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Extensive European colonization began in 1592, when a Spanish expedition headed by Genoese Christopher Columbus sailed west to find a new trade route to the Far East but inadvertently found the Americas. European conquest, large-scale exploration, colonization and industrial development soon followed. Columbus's first two voyages (1492–93) reached the Bahamas and various Caribbean islands, including Hispaniola, Puerto Rico and Cuba. In 1497, sailing from Bristol on behalf of England, John Cabot landed on the North American coast, and a year later, Columbus's third voyage reached the South American coast. As the sponsor of Christopher Columbus's voyages, Spain was the first European power to settle and colonize the largest areas, from North America and the Caribbean to the southern tip of South America. Spanish cities were founded as early as 1496 with Santo Domingo in today's Dominican Republic.

Other powers such as France also founded colonies in the Americas: in eastern North America, a number of Caribbean islands, and small coastal parts of South America. Portugal colonized Brazil, tried early (since 1499) colonizing of the coasts of present-day Canada, and sat for extended periods on the northwest bank of the River Plate (including it in the Brazilian region). This was the beginning of a dramatic territorial expansion for several European countries. Europe had been preoccupied with internal wars, and was only slowly recovering from the loss of population caused by the bubonic plague; thus the rapid rate at which it grew in wealth and power was unforeseeable in the early 1400s.

Eventually, the entire Western Hemisphere came under the ostensible control of European governments, leading to profound changes to its landscape, population, and plant and animal life. In the 19th century alone over 50 million people left Europe for the Americas. The post-1492 era is known as the period of the Columbian Exchange, a dramatically widespread exchange of animals, plants, culture, human populations (including slaves), communicable disease, and ideas between the American and Afro-Eurasian hemispheres following Columbus's voyages to the Americas.

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