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Genetics: From Genes to Genomes

Leland Hartwell, Michael L. Goldberg, Janice Fischer

Chapter 22

The Genetics of Complex Traits - all with Video Answers

Educators

Chapter Questions

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Problem 1

Choose the best matching phrase in the right column for each of the terms in the left column.
$$ \text { a. isogenic lines} \quad \quad\quad\quad\quad \text { 1. fraternal } $$
$$ \text { b. QTL } \quad \quad\quad\quad\quad \text { 2. blocks of association between variants at different loci } $$
$$ \text { c. response to selection } \quad \quad\quad\quad\quad \text { 3. proportion of total phenotypic variance attributed to genetic variance } $$
$$ \text { d. association mapping } \quad \quad\quad\quad\quad \text { 4. homozygous for all genomic regions } $$
$$ \text { e. MZ twins } \quad \quad\quad\quad\quad \text { 5. genes contributing to complex traits } $$
$$ \text { f. $D Z$ twins } \quad \quad\quad\quad\quad \text { 6. identical } $$
$$ \text { g. congenic lines } \quad \quad\quad\quad\quad \text { 7. measure of evolution } $$
$$ \text { h. linkage disequilibrium } \quad \quad\quad\quad\quad \text { 8. 0 .5 for siblings } $$
$$ \text { i. heritability } \quad \quad\quad\quad\quad \text { 9. takes advantage of recombination over the course of a population's history } $$
$$ \text { j. genetic relatedness } \quad \quad\quad\quad\quad \text { 10. contain introgressions } $$

Marisa A
Marisa A
Numerade Educator
01:49

Problem 2

Suppose you grew genetically identical dandelion seeds in an environmentally controlled environment like a greenhouse.
a. Sketch the distribution of stem length phenotypic classes you would expect to see relative to the distributions shown in Figs. 22.5 and $22.5 b$
b. Why would you expect to see a phenotypic variance greater than zero for these genetically identical dandelions grown in a constant environment?
c. How could you use this information to refine the estimate of genetic variance shown originally in Fig. $22.5 b ?$

James Kiss
James Kiss
Numerade Educator
05:03

Problem 3

How can each of the following be used in determining the role of genetic and/or environmental factors in phenotypic variation in different organisms?
a. genetic clones
b. human monozygotic versus dizygotic twins
c. cross-fostering

Jennifer Stoner
Jennifer Stoner
Numerade Educator
02:01

Problem 4

Two different groups of scientists studying a rare trait in ground squirrels report very different heritabilities. What factors influencing heritability values make it possible for both conclusions to be correct?

Jennifer Stoner
Jennifer Stoner
Numerade Educator
03:59

Problem 5

Which of the following statements would be true of a human trait that has high heritability in a population of one country?
a. The phenotypic difference within monozygotic twin pairs would be about the same as the phenotypic differences among members of dizygotic twin pairs.
b. Very little phenotypic variation exists between monozygotic twins but high variability exists between dizygotic twins.
c. The trait would have the same heritability in a population of another country.

Jennifer Stoner
Jennifer Stoner
Numerade Educator
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Problem 6

Studies have indicated that for pairs of twins raised in the same family, the environmental similarity for monozygotic (MZ) twins is not significantly different from the environmental similarity for fraternal (dizygotic or DZ ) twins. Why is this fact important for calculations of heritability?

