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The implications of paternal age mutations and birth defects

The implications of paternal age mutations and birth defects. Andrew OM Wilkie Weatherall Institute of Molecular Medicine, University of Oxford. Maternal age effect and Down syndrome. Maternal age effect: error in meiotic nondisjunction. Thanatophoric dysplasia type II.

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The implications of paternal age mutations and birth defects

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  1. The implications of paternal age mutations and birth defects Andrew OM Wilkie WeatherallInstitute of Molecular Medicine, University of Oxford

  2. Maternal age effect and Down syndrome Maternal age effect: error in meiotic nondisjunction

  3. Thanatophoric dysplasia type II Parental origin of mutations and paternal age Rischet al Am J Hum Genet (1987)

  4. Human spermatogenesis and replication error Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ad Ap Ap Ap Ap Ap Ap B B B B Pl Pl Pl Pl Pl Pl Pl Pl 1st meiosis Ad sp sp Ad 2nd meiosis Ad Ad sd sd Ap Ap Ad Ad Ad • Hypothesis: • mutations accumulate through multiple replication errors in the testis • these errors increase in frequency with age ~ 30 divisions Spermatogonial stem cells puberty 23 divisions/year age 25: 335 divisions age 70: 1370 divisions spermatozoa

  5. FGFR mutations in human disease Pfeiffer Apert Beare-Stevenson Crouzon Coronal synostosis (Muenke) Thanatophoric dysplasia Achondroplasia Hypochondroplasia FGFR1 Kallmann syndrome LADD syndrome FGFR2 CATSHL syndrome FGFR3 Skin-skeleton-brain osteoglophonic dysplasia

  6. 1948A>G in FGFR3 (thanatophoric dysplasia type II) FGFRs have the most common transition and transversion mutations in the entire genome 755C>G in FGFR2 (Apert syndrome) Both mutations elevated ~500 fold over the background rate 1138G>A in FGFR3 (achondroplasia) Why? Wilkie, Cytokine Growth Factor Rev (2005)

  7. Exclusive paternal origin of FGFR mutations Disorder gene Paternal Paternal Ref. origin age Apert syndrome FGFR2 75/75 33.24 Moloney (1996) Hansen (unpubl) Crouzon/Pfeiffer FGFR2 22/22 33.95 Glaser (2000) Syndrome Achondroplasia FGFR3 40/40 35.58 Wilkin (1997) Muenke syndrome FGFR3 10/10 34.69 Rannan-Eliya (2004) 147/147 paternal origins Only 3 other genes/diseases currently known with the collective properties of high apparent germline point mutation rates, strong (>10:1) paternal bias of mutations, strong paternal age effect: HRAS (Costello syndrome) PTPN11 (Noonan syndrome) RET (MEN2A, MEN2B)

  8. Syndromes exhibiting paternal age effect mutation PTPN11 (Noonan syndrome) FGFR2 (Apert, Crouzon, Pfeiffer syndrome) HRAS (Costello syndrome) FGFR3 (achondroplasia, thanatophoric dysplasia, Muenke syndrome) RET (Multiple endocrine neoplasia 2A,2B)

  9. r = 0.39 Mutation Selection Apert 755 levels in sperm DNA 4 3 O/E 755 Apert fathers (n=52) 3 1 5 2 Relative rate of mutation 21 9 1 9 4 0 <25 25-30 30-35 35-40 40-45 45-50 >50 Age 755 Fathers sperm (n=6) Blood (n=11) Sperm (n=99) Apert mutation levels at position 755 1000 100 755G mutation level (per million) 10 1 20 40 60 80 Age 0.1 Goriely et al Science (2003)

  10. Identification of Apert mutant clones in human testes Qin et al PLOS Biol (2007)

  11. Quantification of TDII FGFR3 mutations by massively parallel sequencing Levels of TDII mutation Mutation levels at FGFR3 K650 codon reflect an oncogenic process Goriely et al, Nature Genet (2009)

  12. All paternal age effect genes encode components of growth factor receptor-RAS-MAPK signalling pathway Goriely et al, Nature Genet (2009)

  13. Model of clonal expansion at a cellular level testis * Low probability to fertilize egg Increased probability to fertilize egg Normal phenotype Intrinsic functional significance of mutation Time elapsed Goriely and Wilkie Nature Rev Genet (2010)

  14. Overall increased risk with advanced paternal age: ~0.5% Toriello & MeckGenet Med (2008)

  15. Average age of paternity in England and Wales (1961-2007) About 1/3 of babies are born to fathers aged >35 years OPCS, Census data

  16. Implications for prevention • Prevalence of disorders caused by paternal age effect mutation will increase in an ageing reproductive population • Low recurrence risk for healthy parents of a child with a mutation showing paternal age effect (high level mosaicism unlikely) – may be able to avoid invasive prenatal diagnosis • Potentially detectable by mutation screening of free fetal DNA in maternal plasma

  17. Birth defect Cancer Dichotomy of germline and somatic mutation Germline mutation Somatic mutation

  18. Thanatophoric dysplasia Testicular cancer The same mutation in the germ cell causes both birth defects and tumours

  19. Consequences of selfish testis mutations for human disease Testis is a “bioreactor” for selfish mutations that promote neoplasia and other complex diseases Other complex disease?

  20. Thanks to… WIMM (Oxford) Anne Goriely Ruth Hansen Indira Taylor Jasmine Lim Simon McGowan Statistics Dept (Oxford) Gil McVean Susanne Pfeifer Utrecht University Ans van Pelt Dirk de Rooij Oxford Radcliffe Hospitals NHS Trust Steve Wall David Johnson Gareth Turner Copenhagen University Hospital Ewa Rajpert-DeMeyts Grete Krag Jacobsen Inge Olesen Oxford Fertility Clinic Anonymous sperm donors

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