Anne Goriely - Illumina

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<strong>Goriely</strong> et al., Nat Genet, 2009 All paternal age-effect genes encode components of growth factor receptor-RAS-MAPK signalling pathway Growth factor RTK FGFR1 FGFR2 FGFR3 RET Pfeiffer Apert, Crouzon achondroplasia, Muenke, TD MEN2a, MEN2b cytoplasm Inactive RAS SOS1 GRB2 Active RAS-GTP NRAS KRAS HRAS RAF1 BRAF Costello Cardio-Facio-Cutaneous (CFC) SHP2 MEK1 MEK2 LEOPARD Noonan ERK Nucleus pERK
<strong>Goriely</strong> et al., Nat Genet, 2009 Strongly activating mutation e.g. FGFR3 K650E Moderately activating mutation e.g. FGFR3 G380R, FGFR2 S252W or HRAS G12S Weakly activating mutation e.g. rare sequence variants? Effect of the de novo mutation in the testis (clonal expansion) Consequence as a somatic mutation in the testis Sperm enrichment 100-1000x Spermatocytic seminoma Sperm enrichment ~ 100x Clones in the testis Sperm enrichment >1-50x Consequence as a germline mutation in the embryo Lethal disorder Classical paternal age effect disorders Disease predisposition?
Page 1 and 2: Ageing men, selfish testes and pate
Page 3 and 4: “Paternal age-effect” mutations
Page 5 and 6: Human spermatogenesis and copy-erro
Page 7 and 8: Selection of mutant sequences at FG
Page 9 and 10: Estimated level (per million) Recon
Page 11 and 12: Copy-error hypothesis vs. selection
Page 13 and 14: Proportion on -112G Unequal distrib
Page 15 and 16: FGFR3 mutation in testicular tumour
Page 17 and 18: Clinical genetics of FGFR3 K650 cod
Page 19 and 20: Construction of the GAII libraries
Page 21 and 22: 3 lanes of 36-bp unidirectional GAI
Page 23 and 24: TD mutations in benign skin tumours
Page 25: HRAS mutations in cancer and Costel
Page 29 and 30: Are PAE mutations the tip of the ic
Page 31: Thanks to… WIMM (Oxford) Ruth Han

Anne Goriely - Illumina

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