Epistasis Blog

From the Computational Genetics Laboratory at the University of Pennsylvania (www.epistasis.org)

Thursday, July 30, 2009

Modified Two-Factor Ratios - OR - Why Did it Take Us 50 Years to Embrace Complexity in Human Genetics?

I have been reading the 1940 second edition of "The Principles of Heredity" by Laurence Snyder, Ph.D. (1901-1986). He has a nice chapter on Modified Two-Factor Ratios where he goes through in great detail deviations from the 9:3:3:1 Mendelian ratios that are due to epistasis.

"When a factor of one pair masks the expression of the factors of another pair, it is said to be epistatic to the other pair....The noun formed from the adjective epistatic is epistasis. Epistasis is thus the same effect between factors of two different pairs that dominance is between factors of two different pairs that dominance is between two alleles"

He goes on to describe in detail dominant epistasis (12:3:1), recessive epistasis (9:3:4), dominant and recessive epistasis (13:3), duplicate recessive epistasis (9:7), duplicate dominant epistasis (15:1), and incompletely duplicate epistasis (9:6:1).

He has an interesting chapter toward the end of the book on The Inheritance of Mental Traits in Man where he discusses the role of genetics in musical ability and intelligence, for example. it is important to note that there was a general recognition at this time that these traits were complex and influenced by many genes and the environment. He cites a study by Philiptschenko (1927) suggesting that musical ability is influence by four pairs of genes with modifying effects. He later suggests that intelligence is influenced by the environment and many variable genes.

It is interesting that as early as the 1930s there was a general recognition that epistasis is an important phenomenon and that human traits were likely due to multiple environmental and genetic factors. We lost this complex thinking during the reductionist molecular revolution and are only now, after the failure of genome-wide association studies (GWAS), starting to come back to it. I find it really intriguing that geneticists in the early 1900s had more insight into the complexity of human traits than many of us do now.

Consider, for example, a 1951 Amercian Journal of Human Genetics paper by Snyder on "Old and New Pathways in Human Genetics". In this paper he suggests that "...if human genetics is to progress along fresh pathways, the traditional atomistic [i.e. single gene] approach must be supplemented by new methods which will provide information on multifactorial inheritance". He further states that "We must be able to analyze genetic variability without recourse to classical single-gene analyses". It is hard to believe that more than 50 years later the "atomistic" approach still dominates human genetics.

As a side note, I love the last paragraph of Snyder's paper (below). He recognized more than 50 years ago the importance of team science. Why did it take the rest of the field so long to come around to this?

"The human genetic studies of the future must be cooperative efforts. Only by teamwork involving scientists from many areas can the understanding of the genetics of man be expected to advance appreciably. To those of you in related fields who are willing to lend your aid and advice to such teams, it may be confidently promised that in direct proportion to the data and information thus provided there will emerge a deeper and more significant understanding of human biology, and recurrent new practical ways in which to use the information for the improvement of the health and welfare of all mankind."


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