation for %3/CC# hereditary non polyposis colon cancer and !ased on his pedigree# it is inherited# i.e it is found in other family mem!ers. %o& do you counsel him to deal &ith his genetic diseaseA. 4ncourage him to tell his family B. Contact all of his first degree relati'es and ad'ise them to !e tested C. Treat the disease and forget a!out the genetics

3.

2.

Problems Section 2 1. How would the genetic content of the somatic cells of individual A, who is the product of a meiotic nondisjunctional event, differ from that of B, who experienced a mitotic error early in development? Avoid consideration of exceptional cases. a. b. c. d. As cells would be genetically heterogeneous; Bs cells would be genetically homogeneous. As cells would be genetically homogeneous; Bs cells would be genetically heterogeneous. As and Bs cells would be genetically heterogeneous. As and Bs cells would be genetically homogeneous.

2. How may these patients differ clinically, assuming the same autosome is involved in each case? a. b. c. d. A and B would develop clinical symptoms of similar intensity. A would be clinically affected, but B would be normal. A would be clinically affected. The degree of abnormality in B would depend upon the proportion of aneuploid cells present. B would be clinically affected, but A would be normal.

3. A man and woman have a daughter with Turner syndrome (45,X). The glucose-6-phosphate dehydrogenase genotypes of this family are: Father: G6PDA Mother: G6PDBG6PDB Daughter: G6PDA

G6PD is X-linked. During which stage(s) of meiosis could nondisjunction have occurred? a. b. Anaphase I in the father Anaphase I in the mother c. d. Anaphase II in the father Anaphase II in the mother chromosome. Select

4. Two of the following techniques have proven useful in accurately identifying each the appropriate methods. a. b. c. d. Autoradiography G-banding FISH C-banding

5. Schematically outline meiosis in a male using one pair of autosomal alleles (A and a) and the sex chromosomes (X and Y). If a encodes an abnormal protein, predict the proportion of normal and anomalous gametes. a. b. A,X; a,Y A,X; a,X; A,Y; a,Y c. d. a,X; A,Y A,X; a,X; A,Y

6. A female infant has trisomy (triplication) of chromosome 10. How would you express her karyotype according to standard nomenclature? Assume there are no other abnormalities in her karyotype. a. b. 46,XY,+10 47,XY,+10; 46,XY c. d. 46,XX; 47,XX,+10 47,XX,+10

7. Anaphase lag refers to loss of a chromosome during meiosis or mitosis due to failure to migrate to the proper pole of the dividing cell. Which of the following children most likely originated following mitotic anaphase lag? Semicolons separate karyotypes of different cell lines. a. b. 46,XX ; 45,XX,-21 47,XX,+21 ; 45,XX,-21 c. 46,XX d. 47,XX,+21

8.You have received a report from a clinical cytogenetics lab stating that one of your patients has the karyotype: 46,XX,del(18)(q12). What does this mean? a. b. c. d. Male with a deletion of the short arm of 18 distal to band 12 Female with a deletion of the short arm of 18 distal to band 12 Male with a deletion of the long arm of 18 distal to band 12 Female with a deletion of the long arm of 18 distal to band 12

9.

If this patient was fertile, how would you counsel the patient relevant to future children? Assume that there is no mosaicism for the alteration specified in (15), and that the alteration is present in the gametic cell line. a. b. c. d. The defect is sporadic and will not recur. About half of the male children only will inherit the same alteration. About half of the children, regardless of sex, will inherit the alteration. All of the children will inherit the alteration.

Problems Section 3 1. A patient with a rare inherited syndrome was found to have 10% of normal enzyme X activity. Isolation and characterization of the erythrocyte form of the enzyme indicated that the mutant protein differed from its normal counterpart by a single amino acid substitution. The syndrome a. b. c. d. 2. is due to a regulatory gene mutation. is caused by the presence of an inhibitor. is the result of an exonic base substitution. resulted from a failure in hormonal induction of gene activity.

Based upon your knowledge of biochemistry and genetics, which of the following observations would indicate that a hormone was specifically inducing enzyme A activity? a. b. c. d. An increase in enzyme A activity An increase in mRNA, rRNA, tRNA, and enzyme A activity An increase in enzyme A mRNA and enzyme A activity Accumulation of the hormone in the nucleus and the changes observed in 2b.

Questions 310: Match the following with their appropriate functions in the cell.
3. r53A a. .nitiates protein synthesis

4. 5.
6.

Polysome Promoter
%n53A

b. c.
d.

Shuttles amino acids to ribosomes Pool including nuclear mRNA precursors

Contains *3A elements influencing transcription of a gene

7. 8.

tRNA Methionyl tRNA

e. f.

Aggregate of mRNA and ribosomes Structural component of ribosomes Orders amino acid sequences of proteins Chain terminators

9. 10. 11.

UAA, UAG, UGA mRNA

g. h.

Outline transcription and translation using the appropriate base abbreviations and three code words. Start with DNA: AGCTCCAAA and use the table of the genetic code in your biochemistry textbook.

12.

HbZ has an altered -chain. The amino acid sequence is normal from residue 1 to residue 46 and from residue 70 to the end of the chain. Residues 4769 do not match sequences from any known normal hemoglobin chains. How may this mutant hemoglobin arise? a. b. c. d. e. Substitution of a base in codon 47 Insertion of a base into codon 46 Deletion of a base from codon 47 Insertion of a base into codon 47 and deletion of a base from codon 69 Deletion of a base from codon 47 and insertion of a base into codon 69

13.

Arylsulfatase A is deficient in patients afflicted with the progressive neurological disease, metachromatic leukodystrophy. You have successfully purified this enzyme and have prepared a specific antibody against it. You find that immunotitration of extracts of cells cultured from the patients skin demonstrates very low levels of arylsulfatase A protein. Mutations involving which of the following DNA sequences would explain the low levels of arylsulfatase A protein in this patient? a. b. c. d. The promoter of the arylsulfatase A transcriptional unit. An exon of the arylsulfatase A transcriptional unit. A gene affecting the intracellular distribution of arylsulfatase A. An exon-intron splice junction of the arylsulfatase A transcriptional unit.

14.

Which of the following structures appear to be physical manifestations of the inactive X chromosome in interphase nuclei? a. b. Barr body Nucleolus c. d. Y body Sex vesicle

16.

The genetic code consists of triplets deri'ed from four different !ases. The 7degeneracy8 of the code may generally !e attri!uted to 'ariation in

a. b. c. d.

the first nucleotide of the triplet. the second nucleotide of the triplet. the third nucleotide of the triplet. all three nucleotides.

16.

A simple human gene is illustrated in the above diagram. This gene is transcribed from left to right. A mutation at the position of the arrow (asterisk = ATG) would most likely affect a. b. c. efficiency of transcription. accuracy of transcription. processing of the pre-mRNA. d. e. stability of the mRNA. initiation of mRNA translation.

Problems Section 4 1. Given that base analogs result in the replacement of existing bases in DNA, predict the effect of such a substitution at the molecular level.
a. A ne& amino acid may !e inserted at the corresponding point in the polypeptide

b. c. d. 2.

Chain termination may occur such that an incomplete polypeptide is formed. No change may result. A shift in the reading frame may occur. failed?

Why have most attempts to improve the fitness of organisms through induced mutations a. b. c. d. Mutagens are typically nonselective in their points of action. Most mutations are harmful. Inappropriate experimental systems have been used. Mammals are highly sensitive to these mutagens.

Questions 37: Match the following mutagens with their nuclear effects.
3. 9 rays a. Thymine dimers

4. 5. 6. 7.

Ultraviolet light Nitrogen mustards Base analogs Nitrous oxide

b. c. d. e.

Base substitution Alkylation Ionizations Intercalation

Question 8: True or False 8. The degree of radiation damage is greater in mitotically or meiotically dividing tissue than in nondividing tissue. A mutant -globin chain from a patient with hemolytic anemia contained 157 amino acids rather than the normal 146. The amino acid sequence of the mutant -globin chain was identical to the normal chain through amino acid 135; however, the sequences after that point were markedly different. Describe the mutation most likely responsible for this patients disease. The following patterns are observed for a DNA polymorphism after digestion of genomic DNA with the restriction enzyme Eco RI: in males, a fragment of either 9 or 11 kB; in females a fragment of either 9 or 11 kB or both. What is the likely origin of these patterns?

9.

10.

Problems Section 5 1. A woman with facioscapulohumeral muscular dystrophy (FMD), an autosomal dominant trait, is seeking advice on having children. Her husband, who is 28 and normal, has an uncle with Huntingtons disease (HD; autosomal dominant). His parents are normal, and both are over 50. Symptoms of Huntingtons disease may appear from 12 to 65 years after birth; however, all HD members of his fathers kindred developed signs during their thirties. HD and FMD are fully penetrant. What are the genetic risks for this couples children?
a. 6(: F1*# 6(: %* d. 1((: F1*# (: %*

b. c. 2.

50% FMD, 0% HD 0% FMD, 50% HD

e.

50% FMD, 25% HD

Tuberous sclerosis is characterized by adenoma sebaceum (facial rash across bridge of nose), epilepsy, mental retardation, and risk for multiple tumors. The disease frequently causes early death, usually before age 21. Although penetrance is close to 100%, the disease is quite variable in expression. The disease is inherited as an autosomal dominant and affects about 1/10,000 persons. A normal woman with a slight reddening across the bridge of her nose has one child with the severe disease. What is her risk for a second affected child? a.
!.

About 0
1(:

d.
e.

50%
1((:

c. 3.

25%

Demonstration of allelism in humans is difficult. Assume that two traits are codominant. Which of the following tests would be most helpful in suggesting they are determined by allelic genes? a. b. c. d. e. Failure of a person with both traits to transmit both to the same child Lack of occurrence of both traits in the same person Lack of a doubly affected child among offspring of two parents, each of whom has only one of the traits. Absence of normal children from marriages of doubly affected individuals to normal individuals. Both a and d above

Question 4: True or False 4. A normal ancestry indicates that a trait is not hereditaryeven if two or more affected siblings are present in a family.

5.Sickle cell trait describes individuals who are heterozygous for normal hemoglobin HbA and sickle cell hemoglobin HbS, ie, they are HbS/HbA. Two people have sickle cell trait and marry. Predict the possible phenotypes of their children and their frequencies. Note: sickle cell anemia occurs in HbS homozygotes. a. b. c. d. e. 6. 1/4 sickle cell trait, 1/2 sickle cell anemia, 1/4 normal 1/2 normal, 1/2 sickle cell anemia 1/2 sickle cell trait, 1/2 sickle cell anemia 1/2 normal, 1/2 sickle cell trait 1/4 normal, 1/2 sickle cell trait, 1/4 sickle cell anemia

Phenylketonuria is a disease resulting from lack of the enzyme, phenylalanine hydroxylase. The clinical symptoms of mental and growth retardation, microcephaly, seizures, and eczema are limited to untreated homozygotes. Heterozygotes have intermediate levels of enzyme activity in liver extracts. Select the correct statement(s). a. b. c. d. e. Phenylketonuria is a recessive disease. Phenylketonuria is a dominant disease. Phenylketonuria is a polygenic trait. The effects of the normal allele are dominant to those of the abnormal allele. Both a and d above

7.The genes encoding the variant chains in HbS and HbC are allelic. Homozygosity for either gene results in anemia, with HbC disease being much less severe than sickle cell anemia. Heterozygosity for either allele and the allele determining the normal chain in HbA results in a normal phenotype. What would you predict for the S C heterozygote? a. b. c. d. e. No disease Anemia of intermediate severity with respect to sickle cell anemia and HbC disease Mild problems like HbC disease Sickle cell trait This combination of alleles would be fatal

8.A syndrome characterized by multiple congenital malformations and mental retardation was observed to occur twice in this kindred. What type of inheritance?

a.

