Two Strikes and You’re Out
Gene–Gene Mutation Interactions in HCM
While Ockham’s razor is a useful tool in the physical sciences, it can be a very dangerous implement in biology. It is thus very rash to use simplicity and elegance as a guide in biological research.
Gregor Mendel is credited with first understanding the fundamental characteristics of genetic inheritance through his studies of transgenerational expression of phenotypes in pea plants (Pisum sativum). As every middle schooler knows, through careful cross-breeding he discerned dominant and recessive modes of inheritance for, but not blending of, parental traits. He rightly concluded that inheritance is achieved through vertical transmission of trait-encoding factors that we now call genes.
Article, see p 227
An important underlying assumption to Mendel’s mechanistic view of inheritance is that one inheritance unit (he called them "factors"1; we call them genes) encodes one trait. This relationship holds for the 7 pea phenotypes he cataloged, but is the exception rather than the rule in mammalian biology. For example, stature is an inherited trait, but >50 different genes are thought to contribute to human height.2 Nevertheless, heritable diseases are commonly referred to as Mendelian when they are attributed to mutations in a single gene. The public database Online Mendelian Inheritance in Man (http://www.omim.org) lists >4000 Mendelian disorders with a known molecular basis, plus >1700 others with an unknown molecular basis. Although some of these diseases, such as cystic fibrosis (autosomal recessive mutation of CFTR gene), Huntington disease (autosomal dominant mutation of HTT gene), and hypertrophic cardiomyopathy (HCM; autosomal dominant mutations of the MYH73 and other sarcomeric protein genes), are caused by mutations in one gene, even for so-called Mendelian diseases the contribution of additional genetic modifiers is yet to be well modeled. In this issue of Circulation Research, Blankenburg et al4 show how the combinatorial …