The development of DNA sequencing is progressing at an incredible speed. After geneticists mapped the human genome in 2000, they continued to discover and connect gene aberrations to various diseases.
But they still don’t know very much about DNA mutations behind hereditary afflictions. Even when they suspect a hereditary disease is present in a certain family, they haven’t been able to find any DNA evidence to confirm their suspicions.
‘Regular sequencing techniques cut the DNA into small pieces’, Guryev explains. ‘We then analyse those pieces. But bigger differences can be hard to pinpoint. It’s like trying to read a book that’s been shredded. It’s easy to spot a typo, but it can be very hard to see if a part came from the start of the book or the end.’
Lansdorp and his colleagues at the Human Genome Structural Variation Consortium (HGSVC), which includes Victor Guryev, used eight different techniques to analyse the DNA. Lansdorp developed one of those techniques, the single-cell Strand-seq technique. ‘Lansdorp’s technique can look at the entire chromosome at once’, says Guryev. ‘It also enables us to see the difference between the chromosome that was inherited from the father or the one that came from the mother, which other techniques couldn’t do.’
Parents
Researchers looked at the genomes of three family members: two parents and their child. They discovered that on top of the normal ‘typos’, where one person has a C in a location where their relative has a T, there were also hundreds of thousands of so-called Structural Variants (SVs). This means that either small pieces of DNA have been inserted, or conversely, are missing. Some segments were inverted.
These differences were already visible using existing techniques, but they are much harder to see than the standard letter variations. The research, which was published in Nature Communications this week, shows that there are many more structural differences than had previously been assumed.
‘SVs cause a large number of genetic variations that we currently tend to overlook’, says Guryev. ‘The things we used to see were just the tip of the iceberg.’
The new techniques used in this research will make it possible to inspect how SVs cause disease more closely – which will provide a better understanding of heredity.