CM156-Midterm II-Winter 2021-final KEY

1 CM156/256 Midterm Exam I (February 22, 2021) 1. Please indicate your TA and Discussion section (1 point) : Aileen Nava: 1A 1B 1C Kevyn Hart: 1D 1E 1F EACH MIDTERM QUESTION IS WORTH 3 POINTS 2. You are counseling the 20-year-old son and 22-year-old daughter of a man who developed Huntington Disease at 54 years of age. You tell them that: i) The son is at higher risk of the inheriting disease than the daughter ii) The daughter is at higher risk of inheriting the disease than the son iii) If they inherited the mutation, the son will develop the disease earlier than the daughter iv) If they inherited the mutation, the daughter will develop the disease earlier than the son v) If they inherited the mutation, the age of onset will likely be earlier than the father The principle here is that HD alleles expand upon paternal transmission, leading to the strong possibility that there will be an earlier age of onset among the offspring who inherit the mutation from an HD father. 3. Fragile X syndrome is an X-linked disorder that results from lack of expression of the FMR1 gene. Unaffected parents have a daughter with Fragile X syndrome. This could be explained by: i) Inheritance of a premutation from her father. ii) Expansion of a premutation inherited from her carrier mother. iii) Skewed inactivation of the daughter’s Fragile X mutant allele. iv) Skewed inactivation of the daughter’s normal allele. v) A new mutation in FMR1 The principle here is that although there is maternal expansion of the FMR1 trinucleotide repeat, because FMR1 is subject to X-inactivation, an inherited mutation in a daughter is not expected to result in Fragile X syndrome unless there is skewed inactivation of the normal allele, leading to reduced FMR1 expression. There was a slide in class that showed this, noting that in rare cases there can be mild Fragile X in such daughters but not the full Fragile X syndrome. This question was exploring understanding of that topic. 4. A man with a heteroplasmic mitochondrial disorder has a son and a daughter. Which of the following is true? i) The daughter is at risk for the disorder but the son is not ii) The son is at risk for the daughter but the daughter is not iii) The risk to each child depends on the level of heteroplasmy in the father iv) The children are not at risk for the disorder v) Both children will inherit the disorder The principle here is that mitochondria are not transmitted to the offspring of males. 5. You are counseling a woman with a mitochondrial disease who is homoplasmic for the causal mutation. You can tell her:

2 i) Her offspring will be at reduced risk due to purifying selection during oocyte maturation ii) Her offspring are at unknown risk for the disease iii) Her offspring will be homoplasmic for the mutation and affected iv) Her offspring will be heteroplasmic for the mutation and may or may not be affected v) Since the father is unaffected, there will be reduced risk among her offspring The principle here is that there is exclusively maternal transmission of mitochondria and that when a woman is homoplasmic, the only mitochondria she can transmit will have the mutation so that her offspring would be predicted to be homoplasmic and therefore affected. 6. The UBE3A gene associated with Angelman syndrome is paternally imprinted. A boy has unaffected parents and a brother and sister with Angelman syndrome. What is his risk of having a child with the disorder? i) 100% ii) 50% iii) 25% iv) 0 v) Unable to tell with certainty The principle here is that with two unaffected siblings, the only way the boy will not be affected is if he inherited the normal allele from his heterozygous parent. Consequently, his children are not at risk for the disease. His heterozygous parent is unaffected because the mutant allele is imprinted and therefore not expressed but the other allele is expressed, leading to an unaffected phenotype. 7. Shown below is part of Fig 2A from Carrette et al. (paper #5) on X chromosome reactivation. Which of the following statements is NOT accurate? i) The difference between the red and black curves is due to the addition of 5-aza- 2” - deoxycytidine (Aza) ii) The large fold change in expression between 0-0.25 and 0.75-1.0 cumulative fraction is due to natural and experimental variation iii) The p-value is for the significance of the shift between black and red lines iv) The shift is dependent on the absence of Xist expression v) None of the genes on the X chromosomes is activated more than 1.3-fold 8. What was the purpose of using the hybrid fibroblast line which contained the Mus musculus and Mus casteneus strain used to produce the data above from the Carrette et al. paper (paper #5)?