Autosomal dominant

c.

Autosomal codominant

b.

Autosomal recessive

d.

Autosomal dominant, 2 loci

9. What type of inheritance is responsible for transmission of trait C in this pedigree:

a.
!.

Autosomal dominant
Autosomal recessi'e

c.
d.

Autosomal codominant
Autosomal dominant# 2 loci

10.

A man has been working as an X-ray technician at a community hospital. He and his wife recently had a baby born with cystic fibrosis, an autosomal recessive disease. The man has brought suit against the hospital and radiologist, claiming that his occupational exposure to X-irradiation is responsible for the disease in their child. He supports his claim by saying there is no history of cystic fibrosis in his nor his wifes families. As presiding judge in this case, how would you rule and why?

Problems Section 6 1. The GYPA blood group contains three common phenotypes: M, MN, and N. Calculate the frequencies of the GYPAM and GYPAN alleles, if there are 600 M, 1,200 MN, and 200 N individuals in the population. Let p = the frequency of GYPAM and q = the frequency of GYPAN. a. b. c. 2. p = 0.4, q = 0.6 p = 0.5, q = 0.5 p = 0.65, q = 0.35 d. e. p = 0.6, q = 0.4 none of the above

Which of the following diseases tend to be unequally distributed (more frequent in certain populations than in others) among human populations? a. b. c. G6PD-deficiency Tay-Sachs disease Sickle cell anemia d. e. Cystic fibrosis All of the above

3.

What factors may account for your answer in (2)? a. b. c. d. Large differences in mutation rates between populations Selective advantage of the heterozygote Genetic drift in small founder populations or inbred groups Experimental error in determining gene frequencies

4.

Trait A is an autosomal dominant exhibiting 80% penetrance. Twenty-four affected children out of one million born to normal parents were observed over a period of 20 years at major hospitals in a western country. What is the apparent mutation rate? a. b. c. 3 x 10-5 1.5 x 10-5 2.4 x 10-5 d. e. 1.2 x 10-5 1.9 x 10-5

5.

Do you feel your estimate in question 4 is biased? a. b. c. d. No. The estimate is correct. Yes, because of the possible lack of penetrance in the parents, some of the abnormal alleles were not mutations. The estimate may be too high. Yes, because of the selection of major hospitals only, a bias toward an overestimate or underestimate may be present. Yes, because of the lack of penetrance in the children, some of the mutations may have been missed. The estimate may be too low.

6.

A population has the following ABO blood group distribution: A = 4,900, B = 1,000, O = 4,000, AB = 100. Calculate the frequencies of ABOA (= p), ABOB (=q), and ABOO (=r). p a. b. c. d. e. 0.32 0.50 1.00 0.30 0.49 q 0.05 0.20 0.20 0.60 0.11 r 0.63 0.30 1.00 0.10 0.40

7.

Phenylketonuria occurs with a frequency of approximately 1/15,000 in Illinois (Illinois Department of Public Health). What is the frequency of heterozygotes in this state? a.
!.

1/7,500
1;1#(((

d.
e.

1/62
1;26

c.

1/123

Question 8: True or False 8. 9. Selection against the heterozygote will favor the more common allele. Heterozygous advantage is believed to maintain stable polymorphisms in which the frequency of the rarer allele exceeds 1%. Which of the following diseases may be maintained by stable polymorphisms? a. b. c. d. 10. Cystic fibrosis (aut. rec., 1/2,500) PKU (aut. rec., 1/15,000) Huntington's disease (aut. dom., 1/20,000) G6PD-deficiency (X-linked rec., 1/10 males of Asian, African, or Mediterranean ancestry)

Neighboring Indian tribes in Utah have quite different ABO frequencies. Tribe 1 is 100% Type O, and Tribe 2 is 95% Type A. Cultural barriers prevent marriage between the tribes, even though they are only a few miles apart. What factor is most likely responsible for the difference in allele frequencies? a.
!.

Selection
1utation

c.
d.

Genetic drift
3one of these

11.

Given that Duchenne muscular dystrophy is an X-linked recessive illness, that the hemizygous males are unable to reproduce, and that 1/3 of all X chromosomes are in males, calculate the frequency of this trait in males if the mutation rate is 1/25,000. Assume this population is at equilibrium. a.
!.

1/75,000
3;26#(((

c.
d.

1/100,000
1;2((#(((

12.

Suppose you are practicing where first cousin marriages are legally permitted. Two first cousins come to you for counseling, since they intend to marry. Their common grandfather is known to be heterozygous for an allele that causes severe mental retardation in homozygotes. What is the chance that their child will inherit two copies of this allele, both derived from the grandfather? a. b. 1/4 1/8 c. d. 1/16 1/64

13.

What is the inbreeding coefficient for an aunt-nephew marriage? a. b. 1/4 1/8 c. d. 1/16 1/32

14.

How is this value interpreted? a. b. c. d. It represents the proportion of heterozygous loci in a common ancestor (with respect to parents of child) rendered homozygous in a child by descent. It is the chance that an inbred child will inherit a deleterious dominant gene from an ancestor. It is the chance that an inbred child will develop a recessive disease caused by an allele present in an ancestor. This is the chance that a given locus heterozygous in a common ancestor will be rendered homozygous in a child by descent.

15.

Genetic differences among races generally reflect a. b. c. d. presence or absence of alleles in one race, but not another. differences in relative frequencies of alleles among the races being compared. the effects of migration, isolation, and divergent evolution. the effects of diverse environments upon allele frequencies.

Problems Section 7 1. True or False: Maternal serum alpha fetoprotein levels are diagnostic for neural tube defect.

2.A woman and her husband are carriers for the autosomal recessive disorder Tay-Sachs disease, thus, both have mutant HEX A genes and have requested first polar body diagnosis. PCR and DNA analysis have revealed the presence of a normal HEXA allele in the polar body. How would this result be interpreted? a. b. c. d. The oocyte also has the normal allele. The Tay-Sachs allele is in the oocyte. The oocyte contains both the normal and Tay-Sachs alleles. HEXA alleles are absent from the oocyte.

Questions 3-9. Match the following screening methods with the disease they are designed to detect. 3. 4. 5. 6. 7. 8. 9. Method of obtaining fetal blood for karyotyping Usual time at which amniocentesis is performed a. c. RH immune globulin b. 10th week of pregnancy cordoentesis d. mosaicisim 16th week of pregnancy f. alpha feto protein in materal serum aneuploidy cystic hygroma Chrorionic villus amniotic fluid

Increased level when fetus has a neural tube defect e. Contains fetal cells viable in culture Risk increases with maternal age Usual time at which CVS is performed Derived from extraembryonic tissue g. h. i. j.

10. A maternal serum screen performed on a pregnant woman shows reduced MSAFP, reduced unconjugated estriol and increased human chorionic gonadotrophin, you do which of the following: a. suspect a neural tube defect and order an ultrasound b. suspect down syndrome and order ultrasound to confirm age of the fetus, note the maternal age and suggest amniocentesis c. diagnose the fetus as having Edwards syndrome d. order additional screens like pregnancy associated plasma protein

Problem Section 8
1. ,hich of the follo&ing chromosomal a!errations is;are more fre+uently in a!ortice series than in li'e!orn populations-

a. Sex-chromosomal trisomies b. Triploids 2.

c. d.

X-monosomy Trisomy 21

Laboratory studies have revealed the following groups of mothers. The mothers karyotype is provided at the left of the semicolon, and the babys at the right. A (/) separates karyotypes of two different cell lines in the same person. Assume all mothers are under 30 years of age. a. b. c. d. 46,XX ; 47,XY,+21 45,XX,-14,-21,+t(14q21q) ; 46,XY,-14,+t(14q21q) 45,XX,-21,-21,+t(21q21q) ; 46,XX,-21,+t(21q21q) 46,XX (90%)/47,XX,+21 (10%) ; 47,XY,+21

Rank the mothers in order of increasing risk of recurrence of Downs syndrome. a. b. c. d. abcd dabc cbda adbc

Questions 3: True or False 3. Young mothers with two Downs syndrome children are victims of fate and need not worry about having a third Downs syndrome child until after age 40.

2.

A man is a !alanced carrier for a 13;12 5o!ertsonian translocation. *iagram the di'ision figure that &ould !e o!ser'ed at 1etaphase . of meiotic di'ision.

5. 6.

List the chromosome combinations of gametes derived from adjacent and alternate segregation in his cells. True or False: This man has a slightly elevated risk for having a child affected with Patau syndrome.

Questions 7-11: Match the following karyotypes with their appropriate syndromes. 7. 8. 9. 10. 11. 47,XX,+21 47,XY,+13 46,XX,5p46,XX,-14,+t(13q14q) 45,XY,-14,-21,+t(14q21q) a. b. c. d. e. f. g.
h.

Pataus syndrome Balanced translocation carrier Translocation Pataus syndrome Turners syndrome Edwards syndrome Downs syndrome Cri-du-chat syndrome
<linefelter=s syndrome

Problems Section 9 1. Which of the following chromosome errors would be the most benign relevant to their clinical manifestations? a. b. c. 2. Even-numbered polyploids Odd-numbered polyploids X-monosomy d. e. Autosomal trisomies Sex chromosomal trisomies

Why did you select your answer to question 1? a. b. c. d. e.

3.

Excessive genetic material is not as deleterious if present in even increments. Chromosomes involved in autosomal trisomies are usually smaller than those participating in sex chromosomal trisomies. X-inactivation tends to diminish the effects of extra X chromosomes The Y chromosome carries few active genes. Deficiencies of chromosome material are less severe than excesses.
,hich of the follo&ing chromosomal a!errations is;are more fre+uent in a!ortice series than in li'e!orn populations-

a. b.

Sex-chromosomal trisomies Triploids

c. d.

X-monosomy Trisomy 21

Questions 6 : True or False 4. Maleness is determined by the ratio of Y to X chromosomes (Y/X > 1).

5.

A 27-year-old woman in your care has rarely menstruated, has short stature, neck webbing, and pre-pubertal breast development. She appears to have normal intelligence. She has been married for six years, but she and her husband have been unable to have children. What is your provisional diagnosis? a. b. c. Klinefelters syndrome 47,XYY Downs syndrome d. e. Turners syndrome 47,XXX

6.Why are 46,XY* females infertile (Y* refers to a Y chromosome lacking SRY)? 7.Frequent recombination of genes in the pseudoautosomal regions of the X and Y chromosomes is believed to occur during male meiosis. Rarely this recombination may include SRY, transferring the region to the X chromosome. Predict the appearance of an individual inheriting such a recombinant X chromosome. 8. A gene, SHOX, encodes a DNA-binding protein that activates genes contributing to height. The gene is located within the pseudoautosomal region of both the X and Y chromosomes. SHOX is not X-inactivated. Why may Turner (45,X) women have short stature?

