Merlin—rapid analysis of dense genetic maps using sparse gene flow trees

Abstract

Efforts to find disease genes using high-density single-nucleotide polymorphism (SNP) maps will produce data sets that exceed the limitations of current computational tools. Here we describe a new, efficient method for the analysis of dense genetic maps in pedigree data that provides extremely fast solutions to common problems such as allele-sharing analyses and haplotyping. We show that sparse binary trees represent patterns of gene flow in general pedigrees in a parsimonious manner, and derive a family of related algorithms for pedigree traversal. With these trees, exact likelihood calculations can be carried out efficiently for single markers or for multiple linked markers. Using an approximate multipoint calculation that ignores the unlikely possibility of a large number of recombinants further improves speed and provides accurate solutions in dense maps with thousands of markers. Our multipoint engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.

More evidence supports the association of PPP3CC with schizophrenia

“…However, the SNP markers used in this study were high density and the application of Bonferroni's procedure might yield too conservative results. In this study, we apply simulation study, using Merlin software 47 for simulating the pedigree for 1000 times assuming no linkage/no association on the interested SNP marker identified in TRANSMIT and FBAT programs. The empirical P-value was calculated as a false-positive rate in which on a given SNP, by use of TRANSMIT and FBAT over 1000 times, percentage of a P-value lower than its nominal P-value was counted.…”

Proximal hip geometry is linked to several chromosomal regions: Genome-wide linkage results from the Framingham Osteoporosis Study

“…For the chromosome X, IBD probabilities were computed using the minx subroutine of MERLIN [39], which can perform multipoint linkage analysis on chromosome X, but unfortunately is not able to handle large pedigrees. Therefore, large pedigrees were broken down into smaller ones, by splitting families and/or deleting family members while keeping as many members with genotypes as possible.…”

Evidence for multiple loci from a genome scan of autism kindreds

“…39 Marker genotypes were simulated 20 000-40 000 times, depending on the asymptotic Pvalue, under the assumed marker map but under the null hypothesis of no linkage with the trait, and the resulting data were reanalyzed with the same multipoint methods used to analyze the original data. Simulation analysis was computationally intensive, requiring approximately 1-2 CPU week per chromosome, depending on the chromosome.…”