Emily Himsel
Emily Himsel
Numerade Educator
01:11

Problem 7

A study published in 1937 examined the average differences between pairs of twins [either monozygotic (MZ) or dizygotic (DZ)] and pairs of siblings for three different quantitative traits: height, weight, and intelligence quotient (IQ) as measured by the Stanford-Binet test. (The concept of IQ is extremely controversial as it is unclear to what extent IQ tests measure native intelligence, but for this problem, consider IQ to be a measurable trait even if its significance is unknown.) Some of the MZ twins were raised together in the same household (RT), while other MZ twins were raised apart in different families (RA). The results of this study, shown as average differences, are as follows:
$$\begin{array}{lcccc}
& \text { MZ(RT) } & \text { MZ(RA) } & \text { DZ } & \text { Siblings } \\
\hline \text { Height } & 1.7 \mathrm{cm} & 1.8 \mathrm{cm} & 4.4 \mathrm{cm} & 4.5 \mathrm{cm} \\
\text { Weight } & 1.86 \mathrm{kg} & 4.49 \mathrm{kg} & 4.54 \mathrm{kg} & 4.72 \mathrm{kg} \\
\text { IQ } & 5.9 & 8.2 & 9.9 & 9.8
\end{array}$$
a. Which of these three traits appears to have the highest heritability? The lowest heritability? (Note: You do not have enough data to calculate numerical values for heritability. You are meant to think about this in general quantitative terms.)
b. The Centers for Disease Control and Prevention (CDC) of the National Institutes of Health recently reported that in the United States during the period $1960-2002,$ the average weight of a 15 -year-old boy increased from 135.5 pounds $(61.46 \mathrm{kg})$ to 150.3 pounds $(68.17 \mathrm{kg}) .$ During the same period, the average height of a 15 -year-old boy increased from 67.5 inches $(171.5 \mathrm{cm})$ to 68.4 inches $(173.7 \mathrm{cm}) .$ How well do these statistics match your estimates of relative heritabilities from part (a)?

James Kiss
James Kiss
Numerade Educator
01:06

Problem 8

This problem is about Eq. $22.7,$ which relates heritability to the difference between MZ and DZ twins' correlation coefficients for a quantitative trait: heritability $=2\left(r_{M Z}-r_{D Z}\right)$
a. Explain why Eq. 22.7 is true for the extreme case where all phenotypic variation is due to genes.
b. Do the same for the case where no phenotypic variation is due to genes.

James Kiss
James Kiss
Numerade Educator
01:35

Problem 9

Table 22.2 lists concordance values for $\mathrm{MZ}$ and $\mathrm{DZ}$ twins with respect to a number of discrete complex traits.
a. How do you know at a glance that the heritabilities of all of these traits is less than $1.0 ?$
b. To estimate the heritabilities of these traits, would you use Eq. 22.7 or Eq. $22.8 ?$ Explain why.
c. Calculate heritability estimates for each trait using the data in Table $22.2 .$ For which trait is the contribution of genetic variance to the total phenotypic variance more than any other in the table?

James Kiss
James Kiss
Numerade Educator
01:43

Problem 10

In $1959,$ the Russian geneticist Dmitri Belyaev began an experiment in which he bred silver foxes for tameness. He started with wild foxes, and selected for reproduction the progeny who showed the least fear of and least aggression toward, humans. By 1999 , after 30 generations of inbreeding and outbreeding, Belyaev and his colleagues obtained a population of foxes that behaved essentially like domesticated dogs; they wagged their tails and licked their human caretakers.
a. What does this experiment say about the heritability of docile behavior in foxes? Explain.
b. Remarkably, as shown in the photographs here, along with the behavioral changes came morphological changes, including spotted coats, floppy ears, and curly tails.
A similar domestication phenotype has been observed in other animals bred and selected in a
similar manner. Do you think that this outcome necessarily means that the same genes control both the behavior and the appearance? Explain.

James Kiss
James Kiss
Numerade Educator
04:07

Problem 11

Two traits with similar phenotypic variance exist in a population. One trait has two major genes and six minor loci that influence the phenotypic value, and the second trait has 12 minor loci and no major genes affecting the phenotypic value. Does this information tell you which trait you should expect to respond most consistently to selection? Explain why it does or does not.

Jennifer Stoner
Jennifer Stoner
Numerade Educator
03:02

Problem 12

Two alleles at one locus produce three distinct phenotypes. Two alleles of two genes lead to five distinct phenotypes. Two alleles of six genes lead to 13 distinct phenotypes. (These statements assume that the alleles at any one locus are codominant or incompletely dominant and that each gene makes an equal contribution to the phenotype.)
a. Derive a formula to express this relationship. (Let $n$ equal the number of genes.)
b. Each of the most extreme phenotypes for a trait determined by two alleles at one locus are found in a proportion of $1 / 4$ in the $\mathrm{F}_{2}$ generation. If two alleles of two genes determine the trait, each extreme phenotype will be present in the $\mathrm{F}_{2}$ as $1 / 16$ of the population. In common wheat (Triticum aestivum), kernel color varies from red to white and the genes controlling the color act additively, that is, alleles for each gene are incompletely dominant and each gene contributes equally to the color. A true-breeding red variety is crossed to a true-breeding white variety, and $1 / 256$ of the $\mathrm{F}_{2}$ have red kernels and $1 / 256$ have white kernels. How many genes control kernel color in this cross?

