De novo or "orphan" genes, whose sequence shows no similarity to existing genes, are extremely rare. Estimates of the number of de novo genes in the human genome range from 18 to 60. Such genes are typically shorter and simpler in structure than most eukaryotic genes, with few if any introns. Two primary sources of orphan protein-coding genes are gene duplication followed by extremely rapid sequence change, such that the original relationship is undetectable by sequence comparisons, and formation through mutation of "cryptic" transcription start sites that introduce a new open reading frame in a region of the genome that did not previously code for a protein.