4 that escape X inactivation AND will inherit an X chromosome with either maternal or paternal imprints, but will not have both. This will lead to abnormal gene expression levels of genes that are imprinted. ‘Failure of X chromosome inactivation’ will not be a concern. 11. The genetic basis for differences in phenotypes between a typical man and woman include all EXCEPT : i) Differential expression levels of autosomal genes ii) Differences in the number of Barr bodies in every cell iii) The presence only in women of Xist gene expression iv) Differential expression levels of genes in the pseudoautosomal region of sex chromosomes v) Differential expression levels of several genes that function in gene transcription, splicing, and translation There are two correct answers to this question, as expression of autosomal genes and differential expression of a few pseudoautosomal genes may differ between male and female cells. Either answer is accepted. 12. The following are TRUE of genetic variation in the human genome EXCEPT : i) Simple sequence repeats are highly variable due to errors in replication ii) Linkage disequilibrium is extensive in regions undergoing selective sweep iii) Common variations are a major cause of common diseases iv) Most genetic variations occurred after modern humans migrated out of Africa v) The “Regional Hypothesis” that modern humans evolved separately in various parts of the world, predicts greater variation between populations than the “Out of Africa” hypothesis As discussed in the lecture on population genetics, the vast majority of genetic variation occurred early in the origin of modern humans when the human population was small, perhaps in the hundreds or thousands. Moreover, all ethnic groups share about 90% of the total variation, and this would not be the case if the variations arose after the migration. 13. At linkage equilibrium, what is the frequency of the haplotype SNP1, allele 2 – SNP2, allele 2 – SNP3, allele1, given the below frequencies? SNP Frequency Allele 1 Frequency Allele 2 1 75% 25% 2 80% 20% 3 60% 40% i) 0.03 ii) 0.06 iii) 0.09 iv) 0.012 v) None of these choices The principle here is that even at linkage equilibrium, there are haplotypes on each chromosome. For the haplotype described in the question, the answer is (.25)(.20)(.6)=.03

5 14. Two genetic markers, A and B, reside about 10 kb apart on human Chr. 3. They each have two alleles: A 1 and A 2 , and B 1 and B 2 . What are the likely haplotypes at the Chr. 3 locus that are carried by individual I-1? i) A 1 B 1 and A 2 B 2 ii) A 1 B 2 and A 1 B 1 iii) A 1 B 2 , and A 2 B 1 iv) A 2 B 1 and A 1 B 1 v) None of these choices The idea here is that the two markers are only 10kb apart so it can be assumed that recombination between them will not occur. The haplotype of I-1 can be derived by looking at the genotypes of his offspring. Since II-2 is homozygous for markers A1 and B2, the father must have this haplotype on one allele. Given his genotype, the other haplotype must then be A2B1. Originally the question was stuck under the Fig. We apologize. This was corrected and student questions were answered during the exam. 15. A deletion mutation of the chemokine receptor 5 (CCR5D32) confers resistance to HIV, and individuals carrying the mutation share the same haplotype of the CCR5D32 gene. This suggests that: i) The mutation exhibits a “gain of function” ii) The mutation has been under strong positive selection iii) The mutation occurred only once in history iv) The mutation is most likely recessive v) The mutation is an example of a triplet repeat disease The idea here is that independent occurrence of the same mutation would be most likely to have occurred on a different haplotype (and also would have been under positive selection). Since there is only a single haplotype, the most parsimonious answer is that the mutation occurred only once. II-1 II-2 I-1 I-2 Genotype: A 1 A 2 B 1 B 2 A 1 A 1 B 1 B 2 A 1 A 1 B 1 B 2 A 1 A 1 B 2 B 2

7 20. For the following two questions (#20-21) refer to the figure below. Your GWAS analysis for plasma cholesterol levels identified the lead SNP shown below in red. The following are likely to be true EXCEPT : i) The lead SNP is not present within a protein coding region ii) Dozens of genetic loci are associated with cholesterol levels, suggesting that this locus likely contributes a small effect iii) An examination of linkage disequilibrium may help identify candidates for the causal variant iv) Chromatin Conformation Capture may help identify whether histone marks near the variant suggest a role in gene regulation v) Reporter gene assays may help determine if the causal variant has regulatory activity A GWAS was performed for a complex trait, cholesterol levels, and identified a lead SNP that lies outside of protein coding regions. The figure also shows that the genotype influences expression levels of several genes. Therefore answers i, ii, iii, and v are all true. Answer iv is not true, because Chromatin Conformation Capture is a technique that identifies regions of chromosomes that interact; it does not inform about histone marks.

