reference genome

We've Become Too Single Variant Centric, Says Deanna Church on Genome Analysis

From 1999 to 2013, Deanna Church was a staff scientist at the NCBI where, for a time, she headed the Genome Reference Consortium. This was the effort to continually update, improve and maintain the reference genome. Then Deanna went into private industry, first to Personalis--a genome interpretation company, and now she’s Director of Applications at 10X Genomics--the tools company offering linked read sequencing technology. Deanna's work in the public and private genomics domains has given her a comprehensive and even profound knowledge of the human genome and an authoritative ease in communicating about it.

When we asked about the recent paper out by the 1000 Genomes Project—which includes her name as author—that brings to light hundreds of heretofore unknown structural variants, she says this:

“What I think would be really great is to see the community move toward the integration of structural variant calling and short variant calling. These still tend to be very separate. This paper, of course, only dealt with structural variant calling because it's a very challenging problem. Many times the [different] variant calls end up in separate files. What you’d really like to do is have a wholistic view. Analyzing the whole genome and thinking about how all the variants go together will be an important step for the community.”

Many of the scientists we talk to often begin at a tools company and then move on to an institution where they can work with an array of tools. Deanna has gone the other direction. But she says that working at 10X has “expanded her inner scientist.” There she has access to a lab which wasn't the case at the NCBI and is challenged by an array of hard scientific problems brought by customers of their linked read technology.

So what is new in the world of linked reads? What are Deanna’s thoughts on the incredible uptick in single cell sequencing applications? And in an age when the NIH’s budget has been threatened, how does she see the roles of private and public genomics institutions playing out?

It’s Deanna Church for the first time on Mendelspod.

Reference Genome Making Major Strides in Ethnic Diversity, Says Valerie Schneider, NCBI

A couple months back, we reported on a study showing that genetic tests for an inherited heart disorder were more likely to come back with false positive results for black Americans than for whites. The study provoked many in our industry to urge scientists to incorporate more ethnic diversity in their studies. So far, biology has been too Eurocentric—the databases are implicitly racist, they argue.

Perhaps no dataset for human genomics is referenced more than the human reference genome, or the GRCh38. This is the "Rosetta Stone” of genomics used by scientists and clinicians everywhere who are assembling and studying genomes. Valerie Schneider is a scientist at the NCBI who works everyday on the GRCh38. She says major strides--enabled in part by better sequencing technologies--have been made lately to add diversity to the GRCh38 and to create other reference genomes for various populations around the globe.

The populations represented with these new projects include a Han genome, a Puerto Rican, a Yoruban, a Columbian, a Gambian, a Luhya, a Vietnamese, and one or two more Europeans.

“The sequence from these genomes is planned for correcting errors and adding new "alt loci" to the reference genome. But these new assemblies are also intended to stand on their own as complements to the reference,” says Valerie.

Valerie reminds us that it’s still early days in genomics. There’s so much diversity in the human population that her team is not sure whether having a single reference for each of these ethnic groups will be sufficient.

With more reference genomes comes the challenge of how best to compare and visualize them. There is a major need for tools that can show large nests of sequence as opposed to a linear reference, she says in today’s interview.

What is Valerie's take on the term “reference quality genomes”, and how will a better reference genome improve precision medicine?

BioNano Genomics Stakes Out Sequencing Territory as They Discover Lots of De Novo Variants in Reference Genome Projects

If you attended or followed the recent AGBT conference about all things sequencing, you probably saw a few BioNano Genomics t-shirts with the slogan, “Back to the Map.” They’re referring of course, to a genome map. Just like Google Maps, a genome map consists of landmarks that tell scientists where on the genome they are. But unlike Google Maps and more like the maps North America that were made by European explorers in the 17th century, the map of the human genome is quite incomplete, the map of a frontier.

Erik Holmlin is the CEO of BioNano Genomics which offers unique genome mapping technology. In today’s interview, Erik points out that content is not the only king, context is pretty important as well.

