If you’ve ever relied on the human reference genome, don’t miss this podcast with assembly pioneer Deanna Church. Mendelspod’s Theral Timpson interviews the genome informatics expert who made her name as an integral part of the reference project at the National Center for Biotechnology Information. Today, she’s Senior Director of Applications at 10x Genomics, where she’s working on everything from haplotyping to single-cell genomics.
In the podcast, Church offers insight into various efforts to improve the quality of the human reference genome, as well as a look at robust new work to characterize structural variation. She talks about the importance of phasing for structural variant detection, which explains why her NCBI team was so adamant about moving toward a haplotype-aware genome assembly instead of using “averaged-out alleles,” she says. Short reads can be especially problematic for this use because they can’t always clearly distinguish between two alleles of a heterozygous variant. Using problematic alignments could lead to a confounded analysis, she adds, “because you’re mixing the reads from those two genotypes.”
Church also calls for better integration of variant findings. “As a community we’ve had a very individual variant-centric view of genome analysis,” she tells Timpson, contending that viewing variants and their interactions with each other more holistically would provide much-needed information for genome interpretation efforts. She notes that combining technologies, an approach showcased in a recent preprint she co-authored with the Human Genome Structural Variation Consortium, is essential for a holistic approach. To that end, linked-read technology like 10x’s is a great complement to other methods. Church says linked reads enable de novo assembly and haplotype reconstruction at scale; customers have already published impressive demonstrations of this type of work.
Sample prep came up in the discussion as well. “You definitely want to try to optimize for longer molecules,” Church says about 10x technology, noting that recommended protocols are in place and under development for a range of sample types. (We’re pleased to be included in 10x protocol recommendations.)
Church also spoke about single-cell genomics, an area she is eager to explore. “Single cell is obviously one of the most exciting ways to think about doing science these days because it just allows us to get this level of resolution that’s not accessible with bulk,” she says, suggesting that this approach will be especially useful for understanding developmental biology. In some ways, she adds, the state of single-cell genomics reminds her of the early days of the Human Genome Project: there’s widely recognized potential, but the path forward isn’t completely clear yet.
It’s a great discussion, and we hope you have time to listen!