8 21. Expression analysis in tissue samples from individuals with the genotypes indicated showed the results in the figure above (see Question #20). The following are reasonable conclusions EXCEPT : i) The risk allele acts in a co-dominant manner to enhance gene expression ii) The variant affects gene expression across tissues iii) Likely target genes for the responsible variant are SORT1 , PSRC1 , and CELSR2 iv) The causal variant is likely to have physical interactions with multiple sites in the region v) Studies in mouse models could be used to determine which gene(s) are most critical for determining the cholesterol phenotype The genotype is associated with expression levels of three genes ( SORT1 , PSRC1 , CELSR2 ) in liver, but not in adipose tissue. Therefore ii is a false statement. All other statements are true. 22. You have identified a population that exhibits lactase persistence, but does not contain any of the known SNPs to be associated with this trait. You decide to genotype 200 SNPs in the region surrounding the LCT gene and see if any of the SNPs are correlated with the trait. Approximately how many false positives are you willing to accept if you keep your Type I error rate (p-value) threshold at 0.05? i) 5 ii) 10 iii) 15 iv) 40 v) None of these choices 23. Below is Figure 2 from the paper from Week 6: Tishkoff et al . Convergent adaptation of human lactase persistence in Africa and Europe. Based on the genotypes and phenotypes, which of the following populations exhibit the highest levels of lactase non-persistence? i) Afro-Asiatic in Kenya ii) Nilo-Saharan in Kenya iii) Afro-Asiatic in Tanzania iv) Sandawe in Tanzania ( this is correct ) v) Nilo-Saharan in Sudan (incorrect, but mistakenly considered correct in CCLE)

10 27. Which of the following observations would NOT support the “Out of Africa” hypothesis of origin of modern humans? i) African populations are at the root of the phyl ogenetic tree among the world’s populations ii) European populations have a lower level of genetic diversity than Africans iii) Fossils of modern humans dating to over 100,000 years ago have been found in Australia iv) Some populations but not others show admixture with Neanderthal DNA v) Modern human populations share the majority of genetic variants As discussed in the Human History lecture, although modern humans originated about 100,000 thousand years ago, the migrations out of Africa occurred between about 70,000 and 30,000 years ago. Fossil remains in Australia dating to more than 100,000 years ago would be in conflict with these dates. Moreover, all of the other answers are consistent with “Out of Africa”. 28. Iceland was populated by a founder population from Norway with the mitochondrial haplotype “1, 2, 2, 2, 1”. At present, there are 5 common subpopulations in addition to the ancestral haplotype: "1, 2, 1, 2, 1"; “1, 2, 1, 1, 1”; "1, 2, 1, 1, 2"; “2, 2, 1, 1, 2”; and “2, 1, 1, 1, 2” . Which subpopulation is the more recently derived? i) 2, 2, 1, 1, 2 ii) 1, 2, 1, 1, 1 iii) 2, 1, 1, 1, 2 iv) 1, 2, 1, 2, 1 v) 1, 2, 1, 1, 2 For this question, there was a typo in the prompt such that the derived alleles in the question were not the same as the derived alleles in the answers. While this was corrected in real time during the exam, not everyone had the benefit of the correction. For the derived alleles in the original question ( 1, 2, 2, 1, 1”; “1, 2, 1, 1, 1”; “2, 2, 1, 1, 2”; “1, 2, 2, 1, 1”; and “2 , 2, 1, 1, 1 ” ), the correct answer was i) 2, 2, 1, 1, 2. For the derived alleles in the answers, the correct answer was iii) 2, 1, 1, 1, 2. Either answer will be accepted as correct. The solution to the question was a simple comparison between the ancestral haplotype and the derived haplotypes with the most recent derived haplotype being the one in each instance with the most changes.

11 29. A decomposed body is found in a wall in your family mansion. You suspect it is your distant relative, Jack, a greedy, unpleasant fellow, according to family folklore. Among 5 living individuals (I-V) in the pedigree below, who would be best to genotype to compare to Jack’s DNA? i) I ii) II iii) III iv) IV v) V The principle here is that Jack is related to individual I through his mitochondria so their mitochondrial genotypes would be expected to be identical. 30. Shown below is part of Fig. 2B from the Chen et al. paper (Paper #7). For the European population, what is the width of the locus if one considers SNPs with correlation greater than 0.2 with the lead SNP? i) ~10kb ii) ~50 kb iii) ~100kb (also correct) iv) ~200 kb v) ~1 megabase For this question, the resolution of the figure made it reasonable to estimate the genomic distance between the purple dots to the left and right at either 50 or 100 kb, so either answer is correct. II I V IV III JACK

13 33. Which of the following statements is true about Figure 3A (below) from the Chen et al. paper (paper #7)? i) As the PIP increases, the proportion of likely functional variants increases ii) As the PIP increases, the proportion of likely functional variants decreases iii) As the PIP increases, the proportion of likely functional variants is similar iv) Causal SNPs are most likely going to be located only in the Intergenic + ATAC category v) Causal SNPs are most likely going to be located in the Intronic + Missense categories 34. Shown below is Fig 3D from Chen et al. (paper #7) dealing with blood cell genetics. The authors conclude that rs941616 is an eQTL for PTGRD . This means that: i) The SNP is in an enhancer of PTGRD. ii) The SNP is in linkage disequilibrium with a missense variant in the PTGRD gene. iii) The SNP is associated with PTGRD expression. iv) The SNP interacts with the promoter of PTGRD. v) The SNP is subject to selection.

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