Jennifer Stoner
Jennifer Stoner
Numerade Educator
04:32

Problem 13

In a certain plant, leaf size is determined by four genes whose alleles assort independently and act additively. Thus, alleles $A, B, C,$ and $D$ each add $4 \mathrm{cm}$ to leaf length and alleles $A^{\prime}, B^{\prime}, C^{\prime},$ and $D^{\prime}$ each add $2 \mathrm{cm}$ to leaf length. Therefore, an $A A B B C C D D$ plant has leaves $32 \mathrm{cm}$ long and an $A^{\prime} A^{\prime} B^{\prime} B^{\prime} C^{\prime} C^{\prime} D^{\prime} D^{\prime}$ plant has leaves
$16 \mathrm{cm}$ long.
a. If true-breeding plants with leaves $32 \mathrm{cm}$ long are crossed to true-breeding plants with leaves $16 \mathrm{cm}$ long, the $\mathrm{F}_{1}$ will have leaves $24 \mathrm{cm}$ long and the genotype $A A^{\prime} B B^{\prime} C C^{\prime} D D^{\prime} .$ List all possible leaf lengths and their expected frequencies in the $\mathrm{F}_{2}$ generation produced from these $F_{1}$ plants. (Hint: Recall Problem 45 e in Chapter $2 .)$
b. Now assume that in a randomly mating population the following allele frequencies occur:
frequency of $A=0.9$
frequency of $A^{\prime}=0.1$
frequency of $B=0.9$
frequency of $B^{\prime}=0.1$
frequency of $C=0.1$
frequency of $C=0.9$
frequency of $D=0.5$
frequency of $D^{\prime}=0.5$
Calculate separately the expected frequency in this population of the three possible genotypes for each of the four genes.
c. What proportion of the plants in the population described in part (b) will have leaves that are $32 \mathrm{cm}$ long?

James Kiss
James Kiss
Numerade Educator
02:58

Problem 14

Compare and contrast the use of SNP genotyping:
(i) in the positional cloning of Mendelian disease genes,
(ii) in direct QTL mapping, and (iii) in GWAS.

Jennifer Stoner
Jennifer Stoner
Numerade Educator
05:56

Problem 15

Explain the similarities and differences between the procedures used for the coarse-scale mapping and finescale mapping of QTLs thruugh cuntrulled crusses, as was accomplished for $\mathrm{QTL}$ s involved with tomato size.

Jennifer Stoner
Jennifer Stoner
Numerade Educator
03:38

Problem 16

In Fig. $22.14 \mathrm{c}$, the $f w 2.2$ causal gene was validated by introducing the $S$. pennellii version of the gene into $S$. lycopersicum. Why was the experiment done this way, rather than the other way around?

Jennifer Stoner
Jennifer Stoner
Numerade Educator
02:45

Problem 17

Among the most prevalent pathologies that afflict human beings is heart disease, which can have a severe impact on quality of life and can even result in premature death. While heart disease mostly afflicts those who are older, $1 \%$ or $2 \%$ of people in their 30 s, and even in their $20 \mathrm{s},$ suffer from this disease. Genetic and environmental components of this disease exist. What strategy might you use to choose families to participate in a GWAS of heart disease-causing genes? Explain your reasoning.

Bryan Valdivia
Bryan Valdivia
Numerade Educator
06:08

Problem 18

Human geneticists have found the Finnish population to be very useful for studies of a variety of conditions. The population is small; Finns have extensive church records documenting lineages; and few people have migrated into Finland. The frequency of some recessive disorders is higher in the Finnish population than elsewhere in the world, and diseases such as PKU and cystic fibrosis that are common elsewhere do not occur in the Finnish population.
a. How would a population geneticist explain these variations in disease occurrence?
b. The Finnish population is also a source of information for the study of quantitative traits. The genetic basis of schizophrenia is one question that can be explored in this population. What advantage(s) and disadvantage(s) can you imagine for studying complex traits based on the Finnish population structure?

