The release of the 38th build of the human reference genome gets a well-deserved rock-star greeting by the scientific community.
The new GRCh38 is already a rock-star{credit}Wikimedia Commons/Flickr:Starman/K.Spencer{/credit}
Fans know it is worth the effort to camp out for tickets to a concert by a beloved rock, pop or country star. GRCh38, the newest build of the human reference genome, is that kind of star. Delayed by a few snags and also held up by the US government shut-down, the sequence has just traveled to GenBank for use by the scientific community.
Not only has Genome Reference Consortium build 38 (GRCh38) eliminated some pesky previous gaps, it will be the first human reference assembly to have sequence information for centromeres. Up until now, centromeres, which are specialized structural components of chromosomes, have been represented in the reference by gaps of 3 million base pairs. The news about centromere sequence will be of interest to cell biologists and genomics researchers alike.
“This will be a major boon to evolutionary studies of human populations and to the many groups doing mechanistic work on human centromeres and kinetochores,” says Stanford University researcher Aaron Straight, whose work focuses on cell division and chromosome segregation. “Finally, now we can stop saying ‘mind the gap’.”
The reference genome finishers are the members of the Genome Reference Consortium (GRC) at the European Bioinformatics Institute, the US National Center for Biotechnology Information, The Wellcome Trust Sanger Institute and The Genome Institute at Washington University.
Scientists may not have physically camped like concert-goers in front of the buildings where genome finishers scurry to get the sequence out the door. But the throngs have been virtually present. The GRC, which works on human, mouse and zebrafish reference genomes, is “having to field a lot of questions from folks who want to know the minute they can have the assembly,” says Deanna Church, a genomicist formerly at the US National Center for Biotechnology Information and who has, since this interview, moved to Personalis, a genetic testing and analysis company.
The din has faded from the 2001 celebration marking the end of the Human Genome Project. But the sequence was not complete nor is it complete now. As colleagues at Nature Methods have pointed out here and here, the sequence originally had around 150,000 gaps.
The most recent reference genome, Genome Reference Consortium build 37 (GRCh37), has 357 gaps. And is missing sequence around the centromeres. No longer.
Come here, centromere
The structure and repetitive nature of centromeric regions has made them largely inaccessible to methods used to create the reference assembly, says Church. The concept and the methods to produce the centromere sequences for this reference build were developed by a research team at University of California at Santa Cruz (UCSC). They constructed sequences using the Sanger technique and the data helped the team behind GRCh38 to fill in these important gaps.
The centromere community will be happy to no longer say this.{credit}Wikimedia Commons/Clicsouris{/credit}
In a paper, the UCSC team, led by Karen Miga and Jim Kent, a member of GRC’s scientific advisory board, noted that centromeric regions are replete with near-identical tandem repeats—satellite DNA. Difficult assembly of these regions have led them frequently to be excluded from genomic studies. In the new reference genome, the scientists used reads generated during the Venter genome assembly and created models for the centromeres, says Church.
“These models don’t exactly represent the centromere sequences in the Venter assembly, but they are a good approximation of the ‘average’ centromere in this genome,” she says. And these sequence models are not exact representations of any one centromere, either. But including these sequences in the reference assembly “will likely improve genome analysis using current methods, and allow for some further study of population variation in centromere sequences,” says Church.