Genomics euphoria: ramblings of a scientist on genetics, genomics and the meaning of life

Monthly Archives: September 2013

In situ genotyping

We have glimpsed the future of genetics and it is colorful

Two papers showed up in the last issue of Nature methods that caught my attention:  I mean Levsesque et al of U Penn and Ke et al. from Stockholm University. I’m generally biased towards methods papers and I find them WAY more interesting than your run-of-the-mill biology papers. But why these two papers? I have a conviction… I say conviction because until now there was very little to back it up: the future of biology rests not just in our understanding the populations of cells and observing the “average” phenotypes/phenotypes, but rather a single-cell approach is required to understand all the complex dynamics upon which biological systems thrive. FIrst came single-cell sequencing… then came single-cell barcoded RNA-seq… and now single-cell in situ genotyping/sequencing is here.

There is a magic to watching cells shine under a microscope… there is a feeling of vindication… of assurance. But it is not just that. A cell is already an “average”; an average of paternal and maternal genetic information. And FISH-based methods enable us to distinguish between them. More importantly, in addition to quantity (which to be fair is not its strongest suit), we get a feel for localization in different compartments.

Granted I’ve never done a FISH experiment. So I really don’t know how much of this is real and how much of it cherry-picking. But I’m sure if we can get there, it will be illuminating. And I don’t mean that we should drop the population for single-cells… I think we’ll be in for a surprise. I think we’ll understand, at last, how stupid a single cell is. We’ll know that individual cells make a lot of mistakes and it is the averaging effect of a population that results in a coherent behavior. In other words, I’m not interested in studying single-cells per se, but rather I want to know about them so that I can have smarter models of a population. The same way a thought forms in our brains despite many erratic firings of individual neurons, I want to know how stable phenotypes emerge in spite of, not because of, single-cell variations. Only then we’ll know which pathways are consistently crucial for a single cell and which ones are meaningful only in the context of a population.