Mind the gap! That’s good advice, but it can be hard to follow, particularly if the gap is the genome, in which case, it’s practically invisible. Fortunately, some of the most dangerous genomic gaps, or unmapped genomic regions, can be gauged if the right technologies are used. According to scientists based at the University of Colorado and KU Leuven, combining two genome mapping technologies can illuminate sequence elements called segmental duplications, or low copy repeats (LCRs).

Seeing LCRs clearly is important because they are associated with genomic instability. For example, they can lead to 22q11 deletion syndrome, that is, the loss of DNA on chromosome 22 at a location designated q11.2. The syndrome can cause many health problems, including intellectual disability, dysmorphic features, heart defects, seizures, Autism spectrum disorders, and schizophrenia.

LCRs, which are large blocks of duplicated pseudogenes or repetitive DNA, are difficult to see with conventional sequencing techniques. To get around this difficulty, University of Colorado scientists led by Tamin Shaikh, PhD, and KU Leuven scientists led by Joris Vermeesch, PhD, decided to use fiber FISH (fluorescence in situ hybridization on stretched DNA) in combination with a next-generation mapping technology, specifically, a BioNano Genomics platform for visualizing long DNA molecules in nanochannel arrays.

This approach allowed the scientists to see long DNA molecules and discover an unprecedented and extreme level of variability between individuals and populations. Details of the scientists’ work appeared September 3 in the journal Genome Research, in an article titled, “The 22q11 low copy repeats are characterized by unprecedented size and structural variability.”

“Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines,” the article’s authors wrote. “Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb.”

“The incidence of various LCR22 alleles varied within different populations,” the scientists indicated. They emphasized that some people carried far less and some far more DNA in this part of the genome.

Children with the 22q11 deletion syndrome and their parents were also tested to determine if their 22q11 LCRs were different. “The analysis of LCR22s in 22q11DS patients and their parents,” the scientists wrote, “enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion.”

Such analyses may facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.

“You are mapping these chromosomal fragments back to the genome to see what is different,” Shaikh explained. “We looked at over 150 apparently healthy people. We found the region in question was drastically different in each person.

“Now we can start asking questions like, ‘Is someone with more or less DNA more disposed to have a child with disease?’ If so, then it might be possible to genetically test parents before they have children.”

Shaikh noted that 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,” he said. “That is pretty incredible.”

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