Thread by @CCRobertsARK

Long Reads and Dark Genes (🧵)

Despite common misconception, we’ve never sequenced 100% of the human #genome.

Since the completion of the Human Genome Project in '03, scientists have struggled to fill in numerous small gaps scattered throughout our 23 chromosome pairs. (1/7)

These gaps, sometimes called dark genes, constitute holes in our understanding of #genetics, evolution, and human disease. Dark genes contain long, highly repetitive stretches of DNA that cause short-read sequencers to make errors.

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genomebiology.biomedcentral.com/articles/10.11…

Many of these errors begin during sample preparation, making it difficult or impossible to overcome with software tools. Last week, researchers published a complete copy of chromosome 8—the first non-sex chromosome to be fully sequenced.

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biorxiv.org/content/10.110…

The team filled in the remaining 2.3% of chromosome 8 previously considered dark. They succeeded by using a combination of long-read systems from Oxford Nanopore Technologies (ONT) and PacBio (PACB). Unlike short-reads, long-reads can sequence ‘hard-to-read’ segments.

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Among other discoveries, the researchers found a 644,000 bp region in a gene cluster (DEFB1) potentially implicated in cystic fibrosis (CF). DEFB1 encodes proteins that allow our immune systems to fight off bacterial infections in our airways.

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genecards.org/cgi-bin/carddi…

Conceptually, mutations in DEFB1 could weaken the immune system. Though CF is diagnosed by mutations within the CFTR gene, previous studies have suggested the severity of CF could involve other genetic factors, such as mutations in DEFB1.

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nature.com/articles/63644…

Now that a complete copy of DEFB1 is published, diagnosticians can leverage long-read technology to understand how mutations in this gene affect CF patients. We think that diagnostic providers who don't invest to implement the latest tools will lose product leadership.

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