Mary, Queen of Scots. Catholic. Serial wife. Suspected murderess. And a good deal shorter towards the end of her reign...
Mary's first husband was the French Dauphin Francis. His father died, and he became the French king Francis II, as is the tradition; Mary became Queen Consort. And Queen of Scots. Yes, a Franco-Scottish personal union existed in OTL and nobody has yet pursued a serious TL over it!
Sadly for the couple, Francis died before children could be begotten from the unholy union, and Mary was packed back off to Scotland. Things went downhill from there, and she ended up bald and beheaded in front of a crowd of foreigners, with a dog up her skirt.
So the WI is simple. Have Francis live longer, knock her up (preferably multiple times to secure the dynasty), and give Good Queen Bess the willies (which, the residents of Virginia will assure you, is a real divergence from OTL).
(Should Elizabeth still refuse to marry, we'd likely see a different succession - Lady Margaret Stanley would be the next heir, being descended from Mary Tudor [Henry's sister], or her children if she predeceased Elizabeth.)
Go to it, citizens!