The multiple species de novo gene prediction problem can be stated as follows: given an
alignment of genomic sequences from two or more organisms, predict the location and
structure of all protein-coding genes in one or more of the sequences. Here, we present
a new system, N-SCAN (a.k.a. TWINSCAN 3.0), for addressing this problem. N-SCAN
can model the phylogenetic relationships between the aligned genome sequences, contextdependent
substitution rates, and insertions and deletions. An implementation of N-SCAN
was created and used to generate predictions for the entire human genome and the genome
of the fruit fly Drosophila melanogaster. Analyses of the predictions reveal that N-SCAN's
accuracy in both human and fly exceeds that of all previously published whole-genome
de novo gene predictors.