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In all probability, the world wouldn't have changed much, had it not been for a change in power. In 1505, the War of the League of Cambrai, starting out as a simple war between Portugal, and an Indian state, escalated when Venice and the ottoman empire entered against Portugal. Soon after, more alliances were made (mostly stemming form conflicts in the past, and countries seeking revenge). The war led to two distinct sides. The League of Cambrai, consisting of The Papal States, France, the Holy Roman Empire, Spain, Portugal, Venice and Scotland, Versus England, the Ottoman Empire, the Duchy of Milan, the Duchy of Modena and the Duchy of Ferrara. The war ended after the Spanish sent their navy for an invasion of England. it was a horrendous, miserable failure, but enough to draw English troops to the south. The Scots then entered the war, and defeated the English at the Battle of Flooden Field. Due to this, the English soon quit the war. The Papal States succeeded in occupying the Duchies of Ferrara, Modena, and Milan. The Ottoman Empire remained generally unaffected from the war. They generally expanded the same as OTL.
After the war, the English focused their attention of what would be the English Royal Navy. The French, and Scots followed suit, and the Spaniards rebuilt theirs, and so did every other European power. Then, a new discovery was made.
The Portuguese discovered the New World in 1528. An expedition lead by Estêvão da Gama (the son of The famous explorer who discovered an oceanic route to India) landed in OTL South America during a planned expedition to circumnavigate the globe. However, He landed on the Pacific Side of the continent, (later to be named "South Gamania"), due to the fact that the route was planned to take him around that way. The explorers soon came in contact with the local Incans. He would also make three more expeditions. of the first two, The former discovered The OTL Isthmus of Panama, and the latter discovered the Strait of Gamania (OTL Strait of Magellan). his last expedition (in 1535) was not so much an expedition, but, rather, a military conquest. It was an easy fight however, due to smallpox and malaria that spread rapidly through the population. The colony of New Portugal was founded in that same year.
The Incan Empire was not the only Portuguese conquest. The Portuguese also took over the Aztec empire. However, this conquest was not done alone. The local Tlaxcalans were allied with the Portuguese in this effort. The Portuguese even gave the local ruler a few firearms as a peace offering (because they intrigued them so) this would prove to be a terrible mistake, which the Portuguese wouldn't have committed, had they known they were not going to get those firearms back.
The Portuguese had originally intended to double cross the Tlaxcalans. what the Portuguese didn't know was that this was evident to the Tlaxcalans as well. a local wise man knew that this was a trick, and advised the Tlaxican king to use their superior numbers and knowledge of the local area to defeat the Spaniards. The war began soon after a caravan with Spanish supplies was raided by the Tlaxcalans. Raids would be common, and all weapons would be commandered. any firearms or powder was distributed to the men who were not skilled with spears, knives, or traditional weapons. swords and knives were given to the best men. The Portuguese had some good advantages, but the war soon turned to guerrilla fighting (which the Tlaxcalans were more skilled at), and closely resembled a lower-tech version of the OTL Vietnam War. The war lasted from 1535-1538. Most of the conquistadores that fought for gold simply took their riches home, and refused to fight in a guerra escondida or "the hidden war" contrary to common thought about the war, the firearms used by the Tlaxcalans did not pplay a big part in the war. most of the guns blew up from misuse (one reason why they were given to inexperienced troops) many would simply not work in the jungles of the New World, and the few that could be used properly never had much ammunition to use. (most of the powder was used as an explosive bomb rather than to fire projectiles out of guns. furthermore, many firearms were loaded with stones, wood or animal bone, which did not work very well as lethal projectiles, but had a splintering incapacitating effect) on top of all that, there wasn't enough raids to supply every soldier with a gun. Very few Tlaxcalans had any firearms, so they ened up being more of a liability than an asset.
In 1530, The Spanish explorer Francisco de Orellana landed on the Continent originally named for him, but would soon become "North Gamania." the river located in the central part of the continent would still be known as the Orellana river, however. after this discovery, it became possible for nations to traverse the Atlantic, and find colonies in the New World. New Spain, New France, New England, New Scotland, New Netherland, and other colonies would be founded here.
North Gamania wasn't the only place, however. in Africa, The Portuguese mainly colonized. However, some nations would colonize north africa. Just about every major power was expanding into india, However. Besides Africa and India, Indonesia was the only other place being colonized, and was wholly colonized by the Portuguese. By 1550, all the major colonial powers had gained a foothold on these continents.
Europe, as it would seem, was in a rather peaceful state for the next ten years. more effort was given to expand their colonies, rather than to fight. after that, a major war occurred in 1562, in western Europe. The Papal States, through an effort to extend their power, allied themselves with Spain, and, and attempted to conquer most of northern Italy. France also had their eye on expanding, as did the Swiss. The Swiss, however, remained neutral, and quickly accomplished their goals without any disruption in about a year. this left the French against both the Spanish, and the Papal States in 1565, the war ended with France ceding land to Spain, and the Papal States in control of northern Italy. In these years, the colonies of Portugal grew, and more settlers arrived in the New World. unfortunately for the Tlaxcalans the new settlers brought smallpox to the New World. even though no one crossed the Tlaxcalan-Portuguese border, the disease spread. The Native Plague lasted for several years before finally ending in 1573. Smallpox and a number of other diseases that spread through America wreaked havoc on the natives. Tlaxcala was able, with their high population, to continue being self-soveregn, though over 50% of the native population was decimated.
The Spanish, instead of landing in Mesoamerica, sent most colonists to Spanish Florida. as a result of the plagues that ravaged the New World, the native people living there were almost entirely wiped out. The Spanish were able to expand their colonies far inland, and Santa Elena became the new capital of Florida.