SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens

The spinal muscular atrophy (SMA) region on chromosome 5q13 contains an inv erted duplication of about 500 kb, and deleterious mutations in the surviva l motor neuron 1 (SMN1) gene cause SMA, a common lethal childhood neuropath y. We have used a number of approaches to probe the evolutionary history of these genes and show that SMN gene duplication and the appearance of SMN2 occurred at very distinct evolutionary times. Molecular fossil and molecula r clock data suggest that this duplication may have occurred as recently as 3 million years ago in that the position and identity repetitive elements are identical for both human SMN genes and overall sequence divergence rang ed from 0.15% to 0.34%. However, these approaches ignore the possibility of sequence homogenization by means of gene conversion. Consequently, we have used quantitative polymerase chain rection and analysis of allelic variant s to provide physical evidence for or against SMN gene duplication in the c himpanzee, mankind's closest relative. These studies have revealed that chi mpanzees have 2-7 copies of the SMN gene per diploid genome; however, the t wo nucleotides diagnostic for exons 7-8 and the SMN Delta7 mRNA product of the SMN2 gene are absent in non-human primates. In contrast, the SMN2 gene has been detected in all extant human populations studied to date, includin g representatives from Europe, the Central African Republic, and the Congo. These data provide conclusive evidence that SMN gene duplication occurred more than 5 million years ago, before the separation of human and chimpanze e lineages, bur that SMN2 appears for the first time in Homo sapiens.