Origin of human chromosome 21 and its consequences: a 50-million-year-old story

Great apes (Pongidae) possess a chromosome similar to human chromosome 21 (HSA21), whose trisomy was described in both chimpanzee and orangutan. Having studied more than 200 mammalian species by chromosome banding techniques and reconstructed Primates phylogeny, we reinvestigated, using fluorescence in situ hybridization, primate and non-primate mammals that we considered to possess a karyotype representative of their taxonomic group. DNA sequences from HSA21 and human chromosome 3 (HSA3) are synthenic and form a large and similar chromosome in species from distinct orders, such as Primates, Carnivora, Artiodactyla and Scandentia. In Primates, this syntheny was maintained in lemurs and was disrupted by a fission in Old World monkeys (catarrhines). Another fission occurred in New World monkeys (platyrrhines), conserving a syntheny between HSA21 and a very short segment of HSA3 DNA sequences. Thus, the ancestral HSA21 was formed after the divergence between platyrrhines and catarrhines and before the emergence of Cercopithecidae. This exposed the human and Pongidae ancestry to trisomy 21 for a period of 30-50 million years, while, in other catarrhines, the equivalent of HSA21 was further involved in various translocations forming large chromosomes whose aneuploidy, very probably incompatible with life, protected them against trisomy 21.