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Case 2: SCL17A3

Case 2: SCL17A3. Sodium-dependent phosphate transport protein 4. Overview. chr6:25,953,307-25,982,450. Main questions. 1. Where else is the gene present? 2. How has the selection been acting on the gene? Any specific site? 3. How is the structure of gene? the 5’-UTR and Kozak sequence?

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Case 2: SCL17A3

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  1. Case 2: SCL17A3 Sodium-dependent phosphate transport protein 4

  2. Overview chr6:25,953,307-25,982,450

  3. Main questions • 1. Where else is the gene present? • 2. How has the selection been acting on the gene? Any specific site? • 3. How is the structure of gene? the 5’-UTR and Kozak sequence? • 4. Is there any sign of NMD? • 5. What are the general features of the gene? any disease?

  4. Comparison across species Orthologues are found in mammals but not in other vertebrates.

  5. Human self-chain alignment Paralogoues?

  6. Main questions • 1. Where else is the gene present? • 2. How has the selection been acting on the gene? Any specific site? • 3. How is the structure of gene? the 5’-UTR and Kozak sequence? • 4. Is there any sign of NMD? • 5. What are the general features of the gene? any disease?

  7. Ka/Ks analysis between the gene and its mouse orthologue Sequences_names mm9_refGene_NM_134069 (mouse) hg18_refGene_NM_001098486 (human) ds/dnps/pn 2.9719 2.2479 (strong negative (purifying) selection) • i), n)

  8. Ks/Ka ratio of SCL17A3 to its mouse orthologue The ratio is equally distributed over the DNA. There does not seem to be any site that is particularly under some selection pressure.

  9. The G201R substitution The human 201 aa (Glycine) • The protein itself is well-conserved across species. --> a support for the negative selection.- The substitution is in a not-conserved region.

  10. Main questions • 1. Where else is the gene present? • 2. How has the selection been acting on the gene? Any specific site? • 3. How is the structure of gene? the 5’-UTR and Kozak sequence? • 4. Is there any sign of NMD? • 5. What are the general features of the gene? any disease?

  11. SLC17A3 gene structure • 5’-UTR • ATGs • Kozak sequence

  12. 5’ UTR • UTR overlapping an intron

  13. Alternative splicing & EST

  14. Kozak sequence • ORF starts with an adequate Kozak sequence ATGG. • Stronger Kozak sequences like CCAUGG have not been found to initiate ORF in the gene. • Alternative splicing has also an adequate Kozak sequence ATGG. Common and alternative Kozak sequences. GCTCCAAAAAGTCCAAGGGAGTAAGCTTGGAGGAAACGCTGGGTTCAACT TGAAGCCCTTCCACAGACATTAAGTCGGTGAAAACCATTCACTAGGAGAG GAGAAACACAATGGCCACCAAGACAGAGTTGAGTCCCACAGCAAGGGAGA GCAAGAACGCACAAGATATGCAAGTGGATGAGACACTGATCCCCAGGAAA GTTCCAAGTTTATGTTCTGCTCGCTATGGAATAGCCCTCGTCTTACATTT CTGCAATTTCACAACGATAGCACAAAATGTCATCATGAACATCACCATGG TAGCCATGGTCAACAGCACAAGCCCTCAATCCCAGCTCAATGATTCCTCT GAGGTGCTGCCTGTTGACTCATTTGGTGGCCTAAGTAAAGCCCCAAAGAG TCTTCCTGCAAAGGCTCCTGTGTATGACTGGTCTCCTCAAATCCAAGGCA TCATCTTTGGTGCTGTTGGCTATGGTGGCATACTGACAATGGCTCCCAGT GGATACCTGGCTGGAAGAGTAGGAACAAAGCGAGTGGTTGGCATTTCTTT GTTTGCAACTTCATTTCTCACTCTATGCATCCCTCTGGCCACTGACTTTG GAATAGTCTTGCTCATTGTAACTCGAATAGTCCAGGGCCTAAGCCAGTCC • UTR • CDC • ATG • KOZAK • Exon Junction

  15. Main questions • 1. Where else is the gene present? • 2. How has the selection been acting on the gene? Any specific site? • 3. How is the structure of gene? the 5’-UTR and Kozak sequence? • 4. Is there any sign of NMD? • 5. What are the general features of the gene? any disease?

  16. NMD (Nonsense mediated decay) EJC-Exon Junction Complex Nonsense-mediated mRNA decay: terminating erroneous gene expression, Kristian E Baker and Roy Parker, Current Opinion in Cell Biology 2004, 16:293–299

  17. 3’ UTR >50bp then NMD but this is not case.

  18. Main questions • 1. Where else is the gene present? • 2. How has the selection been acting on the gene? Any specific site? • 3. How is the structure of gene? the 5’-UTR and Kozak sequence? • 4. Is there any sign of NMD? • 5. What are the general features of the gene? any disease?

  19. Disease related? • A heterozygous G-to-A transition at nucleotide 601  G201R substitution. found in a patient, with glycogen storage disease type Ic (GSD1C), who did not have any other mutation in this system, may suggest that it might reduce phosphate transporter efficiency.

  20. General characters of SLC17A3 • Name: Sodium-dependent phosphate transport protein 4 • Variation: 2 splice variants • Length: 401aa and 498aa • Structure: 4 potential transmembrane domains • Expression: mainly in liver, kidney • Function: may regulate the glucose-6- phosphatase (G6-Pase) complex in these tissues.

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