Aspergillus species are medically relevant pathogens. For humans, a range of diseases such as infection to the external ear, skin lesions, and ulcers classed as mycetomas are found. Other species are important in commercial microbial fermentations. For example, alcoholic beverages such as Japanese sake are often made from rice or other starchy ingredients (like manioc), rather than from grapes or malted barley. Typical microorganisms used to make alcohol, such as yeasts of the genus Saccharomyces, cannot ferment these starches. Therefore, koji mold such as Aspergillus oryzae is used to first break down the starches into simpler sugars. Members of the genus are also sources of natural products that can be used in the development of medications to treat human disease. Aspergillus spp. are known to produce anthraquinone which has commercial importance due to its antibacterial and antifungal properties. Perhaps the largest application of Aspergillus niger is as the major source of citric acid; this organism accounts for over 99% of global citric acid production, or more than 1.4 million tonnes (>1.5 million US tons) per year. A. niger is also commonly used for the production of native and foreign enzymes, including glucose oxidase, lysozyme, and lactase. In these instances, the culture is rarely grown on a solid substrate, although this is still common practice in Japan, but is more often grown as a submerged culture in a bioreactor. In this way, the most important parameters can be strictly controlled, and maximal productivity can be achieved. This process also makes it far easier to separate the chemical or enzyme of importance from the medium, and is therefore far more cost-effective. Research A. nidulans (Emericella nidulans) has been used as a research organism for many years and was used by Guido Pontecorvo to demonstrate parasexuality in fungi. Recently, A. nidulans was one of the pioneering organisms to have its genome sequenced by researchers at the Broad Institute. As of 2008, a further seven Aspergillus species have had their genomes sequenced: the industrially useful A. niger (two strains), A. oryzae, and A. terreus, and the pathogens A. clavatus, A. fischerianus (Neosartorya fischeri), A. flavus, and A. fumigatus (two strains). A. fischerianus is hardly ever pathogenic, but is very closely related to the common pathogen A. fumigatus; it was sequenced in part to better understand A. fumigatus pathogenicity. Sexual reproduction Of the 250 species of aspergilli, about 64% have no known sexual state. However,