TY - JOUR
T1 - Locations and patterns of meiotic recombination in two-generation pedigrees
AU - Ting, Jason C.
AU - Roberson, Elisha D.O.
AU - Currier, Duane G.
AU - Pevsner, Jonathan
N1 - Funding Information:
We thank Nathaniel Miller, N. Varg and Drs. Roger Reeves and Stephanie Sherman for helpful discussions. We gratefully acknowledge the resources provided by the AGRE Consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). AGRE Illumina HumanHap550 data were generated at the Center for Applied Genomics, Children's Hospital of Philadelphia. We thank Drs. Hakon Hakonarson and colleagues who generated the SNP data and permitted us to make SNP data available on the pediSNP website, and Dr. Vlad Kustanovich for discussions and assistance in data sharing. J.P. was supported by MRDDRC grant HD24061 from the National Institutes of Health and by the Stem Cell Resource Center of the Institute for Cell Engineering (Johns Hopkins University School of Medicine).
PY - 2009/9/17
Y1 - 2009/9/17
N2 - Background: Meiotic crossovers are the major mechanism by which haplotypes are shuffled to generate genetic diversity. Previously available methods for the genome-wide, high-resolution identification of meiotic crossover sites are limited by the laborious nature of the assay (as in sperm typing). Methods: Several methods have been introduced to identify crossovers using high density single nucleotide polymorphism (SNP) array technologies, although programs are not widely available to implement such analyses. Results: Here we present a two-generation *reverse pedigree analysis* method (analyzing the genotypes of two children relative to each parent) and a web-accessible tool to determine and visualize inheritance differences among siblings and crossover locations on each parental gamete. This approach is complementary to existing methods and uses informative markers which provide high resolution for locating meiotic crossover sites. We introduce a segmentation algorithm to identify crossover sites, and used a synthetic data set to determine that the segmentation algorithm specificity was 92% and sensitivity was 89%. The use of reverse pedigrees allows the inference of crossover locations on the X chromosome in a maternal gamete through analysis of two sons and their father. We further analyzed genotypes from eight multiplex autism families, observing a 1.462 maternal to paternal recombination ratio and no significant differences between affected and unaffected children. Meiotic recombination results from pediSNP can also be used to identify haplotypes that are shared by probands within a pedigree, as we demonstrated with a multiplex autism family. Conclusion: Using *reverse pedigrees* and defining unique sets of genotype markers within pedigree data, we introduce a method that identifies inherited allelic differences and meiotic crossovers. We implemented the method in the pediSNP software program, and we applied it to several data sets. This approach uses data from two generations to identify crossover sites, facilitating studies of recombination in disease. pediSNP is available online at http://pevsnerlab.kennedykrieger.org/pediSNP.
AB - Background: Meiotic crossovers are the major mechanism by which haplotypes are shuffled to generate genetic diversity. Previously available methods for the genome-wide, high-resolution identification of meiotic crossover sites are limited by the laborious nature of the assay (as in sperm typing). Methods: Several methods have been introduced to identify crossovers using high density single nucleotide polymorphism (SNP) array technologies, although programs are not widely available to implement such analyses. Results: Here we present a two-generation *reverse pedigree analysis* method (analyzing the genotypes of two children relative to each parent) and a web-accessible tool to determine and visualize inheritance differences among siblings and crossover locations on each parental gamete. This approach is complementary to existing methods and uses informative markers which provide high resolution for locating meiotic crossover sites. We introduce a segmentation algorithm to identify crossover sites, and used a synthetic data set to determine that the segmentation algorithm specificity was 92% and sensitivity was 89%. The use of reverse pedigrees allows the inference of crossover locations on the X chromosome in a maternal gamete through analysis of two sons and their father. We further analyzed genotypes from eight multiplex autism families, observing a 1.462 maternal to paternal recombination ratio and no significant differences between affected and unaffected children. Meiotic recombination results from pediSNP can also be used to identify haplotypes that are shared by probands within a pedigree, as we demonstrated with a multiplex autism family. Conclusion: Using *reverse pedigrees* and defining unique sets of genotype markers within pedigree data, we introduce a method that identifies inherited allelic differences and meiotic crossovers. We implemented the method in the pediSNP software program, and we applied it to several data sets. This approach uses data from two generations to identify crossover sites, facilitating studies of recombination in disease. pediSNP is available online at http://pevsnerlab.kennedykrieger.org/pediSNP.
UR - http://www.scopus.com/inward/record.url?scp=70349919640&partnerID=8YFLogxK
U2 - 10.1186/1471-2350-10-93
DO - 10.1186/1471-2350-10-93
M3 - Article
C2 - 19761602
AN - SCOPUS:70349919640
SN - 1471-2350
VL - 10
SP - 93
JO - BMC Medical Genetics
JF - BMC Medical Genetics
M1 - 93
ER -