Epistasis Blog

From the Computational Genetics Laboratory at Dartmouth Medical School (www.epistasis.org)

Tuesday, April 03, 2012

The predictive capacity of personal genome sequencing and missing heritability

There are two papers I would like to call your attention two that provide fuel for a healthy debate about the complexity of the genotype to phenotype mapping relationship. The first, from Eric Lander's group (Zuk et al. 2012), calls into question how heritability is estimated. This is an interesting paper that makes the argument that epistasis or gene-gene interaction is likely to explain a significant amount of the missing heritability. Many heritability estimates are based only on additive effects. My only concern with this paper is that this is not a new observation. My group and many others have been writing about the importance of epistasis for many years and much of this work is not acknowledged. The second paper, from Roberts (2012), calls into question the usefulness of personal genomic sequencing for preditcing disease. This paper shows that it is difficult to predict disease in MZ twins. In other words, twins do not always die of the same diseases. These papers both call into question the assumption made by genome-wide association studies (GWAS) of common alleles and whole-genome sequencing for rare alleles that there will be single loci with big effects that will in turn be useful for personalized medicine.

Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: Genetic interactions create phantom heritability. Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1193-8. [PubMed]

Roberts et al., The predictive capacity of personal genome sequencing. Science Transl Med (2012), in press. [PubMed]

Here are several other blog posts and new stories that provide positive and negative perspectives on the Roberts/Vogelstein paper. It is interesting to note that a number of geneticists are upset that the paper got published and that it received so much press (e.g. Nature News Blog). I think they are more worried about the negative publicity for genome technology than the actual science (which they claim is flawed).

Alzheimer Research Forum

Genomes Unzipped

Nature News Blog

Science News