Jennifer Stoner
Jennifer Stoner
Numerade Educator
03:11

Problem 19

Canavan disease, caused by homozygosity for a recessive allele, is a severe neurodegenerative syndrome usually resulting in death by the age of 18 months. The frequency of Canavan disease is particularly high in Jewish populations. In an effort to map the gene causing this condition, researchers looked at $10 \mathrm{SNPs}(1-10)$ spaced at roughly 100 kb distances along chromosome
a. Does the disease-causing mutation appear to be in linkage disequilibrium with any of the SNP alleles? If so, which ones?
b. Where is the most likely location for the Canavan disease gene? About how long is the region to which you can ascribe the gene?
c. How many independent mutations of the Canavan gene are suggested by these data?
d. Suppose that individuals $2-9$ are Ashkenazic (whose ancestors lived in the Rhine river basin of Germany and France after the Jews were expelled from Judea in 70 A.D.) while individual 1 is Sephardic (a non-Ashkenazic Jew). Would these facts provide any information about the history of the mutations causing Canavan disease?
e. For mapping genes by haplotype association, why is it often helpful to focus on certain subpopulations? Does this strategy have any disadvantages? 17 in five affected Jewish patients (Cases) and four unaffected Jewish individuals (Controls). In the accompanying table, each row depicts a single haplotype. (Every individual is diploid and therefore has two haplotypes, although only one is shown in the table.) $\mathrm{G}, \mathrm{C}, \mathrm{A},$ and $\mathrm{T}$ represent the actual nucleotide at the indicated SNP location.
f. Human chromosome 17 is an autosome, so each person has two copies of each region along the chromosome. With this in mind, explain the practical difficulty in determining haplotypes. (Hint:
Consider heterozygosity.) In light of this difficulty, how could the researchers determine any individual haplotype, such as any of those shown in the table?
$$\begin{array}{cccccccccc}
\text { Case } & \text { SNP1 } & \text { SNP2 } & \text { SNP3 } & \text { SNP4 } & \text { SNP5 } & \text { SNP6 } & \text { SNP7 } & \text { SNP8 } & \text { SNP9 } & \text { SNP10 } \\
\hline 1 & \mathrm{G} & \mathrm{T} & \mathrm{G} & \mathrm{T} & \mathrm{T} & \mathrm{T} & \mathrm{C} & \mathrm{A} & \mathrm{G} & \mathrm{T} \\
2 & \mathrm{A} & \mathrm{T} & \mathrm{G} & \mathrm{T} & \mathrm{T} & \mathrm{T} & \mathrm{C} & \mathrm{A} & \mathrm{G} & \mathrm{T} \\
3 & \mathrm{G} & \mathrm{T} & \mathrm{G} & \mathrm{T} & \mathrm{T} & \mathrm{T} & \mathrm{C} & \mathrm{A} & \mathrm{G} & \mathrm{C} \\
4 & \mathrm{A} & \mathrm{A} & \mathrm{G} & \mathrm{T} & \mathrm{T} & \mathrm{T} & \mathrm{C} & \mathrm{T} & \mathrm{C} & \mathrm{C} \\
5 & \mathrm{G} & \mathrm{A} & \mathrm{G} & \mathrm{C} & \mathrm{C} & \mathrm{T} & \mathrm{G} & \mathrm{A} & \mathrm{C} & \mathrm{C} \\
\text { Control } & & & & & & & & & & \\
\hline 6 & \mathrm{A} & \mathrm{A} & \mathrm{G} & \mathrm{T} & \mathrm{T} & \mathrm{T} & \mathrm{C} & \mathrm{A} & \mathrm{G} & \mathrm{T} \\
7 & \mathrm{G} & \mathrm{T} & \mathrm{G} & \mathrm{G} & \mathrm{C} & \mathrm{T} & \mathrm{G} & \mathrm{A} & \mathrm{G} & \mathrm{T} \\
8 & \mathrm{A} & \mathrm{T} & \mathrm{C} & \mathrm{T} & \mathrm{C} & \mathrm{G} & \mathrm{C} & \mathrm{T} & \mathrm{C} & \mathrm{C} \\
9 & \mathrm{G} & \mathrm{T} & \mathrm{C} & \mathrm{G} & \mathrm{T} & \mathrm{G} & \mathrm{G} & \mathrm{A} & \mathrm{C} & \mathrm{T}
\end{array}$$

