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?
Table of contents
- 1. Introduction to Genetics51m
- 2. Mendel's Laws of Inheritance3h 37m
- 3. Extensions to Mendelian Inheritance2h 41m
- 4. Genetic Mapping and Linkage2h 28m
- 5. Genetics of Bacteria and Viruses1h 21m
- 6. Chromosomal Variation1h 48m
- 7. DNA and Chromosome Structure56m
- 8. DNA Replication1h 10m
- 9. Mitosis and Meiosis1h 34m
- 10. Transcription1h 0m
- 11. Translation58m
- 12. Gene Regulation in Prokaryotes1h 19m
- 13. Gene Regulation in Eukaryotes44m
- 14. Genetic Control of Development44m
- 15. Genomes and Genomics1h 50m
- 16. Transposable Elements47m
- 17. Mutation, Repair, and Recombination1h 6m
- 18. Molecular Genetic Tools19m
- 19. Cancer Genetics29m
- 20. Quantitative Genetics1h 26m
- 21. Population Genetics50m
- 22. Evolutionary Genetics29m
15. Genomes and Genomics
Comparative Genomics
Problem 26
Textbook 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 the 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.


1
Step 1: Understand the concept of retrotransposons and their role in genome evolution. Retrotransposons are genetic elements that can copy themselves and insert into new locations in the genome. They often contribute to the evolution of new genes by providing raw genetic material that can be co-opted for new functions.
Step 2: Analyze the data provided in the problem. PEG10 is present in placental and marsupial mammals but absent in platypus, chicken, and fugu genomes. This suggests that PEG10 originated after the divergence of monotremes (like the platypus) from therian mammals (marsupials and placental mammals).
Step 3: Examine the tblastn search results. The similarity between PEG10 and sushi-ichi retrotransposons indicates that PEG10 likely originated from a retrotransposon insertion event. Retrotransposons can acquire mutations and evolve into functional genes, a process known as 'domestication' of retrotransposons.
Step 4: Propose an evolutionary scenario. PEG10 may have originated from a sushi-ichi retrotransposon that inserted into the genome of a common ancestor of therian mammals. Over time, this retrotransposon was co-opted and evolved to perform a critical biological function, such as contributing to placental development.
Step 5: Relate the origin of PEG10 to its biological function. The placenta is a key innovation in therian mammals, enabling live birth and maternal-fetal nutrient exchange. PEG10's role in placental formation suggests that its domestication from a retrotransposon was an adaptive event that supported the evolution of this reproductive strategy.

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Key Concepts
Here are the essential concepts you must grasp in order to answer the question correctly.
Paternally Expressed Genes
Paternally expressed genes are those genes where only the allele inherited from the father is active, while the maternal allele is silenced. This phenomenon is a key aspect of genomic imprinting, which plays a crucial role in development, particularly in the formation of structures like the placenta. Understanding this concept is essential for analyzing the function of PEG10 in placental development.
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Synteny
Synteny refers to the conservation of blocks of order within two sets of chromosomes that are being compared from different species. In the context of PEG10, examining syntenic regions helps identify evolutionary relationships and gene conservation across vertebrates. This concept is vital for understanding how PEG10 has been maintained or lost in various lineages.
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Retrotransposons
Retrotransposons are a type of genetic element that can amplify themselves in a genome and are often involved in gene evolution and regulation. The relationship between PEG10 and retrotransposons, particularly the sushi-ichi retrotransposons, suggests that PEG10 may have originated from a retrotransposon event, which is significant for understanding its evolutionary history and functional role in mammals.
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