That's a long standing question that unfortunately, most commentaries don't offer much help answering. I assume a literal Adam and Eve as the first humans. Therefore for several generations the family tree has only one trunk. Seth and Cain could only have married daughters of Adam and Eve, their sisters.
That always causes some severe consternation. Francis Collins, an evangelical Christian and the new head of NIH, has written that that solution goes against numerous Old Testament laws. How could the God of the Bible allow for such things? Collins opts for an evolved human race and a figurative Adam and Eve. He also seems to think, though he doesn't explain, that Cain marrying his sister goes against the plain reading of the text.
The main societal taboo against incest is a practical one since offspring from these unions, even among distant cousins, carry an increased risk of birth defects. This is a well-known result of what geneticists call inbreeding. BUT Adam and Eve were completely without genetic mutation, the source of inbreeding birth defects. Therefore there was no biological risk from sister/brother marriages.
In the time of Abraham, Isaac, and Jacob, it was still the practice of marrying within one's family, at least twenty generations after Adam and Eve if you assume no extra generations in the genealogies of Genesis 5 and 11.
In Genesis 20:12 Abraham tells Abimelech that he was not completely lying when he told Abimelech that Sarah was his sister; "Besides, she really is my sister, the daughter of my father though not of my mother." Sarah was Abraham's half-sister.
When Isaac needed a wife, Abraham tells his servant to go to his country and even his own family to find a suitable wife for Isaac (Genesis 24:4). Genesis 24:15 tells us that Rebekah was the daughter of Bethuel, who is the son of Nahor, Abraham's brother.
Isaac then tells Jacob to seek a wife from the daughters of Laban, Rebekah's brother. (Genesis 28:2). So Jacob married two of his first cousins, Leah and Rachel.
Before the Law of Moses, these kinds of unions were the norm. But over 400 years later, mutations have accumulated in all populations and such marriages are quite risky. Therefore, I think, that is why you read in Leviticus 20:17 that if you marry your sister who is either the daughter of your father or the daughter of your mother (thus including half-siblings) they shall be cut off. So a marriage like Abraham and Sarah's was specifically outlawed in the Law of Moses. I think times have changed and the offspring of these once-normal arrangements are at significant risk.
Also, there still may have been a reticence to marry a brother or sister with whom one grows up. But when you realize that Seth was born when Adam was 130 years old, certainly there were many more children between Cain and Abel, and Seth. Therefore Cain very conceivably could have married a sister who was twenty or thirty years younger than he was, and therefore they did not grow up together, so there wasn't the same degree of familiarity as with a same-age sibling.
Bottom-line, I find no difficulty either theologically or biologically with Cain and Seth marrying their sisters. Marrying within the family remained the normal practice for over twenty generations.
About the Author
Raymond G. Bohlin is Vice President of Vision Outreach at Probe Ministries. He is a graduate of the University of Illinois (B.S., zoology), North Texas State University (M.S., population genetics), and the University of Texas at Dallas (M.S., Ph.D., molecular biology). He is the co-author of the book The Natural Limits to Biological Change, served as general editor of Creation, Evolution and Modern Science, co-author of Basic Questions on Genetics, Stem Cell Research and Cloning (The BioBasics Series), and has published numerous journal articles. Dr. Bohlin was named a Research Fellow of the Discovery Institute's Center for the Renewal of Science and Culture in 1997, 2000 and 2012.
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