James Kiss
James Kiss
Numerade Educator
01:30

Problem 20

In GWAS analysis, because of the existence of $L D$ blocks (or haplotype blocks), it is not necessary to genotype a person for every one of the 50 million known SNPs. Haplotype blocks are stretches of DNA containing particular SNP variants that tend to be inherited together (as a block) because recombination within the region is rare. In the accompanying figure, three different SNP loci are shown at top (SNP10, SNP11, and SNP12), each with two alleles among the world's population of humans.
Only four of all the possible combinations of these SNP alleles are found in human genomes, as shown in the four chromosome types pictured. These three SNPs are part of a larger block of 20 SNPs that are usually inherited in one of the four configurations, or haplotypes, shown. Because these 20 SNPs are inher-
ited as haplotype blocks, genotyping any individual for the three so-called $\operatorname{Tag}$SNPs$(\text { SNP } 4,$ SNP8, and SNP15 shown in bold) should be sufficient to predict that individual's alleles for the other 17 SNPs.
a. How many configurations of the three SNPs shown at the top of the diagram (SNPs $10,11,$ and 12 ) are theoretically possible?
b. How many haplotype variants are theoretically possible considering all 20 SNPs in the haplotype block, and assuming that each of them has two possible alleles?
c. Given that humans are diploid, every individual has two copies of every (autosomal) haplotype block, one on each homolog. Does heterozygosity for the haplotype blocks interfere with genotyping individuals using the Tag SNPs shown in the diagram? Explain.
d. In part (c), you saw that the three Tag SNPs shown in the diagram are sufficient to type any individual for this particular haplotype block. Is this the only set of three Tag SNPs that could be used?

James Kiss
James Kiss
Numerade Educator
03:41

Problem 21

In Fig. 22.15:
a. Why do some chromosomes in the disease group not carry the disease-causing variant shown in red?
b. Why do some chromosomes in the control group carry the variant shown in red?
c. Discuss how scientists would evaluate data from association mapping studies to find QTLs that contribute to the disease. What would researchers look for? And at the bottom of the figure, why are the nonrandom associations of the disease specifically discussed in terms of the blue alleles?
d. Suppose that researchers identified two different regions of the genome with statistically significant associations of SNPs with the disease in question. In Region $1,$ SNPs extending over 200 kb of DNA showed such associations. In Region $2,$ the region containing disease-associated SNPs was $2 \mathrm{Mb}$ long. If you assume that each of these two regions has only one disease-causing variant, which of the two mutations was likely to have occurred earlier in human history? Explain.
e. Given your answer to part (d), explain why the length of the region containing disease-associated SNPs is nonetheless not a perfect indicator of the time in human history at which the disease-causing mutation occurred.

James Kiss
James Kiss
Numerade Educator
01:38

Problem 22

Consider the triangle diagram shown in Fig. 22.17
a. What feature of the genome is likely to be located between the two LD blocks that allows scientists to visualize them as separate blocks?
b. Even though the figure analyzes eight different SNPs, genotyping just two of these SNPs would allow you to predict the genotype of almost everyone in the population. Explain why this limited genotyping has predictive value.
c. When researchers obtain the data that enables them to build triangle diagrams, do they typically genotype common SNPs or rare SNPs? Explain.
d. Considering your answer to part (c), why are human population geneticists interested in obtaining complete whole-genome sequences, as opposed to genotyping only the small subset of predictive SNPs?

James Kiss
James Kiss
Numerade Educator
01:10

Problem 23

In Fig. 22.18
a. Why are some patients of genotype GG, some of genotype GC, and others of genotype CC? That is, why don't all the patients have the same genotype? Discuss at least two reasons.
b. How many people participated in this study? How many of them were patients (Cases)? Controls?

Marisa A
Marisa A
Numerade Educator
02:29

Problem 24

You conduct a Case/Control study comparing the frequency of a single SNP (with alleles C and T) among individuals who have developed high blood pressure as compared with control individuals of a similar age who show no sign of this condition. You obtain the following results:
$$\begin{array}{lcc}
& \text { Cases } & \text { Controls } \\
\hline \mathbf{C} & 1025 & 725 \\
\mathbf{T} & 902 & 922
\end{array}$$
a. Does a statistically significant association exist between this SNP and the risk of developing high blood pressure, if this is the only SNP that you test?
b. Would this association still be significant if this was one of a million SNPs that you tested in your study? Explain.
c. Which allele (C or T) is associated with a higher risk of developing high blood pressure?
d. Calculate the allelic odds ratio for the risk allele. What does the allelic odds ratio mean about a person's chance of developing high blood pressure?

