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Genomic techniques are providing new insights into the structure of fungal populations, revealing hitherto undescribed fine\u2010scale adaptations to environments and hosts that govern their emergence as infections. Cryptococcal meningitis is a neglected tropical disease that is responsible for a large proportion of <jats:styled-content style=\"fixed-case\">AIDS<\/jats:styled-content>\u2010related deaths across Africa; however, the ecological determinants that underlie a patient's risk of infection remain largely unexplored. Here, we use genome sequencing and ecological genomics to decipher the evolutionary ecology of the aetiological agents of cryptococcal meningitis, <jats:italic>Cryptococcus neoformans<\/jats:italic> and <jats:italic>Cryptococcus gattii<\/jats:italic>, across the central African country of Zambia. We show that the occurrence of these two pathogens is differentially associated with biotic (macroecological) and abiotic (physical) factors across two key African ecoregions, Central Miombo woodlands and Zambezi Mopane woodlands. We show that speciation of <jats:italic>Cryptococcus<\/jats:italic> has resulted in adaptation to occupy different ecological niches, with <jats:italic>C.\u00a0neoformans<\/jats:italic> found to occupy Zambezi Mopane woodlands and <jats:italic>C.\u00a0gattii<\/jats:italic> primarily recovered from Central Miombo woodlands. Genome sequencing shows that <jats:italic>C.\u00a0neoformans<\/jats:italic> causes 95% of human infections in this region, of which over three\u2010quarters belonged to the globalized lineage <jats:styled-content style=\"fixed-case\">VNI<\/jats:styled-content>. We show that <jats:styled-content style=\"fixed-case\">VNI<\/jats:styled-content> infections are largely associated with urbanized populations in Zambia. Conversely, the majority of <jats:italic>C.\u00a0neoformans<\/jats:italic> isolates recovered in the environment belong to the genetically diverse African\u2010endemic lineage <jats:styled-content style=\"fixed-case\">VNB<\/jats:styled-content>, and we show hitherto unmapped levels of genomic diversity within this lineage. Our results reveal the complex evolutionary ecology that underpins the reservoirs of infection for this, and likely other, deadly pathogenic fungi.<\/jats:p>","DOI":"10.1111\/mec.13891","type":"journal-article","created":{"date-parts":[[2016,10,19]],"date-time":"2016-10-19T17:12:52Z","timestamp":1476897172000},"page":"1991-2005","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Genomic epidemiology of <i>Cryptococcus<\/i> yeasts identifies adaptation to environmental niches underpinning infection across an African <scp>HIV<\/scp>\/<scp>AIDS<\/scp> cohort"],"prefix":"10.1111","volume":"26","author":[{"given":"Mathieu","family":"Vanhove","sequence":"first","affiliation":[{"name":"Department of Infectious Disease Epidemiology St Mary's Hospital Imperial College London London W2 1PG UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew 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Zambia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shabir","family":"Lakhi","sequence":"additional","affiliation":[{"name":"School of Medicine University of Zambia Nationalist Road PO Box 50110 Lusaka Zambia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Kwenda","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Zambia PO Box 32379 Lusaka Zambia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sile","family":"Molloy","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity St. George's University of London Blackshaw Road London SW17 0QT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Karunaharan","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity St. George's University of London Blackshaw Road London SW17 0QT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Stone","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity St. George's University of London Blackshaw Road London SW17 0QT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity St. George's University of London Blackshaw Road London SW17 0QT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihana","family":"Bicanic","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity St. George's University of London Blackshaw Road London SW17 0QT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Epidemiology St Mary's Hospital Imperial College London London W2 1PG 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