15. Genomes and Genomics

Comparative Genomics

Open Question
Researchers have compared candidate loci in humans and rats in search of loci in the human genome that are likely to contribute to the constellation of factors leading to hypertension [Stoll, M., et al. (2000). Genome Res. 10:473–482]. Through this research, they identified 26 chromosomal regions that they consider likely to contain hypertension genes. How can comparative genomics aid in the identification of genes responsible for such a complex human disease? The researchers state that comparisons of rat and human candidate loci to those in the mouse may help validate their studies. Why might this be so?
Open Question
Homology can be defined as the presence of common structures because of shared ancestry. Homology can involve genes, proteins, or anatomical structures. As a result of 'descent with modification,' many homologous structures have adapted different purposes.Under what circumstances might one expect proteins of similar function to not share homology? Would you expect such proteins to be homologous at the level of DNA sequences?
Open Question
Homology can be defined as the presence of common structures because of shared ancestry. Homology can involve genes, proteins, or anatomical structures. As a result of 'descent with modification,' many homologous structures have adapted different purposes.Is it likely that homologous proteins from different species have the same or similar functions? Explain.
Open Question
Homology can be defined as the presence of common structures because of shared ancestry. Homology can involve genes, proteins, or anatomical structures. As a result of 'descent with modification,' many homologous structures have adapted different purposes.List three anatomical structures in vertebrates that are homologous but have different functions.
Open Question
In the globin gene family shown in Figure 16.16, which pair of genes would exhibit a higher level of sequence similarity, the human δ-globin and human β-globin genes or the human β-globin and chimpanzee β-globin genes? Can you explain your answer in terms of timing of gene duplications?
Open Question
Comparisons between human and chimpanzee genomes indicate that a gene that may function as a wild-type or normal gene in one primate may function as a disease-causing gene in another [The Chimpanzee Sequencing and Analysis Consortium (2005). Nature 437:69–87]. For instance, the PPARG locus (regulator of adipocyte differentiation) is a wild-type allele in chimps but is clearly associated with Type 2 diabetes in humans. What factors might cause this apparent contradiction? Would you consider such apparent contradictions to be rare or common? What impact might such findings have on the use of comparative genomics to identify and design therapies for disease-causing genes in humans?
Open Question
Yeager, M., et al. [(2007) Nature Genetics 39:645–649] and Sladek, R., et al. [(2007) Nature 445:881–885] have used single-nucleotide polymorphisms (SNPs) in genome-wide association studies (GWAS) to identify novel risk loci for prostate cancer and Type 2 diabetes, respectively. Each study suggests that disease-risk genes can be identified that significantly contribute to the disease state. Given your understanding of such complex diseases, what would you determine as reasonable factors to consider when interpreting the results of GWAS?
Open Question
You are studying similarities and differences in how organisms respond to high salt concentrations and high temperatures. You begin your investigation by using microarrays to compare gene expression patterns of S. cerevisiae in normal growth conditions, in high salt concentrations, and at high temperatures. The results are shown here, with the values of red and green representing the extent of increase and decrease, respectively, of expression for genes a–s in the experimental conditions versus the control (normal growth) conditions. What is the first step you will take to analyze your data? <>
Open Question
Dominguez et al. (2004) suggest that by studying genes that determine growth and tissue specification in the eye of Drosophila, much can be learned about human eye development.

What evidence indicates that the eyeless gene is part of a developmental network?
Open Question
Dominguez et al. (2004) suggest that by studying genes that determine growth and tissue specification in the eye of Drosophila, much can be learned about human eye development.

What evidence suggests that genetic eye determinants in Drosophila are also found in humans? Include a discussion of orthologous genes in your answer.
Open Question
PEG10 (paternally expressed gene 10) is a paternally expressed gene (meaning only the paternal allele is expressed) that has an essential role in the formation of the placenta of the mouse. In the mouse genome, the PEG10 gene is flanked by the SGCE and PPP1R9A genes. To study the origin of PEG10, you examine syntenic regions spanning the SGCE and PPP1R9A loci in the genomes of several vertebrates, and you note that the PEG10 gene is present in the genomes of placental and marsupial mammals but not in the platypus, chicken, or fugu genomes.

The green bars in the figure indicate the exons of each gene. The gray bars represent LINEs and SINEs, and the blue bars represent long terminal repeat (LTR) elements of retrotransposons. Solid black diagonal lines link introns, and dashed black lines connect orthologous exons. Arrowheads indicate direction of transcription.
Using the predicted protein sequence of PEG10, you perform a tblastn search for homologous genes and find that the most similar sequences are in a class of retrotransposons (the sushi-ichi retrotransposons). Propose an evolutionary scenario for the origin of the PEG10 gene, and relate its origin to its biological function. <>