Problems Section 10 1.Activation of genes appears to be associated with a. b. c. d. modification of chromosome structure. interaction of steroid hormone-receptor complexes with promoters. interaction of temporally- and spatially-specific transacting proteins with promoter elements. interaction of peptide hormones with cyclic AMP-generating systems.

2.True or False for 2 and 3: RNA polymerase only needs to find its promoter sequence in order to initiate transcription 3.The Hox genes are human-specific regulatory genes that encode DNA binding proteins. For 4 10, match the disorder with the gene that is mutated: 4.Rubenstein-Taybi syndrome-mental retardation a. Broad thumbs and toes, hirsuit, specific facies 5. Aniridia c. 6. Type 2 Waardenburg syndrome d. 7. Type 1 Waardenburg syndrome e. 8. Type 3 Waardenburg syndrome f. 9. Holoprosencephaly g. 10. Synpolydactyly h. 11. Type 4 Waardenburg syndrome i. j. k.

HoxD13 b. HoxA Sonic hedgehog Pax 3 Pax 6 Creb Pax 4 Mitf CBP Sox10 EDN3

12.

Waardenburg syndrome is an autosomal dominant condition that accounts for 1.4% of the cases of congenital deafness. In addition to deafness, patients with this condition have atypical facies, including lateral displacement of the inner canthi and partial albinism. A mother has Waardenburg syndrome, her husband is unaffected, and they plan to have 3 children. What is the probability that one of the three children will be affected? a. b. c. d. e. 1/8 1/4 3/8 1/3 1/2

Problem Section 11 1.Which of the following are reasons to map genes? a. The map position might suggest candidate genes that map to the same position b. Although the identity of the gene causing disease is not precisely known, knowing the map position might allow carrier detection or prenatal diagnosis by linked markers c. comparison of the human and mouse map in their corresponding regions might point to possible animal models for the disease. 2.Alternate forms of enzymes X and Y are respectively inherited as autosomal codominant traits. Several families have been studied to determine whether these loci are linked. The cumulative Z scores were (Q= recombination frequency): Q 0 0.1 0.2 Z 0.00 +0.25 +0.50 Q 0.3 0.4 0.5 Z +4.25 +0.45 0.00

What would you conclude?

a. The loci are unlin"ed c. The loci are 3(c1 apart

b. 3.

The loci are 10cM apart

d.

X and Y appear to be determined by allelic genes

Consider the following pedigree:

What would you conclude regarding traits A and B? a. b. c. d. 4. The traits are most likely linked. The traits are assorting independently. The traits are allelic. The traits are codominant.

Assuming the traits are linked, what is the most likely configuration in I1? a. b. The genes encoding traits A and B are cis. The genes encoding traits A and B are trans.

5.

Assuming the traits are linked, which individuals are recombinants? a. b. c. d. e. II-1, II-2, II-4, III-1, III-4 II-3, III-2 II-1, II-4, III-3 II-2, III-3, III-4 There are insufficient data to determine recombinants.

6.The F8 gene encodes a clotting factor and is closely linked to G6PD, a second enzyme-encoding locus, on the X chromosome. The daughter of a hemophiliac male (factor 8 deficiency) has two sons, one of whom has hemophilia like his grandfather. The hemophiliac son is G6PD-A, while his normal brother is G6PD-B. The A and B G6PD isozymes are inherited as X-linked codominant traits. Select the correct chromosomal arrays of the F8 and G6PD alleles on the X chromosomes of the woman. A (/) separates genes on one chromosome from those on its homolog. F8+ = normal allele; F8o = hemophilia allele. a. b. 7. F8+ G6PDB/F8o G6PDA F8+ G6PDB/F8o G6PDB c. d. F8o G6PDB/F8+ G6PDA F8+ G6PDA/F8o G6PDA

Treatment of DNA from members of a large kindred with the restriction enzyme, Hind III, produced four different-sized DNA fragments which hybridized with a probe specific for a region of

chromosome 4 containing the Huntingtons disease (HD) gene or its normal allele. Members of the kindred affected by Huntingtons disease are indicated by filled symbols. The combination of restriction fragments containing the HD gene or its normal allele is presented below each symbol. The boy indicated by the arrow a. b. c. d. is excluded from risk for HD. is not excluded from risk for HD. inherited an HD allele from his mother. The boys risk cannot be determined from the information given.

Problems Section 12 1. Which of the hemoglobin designations below best describes the relationship of subunits in the quaternary structure of adult hemoglobin? a. (alpha1-alpha1)(beta1-beta1) b. (alpha1-alpha2-alpha3-alpha4) c. beta-beta-beta-beta d. (beta1-beta2-beta3-alpha1) e. (alpha1-beta1)-(alpha2-beta2)

2.Blood is drawn from a child with severe anemia and the hemoglobin protein is degraded for peptide and amino acid analysis. Of the results below, which change in hemoglobin primary structure is most likely to correlate with the clinical phenotype of anemia? a. ile-leu-val to ile-ile-val b. leu-glu-ile to leu-val-ile c. gly-ile-gly to gly-val-gly d. gly-asp-gly to gly-glu-gly e. val-val-val to val-leu-val 3.An adolescent presents with shortness of breath during exercise and is found to be anemic. A hemoglobin electrophoresis is performed that is depicted in the figure below. The adolescents sample is run with controls including normal, sickle trait, and sickle cell anemia and serum. The adolescent is determined to have an unknown hemoglobinopathy. Which one of the lanes contains the adolescents sample?

a. b. c. d. e. 4.

lane A lane B lane C lane D lane E

Hemoglobin A2 a. b. c. d. is a pathological hemoglobin. is a fetal hemoglobin. is a normal hemoglobin. contains -globin chains rather than -globin chains.

5.A particular -globin allele occurs in northern European populations with an average frequency approximating 1/10,000. This allele is most likely maintained in these populations by a. b. heterozygous advantage. mutation. c. d. assortative marriage. migration.

6.Choose from the following: What is the most common mechanism of mutation giving rise to alpha Thalassemias?
a. !. c. d. une+ual cross o'er !et&een homologous pairs e+ual cross o'ers !et&een homologous pairs point mutations insertional mutagenesis

>.

.n reference to ?6# ho& &ould you ha'e ans&ered if the +uestion &as 7,hat is the most common mechanism of mutation gi'ing rise to !eta Thalassemias-

@.The locus control region is located 2( "! upstream of the !eta genes and their promoters. .t is responsi!le for !oth high le'el e)pression as &ell as the de'elopmental timing of e)pression of the !eta genes. %o& might you imagine this functionsa. the AC5 pro'ides an open chromatin domain that gi'es transcription factors access to the regulatory elements in the cluster. !. .t acts a super enhancer for transcription c. .t is highly homologous to the introns of the immunoglo!ulin locus facilitating class s&itching d. .t pac"s tighly around histones B.A &oman has sic"le cell trait and her mate is hetero0ygous for %! C. ,hat is the pro!a!ility that there child &ill ha'e no normal hemoglo!in1atch the follo&ing for 1( 1BC 1(. comple) !eta thalassemia 11. BDthalassemia 12. ? of alpha glo!in genes missing in %!% 13. 2 different mutant alleles at a locus 12. prenatal diagnosis of sic"le cell disease 16. insolu!le !eta chains 16. ? of alpha glo!in genes missing in hydrops fetalis &ith %! Bart 1>. locus control region 1@. alpha ;alpha genotype 1B. increased %!A2 1. 2. 3. 6. 6. @. B. 1(. *etecta!le %! A Three !eta Thalassemia 2. alpha Thalassemia high le'el !eta chain e)pression alpha Thalassemia trait >. genetic compound delta;!eta genes deleted Four restriction en0yme 1st ..

Problems Section 13 Data for Questions 14: A young girl presented with mental deterioration, failure to thrive, poor motor development, hepatosplenomegaly, and generalized aminoaciduria. The patient died two months after hospitalization. The autopsy report mentioned dense-staining cellular inclusions in neuronal elements of the cerebral cortex, basal ganglia, and cerebellum. Metachromatic granules were also observed in liver, spleen, and kidney. Liver biopsy specimens obtained prior to the patients death lacked superzymase activity, and very low levels of this enzyme were found in fresh brain, kidney, and spleen preparations taken at autopsy. Superzymase is also expressed in leukocytes. Both the father and mother of this patient possessed leukocyte superzymase activities that were about half normal. Both parents have normal clinical phenotypes. An older brother of the patient died several years earlier from a disease that resembled that in the patient. The remainder of the family history is negative for the disease. 1. What type of inheritance best explains the transmission of the disease in this family?
a. Autosomal dominant d. 9 lin"ed recessi'e

b. c.

Autosomal recessive X-linked dominant

e.

Multifactorial

2.How would you explain the patients clinical symptoms? a. b. c. d. The symptoms are most likely caused by two genes: one responsible for the mental effects, and one causing the physical problems. The symptoms are the result of several genes, each causing one feature of the disease. One gene encodes superzymase, and all of the effects are caused by a central block created by deficiency of this enzyme. Two recessive mutations are involved: one causing superzymase deficiency, and the other responsible for loss of a transport substance that is a common carrier for all of the amino acids appearing in the urine. None of the above

e.

3. How would you account for the tissue differences in superzymase activity? a. b. c. Modifiers in each tissue affect the expression of the superzymase structural gene. Inhibitors in the liver totally block superzymase expression in that tissue. More than one isozyme of superzymase exists. Liver has only one isozyme, while other tissues possess more superzymase isozymes. The mutation only affects the isozyme expressed in both liver and other tissues. d. More than one isozyme of superzymase exists. Liver contains at least two isozymes, while other tissues have one. The mutation affects the enzyme shared by all tissues. 4. How would you explain the granules present in the cells of this patient? a. b. c. d. They may be accumulations of the substrate of superzymase. They could be aggregations of a byproduct produced by a salvage pathway that usually does not operate at significant levels in normal cells. The granules may contain the substrate of another enzyme that is inhibited by high quantities of the substrate of superzymase. They are viral particles that were coincidentally observed in these tissues.

5.

Which of the following traits illustrates the concept of genetic predisposition for human disease? a. b. c. Cystic fibrosis Phenylketonuria AAT deficiency d. e. LDL-receptor deficiency All of the preceding

6.

A couple has a child &ho has !een diagnosed &ith a medium chain acyl coen0yme A dehydrogenase deficiency E1CA*F# a condition that affects the !ody=s a!ility to meta!oli0e medium chain fatty acids. This couple is no& e)pecting another child. Gi'en &hat you "no& a!out the inheritance of meta!olic disorders# &hat is the ris" that this child &ill ha'e 1CA*-

7.

How may the blood and urine levels of a patient with a mutation affecting the intracellular metabolism of an amino acid differ from those of a patient who has abnormal transport of that amino acid across his proximal tubule membranes? Consider the following pathway:

8.

