Gregor Mendel in textbooks: should he stay or should he go now? (Credit: Natl Library of Medicine)

Summer reading for most people means magazines, novels, and similar escapist fare, but for me, its the American Journal of Human Genetics (AJHG). Perusing the table of contents of the current issue tells me whats dominating this post-genomic era: information beyond the obvious, a subtext hidden within the sequences of A, C, T and G.

In the decades following the cracking of the genetic code in the 1960s the correspondence between DNA (actually RNA) triplets and the 20 types of amino acids in biological proteins the one gene-one protein mindset guided genetic research. Investigators used indirect methods to map genes to chromosomes, then painstakingly made the gene-protein assignments, describing rare, single-gene diseases one at a time.

I looked at past issues of the AJHG at decade intervals from this time of year, to place the current issue into perspective. The September 1982 journal had crude linkage maps of 4 human chromosomes, the idea of a human genome project not yet uttered. Within the next decade, a flurry of genes behind the more familiar single-gene diseases began to reveal themselves: myotonic dystrophy, cystic fibrosis, Duchenne muscular dystrophy, the first type of osteogenesis imperfecta, and the elusive Huntington disease among them.

The functioning of the human genome is much more than the protein-encoding sequences. (DOE - Genomes to Life)

The 2002 AJHG held the first inklings of moving beyond the single gene approach, with genomewide and associations entering the lingo, soon to be wed into the GWAS genomewide association studies that dominated until the recent takeover by whole exome sequencing. Articles dealt with SNPs and susceptibilities, described mutations in non-amino-acid-coding parts of genes, and included more environmentally-influenced traits and conditions, such height and bipolar disorder.

And now, the tone and content of the August 2012 issue highlight how the information in DNA goes far beyond one-gene-one-protein. Here are some such hidden meanings:

A mutant gene behind a form of amyotrophic lateral sclerosis (ALS) also causes essential tremor. In ALS, a missense mutation, which alters an amino acid, hangs around in motor neurons and does something we still dont know what that shuts down the cells. But in essential tremor, the mutation is nonsense, which halts production of the protein and activates a cellular garbage disposal pathway that removes the incomplete proteins, with less dire consequences. (The gene, FUS, accounts for only 4% of the 10% of ALS cases that are inherited).

A fifth form of osteogenesis imperfecta (brittle bone disease) stems from a mutation in the control DNA sequence that lies before the protein-encoding sequence. So instead of spelling get ready to start, the mutation tacks five amino acids onto the 132-amino-acid protein. The gene had eluded classic linkage studies and even the Sanger sequencing of the human genome project.

A potential biomarker for susceptibility to and prognosis for lung cancer lies in having 4 copies of a particular repeated sequence, compared to having 2 or 3 copies, in the promoter control region of a gene called MAPKAPK2.

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Hidden Meanings in Our Genomes And What To Do With Mendel