What happens to cause Uncle John to have so much guilt about his past in The Grapes of Wrath?
Uncle John's guilt has a single source.
His sense of guilt causes him to blame all the family’s misfortunes on what he thinks of as his sin: his failure to call a doctor when his wife complained of illness.
He feels that he is responsible for his wife's death. When he was a younger man his wife was sick during her first pregnancy. He told her that she was not truly sick and that she would feel better in the morning.
In the morning she died.
Uncle John holds himself responsible for this death and tries to make up for his guilt as the years go by. This trait in him suggests that he is a good man at heart. He learned to sympathize with people through this hardship.
Another thing we see in his character is a strain of "absolutism". He refuses to forgive himself, though he did not cause his wife's illness and he has attempted to make up for what he thinks of as his mistake for years.