Predict the consequences of a block between C and D. 9. Tay-Sachs disease causes cherry red spots in the eye, startleresponses in infancy, neurodegeneration and death. Heterozygotes with an abnormal Tay-Sachs allele are termed carriers. What is the risk that the grandmother of an affected child is a carrier? Questions 1013. Match the following diseases with their enzyme/protein deficiency.
1(. /henyl"etonuria a. Tyrosinase

11. 12. 13.

Tay-Sachs disease Familial Type IIa Hypercholesterolemia Cystic fibrosis

c. d. e. f.

b. CFTR Hexosaminidase B Phenylalanine hydroxylase Hexosaminidase A LDL-receptor

14. A girl seems normal at birth but begins flinching at loud noises (enhanced startle response) at age 6 months. Opthalmologic examination reveals a central red area of the retina surrounded by white tissue (cherry red spot). The child initially can sit up, but then regresses so that she cant roll over or recognize her parents. Her physician suspects a lipid storage disease (neurolipidosis). If the diagnosis is correct, what is the risk that the next child of these parents will be affected with the same disease?

The cause of Tay-Sachs disease is best described by which of the following? a. b. c. d. excess of lysosomal enzyme in blood due to defective uptake deficiency of a lysosomal enzyme that digests proteoglycans deficiency of a membrane receptor that takes up proteoglycans deficiency of a mitochondrial enzyme that degrades glycogen

15. A woman who married her first cousin wants to know what the risk of having a child with cystic fibrosis is because her grandmother, who is also her husbands grandmother, died of cystic fibrosis. 16. Which of the following is most likely in an untreated child with PKU? a. b. c. d. e. elevated tyrosine increased skin pigmentation decreased skin pigmentation normal phenylalanine hydroxylase levels elevated alanine

Problems Section 14 1. A mutation in the pro alpha 1 chain of collagen is in general more deleterious than a mutation in the pro alpha 2 gene of collagen for which of the following reasons: a. post-translational modifications only occur on pro alpha chain1 b. post-translational modifications only occur on pro alpha chain 2 c. collagen molecules are formed by 2 pro alpha 1 chains and 1 pro alpha 2 chain d. pro alpha 1 is the only chain able to associate with elastin
1utations in pro alpha 1 chain lead to &hat "ind of ratio of normal to mutant collagen chains,hich of the characteristics !elo& apply to the amino acid glycinea. has a hydrogen for a side chain# thus# is small !. large molecular diameter interfering &ith alpha heli) formation c. hydrophilic# !asic and charged d. hydropho!ic Amino acid hydro)ylation re+uires the reducing agent ascor!ic acid# &hich is also "no&n as 'itamin C. Gcur'y# results from a deficiency of 'itamin C. ,hich of the follo&ing symptoms might you e)pect to see in indi'iduals &ith scur'ya. !. c. d. neural tu!e defects. 1ental retardation Brittle !ones &ith fractures and !leeding tendencies *igestion pro!lems

2. 3.

2.

6. ,hy did you ans&er 2 the &ay you did-

6.

Aittle /eople of America is a support group for indi'iduals &ith short stature that conducts many &or"shops and social acti'ities. T&o indi'iduals &ith achondroplasia meet and decide to marry and ha'e children. ,hat is their ris" of ha'ing a child &ith d&arfisma. !. c. d. e. 1((: >6: 6>: 26: H(:

7. The diagnosis of osteogenesis imperfecta is most accurately performed by which of the following? a. PCR amplification and DNA sequencing of type I collagen gene segments to look for point mutations b. Gel electrophoresis of labeled type I collagen chains synthesized in fibroblasts c. PCR amplification and ASO hybridization to detect particular alleles d. Northern blot analysis to examine RNA levels and size e. Purfication and trypsin digestion of type 1 collagen to examine the peptides by 2 D gel electrophoresis 8. A patient with Marfans syndrome is evaluated at a clinic. He is noted to have a tall, thin body, loose joints and arachnodactyly. Opthalmologic examinination reveals lens dislocation. Echocardiogram reveals dilation of the aortic root. A family history reveals that the patients parents are normal but that this paternal grandfather and great-grandfather died in their 40s with lens dislocation and dissecting aortic aneurysms. A sister is found to have a similar body habitus, dilation of the aortic root and normal lenses. The different findings in these family members with the same disease is best described as: a. b. c. d. e. a. b. c. d. e. pleiotropy founder effect variable expressivity incomplete penetrance genetic heterogeneity mutation that prevents addition of carbohydrate residues to the fibrillin glycoprotein mutation in a carbohydrate portion of fibrillin mutation that disrupts a secondary structure of fibrillin and blocks its assembly into microfibrils mutation in a lysosomal enzyme that degrades fibrillin mutation in a membrane receptor that targets fibrillin to lysosomes

B. 1arfan=s syndrome is caused !y &hich of the follo&ing mechanisms-

Problems Section 15 1.Bill is the only person in his family affected with Duchenne muscular dystrophy. He has one unaffected brother Joe. DNA analysis shows that Bill has a deletion in the DMD gene. Joe received the same maternal X chromosome but without the deletion. What happened to account for this? a. Bill and Joe have different fathers b. Bill arose from a new mutation on the X chromosome from his mother c. The mother may be a mosaic and the mosaicism occurred in her germline d. The father is a mosaic and the mosaicism occurred in his germline

2.

A woman with a hemophiliac father is married to a man with Becker muscular dystrophy. Both traits are inherited as X-linked recessives. Patients with this mild form of muscular dystrophy are fertile and are usually not confined to a wheelchair until their forties. What types of children may they have? Daughters Sons a. b. c. d. e. 1/2 at risk for dystrophy; 1/2 normal all normal all normal 1/2 hemophiliac; 1/2 at risk for dystrophy 1/2 at risk for dystrophy; 1/2 hemophiliac 1/2 hemophiliac; 1/2 normal 1/2 hemophiliac; 1/2 normal 1/2 at risk for dystrophy; 1/2 normal 1/2 hemophiliac; 1/2 normal 1/2 hemophiliac; 1/2 normal

Question 3: True or False 3. 4. A phenotypically normal woman and a protanopic (red-blind) man cannot have a colorblind son. Anhydrotic ectodermal dysplasia (AED) is inherited as an X-linked recessive trait. A daughter of a normal man and heterozygous woman has AED. What is the most probable cause for the appearance of AED in this girl?
a. !. *eletion of her normal allele 9 inacti'ation of her normal allele d. e. %omo0ygosity for the trait allele Both ! and c a!o'e

c.

Heterozygosity for the trait allele

5. What type of inheritance of the trait

a. !. 9 lin"ed dominant 9 lin"ed recessi'e d. e.

inheritance is most likely responsible for in the above pedigree?

Autosomal dominant I lin"age

c.
6.

Autosomal recessive

Based upon &hat you "no& rele'ant to 9 lin"age and the properties of 9 lin"ed genes# &hat &ould you e)pect for the phenotype of a &oman hetero0ygous for an 9 lin"ed recessi'e trait &ith specific effects# such as G6/* deficiency-

a. She would be intermediate between normal and a homozygous affected woman or hemizygous male. b. She would be normal. c. She would be affected. d. Her phenotype would usually be normal, but occasional affected heterozygotes would be anticipated when X-inactivation in different cells silenced most of their normal G6PD alleles. e. None of the above 7. Duchenne muscular dystrophy has a high mutation rate but shows no ethnic variation in frequency. Using your knowledge of the dystrophin gene and the genetics of this disorder, choose the best explanation for why this disorder is equally frequent in all populations: a. Intrachromosomal recombination occurs on the X chromosome to give rise to this deletion b. The large size of the dystrophin gene makes it an easy target for mutation c. There is heterozygote advantage to having a mutation in the dystrophin gene d. Point mutations in tbe promoter can occur in all races

8.

XGA is an X-linked trait with lack of Xg(a) antigen being recessive to its presence. G6PD is also X-linked, and the presence of enzyme activity is dominant to its absence. Phenotypes of individual erythrocytes can be scored by using a fluorescent antibody specific for Xg(a) and a stain for G6PD activity. If a woman is heterozygous at both loci and G6PD but not XGA is subject to X-inactivation, what pattern of erythrocytes would you expect to see after treating them with the two reagents? Amelogenesis imperfecta (hereditary enamel hypoplasia) is inherited as an X-linked dominant trait. Males have a very thin, smooth layer of enamel which appears homogeneous. Heterozygous females have irregularly thick and thin enamel, often having the appearance of vertical grooves. How would you explain this sex difference? a. b. c. d. Random X-inactivation leads to sectors of mutant and normal cells. Somatic mutation limited to the female The trait is really dominant in males and recessive in females. The groove pattern is environmentally determined.

9.

Data for Questions 1014: The Bruton form of hypogammaglobulinemia is inherited as an X-linked recessive. Circulating antibodies in these patients are grossly deficient. A woman had two brothers die from the disease. Both of her parents and her husband have normal levels of gamma-globulin and normal antibody function. 10. What is the probability that this woman is a heterozygote?
a. !. 1 2;3 c. d. 1;2 (

11.

If her first child is an affected male, what is the chance that the next child will be affected? a. b. 1/8 1/4 c. d. 1/2 1

12.

If the first child is a normal male, would the risk for an affected child a. b. c. Increase? Decrease? Remain unchanged?

13.

Why did you select the above response? a. b. c. d. e. Risks based upon single-factor inheritance never change. The genotype of the mother is established. The genotype of the mother is unknown. Risk to a future child decreases with increasing numbers of normal events, as long as the mother's genotype has not been established. Both c and d above

14.

Suppose this woman produced a normal daughter and two normal sons. What is the probability that the woman is a carrier? a. b. 1/7 1/5 c. d. 1/3 1/2

16.

A 3igerian medical student studying in the J.G. de'elops hemolytic anemia after ta"ing the o)idi0ing antimalarial drug pama+uine. This se'ere reaction is most li"ely due to a. glucose 6 phosphate dehydrogenase deficiency !. concomitant scur'y c. 'itamin C deficiency d. dia!etes e. sic"le cell anemia

16.

In most patients with gout as well as those with Lesch-nyhan syndrome, purines are overproduced and overexcreted. Yet the hypoxanthine analog allopurinol, which effectively treats gout, has no effect on the severe neurological symptoms of Lesch-Nyhan patients because it does not a. decrease de novo purine synthesis b. decrease de novo pyrimidine synthesis c. diminish urate synthesis d. increase phosphoribosylpyrophosphate levels

17. The most common intrachromosomal recombination event resulting in an inversion is the cause of which of the following diseases: a. b. c. d. e. Duchenne muscular dystrophy Becker muscular dystrophy Glucose 6 phosphate dehydrogenase deficiency Hemophilia A Hemophilia B

Problems Section 16 For 1-13, match the disorder with the description 1. RNA binding protein a. Friedreichs ataxia 2. founder effect b. Fragile X syndrome 3. protein kinase c. myotonic dystrophy 4. mitochondrial protein d. Huntingtons disease 5. hyper-methylation inhibits RNApolymerase from transcribing the gene 6. coding-region polyglutamine expansion 7. anticipation 8. abnormally high levels of iron in their heart tissue 9. free radical damage 10. expansion occurs during male meiosis 11. expansion occurs during female meiosis 12. may be caused by depletion of an RNA binding protein 13. autosomal recessive

12.

