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11.09.19 'Herculean' project catalogues over 4,500 mutational signatures of the Yeast Knockout Collection

last modified Sep 11, 2019 07:35 PM
Jackson lab researchers create unique genomics resource from > 4,500 yeast strains to identify genes protecting cells from DNA alterations that are implicated in human disease and ageing
11.09.19 'Herculean' project catalogues over 4,500 mutational signatures of the Yeast Knockout Collection

Fig. 1 (extract): Variation in repetitive DNA copy number across the yeast strains

Genome architecture and stability in the Saccharomyces cerevisiae knockout collection

Puddu F et al. (2019) Nature  DOI: 10.1038/s41586-019-1549-9

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The research, published in Nature, is the first to systematically apply next-generation DNA sequencing to the full range of strains in the Saccharomyces cerevisiae Gene Knockout Collection. The resulting comprehensive resource identifies new genes responsible for maintaining the stability of DNA in cells, and whose absence or mutation leads to a variety of effects, from changes in short sequence repeats to the loss of whole chromosomes. These 'mutational signatures', that in humans are connected to disease and ageing, can now also be studied in human cells, which contain genes with similar functions.

All life forms must maintain their genome in a stable form, to preserve the fully functioning set of DNA instructions for maintaining and reproducing the organism. Some genes are known to have roles in regulating genome stability and maintenance, for example preventing or correcting errors in DNA. Changes in numbers of repetitive DNA sequences, or loss of parts of genes or even whole chromosomes, can lead to cell dysfunction or death.

Researchers at the Gurdon Institute, University of Cambridge, have taken advantage of the Saccharomyces cerevisiae yeast Knockout Collection to study the impact of each single gene in maintaining genome stability. Each individual strain in the collection has had one gene that is not essential for life 'knocked out' (i.e. removed).  Researchers around the world have used these strains in many different experiments, but until now each strain's full DNA sequence was not available. This resource now illustrates how a missing gene might produce deleterious changes in other parts of the genome.

The team in Steve Jackson's lab at the Gurdon Institute, led by postdoc Fabio Puddu, ran the Herculean project around the clock for five years, preparing duplicate samples of every yeast strain for sequencing on the world-leading next-generation DNA sequencing platforms at the Wellcome Sanger Institute.

By sequencing the whole genome in each of the different 4,500 knockout strains, the team was able to find, measure and catalogue changes in the genome caused by each single knockout. These included changes in repetitive genomic features called retrotransposons and telomeres in nuclear DNA, as well as changes in the number of copies of mitochondrial DNA.

"We knew about some of these ‘genome instability’ genes already, but this systematic project has uncovered many new ones that affect genome stability," said Professor Steve Jackson. "It has also identified new types of mutational signatures, such as variations in the number of repetitive elements, loss or gain of chromosomes in whole or part, and alterations in mitochondrial DNA copy-number." 

Dr Fabio Puddu, the paper's lead author, added: "This study is one of its kind. It will help us and others around the world who use the Yeast Knockout Collection for functional genomic studies, and it is already paving the way for follow-on investigations, in both yeast and human cells."

The extensive dataset has been made freely available on the project website at URL: http://sgv.gurdon.cam.ac.uk

The work was funded largely by the Wellcome Trust and by core funding to the Gurdon Institute from the Wellcome Trust and Cancer Research UK.

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Text reproduced from media release issued by the Gurdon Institute

 

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Read more about research in the Jackson lab.

Hear Steve Jackson describe his research in this short video.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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