Monday, December 27, 2010

Genes and the Ignorant

Genes are most evident in some strange way to the gardener. Mendel did peas, and of course when you plant a hydrangea you find its color varies greatly depending on the soil, the rainfall, the location, and lots of things well beyond the genes. I can have dozens of clones of plants and they may all look different. They are clone, the very same genes, but phenotypically they are different, the genes are working differently. Any gardener has know this for centuries, albeit without the gene paradigm.

Along comes a paper in Technology Review which states that genes are not the same everywhere. Wow, what insight. The author starts with stating:

The message boils down to a single premise: your unique mix of physiological traits and disease risks (collectively known as your phenotype) can be read in the precise sequence of chemical bases, or letters, in your DNA (your genotype). 

 Not really, and we all knew this for ages. One need just look for example at prostate cancer. One can inherit a predisposition but it may require methylation of a set of genes enhanced by inflammation, for example the inflammation may be induced by excess blood glucose due to Type 2 Diabetes which is due to excess caloric consumption. Thus the linkage, albeit on a genetic underpinning, is driven by diet. There is a paper by Donkena et al which starts with an Ayurvedic Proverb:

When diet is wrong medicine is of no use
When diet is correct medicine is of no need.

This applies to man and plants! He continues:

What if the DNA sequence of an individual explains only part of the story of his or her inherited diseases and traits, and we need to know the DNA sequences of parents and perhaps even grandparents to understand what is truly going on? Before the Human Genome Project and the era of widespread DNA sequencing, those questions would have seemed ridiculous to researchers convinced they knew better. But modern genomics has run into a Mendelian wall.

Again back to plants, you can get millions of clones in plants, just vegetatively propagate them.  Then you have the same genes. Now plant them in different conditions and you get different looking plants. Epigenetics! They may be methylated, may have Mg bonding or gene suppression, they may have some miRNA issue arise, and so on and so forth. Just look at color, the secondary anthocyanin pathways can be influenced by a number of secondary genes, which in turn get influenced by environmental factors. Not just one gene but dozens.

The author then hits one of my favorite topics, obesity and type 2 diabeytes. He states:

Large-scale genomic studies over the past five years or so have mainly failed to turn up common genes that play a major role in complex human maladies. More than three dozen specific genetic variants have been associated with type 2 diabetes, for example, but together, they have been found to explain about 10 percent of the disease's heritability—the proportion of variation in any given trait that can be explained by genetics rather than by environmental influences.

 Heritability! Why if mom and dad are obese do you think junior will be a bit on the fat side? You can have as many genes as you want, but the law of mass balance still works. And this was an MIT related article, albeit by some non technical author. I guess anything to fill pages.

The author continues:

The "missing heritability" in the height study typifies many recent research reports in which large-scale genetic screens, known as genome-wide association studies, have identified a multitude of genes (or at least genetic neighborhoods) that are statistically associated with a biological trait like height or a disease like obesity, yet account for mystifyingly little of its propensity to run in families. 

Yes, genes exist, they are complex, and if a child is fed one way it may grow tall and if fed another is may be stunted. Not mystifying. If you feed a plant a high nitrogen diet then you get lots of leaves and if you feed its clone lots of P and K you may likely get lots of flowers. Again so what is new here.

It would help to have writers who can question, doubt, and have detailed knowledge of what has transpired.

So is the author introducing something dramatically new. Hardly. One need just read the opening of a NEJM article a few years ago by Esteller:

Classic genetics alone cannot explain the diversity of phenotypes within a population. Nor does classic genetics explain how, despite their identical DNA sequences, monozygotic twins or cloned animals can have different phenotypes and different susceptibilities to a disease. The concept of epigenetics offers a partial explanation of these phenomena. First introduced by C.H. Waddington in 1939 to name “the causal interactions between genes and their products, which bring the phenotype into being,”epigenetics was later defined as heritable changes in gene expression that are not due to any alteration in the DNA sequence.

The best-known epigenetic marker is DNA methylation. The initial finding of global hypomethylation of DNA in human tumors was soon followed by the identification of hypermethylated tumor-suppressor genes, and then, more recently, the discovery of inactivation of microRNA (miRNA) genes by DNA methylation. These and other demonstrations of how epigenetic changes can modify gene expression have led to human epigenome projects and epigenetic therapies. Moreover, we now know that DNA methylation occurs in a complex chromatin network and is influenced by the modifications in histone structure that are commonly disrupted in cancer cells.

Is there some new insight made by the author and the researchers? Hardly. Epigenetics Oh that MIT had an alumni magazine like Harvard, in my opinion, since the time that Tech Review was taken over by some west coast IPO rag folks, it looks like Popular Science combined with some IPO hit sheet rather than a product of a quality educational establishment.