A &oman presents to you !ecause she is concerned a!out her un!orn child. Ghe tells you that she has a

!rother &ho loo"s normal !ut is 7 a little slo&8 and &hose speech is difficult to understand. Although he is an adult and &or"s at a local grocery store shel'ing produce# he still li'es &ith his parents. Iou suspect that he may ha'e fragile 9 syndrome so you test her *3A and find that she has a repeat si0e of >6. %o& do you counsel hera. b. c. d. Her children will all be normal because her repeat size is not greater than 200 She may have an increased risk of experiencing premature menopause All of her children will have fragile X syndrome. She is at increased risk of having fragile X sons and daughters, although affected daughters will be more mildly affected.

15.

The ship Hopewell arrived on a small island several hundred years ago carrying numerous pilgrims with diabetes insipidus. The disease is now known to be caused by mutant allele A and all of the island residents have 10x the frequency of this allele than do people living on the mainland. Which of the following terms best describes this phenomenon? a. b. c. d. e. selection for allele A linkage disequilibrium with allele A linkage to allele A founder effect for allele A assortative mating for allele A

Problems Section 17 Kuestions 1 16C For the follo&ing 'iral 'ectors# match the follo&ing characteristicsC 1. infects all cell types a. retro'iruses 2. only infects di'iding cells !. adeno'iruses 3. integrates into the host *3A c. adenoassociated 'iruses 2. descri!es the %.L 'irus d. Aenti'iruses 6. .s capa!le of replication 6. Can hold 3( 36 "! of insert >. Can hold only small inserts E6 1( "!F @. %as no "no&n ad'erse effects in humans B. .s nonto)ic to cells 1(. Can e)ist as an episome Enot integrated into the host *3AF 11. %as potential for insertional mutagenesis 12. /otential for a strong immunological response 13. Mnly pro'ides transient e)pression of a gi'en gene 12. 53A 'irus 16. *3A 'irus 16. ,hat are the ad'antages and disad'antages of introducing non 'iral *3A1>. Aist the possi!le &ays gene therapy could !e used to treat tumor cellsC 1@. %o& does e)pression of thymidine "inase in tumor cells mediate cell death in the presence of gancyclo'ir-

For pro!lems 1B 23. .n the 53Ai Einterfering 53AF path&ay# match the en0yme &ith the functionC

1B. 2(. 21. 22. 23.

*icer Guide 53A %elicase 5.GC comple) target 53A

a. performs nucleolytic degradation of the 53A !. 53A that is degraded c. 53A that is found in the 5.GC comple) that associates &ith the target 53A d. The en0yme that processes the introduced dou!le stranded 53A into 21 23 mers e. an en0yme &ith un&inding acti'ity

22. Choose the correct se+uence for therapeutic cloningC a. !. c. d. 26. 26. isolate the nucleus from the adult somatic cell of interest# inject it into an enucleated o'um# induce cell di'ision# isolate the inner cell mass# induce differentiation into the tissue of interest isolate the nucleus from the adult somatic cell of interest# inject it into an enucleated o'um# induce cell di'ision# inject the !lastocyst into a pseudopregnant carrier female. .solate the nucleus from the o'um# inject it into an enucleated somatic cell of interest# induce the somatic cell to differentiate into the tissue of interest. .solate 4G cells from the germ line of a!orted fetuses and induce them to differentiate into the tissue of interest.

,hich of the a!o'e is the correct se+uence for reproducti'e cloning,hy can=t you just ta"e the e)isting 6( or so 4G cell lines# figure out ho& to induce tissue specific differentiation and then transplant into the &aiting recipients-

Problems Section 18
1. A family comes to clinic &ith multiple affected mem!ers. As you are ta"ing do&n the information# you produce the follo&ing pedigreeC

,hat do you conclude from this pedigree and &hy2. A 6 year old child is referred to you !ecause of de'elopmental delays and mental retardation# reduced speech and sei0ures. Iou note that the child has a stiff# jer"y gait. The parents note that e'enthough the child does not spea" much# he laughs e)cessi'ely. Iour pro'isional diagnosis is &hich of the follo&ingC a. Angelman syndrome !. /rader ,illi syndrome c. Fragile 9 syndrome d. 1yotonic dystrophy

3.

For the a!o'e child# you ha'e access to a genetic clinic and ha'e suspicians a!out the molecular defect. Iou order

G3/ analysis of the parents and child focusing on the JB4 gene or the regions around it. ,hich of the follo&ing outcomes are a possi!ilityC a. .n the patient there is a deletion of the JB4 gene on the maternally inherited chromosome !. .n the patient there is a deletion of the JB4 gene on the paternally inherited chromosome c. The patient inherited !oth chromosome 16s from the father d. The patient inherited !oth chromsome 16s from the mother e. The patient inherited chromosomes 16 from each parent# ho&e'er# the maternal chromsome 16 has a deleted imprinting center 2. 6. 6. ,hat is the name of the phenomenon that gi'es rise to ans&ers EcF and EdF a!o'e1olecularly spea"ing# ho& is the phenomenon of imprinting maintainedThe genesis of /rader ,illi syndrome !y inheritance of 2 normal chromosomes from a single parent is an e)ample of &hich of the follo&ingC a. germinal mosaicisim !. genomic imprinting c. chromosome deletion d. chromosome rearrangement e. anticipation A child &ith se'ere epilepsy# autistic !eha'ior# and de'elopmental delay has characteristics of a condition "no&n as Angelman=s syndrome. Because of the syndromic nature of the disorder and the de'elopmental delay# a "aryotype is performed that sho&s a missing !and on one chromosome 16. ,hich of the follo&ing !est descri!es this a!normalitya. interstitial deletion on chromosome 16 !. terminal deletion on chromosome 16 c. pericentric in'ersion on chromosome 16 d. paracentric in'ersion on chromosome 16 e. 16+ @. /rader ,illi syndrome in'ol'es a 'oracious appetite# o!sesity# short stature# hypogonadisim# and mental disa!ility. At least 6(: of /rader ,illi patients ha'e a small deletion on the pro)imal long arm of chromosome 16. .n detecting /rader ,illi deletion# &hich of the follo&ing techni+ues &ould !e the most accuratea. standard "aryotyping !. northern !lotting of m53As transcri!ed from the deleted region c. restriction analysis to detect *3A fragments from the deleted region d. rapid "aryotyping of the !one marro& e. fluorescent in situ hy!ridi0ation EF.G%F analysis of peripheral !lood lymphocytes using fluorescent *3A pro!es from the deleted region

>.

B.

A "aryotype is performed on an o!ese child and is entirely normal. Because you suspect /rader ,illi syndrome#

Gouthern !lotting is performed to determine the origin of the patient=s chromosome 16. .n the figure !elo&# pro!e *16G@ defines the four restriction fragment length polymorphisms E5FA/sF present in the *3A from the mother E1F# child ECF# and father EFF. Based on the *16G@ locus# &hat is the origin of the child=s t&o num!er 16 chromosomesa. one from the mother and one from the father !. !oth from the father c. !oth from the mother d. from neither parent e. cannot tell !ecause the locus is deleted in the child

M C F

1(.

Because the figure in +uestion 2>@ demonstrates that the child is missing !oth paternal chromosome 16 alleles# nonpaternity is a more plausi!le e)planation than uniparental disomy. The hypothetical southern !lot !elo& illustrates a *3A fingerprinting analysis to e)amine paternity# &here maternal E1F # child ECF# and paternal EFF *3A samples ha'e !een digested# !lotted and hy!ridi0ed simultaneously to the pro!es *>N6 and *2(N1. The distri!utions of the restriction fragment alleles suggestC a. The child is adopted !. False maternity E!a!y s&itched in the nurseryF c. False paternity d. Correct maternity and paternity e. 3one of the a!o'e

11.

1any family studies employing *3A ha'e the potential to demonstrate nonpaternity. .f the physician ordering these analyses does not discuss this possi!ility &ith the couples in'ol'ed# she or he is in 'iolation of &hich of the follo&ingC a. !. c. d. e. patient confidentiality patient rights informed consent standards of care malpractice guidelines

Problems Section 19 1. The age of onset of a degenerative neurologic disease is 35 years old. epidemiologic study of affected persons indicates that most cases occur in the spring, are isolated (no neighbors or relatives are affected) and occur equally among men and women. However, subset of cases consists of two affected siblings in a family. The best description of this disease is: a. inherited b. genetic c. sporadic d. congenital e. familial A couple in your care has had three pregnancies. The first died shortly after birth from complications of anencephaly. The second pregnancy resulted in a child with spina bifida. This child has paralysis of the legs but is otherwise OK. Their third infant is free of handicaps. How would you counsel this family? Based upon what you have learned about the multifactorial nature of birth defects, which of the following are likely to be true? a. b. c. d. 4. Uniform occurrence of abnormalities in fetuses exposed to a teratogenic drug Occurrence of birth defects in some infants exposed to a teratogenic drug but not in others Fetuses exhibiting signs of teratogen-induced defects will display variable expressivity of the abnormalities involved Teratogenic drugs will have stage-specific effects on embryos and fetuses

2.

3.

Trait X occurs among 40% of first-degree relatives, 20% of second-degree relatives, and 10% of thirddegree relatives. The population incidence of this trait is 1/5,000 persons. What type of inheritance is responsible for transmission of Trait X? a. b. c. d. e. Chromosomal anomaly Multifactorial Autosomal dominant with reduced penetrance Two interacting loci None of the above

5.

A couple comes to you for counseling regarding an undifferentiated form of mental retardation. This form of mental retardation occurs about twice as often in males as in females. The couple, both of whom have normal intelligence, have a retarded daughter and a normal son. The woman has a retarded sister, and her husband has a retarded brother. The couple is expecting their third child. If the average risk for mental retardation to first-degree relatives is about 14%, how would you counsel this family? a. Their third child will have normal intelligence.

b. c. d. e.

Their third child will have moderate to severe mental retardation. Risk to their third child will be somewhat higher than 14% if they have a son. Risk to their third child will be somewhat lower than 14% if they have a daughter. Both c and d above

6.

A womans first pregnancy produced an anencephalic child. Her second child is normal, and her third child has spina bifida. How would you counsel this family? a. b. c. d. e. The occurrence of the two malformations in siblings was coincidental. Their risk is less than 5% that another child will be born with a neural tube defect of either or both types. The fourth child will be normal. The two neural tube defects have a common etiology, and risk of recurrence is about 10%. This family appears to have an autosomal dominant mutation, risk for either or both defects in a subsequent child is about 50%. Risk to the next child for either or both defects is 25%.