“You can go back and look at some of the early discussions that were happening around the beginning of the Human Genome Project. And in fact a lot of the leading scientists of the time, Maynard Olson, Bob Moyzis, and others, emphasized that as we’re doing this sequencing it’s going to be very important that we put the sequence in context of the physical organization of the genome. Otherwise we’re never going to understand it,” Holmlin says.

After the market has become dominated by “short read” sequencing with the race to the $1,000 genome—a drive many say has been steered by the NHGRI—BioNano is now cutting out some territory for their genome mapping technology. Their flagship projects have no doubt been their work on the reference genomes. Erik says that in a recent trio sequencing project of genomes of Ashkenazi Jewish descent, they were able to find “a lot of de novo variants,” or variants which had not been found with other sequencing technologies.

Though Erik has always had his eye on the clinic—in fact, he came to the tools space from the clinical diagnostics industry because he felt passionately that we needed better tools to develop clinically actionable genomic data—he admits at the end of today’s show that his time at BioNano has pulled him more into basic research.

“In some respects I underestimated the need for more basic research,” he says. “And what really needs to happen is we need to get the translational research efforts to focus on the structural picture much more because that’s going to break through and lead to many clinically significant discoveries.”

Frontiers of Sequencing: Putting Long Reads and Graph Assemblies to Work

OK, so we get it. Long read sequencing technology is cool. But how cool? Is it another great player on the field, or does it change the game altogether? 

The Mike Schatz lab at Cold Spring Harbor is well know for de novo genome assemblies and their work on structural variation in cancer genomes, so we were curious to hear how long reads have impacted their work. In todays show, lab leader, Mike Schatz, and doctorate student, Maria Nattestad tell of two new projects that include the de novo assembly of a very difficult but important flatworm genome and, secondly, making better variant calls for oncogenes such as HER2.

In the case of the flatworm, Mike says that the move to using PacBio’s long reads improved the assembly by more than a 100 times. That means the difference of looking at a super high resolution picture versus a fuzzy, blurry one, he says. With her work on cancer cell lines, Maria is seeing variants that just weren’t there with short reads. Will her work translate to lower false positive rates for HER2 in clinical diagnostics?

What will be the major headline for sequencing and informatics in 2016?

Mike says we’ll see many more reference genomes done, that the term “reference genome” itself is changing as we go from the one standard reference genome to multiple reference genomes representing the broader population. These new reference genomes are pushing bioinformaticians to come up with new ways to visualize and compare the genomes. Maria details her work into using “graph” assemblies as opposed to the linear approach made popular by the Genome Browser. She says that already a new generation of informaticians are rethinking genome visualization using graph assemblies. (Included below is an image representing her work.)

Neither mentioned it, so we ask at the end, what about Oxford Nanopore’s tech?


(The spectral karyotype of the Her2-amplified breast cancer cell line SK-BR-3. The original chromosomes are different colors, so this genome is a complex mixture of various chromosomes. The total number of chromosomes has also jumped from 46 to 80, and there is approximately twice as much DNA as in a normal human genome. Maria Nattestad and Mike Schatz are studying this genome to see how oncogenes like Her2 became amplified while all these changes took place in the big picture of the genome.)

Creating the Foundation of Genomics: Marc Salit, NIST

What is a human genome? Well it’s the three billion letters of our DNA. But how is it measured? How do we know when we have it accurately represented?

These are questions that will have to be answered as precision medicine takes hold; for we must have defined standards that will be the basis for regulatory policy, commerce, and better research. These are also the questions that are foremost on the mind of today’s guest.

Marc Salit is the leader of the Genome Scale Measurement Group at the National Institute of Standards and Technology or NIST. In today’s show, he explains how NIST played a pivotal, foundational role in enabling the ‘Century of Physics.' Now Marc and NIST are looking for the right set of standards to enable the already-upon-us “Century of Biology.”

The human reference genome is an example of a standard that Marc and his team are developing. Currently they are piloting what they call “Genome in a Bottle,” a physical reference standard to which all other human genomes can be measured. How far is the team to having a complete reference genome, and what is an example of the way they are working with the FDA to ensure safe and meaningful genomic tests? Join us as we peer in at the foundation of genomics.

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