James Kiss
James Kiss
Numerade Educator
01:12

Problem 25

In Fig. 22.21 , the association of the SNP $r s 1333049$ with coronary artery disease has a $-\log _{10}(p$ value) greater than the cutoff of 7 in one GWAS but not in a second such study. Assuming that this SNP is indeed associated with the condition, provide two possible reasons that the $-\log _{10}(p$ value) in the second study was less than the cutoff..

James Kiss
James Kiss
Numerade Educator
01:55

Problem 26

ALS (amyotrophic lateral sclerosis) is a rare, fatal neurodegenerative disease that is genetically complex. During the last several years, using GWAS analyses and other methods, 11 different genes have been identified that are thought to be connected with ALS. The most recently discovered of these genes, $T B K I$, was identified through analysis of the whole exome sequences of several thousand Cases and Controls. Recall from Chapter 11 that the exome is the approximately $1 \%$ of the human genome that corresponds to exons. Each person's exome sequence was evaluated on a gene-by-gene basis as to whether or not a SNP variant likely to alter gene function was present. The $T B K 1$ gene was not identified in previous GWAS analyses that genotyped similar numbers of individuals for common SNPs. Cite possible explanations for the different outcomes of these two experiments.

James Kiss
James Kiss
Numerade Educator
01:08

Problem 27

Through GWAS explorations, scientists have identified several SNPs linked to obesity in people who live in the United States. One of these SNPs was within a gene called $F T O$. Interestingly, a common $F T O$ variant is associated with obesity, but only in people born after $1945 .$ Moreover, the later the birth year, the higher the risk for obesity associated with this variant of $F T O$. Why would a genetic risk factor for obesity vary by birth year?

James Kiss
James Kiss
Numerade Educator
02:57

Problem 28

In domesticated dogs, size has a high heritability, and the trait is determined by only a small number of genes. In contrast, genetic variation at more than 180 QTLs explains only a very small proportion of the high heritability for height in humans. What could explain the missing heritability in humans, and how could you test your hypothesized explanations?

Jennifer Stoner
Jennifer Stoner
Numerade Educator
05:12

Problem 29

Suppose a GWAS investigation found a particular LD block to be associated with people's preference for chocolate or vanilla ice cream. How could you identify the specific gene within this region of the genome whose alleles help determine this preference?

Jennifer Stoner
Jennifer Stoner
Numerade Educator
02:36

Problem 30

In $2008,$ Time magazine named as its invention of the year the development of personal genomics services by a company named 23 andMe. Customers sent saliva samples to the company, which then genotyped approximately one million SNPs located across the genome, and communicated the data online to the customer along with what was claimed to be a "for education use only" assessment of potential risk for a variety of traits. However, on November $22,2013,$ the United States Food and Drug Administration (FDA) ordered 23 and $\mathrm{Me}$ to stop marketing its personal genomics services because the accuracy of its SNP genotyping and risk predictions had not been validated as sufficiently accurate for medical use. The FDA was concerned that people might make serious medical decisions based on information from a test that was not clinically approved. Some elements of this ban were relieved in 2015 and 2017 , but DNA testing services are still restrained from offering their customers all the pre-ban predictions. Defining these limits remains a contentious and unresolved issue.
a. Can the information you would obtain from this personal genomics service tell you whether or not you have a Mendelian genetic disease? Explain.
b. Can the information you would obtain from this personal genomics service inform you about your likelihood of having a disease that is a complex trait? Explain.
c. In December $2013,$ a reporter for The New York Times reported that she sent samples of her own DNA to three different companies (one of which was 23 and $\mathrm{Me}$ ), but the three companies provided very different estimates of her risk for a variety of complex traits. What were the likely causes of the differences in these estimates?
d. Do you think new scientific developments will help resolve these issues in the near future?

James Kiss
James Kiss
Numerade Educator