7. Jane and Michael have a child with Bellweather syndrome, a multifactorial disorder that results in severe malformation of the facial bones. Found at a higher incidence among males than among females, there are four clinical subgroups of Bellweather syndrome, numbered in order of increasing severity from one to four. Jane and Michael are contemplating having another child, but are concerned about the their next child could have Bellweather syndrome. Which of the following descriptions about Jane and Michaels current affected child is likely to result in the HIGHEST recurrence risk for this family? Jane and Michaels affected child is: A. a male with clinical subtype four B. a female with clinical subtype two C. a male with clinical subtype two D. a female with clinical subtype four E. the recurrence risk remains the same for all possible combinations 8.10. Formation of the neural tube occurs during the first month of embryonic life. The groove begins to close in the mid-cervical region on day 18, proceeding rostrally and caudaly until it closes completely around day 28. Neural tube defects arise when there is incomplete closure. The position of the opening dictates the type of defect that arises. Match the position of the lack of closure with the defect: 8. Anterior a. spina bifida 9. Hindbrain b. anencephaly 10. lumbar-sacral c. encephalocele

Match the following: 11. Meningocele 12. Meningomyelocele (Myelomeningocele)

a. b.

both meninges and neural tissue protrude meninges are exposed and incorporated into overlying skin

Problems Section 20

Match the following: a. qualitative trait 1. 2. 3. 4. 5. 6. 7.

b. quantitative trait

describes a trait that is either present or absent describes a trait that can be measured and described by a mean and variance familial aggregation is observed To assess the role of heredity, correlation of a particular physiological quantity among relatives can be quantified using coefficient of correlation genetic analysis of these traits can be measured by relative risk ratios genetic analysis of these traits can be measured by case-control studies Congenital deafness often is inherited as an autosomal recessive trait. However, marriages of two deafmutes, each from a family exhibiting an autosomal recessive pattern for the trait, may have families in which all of the children have normal hearing. This is most likely an example of a. b. c. phenocopies. genocopies. pleiotropism. d. e. variable expressivity. incomplete penetrance.

@.

,hich of the follo&ing approaches &ould !e most 'alua!le in determining the degree of genetic determination of a continuous trait-

a. b.
c.

Pedigree analysis Tissue culture

Ain"age studies

d. e.

Twin studies None of the above

Questions 915: Match the following terms with their appropriate definitions. 9. 10. 11. 12.
13.

Modifier Incomplete penetrance Concordance Genocopies

%erita!ility

a. b. c.
e.

Environmental traits resembling a genetic trait Additive genetic component of a trait Clinical trait varying in severity among individuals d. Nonallelic gene affecting the action of another gene
Aac" of appearance of a trait in a person &ith the predisposing genotype for that trait

14. 15. 16.

Phenocopies Variable expressivity

f. g.

Proportion of twin pairs in which both members have the trait Identical or very similar traits determined by mutations at different loci

Trait X occurs among 40% of first-degree relatives, 20% of second-degree relatives, and 10% of thirddegree relatives. The population incidence of this trait is 1/5,000 persons. What type of inheritance is responsible for transmission of Trait X? a. b. c. d. e. Chromosomal anomaly Multifactorial Autosomal dominant with reduced penetrance Two interacting loci None of the above

17.

The genetic component of mental retardation

a. b.

c. d. 18.

consists entirely of Mendelian forms and chromosome errors. varies among groups. The major type is polygenic and constitutes the lower tail of the normal distribution of intelligence. A much smaller group includes Mendelian and chromosomal forms of mental retardation. is relatively unimportant when compared to the environmental component. is much more important than the environmental component.

A rare birth defect is thought to have a multifactorial etiology. No reliable data are available for recurrence risks among relatives. If the birth defect affects about 1/10,000 newborn infants, estimate its risk of recurrence among first-degree relatives. (Hint: when no other data is available, risk to primary relatives approximates the square root of the population frequency). a. b. c. 1% 5% 10% d. e. 25% 50%

19.

You are a great cardiac researcher interested in thrombosis. You hypothesize that a variant in the prothrombin gene predisposes individuals to thrombosis. You undertake a study with 120 patients and with 120 controls. You perform PCR on the region containing the variant and sequence it in all of the study members. You find that the variant is present in 23 of the patients (the other 97 patients lack it). You also find the variant present in 4 of the controls, while the other 116 controls lack it. What kind of study is this? a. b. c. d. Affected sib pair Twin study Parametric linkage analysis Association study

20. In reference to the above study, what are the odds of an individual developing thrombosis who has this variant in their prothrombin gene?

Problems Section 21 1. Coronary artery disease is the number one cause of morbidity and mortality in the developed world. Select the correct order of events leading to formation of a fibrous plaque, which becomes problematic after rupture, triggering thrombosis (clot formation): a. LDL (low density lipoprotein) enters the arterial wall and is modified, which attracts monocytes that enter the wall and differentiate into macrophages, which take up LDL to become foam cells, collectively creating extracellular matrix to form a plaque b. macrophages enter the cell wall, which then take up LDL to become foam cells that generate modified LDLs, which form plaques. c. Foam cells enter the endothelium where they secrete LDLs to form the large lipid dropule that is encased by the atherosclerotic plaque d. Chylomicrons enter the arterial wall and is modified, which attracts monocytes that enter the wall and differentiate into macrophages, which take up LDL to become foam cells, collectively creating extracellular matrix to form a plaque

2.

Of the types of lipoprotein, chylomicrons, VLDL, LDL, and HDL, which one is considered the good cholesterol and why? True or False: Fatty streaks appear in arteries only later in life. A study on insulin dependent diabetes in some far-away country calculated the heritability using a group of monozygotic twins as study subjects. The estimated value was 0.85. Assuming that the researchers examined their study population correctly, which of the following conclusions can be made: a. Because the heritability score is greater than .75, genetic influences likely function in an autosomal dominant manner b. The majority of the variance observed is due to non-inherited environmental factors c. The high heritability suggests the presence of a single gene that causes diabetes d. The heritability score suggests that there are no genetic factors at all e. A very large fraction of the variance observed is determined by genetic factors With regard to the question above, what would you conclude if the heritability was .15? You have a patient with a serum cholesterol level exceeding the high normal threshold for his age, sex and race. Suggest a possible cause of his hypercholesterolemia. a. b. c. d. e. High dietary source of cholesterol and saturated fats. Heterozygosity for a LDL-receptor mutation Large number of additive genes predisposing to hypercholesterolemia Alcohol consumption All of the above

3. 4.

5. 6.

7.

Genetic factors appear to be especially important in the etiology of a. b. c. d. chronic obstructive pulmonary disease: onset prior to 50 years of age. chronic obstructive pulmonary disease: onset after 50 years of age. myocardial infarction prior to age 60. myocardial infarction after age 60.

8.

Clearance rates for a certain drug were determined for monozygous and dizygous twin pairs. The variances for monozygous and dizygous twins were 200 and 1,000, respectively. Calculate the heritability.
a. (.2( c. (.@3

b. 9.

0.80

d.

1.00

The primary biochemical lesion in homozygotes with familial hypercholesterolemia (type IIa) is: a. The loss of feedback inhibition of liver hydroxymethylglutaryl CoA reductase. b. The increased production of low-density lipoproteins from very low density lipoproteins c. The loss of apolipoprotein B d. The malfunctioning of acy CoA-cholesterol acyl transferase (ACAT). e. The functional deficiency of plasma membrane receptors for low-density lipoproteins.

10.

A 45 year old male is hospitalized for treatment of myocardial infarction. His father and paternal uncle also had heart attacks at an early age. His cholesterol is elevated, and lipoprotein electrophoresis demonstrates an abnormally high ratio of low- to high-density lipoproteins (LDL to HDL). Which of the following is the most likely explanation for this problem? a. Mutant HDL is not responding to high cholesterol levels b. Mutant LDL is not responding to high cholesterol levels c. Mutant caveolae proteins are not responding to high cholesterol levels d. Mutant LDL receptors are deficient in cholesterol uptake e. Intracellular cholesterol is increasing the number of LDL receptors Which of the following steps in the biosynthesis of cholesterol is thought to be rate-controlling and the locus of metabolic regulation? a. geranyl pyrophosphate- farnesyl pyrophosphate b. squalene- lanosterol c. Lanosterol--cholesterol d. 3-hydroxy-3-methylglutaryl CoAmevalonic acid e. Mevalonic acid geranyl pyrophosphate

11.

Problems Section 22 1. The 7Big Fi'e8 is a method used to measure certain personality traits. ,hich of the follo&ing correctly lists the !road personality dimensions characteri0ed !y the Big Fi'eA. 4)tra'ersion# 3euroticism# Altruism# Mpenness# /ercepti'eness B. Gocia!ility# Am!ition# 4)tra'ersion# 3euroticism# Altruism C. /ercepti'eness# Agreea!leness# *ependa!ility# 4)tra'ersion# 3euroticism *. *ependa!ility# /ercepti'eness# 4)tra'ersion# 3euroticism# Mpenness 4. Mpenness# Conscientiousness# 3euroticism# Agreea!leness# 4)tra'ersion Additi'e genetic factors account for nearly 6(: of the 'ariance in t&in studies on personality. Further# correlations !et&een mono0ygotic t&ins &ith regard to personality approach 6(:. .n contrast# correlations !et&een !iological si!lings can !e less than 1(:. Choose from !elo& the !est description of &hat is going on that e)plains these resultsC a. 3on shared en'ironmental effects !. 3on additi'e genetic effects c. Ghared en'ironmental effects d. Additi'e en'ironmental effects e. 4pistatic effects ,ith regard to the ans&er you ga'e a!o'e# &hat is this phenomenon caused !y-

2.

3.

1atch the term &ith the definitionC 2. *opamine 6. 6. >. @. B. 10. Gerotonin transporter Gerotonin Gerotonin 1A receptor 3itric o)ide synthase 1onoamine o)idase fos B a. !. c. d. e. f. g. neurotransmitter implicated in neuroticism alleles are repeat num!ers 3eurotransmitter in'ol'ed in re&ard systems Transcription factor <noc"outs result in aggressi'e mice <noc"out results in a non nurturing mother ele'ated le'els in the synapse are implicated in mood sta!ili0ation Eless depression and an)ietyF

11. dopamine receptor

h. /olymorphisms in the receptor are implicated in no'elty see"ing !eha'ior.

i. Targeted !y /ro0ac j. <noc"out sho&s ele'ated le'el of an)iety ". 4)cess of this neurotransmitter has !een implicated in schi0ophrenia 12. Choose the correct statements a!out schi0ophreniaC a. caused primarily !y mutations in the dopamine *3 receptor !. 1N concordance is 2( 6(: c. 4n'ironmental ris" factors include 7maternal stressors8 d. Lery rareOpopulation ris" is 1;1(#((( e. Gplit personality disorder f. 1(: lifetime ris" for first degree relati'es g. 1: of the population &ill e)perience a schi0ophrenic episode h. men are more li"ely to de'elop than &omen i. men &ill de'elop it at an earlier age than &omen j. caused !y e)cessi'e consumption of shell fish

Problems Section 23 1. Production of the beta amyloid peptide42 is implicated in Alzheimers disease because it is more fibrillogenic. Identify the proteins that increase production of this peptide: a. apolipoprotein E b. alpha secretase c. presenilin 1 and/or 2 d. trypsin e. lypase

2. True or False: Over-expression of alpha secretase would be expected to precipitate Alzheimers disease by increasing production of beta amyloid peptide 42 3. Alleles of apolipoprotein E have been implicated in Alheimers disease. Apolipoprotein E is involved in the transport of cholesterol. Choose the correct statement from the choices below: a. Apolipoprotein E facilitates the cleavage of amyloid precursor protein into beta amyloid peptide 42 b. Apolipoprotein E makes up neurofibrillary tangles c. Having allele E2 is protective whereas having allele E4 correlates with increased risk and/or accelerated rate of onset d. Causes Alzheimers patients to die of heart attacks caused by high serum cholesterol

