title: Global and disease-associated genetic variation in the human Fanconi anemia gene family.
abstract: Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population genetic variation in FANC genes and the segregation of this variation in the human population, we identified 2948 unique FANC gene variants including 493 FA DA variants across 57,240 potential base pair variation sites in the 16 FANC genes. We then analyzed the segregation of this variation in the 7578 subjects included in the Exome Sequencing Project (ESP) and the 1000 Genomes Project (1KGP). There was a remarkably high frequency of FA DA variants in ESP/1KGP subjects: at least 1 FA DA variant was identified in 78.5% (5950 of 7578) individuals included in these two studies. Six widely used functional prediction algorithms correctly identified only a third of the known, DA FANC missense variants. We also identified FA DA variants that may be good candidates for different types of mutation-specific therapies. Our results demonstrate the power of direct DNA sequencing to detect, estimate the frequency of and follow the segregation of deleterious genetic variation in human populations.
authors.affiliation: Department of Microbiology.
authors.forename: Kai J
authors.initials: KJ
authors.lastname: Rogers
authors.affiliation: Department of Genome Sciences and.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Genome Sciences and.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.affiliation: Department of Genome Sciences and Department of Pathology, University of Washington, Seattle, WA 98195, USA monnat@u.washington.edu.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Monnat
mesh_terms: D000465:Algorithms; D024682:BRCA2 Protein / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D000076164:Fanconi Anemia Complementation Group N Protein; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D015870:Gene Expression; D005808:Genes, Recessive; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D005810:Multigene Family; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000235:genetics; D020365:RNA Helicases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; D000076164:Fanconi Anemia Complementation Group N Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C448305:RAD51C protein, human; D025521:Tumor Suppressor Proteins; C095888:xeroderma pigmentosum group F protein; C000618935:BRIP1 protein, human; D020365:RNA Helicases
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