Final Report Summary - ROOTS (Role of telomeres and stem cells in ageing)
Rapid developments in sequencing technology have opened up unprecedented opportunities to address questions not only in genetics but also in basic biology including questions about the molecular mechanisms involved in development and ageing. The ERC funded ROOTS proposal was aimed to use genomics approaches to answer fundamental questions about stem cells, human genomes and aging. During the project the emphasis has been mainly focused on application of our single cell DNA template strand sequencing technology called Strand-seq.
The reason for this narrowing of focus has been the realization, enabled by data generated with ERC funds, that Strand-seq is an extraordinarily powerful tool to address questions about structural variations in human genomes (1) and the separation of parental genome information (2) from sequence data (also known as “haplotyping”). Both advances are key to a better understanding of human genetics in relation to diseases and disease predisposition and as such will provide the basis for many future “precision medicine” approaches. The advances enabled by ERC funding re studies of human genomes are expected to become routine for a variety of medical problems in the next decade. Below I will try to explain the fundamental nature of the advances enabled by ERC support for the ROOTS project.
The human genome is diploid. That is, for each autosomal chromosome, we inherit one copy from our mother and one copy from our father. This diploid nature of the genome is neglected in many analyses done today, where a genome is perceived as a set of unphased variants with respect to a reference genome. Many important biological phenomena such as compound heterozygosity and epistatic effects between enhancers and target genes, however, can only be studied when haplotype-resolved genomes are available. This lack of haplotype-level analyses can be explained by a lack of methods to produce dense and accurate chromosome-length haplotypes at reasonable cost. We found that sparse chromosome-length haplotypes obtained by Strand-seq can be used to complete haplotype information when combined with long-read or linked-read sequencing data. Phasing is a very useful first step to better understand larger genomic rearrangements such as polymorphic inversions. We have established using Strand-seq that polymorphic inversions account for up to 2% of human DNA (1). Haplotyping and the characterization of polymorphic inversions using Strand-seq are expected to provide the basis for better maps of human genomes. Better maps of human genomes will provide the basis for future “precision” medicine approaches.
On a personal note, in 2011 I was recruited as Founding Scientific Director of the European Research Institute for the Biology of Ageing (ERIBA) at the University Medical Center in Groningen, the Netherlands. ERIBA officially opened its doors in November 2013. After having served a 5 year term I returned to Vancouver, Canada. This decision was triggered by family circumstances in the first place. Strand-seq is currently operational in my laboratory at ERIBA and will continue to be so for the foreseeable future with funding to PI’s that reside in the Netherlands and Europe and with scientific input from myself.
In summary, ERC funding has helped to create a Strand-seq Center of Excellence at ERIBA in Groningen which will serve the European scientific community hopefully in many years to come.
1. Sanders, A.D. Hills, M., Porubsky, D., Guryev, V., Falconer, E. and Lansdorp, P.M. (2016) Characterizing polymorphic inversions in human genomes by single-cell sequencing. Genome Res, 26, 1575-1587.
2. Porubsky, D., Sanders, A.D. van Wietmarschen, N., Falconer, E., Hills, M., Spierings, D.C. Bevova, M.R. Guryev, V. and Lansdorp, P.M. (2016) Direct chromosome-length haplotyping by single-cell sequencing. Genome Res, 26, 1565-1574.
The reason for this narrowing of focus has been the realization, enabled by data generated with ERC funds, that Strand-seq is an extraordinarily powerful tool to address questions about structural variations in human genomes (1) and the separation of parental genome information (2) from sequence data (also known as “haplotyping”). Both advances are key to a better understanding of human genetics in relation to diseases and disease predisposition and as such will provide the basis for many future “precision medicine” approaches. The advances enabled by ERC funding re studies of human genomes are expected to become routine for a variety of medical problems in the next decade. Below I will try to explain the fundamental nature of the advances enabled by ERC support for the ROOTS project.
The human genome is diploid. That is, for each autosomal chromosome, we inherit one copy from our mother and one copy from our father. This diploid nature of the genome is neglected in many analyses done today, where a genome is perceived as a set of unphased variants with respect to a reference genome. Many important biological phenomena such as compound heterozygosity and epistatic effects between enhancers and target genes, however, can only be studied when haplotype-resolved genomes are available. This lack of haplotype-level analyses can be explained by a lack of methods to produce dense and accurate chromosome-length haplotypes at reasonable cost. We found that sparse chromosome-length haplotypes obtained by Strand-seq can be used to complete haplotype information when combined with long-read or linked-read sequencing data. Phasing is a very useful first step to better understand larger genomic rearrangements such as polymorphic inversions. We have established using Strand-seq that polymorphic inversions account for up to 2% of human DNA (1). Haplotyping and the characterization of polymorphic inversions using Strand-seq are expected to provide the basis for better maps of human genomes. Better maps of human genomes will provide the basis for future “precision” medicine approaches.
On a personal note, in 2011 I was recruited as Founding Scientific Director of the European Research Institute for the Biology of Ageing (ERIBA) at the University Medical Center in Groningen, the Netherlands. ERIBA officially opened its doors in November 2013. After having served a 5 year term I returned to Vancouver, Canada. This decision was triggered by family circumstances in the first place. Strand-seq is currently operational in my laboratory at ERIBA and will continue to be so for the foreseeable future with funding to PI’s that reside in the Netherlands and Europe and with scientific input from myself.
In summary, ERC funding has helped to create a Strand-seq Center of Excellence at ERIBA in Groningen which will serve the European scientific community hopefully in many years to come.
1. Sanders, A.D. Hills, M., Porubsky, D., Guryev, V., Falconer, E. and Lansdorp, P.M. (2016) Characterizing polymorphic inversions in human genomes by single-cell sequencing. Genome Res, 26, 1575-1587.
2. Porubsky, D., Sanders, A.D. van Wietmarschen, N., Falconer, E., Hills, M., Spierings, D.C. Bevova, M.R. Guryev, V. and Lansdorp, P.M. (2016) Direct chromosome-length haplotyping by single-cell sequencing. Genome Res, 26, 1565-1574.