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Scientists at the Sanger Center, Cambridge, UK, the Max Planck Institute for Molecular Genetics, Berlin, Germany and the University of Oxford have sequenced and analyzed the entire genome of Neisseria meningitidis . These pathogenic bacteria are unusual due to the frequent occurrence of repetitive DNA and extensive genetic variation (Nature, 30 March 2000).
N. meningitidis colonizes the nasopharynx of many healthy individuals but also causes life-threatening meningitis and septicemia in a certain proportion. In industrialized countries, serogroup B and C strains of N. meningitidis are most commonly isolated from endemic disease and localized outbreaks. However, serogroup A strains are associated with large epidemic outbreaks in developing countries, particularly the Sahel region of Africa. In 1997, 500,000 cases of meningococcal meningitis were reported, half of them from Africa. Vaccines based on purified capsular polysaccharides can help stop epidemic serogroup A and C outbreaks but no vaccine is yet available against serogroup B.
Two genomes were described in March, 2000, that of a serogroup B strain (Science 287: 1809-1815) and that of a serogroup A strain (Nature 404: 502-506). Only 91% of the coding sequences of each genome is present in the other strain and other coding sequences are unrelated. Two genomes have also been published for Helicobacter pylori and they also share only 93% of their coding sequences (Nature 397: 176-180, 1999). Comparisons of the sequences of diverse strains showed that both species are characterized by unusually high levels of sequence diversity, even within conserved genes encoding metabolic proteins (PNAS 95: 12619-12624, 1998; Mol Microbiol 32: 459-470, 1999). The present report demonstrates that the genome of N. meningitidis also contains many hundreds of repetitive elements, ranging from short repeats, arranged singly or in multiple arrays, through to insertion sequences and gene duplications of 1 kb or more; many of these repeats appear to be involved in genome fluidity and antigenic variation in this important human pathogen. Repetitive DNA is commonplace in eukaryotes but had been previously considered to be rare in prokaryotes. In addition, the 2,184,406 bp long serogroup A genome contains at least 42 pseudogenes (among 2,121 predicted coding regions) and at least five complete or partial prophages.
The most obvious repetitive element is the 10 bp neisserial DNA uptake sequence, which is present in nearly 2,000 copies (Fig. 1). This sequence facilitates the uptake of DNA by transformation among the different neisserial species. Other repetitive sequence elements are concentrated within intergenic repeat arrays of 200 2,700 bp in length. The most abundant are the ³neisserial intergenic mosaic elements ³ (NIMEs) which comprise repeat units of 50 to 150 bp in length, each flanked by 20 bp inverted repeats (dRS3 elements). The remainder of the repeat arrays consist of larger dispersed repeats, including the 37-160 bp Correia elements which are present 257 times and copies of the three common insertion elements. The larger repeat arrays are exclusively associated with genes that encode functions associated with the cell surface. Due to sequence homology between different repeat arrays, they can facilitate chromosomal fluidity through recombination, deletion, duplication and other forms of illegitimate recombination. A number of examples of such events have been described previously. The complete genome also contains 26 homo- or hetero-polymeric tandem repeats. Changes in the length of such repeats can change the translational or transcriptional status of a gene, leading to the on/off switching called phase variation. The majority of the phase-variable genes encode proteins associated with the cell surface, suggesting a role in virulence and/or immune avoidance.
Published: 30-03-2000
Contact: Mark Achtman
Max Planck Institute for Molecular Genetics,
Berlin, Germany
Phone: (+49 30) 8413 1262
Fax: (+49 30) 8413 1385
e-mail: achtman@molgen.mpg.de
Contact: Julian Parkhill
The Sanger Center,
Hinxton, Cambridge, UK
Phone: (+44 1223) 494975
Fax: (+44 1223) 494919
e-mail: parkhill@sanger.ac.uk
Contact: Brian Spratt
Wellcome Trust Centre for the Epidemiology
of Infectious Disease
Department of Zoology
Oxford University
South Parks Road
Oxford, UK
Journal
Nature