1. If you knew that a locus that affected earlobe shape was tightly linked to a locus that affected susceptibility to cardiovascular disease human, under what circumstances would this information be clinically useful?

2. In a previous chapter, we said a 9:3:3:1 phenotypic ratio was expected among the progeny of a dihybrid cross, in absence of gene interaction.

1. What does this ratio assume about the linkage between the two loci in the dihybrid cross?
2. What ratio would be expected if the loci were completely linked? Be sure to consider every possible configuration of alleles in the dihybrids.

3. In corn (i.e. maize, a diploid species), imagine that alleles for resistance to a particular pathogen are recessive and are linked to a locus that affects tassel length (short tassels are recessive to long tassels). Design a series of crosses to determine the map distance between these two loci. You can start with any genotypes you want, but be sure to specify the phenotypes of individuals at each stage of the process. Outline the crosses similar to what is shown in Figure 9, and specify which progeny will be considered recombinant. You do not need to calculate recombination frequency.

4. In a mutant screen in Drosophila, you identified a gene related to memory, as evidenced by the inability of recessive homozygotes to learn to associate a particular scent with the availability of food. Given another line of flies with an autosomal mutation that produces orange eyes, design a series of crosses to determine the map distance between these two loci. Outline the crosses and specify which progeny will be considered recombinant. You do not need to calculate recombination frequency.

5. Image that methionine heterotrophy, chlorosis (loss of chlorophyll), and absence of leaf hairs (trichomes) are each caused by recessive mutations at three different loci in Arabidopsis. Given a triple mutant, and assuming the loci are on the same chromosome, explain how you would determine the order of the loci relative to each other.

6. If the progeny of the cross aaBB x AAbb is testcrossed, and the following genotypes are observed among the progeny of the testcross, what is the frequency of recombination between these loci?

• AaBb, 135
• Aabb, 430
• aaBb, 390
• aabb, 120

7. Three loci are linked in the order B-C-A. If the A-B map distance is 1cM, and the B-C map distance is 0.6cM, given the lines AaBbCc and aabbcc, what will be the frequency of Aabb genotypes among their progeny if one of the parents of the dihybrid had the genotypes AABBCC?

8. Genes for body color (B black dominant to b yellow) and wing shape (C straight dominant to c curved) are located on the same chromosome in flies. If single mutants for each of these traits are crossed (i.e. a yellow fly crossed to a curved-wing fly), and their progeny is testcrossed, the following phenotypic ratios are observed among their progeny.

1. Calculate the map distance between B and C.
2. Why are the frequencies of the two smallest classes not exactly the same?

9. Given the map distance you calculated between B-C in question 12, if you crossed a double mutant (i.e. yellow body and curved wing) with a wild-type fly, and testcrossed the progeny, what phenotypes in what proportions would you expect to observe among the F₂ generation?

10. In a three-point cross, individuals AAbbcc and aaBBCC are crossed, and their F¹ progeny is testcrossed. Answer the following questions based on these F² frequency data.

1. Without calculating recombination frequencies, determine the relative order of these genes.
2. Calculate pair-wise recombination frequencies (without considering double cross overs) and produce a genetic map.
3. Recalculate recombination frequencies accounting for double recombinants.

11. Wild-type mice have brown fur and short tails. Loss of function of a particular gene produces white fur, while loss of function of another gene produces long tails, and loss of function at a third locus produces agitated behavior. Each of these loss of function alleles is recessive. If a wild-type mouse is crossed with a triple mutant, and their F1 progeny is test-crossed, the following recombination frequencies are observed among their progeny. Produce a genetic map for these loci.

12. This module spends a great deal of time talking about building linkage maps of a chromosome. These are classical genetics experiments, but they are no longer performed very often (or at least not in this manner). Nonetheless, this topic is still included in most introductory Genetics textbooks.

Make a case for why linkage should (or should not) still be covered in introductory genetics textbooks. How is linkage connected to more contemporary methods for mapping genes to chromosomes?

13. Every child will have de novo mutations that make their genome different slightly different from that of their parents. Most are not associated with any change in phenotype, although occasionally some result in a change in phenotype. For example, would a SNP microarray, exome sequencing, or whole genome sequencing be most suitable for identifying de novo

14. Discuss the importance of GWAS in understanding human genetic diversity. How do these studies contribute to our understanding of the genetic basis of complex traits and diseases?

Science and Society

15. The Ice Bucket Challenge drew in $115 million in funding for ALS research, in just a few weeks after gaining attention on social media. The privately-funded ALS Association used these funds to sponsor ALS research. But much of the medical research in the United States is actually government funded. Interestingly, the increased attention on ALS may have subsequently driven government funding for ALS as well. The National Institutes of Health allocated $60 million to ALS research in 2014, but almost twice that in 2017^[1]. Between 2020-2023, the estimated NIH funding for ALS research nearly doubled again, from $107-$206 million^[2].

The additional attention and private funding almost certainly influenced NIH funding, either directly or indirectly. However, there are known gender-based and race-based disparities in research funding^[3].

By what criteria should the NIH allocate funds? Some factors to consider might be the overall number of people affected by a disease, the severity of disease, who is affected by the disease, the likelihood of developing treatment quickly, the attention a disease receives in media (including awareness campaigns), etc.

16. GWAS compare the genomes of hundreds, thousands, or even millions of individuals^[4], looking for variants associated with particular traits. Careful consideration must be given to ensure that the populations compared are appropriate. For example, certain genetic disorders are more common in people of specific geographic ancestry. An example is cystic fibrosis, which is most common among people of European ancestry. A GWAS comparing cystic fibrosis patients with a control group of varying ancestry might flag other SNPs common in people of European ancestry rather than SNPs associated with cystic fibrosis.

The GWAS in Figure 23 are from a study looking at skin, hair, and eye pigmentation in European populations: specifically people from Ireland, Poland, Italy, and Portugal. What are the benefits in looking for this type of variation in these populations? Do the results of this study reflect the variation seen in the human population as a whole? Explain your reasoning.

17. Reflect on the ethical implications of GWAS. Consider issues such as privacy concerns, potential misuse of genetic information, and disparities in genetic research representation.