Anne Goriely - Illumina

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Clinical features of Apert Syndrome • Autosomal dominant • > 98% cases occur by de novo mutation • Birth prevalence: 1 in 65,000 • 99% of cases are caused by one of 2 specific nucleotide transversions in FGFR2 66%: 755C>G (Ser252Trp) 33%: 758C>G (Pro253Arg) • 755C>G spontaneous mutation rate: 1:100,000 Craniosynostosis (premature fusion of cranial sutures) Severe syndactyly of hands and feet = ~ 1000-fold higher than background • Paternal age effect and exclusive paternal origin Mutation occurs during spermatogenesis Fibroblast Growth Factor Receptor 2 structure Immunoglobulin-like domains FGF Tyrosine kinase domain L I A II IIIa IIIb IIIc TM TK1 TK2 755 758 TCG p CCT Ser Pro 252 253 Wilkie et al, Nature Genet (1995)
Human spermatogenesis and copy-error hypothesis Spermatogonial stem cells ~ 30 divisions Ad Ad Ad Ad Ad Ad Ad Ad* Ad Ad* Ad* Ap Ap Ad* Ap* Ap* Ad Ad Ad Ad Ad Ap B B B B Pl Pl Pl Pl Pl Pl Pl Pl sd Ad sp sp Ap Ad 1 st meiosis 2 nd meiosis sd Ad Ad Ad* puberty 23 divisions/year age 25: 335 divisions age 70: 1370 divisions spermatozoa Hypothesis: • mutations accumulate through multiple replication errors Positive selection of mutant stem • these errors increase cells/progenitors in frequency with age
Page 1 and 2: Ageing men, selfish testes and pate
Page 3: “Paternal age-effect” mutations
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 and 26: HRAS mutations in cancer and Costel
Page 27 and 28: Goriely et al., Nat Genet, 2009 Str
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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