Using advanced imaging techniques, researchers have mapped a region of the human genome that was once uncharted. This could prompt new genetic testing, as that region gives rise to a variety of diseases. The team, led by researchers from the University of Colorado Anschutz Medical Campus in conjunction with the University of California, San Francisco and Katholieke Universiteit Leuven in Belgium, used fiber-FISH (fluorescence in situ hybridization) mapping and Bionano optical mapping technologies to see long DNA molecules. They were able to discover “an unprecedented and extreme level of variability” between individuals and populations. Such differences are potentially hundreds of thousands to over two million base pairs of DNA. “The large differences between people cannot be assessed without the mapping technologies deployed in this study,” said Dr. Pui-Yan Kwok, a researcher and Henry Bachrach Distinguished Professor at UCSF. “Our approach brings clarity to the organization of the highly complex region studied.” The researchers focused specifically on 22q11, a region on chromosome 22, and discovered numerous gaps in its sequence due to unmappable genetic sequences called low copy repeats (LCRs), which provide a significant source of genetic instability and can break chromosomes. This leads to a loss or gain of large pieces of DNA, which can cause serious diseases. “You are mapping these chromosomal fragments back to the genome to see what is different,” said researcher Tamim Shaikh, a professor of pediatrics in genetics and metabolism at the University of Colorado School of Medicine. “We looked at over 150 apparently healthy people. We found the region in question was drastically different in each person.” He noted that some people carried far less and some far more DNA in this part of the genome. Children who have the 22q11 deletion syndrome and their parents were also tested to determine if their 22q11 LCRs were different. “Now we can start asking questions like, ‘Is someone with more or less DNA more disposed to have a child with disease?’” Shaikh said. “If so, then it might be possible to genetically test parents before they have children.” According to the researchers, the loss of DNA in 22q11 leads to the 22q11 deletion syndrome, which can cause intellectual disability as well as dysmorphic features, heart defects, seizures, autism spectrum disorders, and schizophrenia. The study’s findings defy a common view: that the human genome was fully mapped in 2001 with the completion of the Human Genome Project. “We have realized over time that this is not entirely true, as there are numerous gaps that remain in the reference human genome sequence,” Shaikh said. “These gaps are present in regions that are unmappable and often ‘invisible’ to past and most current sequencing technologies.” The researchers say this region of the genome is constantly evolving. “If you look from one generation to the next, you may see changes within the same family,” Shaikh said. “That is pretty incredible.” The study was published in the journal Genome Research (https://doi.org/10.1371/journal.pone.0075674).