Wednesday, 9 September 2015

#GenSci15 plenary session and wrap up

Sorry about the accidental's the final version.

Innes Barroso, Head of Human Genetics at Sanger Institute "Genomics and Metabolic Disease – what have we learned so far"

Type 2 diabetes, many patients controlled by table some on insulin, it is a very complex disorder, both genetic and environmental effects (particularly obesity, diet, exercise). Incomplete understanding of Type2 diabetes genetics, extended families are hard to obtain due to generally late onset. Progress has been slow, early studies failed to find robust loci that replicated across studies. However as power of GWAS studies improved six loci were found outside previously suspected candidate genes, but with small effect. Analysis of extremes can be very powerful i.e. young, lean patients vs old obese controls (similar approach being pursued in smoking with some success). Development of genotype imputation and meta-analysis had big impact on how GWAS could impact Type2 diabetes genetics. But still lots of "hidden heritability", drove development of custom GT chips e.g. Metabochip and UK Biobank Axiom array.

So what has GWAS taught us? Innes described two negative types the GWAS skeptics and GWAS cynics, and her talk focused on debunking common issues; e.g. "the effect size is too small", the effect size of a natural variant is not predictive of the effect a drug can have PPARG and thiazolidinediones, or KCNJ11 and sulfonylureas. GWAS can also highlight new areas for drug discovery/re-purposing.

SLC30A8 locus is a loss of function variant which is protective of type2 diabetes and could be a great drug target. Sequencing of cases found 12 protein truncating variants associated with a 65% risk reduction.

GWAS is helping understand Type2 diabetes genetics, identify new areas for therapeutic development, and even find causal genes and unexpected pathways. Combining data allows very powerful analysis to understand the complexity of risk for hyperglycemia, insulin resistance, decreased fasting proinsulin, beta cell function, unclassified. The unclassified variants appear to impact type2 diabetes risk but without affecting fasting glucose levels.

GWAS does have clinical utility; some subsets of associated variants identify a set of metabolically obese lean individuals. These people would not be identified out by a clinician and could be improperly treated, genotyping could help.

Lots of work still to do, trans-ethnic efforts are yielding additional risk loci. Integration with other data will continue to add power, particularly non-coding regions of the genome. Rare variant analysis in huge studies are yielding positive results, but needs massive sequencing-by-genotyping approaches, exome/custom arrays, etc.

Final vignette on the effect of genetic loci on HbA1c (reflects average blood sugar concentration over about three months). Some variants can reduce red blood cell "lifespan" and reduce HbA1c accuracy. Large worldwide analysis of variant data ongoing.

Matt gave a great account of the history of the stuff we've all been talking about: sequence, bases and information. I tried to kee up but will probably be putting his most recent book on my Christmas list!

Matt discussed Avery's transforming principle, and the apparent conundrum that with only four bases DNA did not appear to be complex enough. Andre Boivin and Joshua Lederberg amongst others, Boivin argued that genes were made from DNA, predicted the ability to swap genes between species to understand biology, Lederberg dropped everything else to work on DNA and he won the 1958 Nobel Prize in Physiology or Medicine for discovering that bacteria can mate and exchange genes.

Watson and Crick cracked the code. But would you be happy to have them in your lab? One an over-eager over-ambitions young scientist, the other a layabout PhD student struggling to write up!

The combination of work by Watson, Crick, Wilkins and Franklin were key to building the double-helix model. See the play now at the Noel Coward theatre! However Matt made the point that the data were not stolen. In June of this year Matthew described Watson's epilogue in "The Double Helix" as "a generous and fair description by Watson of Franklin’s vital contribution and a recognition of his own failures with respect to her".

Matt went on to describe the work of Schrodinger, Shannon, Weiner, and others. Schrodingers code: "What is life" well worth reading according to Matt, describes a hereditary material that must contain a code script (the first use of this term related to genes), that contains the means to put the code into operation. Shannon and Weiner's books on communication and cybernetics. Discussed the infamous RNA tie club, a drinking club for select attendees of UK Genome Science!

After the 1953 paper Genetical Implications of the structure of Deoxyribonucleic Acid , Gamow suggested in a letter 20 "spaces" in the double helix that code for proteins. Gamow was thinking along slightly the wrong lines, but the letter stimulated discussion on the magic number 20. Settled on triplet code with redundancy and non-use of some triplets e.g. palindromes, homopolymers. Watsons central dogma (almost exactly what we know today): a flow of information as a sequence of bases, and the possibility of going from RNA-DNA but never from Protein backwards! Matt pointed out that Watson's more or less invents phylogenomics, and the existence of tRNA!

Lastly Matt discussed the aspect of control by DNA of "the genes are like information tapes that programme the organism" John von Neumann's universal constructor.

The final cracking of the code came from Nirenberg and his experiments with UUU RNA, discounted by the RNA Tie Club as not likely to be important. This experiment was the first step in deciphering the codons of the genetic code and the first demonstration of messenger RNA. Matt described his "very boring" talk in Moscow possibly only understood by a handful of attendees. Showed Cricks copy of the programme with Nirenberg added to the agenda to explain the significance of his discovery. Nirenberg shared the 1968 Nobel Prize in Physiology or Medicine.

One question remains unsolved: How did the genetics code come into existence? Jaques Monod "evolution tinkers, it does not design".

Lessons from Matt's talk: stupid experimetns can be vital, theory is imprtant but you must experiment, and the future can be difficult to predict!

I reviewed the recent biography of Fred Sanger, I posed the question as to whether Sanger sequencing would have happened without Fred, I think the pressure to decode the genome was so great that DNA sequencing was an inevitability. I wonder if Matt would get to a similar conclusion?

Neil Hall closing remarks: Thanks to everyone for coming, speaking, helping out; and especially thanks to Nick for the best burger Neil has ever had!

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