title: Recombination as a mechanism for sporadic mutation in the surfactant protein-C gene.
abstract: OBJECTIVE
  To determine haplotype background of common mutations in the genes encoding surfactant proteins B and C (SFTPB and SFTPC) and to assess recombination in SFTPC.
  
  
  METHODS
  Using comprehensive resequencing of SFTPC and SFTPB, we assessed linkage disequilibrium (LD) (D'), and computationally inferred haplotypes. We computed average recombination rates and Bayes factors (BFs) within SFTPC in a population cohort and near SFTPC (+/-50 kb) in HapMap cohorts. We then biochemically confirmed haplotypes in families with sporadic SFTPC mutations (n = 11) and in individuals with the common SFTPB mutation (121ins2, n = 30).
  
  
  RESULTS
  We detected strong evidence (weak LD and BFs > 1,400) for an intragenic recombination hot spot in both genes. The 121ins2 SFTPB mutation occurred predominantly (89%) on 2 common haplotypes. In contrast, no consistent haplotypes were associated with mutated SFTPC alleles. Sporadic SFTPC mutations arose on the paternal allele in four of five families; the remaining child had evidence for somatic recombination on the mutated allele.
  
  
  CONCLUSIONS
  In contrast to SFTPB, disease alleles at SFTPC do not share a common haplotype background. Most sporadic mutations in SFTPC occurred on the paternal allele, but somatic recombination may be an important mechanism of mutation in SFTPC.
authors.affiliation: Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Amy D
authors.initials: AD
authors.lastname: McBee
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wegner
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wambach
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Hillary B
authors.initials: HB
authors.lastname: Heins
authors.forename: Ola D
authors.initials: OD
authors.lastname: Saugstad
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Trusgnich
authors.forename: Julie
authors.initials: J
authors.lastname: Watkins-Torry
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nogee
authors.forename: Howard
authors.initials: H
authors.lastname: Henderson
authors.forename: F Sessions
authors.initials: FS
authors.lastname: Cole
authors.forename: Aaron
authors.initials: A
authors.lastname: Hamvas
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D001499:Bayes Theorem; D015331:Cohort Studies; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D017563:Lung Diseases, Interstitial / Q000235:genetics*; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics*; D012737:Sex Factors; D044465:White People / Q000235:genetics
chemical_list: D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C