|Gene map of Mycoplasma genitalium. Circularly arranged coloured bands are the genes (525 in number) in their position in the DNA. The genome has 580,070 nucleotide base pairs (580 kb).|
Tully et al., 1983
Mycoplasma genitalium is a small parasitic bacterium that lives on the ciliated epithelial cells of the urinary and genital tracts in humans. Its existence was first reported in 1981, and was eventually identified as new species of Mycoplasma in 1983. It is a sexually transmitted pathogen which can cause significant morbidity in men and women, and is a co-factor in HIV transmission. Specifically, it causes urethritis (inflammation of the urinary tract) both in men and women, and also cervicitis (inflammation of cervix) and pelvic inflammation in women. Its complete genome sequence was published in 1995. Up until 2003, when a new species of Archaea Nanoarchaeum equitans had its genome sequenced, it was regarded as a cellular unit with the smallest genome. With the genome sequence of Candidatus Carsonella ruddii in 2006, it remains the third smallest genome-sized organism.
The synthetic genome of M. genitalium named Mycoplasma genitalium JCVI-1.0 (after the research centre, J. Craig Venter Institute, where it was synthesised) was produced in 2008, becoming the first organism with synthetic genome. In 2014, researchers at The Scripps Research Institute discovered a new protein called Protein M from M. genitalium.
Discovery and description
Mycoplasma genitalium was originally isolated in 1980 from urethral specimens of two male patients suffering from non-gonococcal urethritis in the genitourinary medicine (GUM) clinic at St Mary's Hospital, Paddington, London. It was reported in 1981 by a team led by Joseph G. Tully. Under electron microscopy, it appears as flask-shaped cell having a narrow terminal portion that is crucial for its attachment to the host cell surfaces. The bacterial cell is slightly elongated somewhat like a vase, and measures 0.6-0.7 μm in length, 0.3-0.4 μm at the broadest region, and 0.06-0.08 μm at the tip. The base is broad while the tip is stretched into a narrow neck, which terminates with a cap. The terminal region has a specialised region called nap, which is absent in other Mycoplasma. Serological tests indicated that the bacterium was not related to known species of Mycoplasma. The comparison of genome sequences with other urinogenital bacteria such as M. hominis and Ureaplasma parvum revealed that M. genitalium is significantly different, especially in the energy-generating pathways, although it shared a core genome of ~250 protein-encoding genes. Infection by M. genitalium seems fairly common, can be transmitted between partners during unprotected sexual intercourse, and can be treated with antibiotic.
On 6 February 2014, The Scripps Research Institute announced the discovery of a new protein named Protein M from M. genitalium. The protein was identified during investigations on the origin of multiple myeloma, a B-cell carcinoma. To understand the long-term Mycoplasma infection, it was found that antibodies from multiple myeloma patients' blood were recognised by M. genitalium. The antibody reactivity was due to a protein never known before, and is chemically responsive to all types of human and nonhuman antibodies available. The protein is about 50 kDa in size, and composed of 556 amino acids. Contrary to their initial hypothesis that the antibody reactions were in response to mass infection with the bacterium, they found that Protein M evolved simply to bind to any antibody it encounters. By this property the bacterium can effectively evade the immune system of the host.
The genome of M. genitalium consists of 525 genes in one circular DNA of 580,070 base pairs. Scott N. Peterson and his team at the University of North Carolina at Chapel Hill reported the first genetic map using pulsed-field gel electrophoresis in 1991. They performed an initial study of the genome using random sequencing in 1993, by which they found 100,993 nucleotides and 390 protein-coding genes. Collaborating with researchers at the Institute for Genomic Research, which included Craig Venter, they made the complete genome sequence in 1995 using shotgun sequencing. Only 470 predicted coding regions (out of 482 protein encoding genes) were identified, including genes required for DNA replication, transcription and translation, DNA repair, cellular transport, and energy metabolism. It was the second complete bacterial genome ever sequenced, after Haemophilus influenzae. In 2006 the team at the J. Craig Venter Institute reported that only 382 genes are essential for biological functions. The small genome of M. genitalium made it the organism of choice in The Minimal Genome Project, a study to find the smallest set of genetic material necessary to sustain life.
Symptoms of infection
Infection with M. genitalium generally produces severe clinical symptom, or a combination of symptoms; but sometimes can be asymptomatic. It causes inflammation in the urethra (urethritis) both in men and women, which is associated with mucopurulent discharge in the urinary tract, and burning while urinating. In women, it causes cervicitis and pelvic inflammatory diseases, including endometritis and salpingitis. It is also supected with tubal factor infertility. Polymerase chain reaction analyses indicated that it is a cause of acute non-gonococcal urethritis (NGU) and probably chronic NGU. Unlike other Mycoplasma, the infection is not associated with bacterial vaginosis. It is highly associated with the intensity of HIV infection. It is also suspected to play a role in the development of prostate and ovarian cancers and lymphomas.
The U.S. Centers for Disease Control and Prevention has one specific recommended regimen, with azithromycin and another specific recommended regimen with doxycycline. As alternative regimens, the agency has specific regimens each with erythromycin or erythromycin ethylsuccinate or ofloxacin or levofloxacin.
Studies have demonstrated that a 5 day course of azithromycin has a superior cure rate than a single dose. Further, a single dose of azithromycin can lead to the bacteria becoming resistant to azithromycin. Based on these findings, UK doctors are moving to a 5 day azithromycin regimen. Doxycycline is also still used but moxifloxacin is seen as an alternative treatment. Among Swedish patients, doxycycline is relatively ineffective (with a cure rate of 48% for women and 38% for men); and a five-day treatment with azithromycin is neither prescribed due to drug resistance.
On 6 October 2007, Craig Venter announced that a team of scientists led by Nobel laureate Hamilton Smith at the J. Craig Venter Institute had successfully constructed a synthetic DNA using which they planned to make the first synthetic genome. Reporting in The Guardian, Venter said that they have stitched together a DNA strand of 381 genes long and contained 580,000 base pairs, based on the genome of M. genitalium. On 24 January 2008 they announced the successful creation of a synthetic bacterium which they named Mycoplasma genitalium JCVI-1.0 (the name of the strain indicating J. Craig Venter Institute with its specimen number). They synthesised and assembled the complete 582,970-base pair genome of the bacterium. The final stages of synthesis involved cloning the DNA into the bacterium E. coli for nucleotide production and sequencing. This produced large fragments of approximately 144,000 base pairs or 1/4th of the whole genome. Finally, the products were cloned inside the yeast Saccharomyces cerevisiae to synthesize the 580,000 base pairs. The molecular size of the synthetic bacterium is 360,110 kilodaltons (kDa). Printed in 10 10-point font, the letters of the genome cover 147 pages.
On 20 July 2012, Stanford University and the J. Craig Venter Institute announced successful simulation of the complete life cycle of a Mycoplasma genitalium cell, in the journal Cell. The entire organism is modeled in terms of its molecular components, integrating all cellular processes into a single model. Using object oriented programming to model the interactions of 28 categories of molecules including DNA, RNA, proteins, and metabolites, and running on 128-core Linux cluster, the simulation takes 10 hours for a single M. genitalium cell to divide once — about the same time the actual cell takes — and generates half a gigabyte of data.
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