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Identifying the patterns of land cover change (LCC) and their main proximate causes and underlying driving forces in tropical rainforests is an urgent task for designing adequate management and conservation policies. The Lachuá region maintains the largest lowland rainforest remnant in Guatemala, but it has been highly deforested and fragmented during the last decades. This is the first paper to describe the patterns of LCC and the associated political and socioeconomic factors in the region over the last 50� years. We estimated spatial and temporal variations in LCC from a random sample of 24 1-km² landscape plots during three time periods (1962–1987, 1987–2006, and 2006–2011) and evaluated how they were related to some important proximate causes and underlying driving forces. During the study period, 55� % of forest cover disappeared, at an annual rate of 1.6� %. The deforestation rate increased from 0.6� % (during the first study period) to 2.8� % (last period), but there was very high spatial variation. Landscape plots located outside conservation areas and close to roads lost between 80 and 100� % of forest cover, whereas the forest cover in landscapes located within protected areas remained intact during the study period. The establishment of new human settlements, roads, and annual crops was the main proximate cause during the first period, but during the second and third periods, open areas were mainly created to establish cattle pastures. Because ~75� % of forest cover has disappeared outside the protected areas, the conservation of this biodiversity hot spot will depend on the expansion of protected areas, and the promotion of forest regrowth and alternative biodiversity-friendly land uses in the landscape matrix.