19 September 2004. In the September 16 issue of Nature, another legion of geneticists, this one led by Jeremy Schmutz of the Stanford Human Genome Centre in California, pulls the curtain back on a chromosome: number 5. This relatively gene-poor chromosome holds a special interest for researchers in neurodegenerative disease, as it contains the genes responsible for spinal motor atrophy (SMA).
The initial effort to analyze the human genome is now halfway done: 12 down and 12 to go. Here are some Fun Facts about chromosome 5:
- This very long chromosome contains only 923 gene loci—of which 827 are known, 55 novel, and 41 putative—spread along its 177.7 million base pairs.
- The "desert regions" likely contain many long-range enhancers that influence gene expression, judging by the high degree of conservation of these regions between the human, chimp, rat, and even chicken genomes.
- There is 99 percent homology between human and chimp chromosomes 5, but a large section has been reversed in humans. Is this the reason our species parted ways back in the dawn of human time?
- The chromosome contains a cluster of interleukin genes (IL3, CSF2, IL5, IL13, and IL4).
Researchers in SMA are focused on this chromosome because it contains the survival motor neuron (SMN1) gene, along with its less efficient sibling, SMN2. SMN1 protein is involved in transcription, and when both copies of the gene are defective or missing, motor neurons in the spinal cord degenerate. The disease is characterized by a progressive, symmetrical limb and trunk paralysis associated with muscular atrophy.
There is one back-up system that occasionally compensates. SMN2 also produces the protein, but much less efficiently and often with errors. If only one or two copies of SMN2 are present (as is the case in nearly 90 percent of the population), the absence of SMN1 is critical: The disease is apparent at birth and death typically occurs before age 2. The more copies of SMN2, the longer a person can survive without SMN1. With four or more copies, survival extends into adulthood. The mildest form of the disease may only appear as weakness in the limbs later in life. (For a brief primer on the gene/symptoms relationship, and more information, visit the SMA Foundation website).
In their article, Schmutz and colleagues report that the duplicated regions on this chromosome have a greater degree of sequence identity than duplications on other chromosomes. In a 1-2 Mb interval in 5q13.3, the "SMA region," the researchers found a high number of duplications, including duplications of areas on chromosome 6. The area is gene-rich, and along with the SMN genes, the authors identified genes for small EDRK-rich factor (SERF1), and baculoviral IOP repeat containing 1 (BIRC1).—Hakon Heimer.
Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S, Gordon LA, Scott D, Xie G, Huang W, Hellsten U, Tran-Gyamfi M, She X, Prabhakar S, Aerts A, Altherr M, Bajorek E, Black S, Branscomb E, Caoile C, Challacombe JF, Man Chan Y, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Lopez F, Lou Y, Martinez D, Medina C, Morgan J, Nandkeshwar R, Noonan JP, Pitluck S, Pollard M, Predki P, Priest J, Ramirez L, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wheeler J, Wu K, Yang J, Dickson M, Cheng JF, Eichler EE, Olsen A, Pennacchio LA, Rokhsar DS, Richardson P, Lucas SM, Myers RM, Rubin EM. The DNA sequence and comparative analysis of human chromosome 5. Nature. 2004 Sep 16;431(7006):268-74. Abstract