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# science: worthwhile

See you at Shonan Meeting 167 — Formalizing Biomedical Visualization

# What if we were to print what we sequence?

Expressing the amount of sequence in the human genome in terms of the number of printed pages has been done before. At the Broad Institute, all of the human reference genome is printed in bound volumes.

At our sequencing facility, we sequence about 1 terabases per day. This is equivalent to 167 diploid human genomes (167 × 6 gigabases). The sequencing is done using a pool of 13 Illumina HiSeq 2500 sequencers, of which about 50% are sequencing at any given time.

A single letter-size page (8.5" × 11") of 6pt Courier using 0.25 inch margins accomodates 18,126 bases on 114 lines. Shown here is a portion of sequence from human chromosome 1. (PDF)

This sequencing is extremely fast.

To understand just how fast this is, consider printing this amount of sequence using a modern office laser printer. Let's pick the HP P3015n which costs about $400—a cheap and fast network printer. It can print at about 40 pages per minute. If we print the sequence at 6pt Courier using 0.25" margins, each 8.5" × 11" page will accomodate 18,126 bases. I chose this font size because it's reasonably legible. To print 1 terabases we need $10^12 / 18126 = 55.2$ million pages. If we print continuously at 40 pages per minute, we need $10^12 / (18126*40*1440) = 957.8$ days. If we had 958 printers working around the clock, we could print everything we sequence and not fall behind. This does not account for time required to replenish toner or paper. ## what's cheaper, sequencing or printing? It costs us about$12,000 to sequence a terabase in reagents. If we do it on a cost-recovery basis, it is about twice that, to include labor and storage. Let's say $25,000 per terabase. Coincidentally, this is about$150 per 1× coverage of a diploid human genome. The cost of sequencing a single genome would be significantly higher because of overhead. To overcome gaps in coverage and to be sensitive to alleles in heterogenous samples, sequencing should be done to 30× or more. For example, we sequence cancer genomes at over 100×. For theory and review see Aspects of coverage in medical DNA sequencing by Wendl et al. and Sequencing depth and coverage: key considerations in genomic analyses by Sims et al.. (Thanks to Nicolas Robine for pointing out that redundant coverage should be mentioned here).

Printing is 44× more expensive than sequencing, per base: 25 n$vs 1.1 μ$.

I should mention that the cost of analyzing the sequenced genome should be considered—this step is always the much more expensive one. In The $1,000 genome, the$100,000 analysis? Mardis asks "If our efforts to improve the human reference sequence quality, variation, and annotation are successful, how do we avoid the pitfall of having cheap human genome resequencing but complex and expensive manual analysis to make clinical sense out of the data?"

The cost of a single printed page (toner, power, etc) is about $0.02–0.05, depending on the printer. Let's be generous and say it's$0.02. To print 55.2 million pages would cost us $1.1M. This is about 44 times as expensive as sequencing. To print what we sequence we would require 958 office laser printers (shown here as HP3015n) at a cost of$1,100,000 per day. (PDF)

Think about this. It's 44× more expensive to merely print a letter on a page than it is to determine it from the DNA of a cell. In other words, to go from the physical molecule to a bit state on a disk is much cheaper than from a bit state on a disk to a representation of the letter on a page.

Per base, our sequencing costs $$25000/10^12 =$25*10^-9$, or 25 nanodollars. At $0.02 and 18,126 bp per page, printing costs $0.02/18126 =$1.1*10^-6$ or 1.1 microdollars.

If at this point you're thinking that printing isn't practical, the fact that the pages would weigh 248,000 kg and stack to 5.5 km should cinch the argument.

The capital cost of sequencing is, of course, much higher. The printers themselves would cost about $400,000 to purchase. The 6 sequencers, on the other hand, cost about$3,600,000.

We sequence at a rate close to the average internet bandwidth available to the public.

At 3.86 Mb/s, we could download a terabase of compressed sequence in a day, assuming the sequence can be compressed by a factor of 3. This level of compression is reasonable—the current human assembly is 938 Mb zipped).

In other words, you would have to be downloading essentially continuously to keep up with our sequencing.

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# Using Circos in Galaxy Australia Workshop

Thu 20-02-2020

A workshop in using the Circos Galaxy wrapper by Rasche and Hiltemann. Event organized by Australian Biocommons.

Using Circos in Galaxy Australia workshop. (zoom)

Galaxy wrapper training materials, Saskia Hiltemann, Helena Rasche, 2020 Visualisation with Circos (Galaxy Training Materials).

# Essence of Data Visualization in Bioinformatics Webinar

Thu 20-02-2020

My webinar on fundamental concepts in data visualization and visual communication of scientific data and concepts. Event organized by Australian Biocommons.

Essence of Data Visualization in Bioinformatics webinar. (zoom)

# Markov models — training and evaluation of hidden Markov models

Thu 20-02-2020

With one eye you are looking at the outside world, while with the other you are looking within yourself.
—Amedeo Modigliani

Following up with our Markov Chain column and Hidden Markov model column, this month we look at how Markov models are trained using the example of biased coin.

We introduce the concepts of forward and backward probabilities and explicitly show how they are calculated in the training process using the Baum-Welch algorithm. We also discuss the value of ensemble models and the use of pseudocounts for cases where rare observations are expected but not necessarily seen.

Nature Methods Points of Significance column: Markov models — training and evaluation of hidden Markov models. (read)

Grewal, J., Krzywinski, M. & Altman, N. (2019) Points of significance: Markov models — training and evaluation of hidden Markov models. Nature Methods 17:121–122.

Altman, N. & Krzywinski, M. (2019) Points of significance: Hidden Markov models. Nature Methods 16:795–796.

Altman, N. & Krzywinski, M. (2019) Points of significance: Markov Chains. Nature Methods 16:663–664.

# Genome Sciences Center 20th Anniversary Clothing, Music, Drinks and Art

Tue 28-01-2020

Science. Timeliness. Respect.

Read about the design of the clothing, music, drinks and art for the Genome Sciences Center 20th Anniversary Celebration, held on 15 November 2019.

Luke and Mayia wearing limited edition volunteer t-shirts. The pattern reproduces the human genome with chromosomes as spirals. (zoom)

As part of the celebration and with the help of our engineering team, we framed 48 flow cells from the lab.

Precisely engineered frame mounts of flow cells used to sequence genomes in our laboratory. (zoom)

Each flow cell was accompanied by an interpretive plaque explaining the technology behind the flow cell and the sample information and sequence content.

The plaque at the back of one of the framed Illumina flow cell. This one has sequence from a patient's lymph node diagnosed with Burkitt's lymphoma. (zoom)

# Scientific data visualization: Aesthetic for diagrammatic clarity

Mon 13-01-2020

The scientific process works because all its output is empirically constrained.

My chapter from The Aesthetics of Scientific Data Representation, More than Pretty Pictures, in which I discuss the principles of data visualization and connect them to the concept of "quality" introduced by Robert Pirsig in Zen and the Art of Motorcycle Maintenance.