title: Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.
abstract: Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.affiliation: Department of Statistics, Rice University, Houston, TX 77005, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Stewart
authors.affiliation: Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Regis A
authors.initials: RA
authors.lastname: James
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Institute of Mother and Child, Warsaw 01-211, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: Mathematics Department, Trinity University, San Antonio, TX 78212, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Olofsson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Statistics, Rice University, Houston, TX 77005, USA; Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: cashaw@bcm.edu.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations / Q000235:genetics; D005220:Fathers; D005260:Female; D005718:Gametogenesis / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D023281:Genomics; D005854:Germ Cells / Q000166:cytology; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009030:Mosaicism; D009035:Mothers; D011247:Pregnancy; D012008:Recurrence; D012307:Risk Factors; D055815:Young Adult