Like well-displayed shoes and garments, human chromosomes line up neatly by size from No.1 to No. 22 (plus X and Y). "One-third of the way down the row, chromosome 6 is the largest and richest display in the human genome sequenced so far," observes genomicist Andrew Mungall, project leader for the analysis of chromosome 6. The journal Nature, dated Oct. 23, 2003, presents a paper titled "The DNA sequence and analysis of human chromosome 6." The article lists an awesome 171 co-authors.
Commenting on chromosome 6, which weighs in at 166,880,988 base pairs, Mungall observed, "The finished sequence comprises a little less than 6 percent of the total human genome."
Mungall is joint senior author with Stefan Beck, both of the Wellcome Trust Sanger Institute in Cambridge, UK. "Those of us who are working on chromosome 6," Mungall told BioWorld Today, "are part of the International Human Genome Consortium. We are an integral part of that consortium," which submitted its near-total human genome to Nature on Feb. 13, 2001.
"The chromosome 6 sequencing," he continued, "was finished and announced together with the rest of the Human Genome Project on the 14th of April 2003. That's what culminated in the Nature publication late last month."
It's accompanied by a two-page "News & Views" commentary titled "Six is seventh," authored by Jane Grimwood at Stanford University. Her editorial observes that, "The human genome is divided into 24 chromosomes. Each is unique in its composition and contribution to the biological basis of being human."
Mungall noted, "The human specimens that produced the chromosome sequence consisted of many anonymous individuals - at least a dozen different libraries used in total - so that chromosome 6 is a mosaic of the map that was used for sequencing."
633 Pseudogenes: A Blast From The Past
"Technically," Mungall said, "what we are announcing is the largest human chromosome sequenced to date, namely chromosome 6. It adds up to 1,167 protein-coding genes, together with 633 pseudogenes, which are the now-dead relics of genes in the past. A quick search of the database," he added, "gives us 130 genes implicated in some way in disease, or protected from disease. At the moment there are 84 positively identified disease-causing genes. These multifactorial maladies go to cardiovascular disorders, cancer and the like."
Mungall called the roll of the main medical genomic disease entities that are specific to chromosome 6. "Juvenile Parkinson's disease [JPD] is one of them," he cited. "It's called the Park-2 gene that maps to the long arm of chromosome 6. That gene, and its implication in JPD disease, was initially described by a group at Keio University in Tokyo. We helped them with the sequence of the genomic region containing that gene. It turns out that it's the largest gene we have on chromosome 6. It covers a huge region - 1.4 megabases - of DNA. Certainly," he commented, "there are other investigators worldwide who are looking at that gene and other such sequences in juvenile Parkinson's disease.
"Another noteworthy disease is Lafora's myoclonic epilepsy," Mungall added. "It's a fairly rare form of the seizure. And the gene mutated in this disease is called EPM2A. It was discovered as part of the total sequencing project in 1968 in Toronto.
"Of course," Mungall went on, "chromosome 6 encodes the major histocompatibility complex - MHC. So most, if not all, of the autoimmune diseases is the genetic factor involved in these self-diseases encoded within the MHC. This is a 3.6 megabase on the short arm of chromosome 6. That includes maladies like psoriasis, diabetes mellitus, rheumatoid arthritis, multiple sclerosis and all sorts of autoimmune disorders, as well as glaucoma and orofacial cleft palate.
"Among these are mutations that cause hereditary hemochromatosis," Mungall continued, "a condition that affects 400 people, and results in multiorgan dysfunction. Though not confirmed, schizophrenia is on that list.
"One human application that seems to be getting a lot of attention in the scientific community," Mungall observed, "is comparative genomic hybridization. That's using the underlying mapping resource that we sequenced and lay down on these microarrays, or chips, then hybridize. Often it will be a patient's DNA in which we go looking for deletions or insertions, which could lead to narrowing regions of chromosome 6 implicated in certain disorders. Cancer is one of those that people are analyzing at the moment, comparing patient DNA with normal DNA on these chips. For example, deletion of particular genes."
Cross-Species: Mice To Puffer Fish
Grimwood's commentary observed that "Mungall's group has been the first to fully apply for multiple cross-species comparative power for the entire comparison of chromosome 6. This is now available as the DNA sequences become available. The assembled draft genomes cover the mouse (Mus musculus), Norway rat (Rattus norvegicus), spotted green puffer fish (Tetraodon), tiger puffer fish (Fugu rubripes), and zebrafish (Danio rerio).
"This comparative approach," the commentary pointed out, "allows refined predictions of which stretches of DNA are actually genes. The power of comparative genomics will grow as the genome sequences of the chicken, chimpanzee, frog, dog and cow, already in the production queue, become available," it concluded.