Dutch genome deciphered

The family tree of the Dutch people has been deciphered by researchers at 5 Dutch universities under the leadership of Prof. Cisca Wijmenga of the UMCG in Groningen. The early history of the Dutch can be re-written and diseases can be better predicted. The research is described in a Nature Genetics article published yesterday.

The newspaper of the Northern Netherlands has published an interview met Cisca Wijmenga on the ´Genome of the Dutch people´ by A van Wijngaarden, Dagblad van het Noorden, 30 juni 2014, blz 4 (in Dutch, artikel). See also the UMCG press release below.

Whole-genome sequence variation, population structure and demographic history of the Dutch population
The Genome of the Netherlands Consortium
Published online: 29 June 2014| doi:10.1038/ng.3021

`Paul de Bakker, Cisca Wijmenga and colleagues report on The Genome of the Netherlands Project, including whole-genome sequencing of 769 individuals of Dutch ancestry from 250 parent-offspring families and construction of a phased haplotype map. Their intermediate-coverage population sequencing data set provides a complementary resource to other publicly available data sets, including the 1000 Genomes Project.´

Abstract
Whole-genome sequencing enables complete characterization of genetic variation, but geographic clustering of rare alleles demands many diverse populations be studied. Here we describe the Genome of the Netherlands (GoNL) Project, in which we sequenced the whole genomes of 250 Dutch parent-offspring families and constructed a haplotype map of 20.4 million single-nucleotide variants and 1.2 million insertions and deletions. The intermediate coverage (~13×) and trio design enabled extensive characterization of structural variation, including midsize events (30–500 bp) previously poorly catalogued and de novomutations. We demonstrate that the quality of the haplotypes boosts imputation accuracy in independent samples, especially for lower frequency alleles. Population genetic analyses demonstrate fine-scale structure across the country and support multiple ancient migrations, consistent with historical changes in sea level and flooding. The GoNL Project illustrates how single-population whole-genome sequencing can provide detailed characterization of genetic variation and may guide the design of future population studies.  full text in Nature Genetics

The Genome of the Netherlands Consortium includes: Freerk van Dijk, Pieter B T Neerincx,  Patrick Deelen, Joeri van der Velde, Morris A Swertz, and Cisca Wijmenga from the Dept of Genetics, UMCG

The Genome of the Netherlands

" Researchers from 5 Dutch universities have been working together under Prof. Cisca Wijmenga from the UMCG to compile a genetic profile of the Netherlands. ‘This profile will help us to identify connections between genetic variation and disease. The genealogy of the Netherlands will also provide information about historical large-scale migrations’, explains Wijmenga. The researchers’ findings are published in today’s edition of Nature Genetics.

The researchers mapped the DNA sequences of 250 family trios comprising two parents and a child from all around the Netherlands. This is the first time that genes from so many healthy Dutch people have been analysed with such precision.

Significance to genetic research

‘The Genome of the Netherlands project represents a huge step forwards in our research into the specific genes that play a role in chronic illness or diseases affecting the elderly’, says project leader Prof. Cisca Wijmenga from the University Medical Centre Groningen. ‘Thanks to this project, we are now able to focus our research on specific pathogenic genes much more quickly than in the past’. She expects that their work will be particularly significant for the field of clinical genetics. ‘The Genome of the Netherlands provides a catalogue showing which variations in DNA are tolerated and which can lead to a disease. If we are able to combine this information with data derived from gene expression, our predictions will be even better’.

Information about gene expression and other ‘omics’ data was also collected during the Genome of the Netherlands project. Wijmenga: ‘This will enable us to identify real connections between variations in our DNA and their impact on all kinds of molecular systems. The Genome of the Netherlands is a prime example of big data research, in which the huge amount of data collected is helping us to detect and understand unexpected connections.’

Mutations not necessarily pathogenic

In one of the more striking findings from the Genome of the Netherlands work, researchers found that every participant had an average of twenty mutations that they had previously thought would cause a rare disease. ´The variation in our DNA is far greater than we expected. This means that the link between differences in DNA and the development of disease, for example, is much more complex than we originally thought’, explains researcher Prof. Paul de Bakker from the UMC Utrecht. ‘We found numerous mutations that we had always assumed would cause disease. But the people taking part in the Genome of the Netherlands are all in good health, so it seems that these mutations do not necessarily cause disease.’ For example, two of the people examined were found to have a mutation that should have led to a rare metabolic disorder (Alpha-1 antitrypsin deficiency) at an early age;however both subjects were perfectly healthy.

Older fathers

The research also confirmed another observation. Children of older fathers have more mutations in their DNA. This may explain why these children have a higher risk of developing certain diseases.

Migrations and floods

The study provided interesting information about historical migrations in the Netherlands. The traditional view is that people gradually colonized the Netherlands thousands of years ago, starting in the south and moving northwards. This should be reflected in more genetic variation in the south and less in the north. Although the researchers noted this trend, another analysis showed the exact opposite, seeming to show that the Netherlands was colonized from the north downwards. In order to link up these differing genetic results, the researchers produced highly refined models of migration patterns. According to the models, several migrations in various directions took place in the period between 4,000 to 500 years ago. The patterns could be linked to recorded events in history, such as major floods and the mass migrations that followed.

‘It just goes to show how much unique information about our ancestors is hidden in our DNA’, says De Bakker. ‘But the most important aspect of our project is to try to understand which genes play a part in disease.’

Unique collaboration

This unique, large-scale research project was set up by BBMRI-NL, the Dutch organization for biobank collaboration. Programme director Gertjan van Ommen: ‘The Genome of the Netherlands is unique in the Netherlands and a flagship project for BBMRI-NL. Exchanging information for biomedical research is one of the mainstays of BBMRI-NL and the Genome of the Netherlands has made serious progress in this respect. It has not only produced some surprising results, but it is also acting as a facilitator for other innovative research projects, both at home and abroad. It has proved itself to be the perfect long-term investment.’

The study was carried out by researchers from the UMC Groningen, UMC Utrecht, Leiden UMC, VU Amsterdam, AMC Amsterdam, UMC St. Radboud Nijmegen, the Centre for Mathematics and Computer Science in Amsterdam and the Erasmus MC in Rotterdam. Groups from various other countries also worked on the project."