4. The brains of patients with Alzheimers disease display atrophy and some other abnormal pathology. Closer examination of their neurons reveals large, nonmembrane bound bundles of abnormal fibers, which are called which of the following: a. neurofibrillary tangles b. plaques c. nuclei d. polyglutamine aggregates e. mitochondria 6. True or FalseC Bloc"ing the "inase that phosphorylates tau# the protein present in the neurofi!rillary tangles should accelerate de'elopment of Al0heimer=s disease. 6. P 26 year old male presents to you &ith the symptoms of Al0heimer=s disease# i.e# his spouse tells you that he has !ecome increasingly forgetful# has !ecome much more sedentary# &atching a lot of tele'ision &hereas he used to !e 'ery acti'e. %e is also more confused# not sure &hat day it is and &ears a hea'y do&n coat regardless of the &eather. Jpon further discussion# you find out this his mother and his uncle died of Al0heimer=s disease. a. !. ,hich "ind of inheritance pattern do you suspect# ie# autosomal recessi'e# autosomal dominant# 9 lin"ed recessi'e# 9 lin"ed dominant,hich of the 2 genes implicated in Al0heimer=s disease do you suspect as !eing mutated-

>. A young &oman presents at clinic and is concerned a!out her ris" of de'eloping Al0heimer=s disease !ecause her maternal grandmother and paternal grandfather died of it. Iou find out that her apolipoprotein 4 alleles ha'e !een typed and she has is hetero0ygous 43;42. %o& do you counsel hera. Ghe has an autosomal dominant form of the disease and has a 6(: chance of de'eloping Al0heimer=s disease. !. Ghe has t&ice the population ris" of de'eloping Al0heimer=s disease. c. Iou don=t ha'e enough information a!out her pedigree so tell her that she has the same ris" as someone in the population d. The presence of 1 42 allele increases the lifetime A* ris" from B 2B:. @. ,hich of the follo&ing ma"e up the e)tracellular pla+ues o!ser'ed in indi'iduals &ith Al0heimer=s diseasea. b. c. d. e. apolipoprotein E beta amyloid presenilin 1 and/or 2 beta amyloid peptide tau

Problems Section 24 1. Choose the statement about the protooncogene Ras that is INCORRECT: a. Ras is mutated in a number of tumor types b. Ras is a GTP-binding protein that acts as a molecular switch between the cell surface and the nucleus c. Ras mutants can signal continuously d. Ras oncogenesis is caused by haploinsufficiency e. Ras mutants are unable to hydrolyze GTP 2. Choose from among the following choices the form of mutation that leads to oncogene activation: a. point mutation b. chromosome translocation c. amplification d. deletion e. frame-shift mutations 3. You decide to travel to Africa to do an internship in a pediatric clinic. A child presents to you with an enlarged jaw. Upon physical examination, you also notice swollen lymph nodes in the neck and a mildly swollen abdomen. You suspect this child has Burkitt lymphoma which is causes by aberrant expression of which of the following oncogenes? a. b. c. d. myc ras erbB2 hsr

4. Although most breast cancer appears to follow multifactorial inheritance, there are a handful of genes that when mutated or misregulated, have been implicated in causing breast cancer. Choose those candidate genes from among the following: a. b. c. d. e. erbB2 BRCA1 BRCA2 Estrogen Prolactin

6. Gtudies of the eye tumor retino!lastoma ha'e re'ealed an 5! locus on the long arm of chromosome 13 that influences retino!lastoma occurrence. /atients &ith 13+ deletions often de'elop !ilateral tumors E!oth sidesF# in contrast to more common forms of retino!lastoma that occur on one side. ,hich of the follo&ing phrases !est e)plains this phenomenon-

a. b. c. d. e.

Rb is an oncogene Rb is a tumor suppressor gene Rb mutations ablate a promoter sequence Rb mutations ablate an enhancer sequence Rb mutations must always involve chromosome abnormalities

6. A couple requests genetic counseling because the wife has contracted early-onset breast cancer at age 23. The husband has a benign family history but the wife has several relatives who developed cancers at relatively early ages. Affected relatives include a sister (colon cancer, age 42), a brother (colon cancer, age 46), mother (breast cancer, age 56), maternal aunt (leukemia, age 45), maternal uncle (muscle sarcoma, age 49), and a nephew though the brother with colon cancer (leukemia, age 8). The most likely conclusion from the family history is: a. No genetic predisposition to cancer since most individuals have different types of cancer b. Possible autosomal dominant inheritance or multifactorial inheritance of cancer predisposition c. Germ-line mutations in an oncogene, with somatic mutations that suppress the oncogene d. Germ-line mutations in a tumor suppressor gene, with neoplasia resulting from a second somatic mutation in the homologous gene e. Mitochondrial inheritance of tumor predisposition evidenced by the affected maternal relatives 7. Which gene is likely affected in the above family? 8. A normal 6 year-old girl has a strong family history of cancer, including several relatives with Li-Fraumeni syndrome, an autosomal dominant condition that predisposes to breast and colon cancer. Her parents request that she have genetic testing for possible cancer genes. The major ethical concern about such testing is: a. nonmalificence b. beneficience c. autonomy d. informed consent e. confidentiality 9. Patients with hereditary nonpolyposis colon cancer (HNPCC) have genes with microsatellite instability, that is, many regions containing abnormal, small loops of unpaired DNA. This is a result of a mutation affecting which of the following: a. Mismatch repair b. Chain break repair c. Base excision repair d. Depurination repair e. Nucleotide excision repair 10. Mammalian chromosomes have specialized structures with highly repetitive DNA at their ends (telomeres). Which aspect of telomeric DNA replication is different from that of other chromosomal regions? a. The DNA polymerase uses an RNA primer but does not degrade it. b. The DNA polymerase contains an RNA molecule that serves as a template for DNA synthesis c. The DNA polymerase must cross-link the 5 and 3 termini d. The DNA polymerase has a subunit that facilitates binding to repetitive DNA e. The DNA polymerase does not use an RNA template or primer 11. A middle-aged man presents with markedly enlarged tonsils and recurrent infections with serum immunoglobulin deficiency. Chromosome analysis demonstrates a translocation between the immunoglobulin heavy chain locus on chromosome 14 and an unidentified gene on chromosome 8. Which of the following is the most likely cause of his phenotype? a. The translocation has deleted constant chain exons on chromsome 14 and prevented heavy class switching. b. The translocation has deleted the interval containing diversity (D) and joining regions (J). c. The translocation has activated a tumor-promoting gene on chromosome 8.

d. e.

The translocation has deleted the heavy chain constant chain mu so that virgin B cells cannot produce IgM on their membranes. The translocation has deleted an immunoglobulin transcription factor gene on chromosome 8

For the following genes, choose the correct cancer (when the gene is mutated) and the accurate descriptors: 12. myc 13. Rb 14. BRCA1,2 15. Abl 16. MLH1, MSH2 17. APC 18. TP53 a. Mismatch repair b.Retinoblastoma c. regulated by phosphorylation d. transcription factor e. binds beta catenin f. double-stranded break repair of DNA g. increases DNA stability h Hereditary Non Polyposis colorectal cancer i. Hereditary breast cancer j. Familial Adenomatous Polyposis k. Li Fraumeni syndrome l. Burkitts lymphoma m. Chronic myelogenous leukemia n. Associated with cervical carcinoma o. Causes cells with DNA damage to arrest p. Tyrosine kinase

Ans&ers for section 1. 1. ! 2. ! 3. c 2. a Answers for section 2: 1. 2. 3. 4. 5. b c b,d b,c

Correct Answer: b 6. d 7. a

8. d 9. c Answers for section 3:

1. 2. c c

3. 4. 5. 6. 7. 8. 9. 10. 11.

f e d c b a h g DNA (coding or template strand): AGCTCCAAA

12. 13. 14. 15. 16.

mRNA tRNAs polypeptide d,e a,b,c,d a c e

UCGAGGUUU AGCUCCAAA H2N-Ser-Arg-Phe-

Answers for section 4: 1. a,b,c 2. a,b 3. d 4. a 5. c,b 6. b 7. b 8. True. Cell division is required for consolidation of a mutation. 9. This patient or an ancestor experienced a mutation, which produced an insertion or deletion of one or two bases in the nucleotide triplet specifying the 136th amino acid of the -globin chain. This alteration produced a frame shift resulting in the change in the amino acid sequence downstream from the deletion/insertion and extension of translation beyond the normal translational stop.
1(. 9 lin"ed restiction fragment length polymorphism

Answers for section 5: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. b d e False. Recessive inheritance is often associated with lack of affected ancestors. e e b b a Physicians will tend to refer more severely affected patients, while the mildly involved patients may escape ascertainment. Families with two or more cases of the disorder are also more likely to be referred than families with one affected child. Furthermore, heterozygous parents who produce only clinically normal children will not be included in the sample. The net effect of these biases is to inflate the frequency of affected children, most likely distorting the apparent mode of inheritance. The man has no case. Both parents could be heterozygous for the cystic fibrosis allele. By chance none of their ancestors who may also have been heterozygous married another heterozygote. Hence, both family histories could be negative for the disease, but still carry the allele. * Hint: proportion of normal carriers
/Ecarrier;normalF Q proportion normal carriers D proportion normals

22.

Solution: Prior Probability

Heterozygous 1/2

Normal Homozygote 1/2

Likelihood of normal phenotype Joint probability 1/4

1/2 2/4

Posterior probability = (1/4), (1/4 + 2/4) = 1/3 P(Affected Child) = P(carrier) x P(Transmission of allele) x Penetrance = 1/3 x 1/2 x 1/2 = 1/12. Answers section 6: 1. 2. 3. 4. 5. 6. d. p = [2(600) + 1,200] [2(2,000)] = 2,400 4,000 = 0.6; q = 1 p = 0.4. e b,c b. = 24 [(2)(0.8)(1,000,000)] = 1.5 x 10-5. b,c 1(#((( = 0.63 a r = fre+uency of Type M = 2#((( p=
fre+uency of A +M

r=

E2#B(( +2#(((F 1(#(((

0.63 = 0.32

q = 1 p r = 0.05 7. 8. 9.
1(.

d. q= True a,d
c

1;16#(((

1/123; 2q (2)(1/123) 1/62

11. 12.

13.

14.
16.

b. = 1/3sX; X = 3 /s = 3 = 3/25,000. Note: the selection coefficient for Duchenne muscular dystrophy = 1, since affected males do not reproduce. d. Draw the pedigree and trace the line of descent of the allele to each of the first cousins. The chance the male first cousin inherits the allele = 1/4. The chance that the female first cousin inherits the allele = 1/4. The chance that both first cousins transmit the allele to their child = 1/4. Law of simultaneous events: 1/4 x 1/4 x 1/4 = 1/64. The chance that the child from an aunt-nephew union will be homozygous for one of the four possible alleles in their common ancestors is 1/32 (determined as in problem 12). The chance that he will be homozygous for any of the four alleles is 4 x 1/32 = 1/8 = F. a,d
!#c#d

Answers for section 7: 1. 2. 3. 4.. 5. 6. e c,d b,c,d False. Maleness is determined by SRY on the Y chromosome. 47,XXY persons are males. d This woman has a single copy of each X-linked gene required for normal ovarian development and function. Normal female sexual development and fertility require two copies of each of these genes.

