title: Variation in genome-wide mutation rates within and between human families.
abstract: J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.forename: Jonathan E M
authors.initials: JE
authors.lastname: Keebler
authors.forename: Mark A
authors.initials: MA
authors.lastname: DePristo
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lindsay
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ferran
authors.initials: F
authors.lastname: Casals
authors.forename: Youssef
authors.initials: Y
authors.lastname: Idaghdour
authors.forename: Chris L
authors.initials: CL
authors.lastname: Hartl
authors.forename: Carlos
authors.initials: C
authors.lastname: Torroja
authors.forename: Kiran V
authors.initials: KV
authors.lastname: Garimella
authors.forename: Martine
authors.initials: M
authors.lastname: Zilversmit
authors.forename: Reed
authors.initials: R
authors.lastname: Cartwright
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.forename: Eric A
authors.initials: EA
authors.lastname: Stone
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
mesh_terms: D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction