High-throughput imaging and quantitative analysis for behavioural genomics in C. elegans

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

Our goal is to understand how genes affect brain function and behaviour. This can be difficult to do directly in humans so we study a much simpler organism, the nematode worm C. elegans. C. elegans is anatomically simple, but because we are related through evolution, it shares thousands of genes with us. That means that studying worm behaviour can teach us about the function of human genes.
The genomics revolution has made available the sequences of hundreds of thousands of genes and figuring out what they do is a major challenge. One approach is to delete a gene and look for behavioural effects. The problem is that deleting most genes does not lead to a change in behaviour that is visible by eye, even to trained experts.
We are teaching computers to interpret worm behaviour and find the subtle differences that have been missed by human observers. Using automated microscopes, we can observe a large number of worms to discover behavioural roles for many more genes, giving us an entry point to studying their function. We will use the same approach to discover candidate psychiatric drugs because chemicals that affect worm behaviour may also modulate brain function in humans.

Technical Summary

The goal of behavioural genomics is to determine how genome variation in natural populations and genetic perturbation in laboratory populations affect how organisms behave. Most research has been limited to mapping genetic perturbations to particular human-defined behaviours. However, recent advances in genome sequencing and editing are not having the impact on the study of behaviour in model organisms that they should because manual observation is insufficient to properly assess behavioural phenotypes. To continue making progress we require organism-scale phenotyping methods that are commensurate with modern genomics technology in terms of their speed and applicability across organisms.
We have used tracking microscopes to collect comprehensive datasets of freely behaving worms covering more than 10,000 individuals from more than 300 mutant strains. By developing new quantitative analysis algorithms we have described precise behavioural phenotypes for all of these strains, including 76 with no previously reported phenotype. We have also shown that worms with related phenotypes can be meaningfully clustered into classes to generate hypotheses for gene function. To achieve truly genome-scale behavioural experiments, we will build multi-worm trackers with megapixel cameras to increase throughput without sacrificing resolution and analysis algorithms to understand the nature of the many-to-many mapping between gene networks and complex behaviours. We will initially focus on the nematode worm C. elegans because of its tractable behavioural repertoire and well-characterised nervous system. As we develop better representations of behaviour that are unbiased, quantitative, and exhaustive, we will extend our analysis to other model organisms.
In addition to advancing our understanding of locomotion and nervous system function, a systems biology of behaviour will advance the study of emerging worm models of human diseases and allow more sophisticated phenotype-based drug screens for compounds that modulate nervous system function—currently a particularly challenging area of drug discovery. The tools we will develop will eventually be applied to other model organisms and even humans. For example, it has recently been shown that gait analysis can be used for early diagnosis of disorders affecting human locomotion such as Parkinson's disease. More sensitive and general methods will push detection earlier and find application in a wider variety of diseases.

Publications


10 25 50
 
Description BBSRC DTP
Amount £69,125 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2014 
End 03/2018
 
Description Imperial College Junior Research Fellowship
Amount £150,000 (GBP)
Organisation Imperial College London (ICL) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 12/2014 
End 12/2017
 
Description Integrated Experimental and Computational Biology Studentship
Amount £69,125 (GBP)
Organisation Imperial College London (ICL) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2014 
End 03/2018
 
Description Starting Grant
Amount € 1,917,847 (EUR)
Funding ID 714853 
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 01/2017 
End 12/2021
 
Description WormWatch Lab (Citizen Science project) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Over 6,800 members of the public have contributed over 200,000 classifications of videos of worm behaviour so far. Citizen scientists provide us with critical data that is difficult to collect any other way and are given the opportunity to discuss the data with project scientists and each other.

Feedback from Worm Watch Lab users has been positive: 'Hi, I'm Furat. I'm 19 years old and from London, UK. I'm hoping to attend university next year. I'll be on here as much as I can to contribute to your research.' ---- 'I'm Matt and a sixteen year old in rural Ontario. Sure beats anything else I have to do, since I love science. I like to give all the Zooniverse projects a whirl. I think this one is growing on me.' ---- 'G'day, I'm Lynda from Perth Western Australia. A 60 year old who is facinated with the idea of crowdsourcing scientific research. Only recently discovered Zooniverse and still not sure which area is my favorite. Worms are winning by a head..or is it a tail???'
Year(s) Of Engagement Activity 2013,2014
URL http://wormwatchlab.org/