>. @.

This person &ill ha'e testes and male e)ternal features. Gpermatogenesis &ill !e defecti'e due to presence of a dou!le dose of certain 9 lin"ed genes and a!sence of critical I lin"ed genes. .nfertility &ould !e anticipated. T&o functional alleles of SHOX occur in !oth 99 &omen and 9I men EI copy Q SHOYF. Turner=s females possess only one copy of SHOX. Their short stature may !e caused !y haploinsufficiency of the G%M9 protein.

Answers section 8: 1. 2. 3. 4. b,c,d d False. Translocations, mosaicism, or nondisjunctional genes increase risk of recurrence.

5.

6.

Adjacent I: 13,13/14 14 Adjacent II: 13 13/14,14 Alternate: 13/14 13,14 True: Sperm carrying complements derived from alternate segregation and normal ova would produce balanced carrier and chromosomally normal concepti, respectively. Three of the four adjacent segregation products would produce nonviable concepti: monosomy 13, monosomy 14, and trisomy14. Theoretically, 1/6 of the liveborn concepti would be expected to have Pataus syndrome, however,almost all of these would die shortly after birth

7.f 8.a 9.g 10.

11

c
!

Answers for section 9: 1.F 2.b 3.c 4.e 5.f 6.j 7.g 8.b 9.i 10. b
11. c Carrier 3ormal

12. 13. 14. 15. 16. 17. 18.

1B.

Prior 1/2 1/2 Likelihood normal son 1/2 1 Joint probability 1/4 2/4 Posterior probability = (1/4) (1/4 + 2/4) = 1/3. e c d b e a e
a#!#c#d

Answers for section 10: 1. 2. 3. a,b,c,d False. There are a number of additional factors that bind the promoter that recruit and regulate RNA polymerase binding and initiation. False. The Hox genes are DNA binding proteins but they are conserved as well as ordered in the genome with regard to when they are active in the developing organism.

2.i 6.e 6.h >.d @.d B.c 1(. a 11. j#" 12. c. For each pregnancy# the pro!a!ility of ha'ing an affected child E,F is 1;2 and the pro!a!ility of ha'ing an unaffected child E&F is 1;2. The +uestion is# &hat is the pro!a!ility that 1 of 3 children &ill !e affected. The possi!le !irth orders are C ,&&# ie# the first child is affected !ut the ne)t 2 are notOthe pro!a!ility of this occurring is 1;@R or &,& the second child is affected 1;@ and the others are not# or &&, 1;@ &here the last child is affected. Gince ,&& or &,& or &&, could happen# the pro!a!ility is 1;@ D 1;@ D1;@ Q 3;@ Eremem!er the addition rule from lecture 6.

Answers for section 11: 1. 2. 3. 4. 5. 6.

>

a, b, c c a a b a
!. The !oy=s paternal grandmother contri!uted !oth the %* allele and the B restriction fragment to her descendants. The !oy=s father is still !elo& the oldest age for onset of %untington=s disease.

Answers for section 12: 1. e. The hemoglobin tetramer is best represented as being composed of 2 dimers, each containing alpha and beta.

2. 3. 4. 5.
6. >. @. B. 1(. 11. 12. 13. 12. 16. 16. 1>. 1@. 1B.

b amino acid substitutions that alter the charge of an amino acid, like the change from glutamic acid (acidic) to valine (nonpolar) are the most likely to change the secondary and tertiary structure. c c,d b
a c a#! 1;2 @ 1 2 > 1( 2 B 6 6 3

Answers for section 13: 1. 2. 3. 4. 5. 6. 7. b c a, b, and c are possible answers a, b, and c are possible e 25%. Most metabolic disorders are recessive Metabolic errors involving amino acids most commonly produce overflow aminoacidurias, where both blood and urinary levels of the amino acid are elevated. A mutation affecting a renal transport system usually results in high urinary levels of the amino acid accompanied by normal or low blood levels of the amino acid. C will be diverted to I which will accumulate. Lack of E will cause a deficiency of both F and Z. Accumulating X will be diverted to Y and W which will both accumulate. Therefore, the block will lead to deficiencies of F and Z and excesses of I, W, and Y. 50%-- the childs parents had a 100% chance of being carriers, ie are obligate carriers. Grandparents have a 50% chance of being carriers because one or the other must have transmitted the mutant allele to their carrier child. d e f b

8.

9.

10. 11. 12. 13.

12.

26: meta!olic diseases usually e)hi!it autosomal or 9 lin"ed recessi'e inheritance. Autosomal recessi'e inheritance is most li"ely !ecause the affected patient is a female. .n this case# the parents are o!ligate carriers. The symptoms suggest Tay Gachs disease. 16. ! 16. 1;16Odra& the pedigree &ith the grandparents as common ancestors and calculate the in!reeding coefficient# &hich is the pro!a!ility that any gi'en locus Ein this case# CFT5F is identical !y descentOthere &ill !e 2 Spaths= !y &hich the gametes can !e commonOthe sum of these 2 pathsO1;32 D 1;32 Q 1;16. Alternati'ely# you can thin" of it that since the grandmother has CF# her children are o!ligate carriers. 4ach cousin# therefore# has a 6(: chance of !eing a carrier and then a 26: chance of producing an affected childOthus # 1;2 ) 1;2 ) 1;2 Q 1;16 1>. c

Answers for section 14: 1. c 2. 1:3 3. a 4. c 5. hydroxyproline and hydroxylysine are post-translationally modified amino acids that make up newly synthesized collagen. Hydroxylation requires vitamin C. Insufficient hydroxylation of collagen causes abnormal collagen fibrils.
6. >. @. B. cOall AA children &ill die thus of the 3 types left# 2 &ill !e Aa and 1;3 &ill !e normal !Othere are too many mutations Ealmost e'ery patient has a different mutationF# thus# it is more efficient to do ! c c

Answers for section 15: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

16. 16. 1>.

b,c b False. The woman could be heterozygous for a colorblind allele. e b d b Since XGA is not subject to X-inactivation, all of the cells should stain with the fluorescent antibody. Onehalf of these cells would also stain with the G6PD activity stain, and one-half would not stain. a c P(affected child) = P(male) x 1/2 = 1/4. b b e P(carrier) = [P(carrier) x P(2 normal sons)] [(Numerator) + {(P(Normal) x P(2 N. S.)}] = ( x ) [( x ) + ( x 1)] = 1/5. b
a a d

Answers for section 16: 1. b 2. d 3. c 4. a 5. b 6. d 7. a,b,c,d 8. a 9. a 10. c, d 11. b,c

12. 13. 14. 15.

c a b,d d

Ans&ers for section 1>C 1. a# !# c# d 2. a 3. a# !# c# d 2. a#d 6. noneOthese are engineered not to replicate 6. ! >. a#c @. c B. a 1(. !# c 11. a# c 12. ! 13. ! 12. a# d 16. !#c 16. Ad'antagesC n o contaminating 'irus and no limit on si0e of the insert. *isad'antagesC lo& efficiency of infection# the lipsomes are difficult to target to a tissue of interest and artificial chromosome construction is in preliminary stages 1>. .ntroduction of a tumor suppressor gene# antisense oligos# cyto"ine genes to stimulate the immune response# suicide genes 1@. Gancyclo'ir is phosphorylated !y thymidine "inase into an acti'e form &hich is to)ic to cells e)pressing thymidine "inase. 1B. d 2(. c 21. e 22. a 23. ! 22. a 26. ! 26. Tissue specific incompati!ility due to 1%C differences. The 4G cell lines currently a'aila!le e)press the 1%C antigens of the donor. 3uclear transplant is re+uired to ma"e indi'idual specific tissues. Alternati'ely# if adult stem cells could !e isolated and induced to differentiate# that &ould &or" as &ell. Ans&ers for section 1@C 1. 2. 3. 2. 6. 6. >. @. B. This disorder is caused !y a mitochondrial defect !ecause all of the children of the affected mother inherit the disorder# regardless of gender &hile none of the children of affected males inherit the disorder. a a# c#e Jniparental disomy methylation ! a e this is the !est ans&er for rapid and une+ui'ocal detection of a small deletion c

1(. 11.

d c

Answers for section 19: 1. e 2. Empiric risks for a fourth pregnancy producing an infant with either or both birth defects is about 10%. 3. b,c,d 4. c 5. e 6. c 7. d 8. b 9. c 10. a 11. b 12. a

Answers for section 20: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. a b a b a a b d d e f g b a an example of a phenocopy is a human prion disorder that has a very similar phenotype to Huntingtons disease 15. c
16. c 1>. !

18. 19. 20.

1 ; 1(#((( = 1/100 a. d Approximately 7. [(23)(116)]/[(4)(97)] = ~7

Answers for section 21: 1. 2. a In contrast to the other lipoproteins, HDL is potentially anti-inflammatory. It also transfers cholesterol for disposal

3.

False. Fatty streaks can be present in children and teenagers, although they are the first step in atherosclerosis, they do not all develop into plaques. e Genes contribute very little to the variance. To get this result, one would conclude that the variance within pairs of dizygotic twins is very similar to that seen within monozygotic twins.

4. 5.

6. e 7. a,c 8. b. H = (s2DZ s2MZ) s2DZ = (1,000 - 200) 1000 = 0.80 9. e 10. d 11. d

Ans&ers for section 22C 1. 4 2. B 3. 1ono0ygotic t&ins share all of their *3A &hile *N and si!lings share 6(:. 3on additi'e genetic effects occur !y the interactions of the multiple shared genes in 1N t&ins. First degree relati'es are not li"ely to share all of these components# thus# &ill not ha'e the same phenotype. 2. 6. 6. >. @. B. 1(. 11. 12. c# " !# i a# g j e e d# f !# h !#c#f#g#i

Answers for section 23.

1. 2. 3. 4. 5. 6.

c F C A Falseit should stop progression of the disease A. Autosomal dominant i. Presenilin 150% of familial AD is caused by mutations in this gene

7. D 8. all of them

Answers for section 24: 1. 2. 3. 4. 5 6. d a, b, c a a,b,c b d This family is an example of a cancer family that exhibits bone, breast, colon, and blood cancers that are typical of Li Fraumeni syndrome 7. The affected gene is TP53. 8. d Presymptomatic DNA testing of individuals in cancer families is increasingly available. However, testing of minors is controversial because thy may not be old or mature enough to understand the personal medical and financial implications. They therefore cannot give truly informed consent. Beneficence is the ethical imperative to do good for patients, while nonmaleficence is the imperative to do not harm. Autonomy refers to a patients right to make decisions regarding his or her health care, and confidentiality to the privilege of the doctor-patient communication. 9. a 10. b. A special DNA polymerase called telomerase is responsible for replication of the telomeric DNA. Telomerase contains as RNA molecule that guides the synthesis of complementary DNA. Telomerase is an RNA-dependent DNA polymerase in a category with reverse transcriptase. 11. c. This is Burkitts lymphoma. A translocation has placed myc downstream of the highly active heavy chain locus. 12. d, l 13. b,c 14. c, d, f,i 15. m, p 16. a,g, h 17. e, j 18. c, k, n, o