Interactions between chromosomal and nonchromosomal elements reveal missing heritability
- aComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139;
- bWhitehead Institute for Biomedical Research, Cambridge, MA 02142;
- cBroad Institute of MIT and Harvard University, Cambridge, MA 02142; and
- dDepartment of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, Cambridge, MA 02138
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Contributed by Gerald R. Fink, April 22, 2014 (sent for review February 28, 2014)

Significance
We show that the phenotype of an organism can be affected both by chromosomal and nonchromosomal information. The influence of the cytoplasmic, nonchromosomal information can have a profound effect on the phenotype and can be great enough to mask the effect of a chromosomal mutation. Our ability to quantify the contribution of this cytoplasmic component shows that it could comprise a significant portion of the “missing heritability.” In addition, our findings highlight the possibility of mitochondrial/nuclear incompatibility, which could be an important consideration in evaluating the feasibility of mitochondrial replacement therapy in humans.
Abstract
The measurement of any nonchromosomal genetic contribution to the heritability of a trait is often confounded by the inability to control both the chromosomal and nonchromosomal information in a population. We have designed a unique system in yeast where we can control both sources of information so that the phenotype of a single chromosomal polymorphism can be measured in the presence of different cytoplasmic elements. With this system, we have shown that both the source of the mitochondrial genome and the presence or absence of a dsRNA virus influence the phenotype of chromosomal variants that affect the growth of yeast. Moreover, by considering this nonchromosomal information that is passed from parent to offspring and by allowing chromosomal and nonchromosomal information to exhibit nonadditive interactions, we are able to account for much of the heritability of growth traits. Taken together, our results highlight the importance of including all sources of heritable information in genetic studies and suggest a possible avenue of attack for finding additional missing heritability.
Footnotes
- ↵1To whom correspondence may be addressed. E-mail: gifford{at}mit.edu or gfink{at}wi.mit.edu.
Author contributions: D.K.G. and G.R.F. designed research; M.D.E., A.S.-N., and L.D. performed research; M.D.E., A.S.-N., and L.D. contributed new reagents/analytic tools; M.D.E. analyzed data; and M.D.E., D.K.G., and G.R.F. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1407126111/-/DCSupplemental.