Throughout Middlesex, Cal wrestles with the idea of genetic destiny—that his genes, decided by forces outside of his control, will ultimately decide the direction of his life. Cal ties genetics to mystical notions of fate and destiny, something that can’t truly be changed. For example, no matter how much Desdemona and Lefty hide the truth, human desire cannot erase genetics, as evidenced by Cal’s genetic mutation. However, the supremacy of genetic destiny over free will is not so clear cut. Genetics themselves operate randomly, as seen by Tessie inheriting Sourmelina’s complexion instead of Gizmo’s or Chapter Eleven not getting the same mutation as Cal. Sometimes a character’s choices circumvent the circumstances of their birth, as when Milton’s ability to pay cash allows the family to move to Grosse Pointe despite the suburb’s efforts to keep immigrants out. Cal ultimately cites himself as proof of the possibility of free will because his choice to live as a man stemmed from his desire to do so. He espouses this idea again to Desdemona when he promises her that he will have a good life, a statement that rejects the idea that Cal is doomed to be outcast. He therefore opens the possibility that people can choose to do what they will with the genetic cards they are dealt.
While members of the Stephanides family consistently reinvent themselves to better cope with the travails of immigrant life, they never fully manage to erase the person they once were. Lefty reinvents himself as an American and Desdemona’s suitor, yet as he ages, he mentally regresses to a Greek village boy who knows Desdemona only as his sister. After joining the Navy, Milton goes from an impulsive boy to a powerful man who admonishes others for their foolish behavior. Nevertheless, at the end of the novel, Milton impulsively confronts Father Mike alone and dies in a ridiculous car chase that even he acknowledges as foolish. However, the novel doesn’t suggest that these incomplete reinventions are inauthentic, merely that people cannot completely eradicate their previous selves. We see this most clearly in Cal, who still sees Callie appear in his mannerisms. When he gets his hair cut, Cal refuses to look at Calliope in the mirror, as if he believes he will be destroying her by cutting his hair. That she still comes back into his body suggests she remains a part of him, a part of his history that he cannot erase.
In Middlesex, secrets keep people from feeling close to each other, damaging the potential for emotional and physical intimacy. Cal’s need to keep his intersex body a secret causes him to break off relationships with women he dates, making him believe that he will never find love. Cal learned this behavior of secret-keeping from his family. Zizmo keeps almost everything about himself a secret, meaning no one in the family truly knows who he is or where he comes from. Sourmelina keeps her sexual identity secret from her husband, causing him to believe she is an adulteress. When Desdemona wants to acknowledge the potential consequences of incest, Lefty’s desire to continue living in self-deception drives a wedge between them. They can no longer communicate honestly, and the secret of their incest keeps them emotionally apart. When Lefty’s dementia causes him to blurt out the truth, the rest of the family knows so little about Desdemona and Lefty’s past that they do not even recognize it, leaving Desdemona alone with her knowledge. After Lefty dies, Desdemona no longer has anyone with whom she shares her secret, and accordingly she shuts herself away from the rest of the family.