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science + genomics

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.

Martin Krzywinski @MKrzywinski
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.

Martin Krzywinski @MKrzywinski
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.

sequencing is as fast as downloading

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.

news + thoughts

Cell Genomics cover

Mon 16-01-2023

Our cover on the 11 January 2023 Cell Genomics issue depicts the process of determining the parent-of-origin using differential methylation of alleles at imprinted regions (iDMRs) is imagined as a circuit.

Designed in collaboration with with Carlos Urzua.

Martin Krzywinski @MKrzywinski
Our Cell Genomics cover depicts parent-of-origin assignment as a circuit (volume 3, issue 1, 11 January 2023). (more)

Akbari, V. et al. Parent-of-origin detection and chromosome-scale haplotyping using long-read DNA methylation sequencing and Strand-seq (2023) Cell Genomics 3(1).

Browse my gallery of cover designs.

Martin Krzywinski @MKrzywinski
A catalogue of my journal and magazine cover designs. (more)

Science Advances cover

Thu 05-01-2023

My cover design on the 6 January 2023 Science Advances issue depicts DNA sequencing read translation in high-dimensional space. The image showss 672 bases of sequencing barcodes generated by three different single-cell RNA sequencing platforms were encoded as oriented triangles on the faces of three 7-dimensional cubes.

More details about the design.

Martin Krzywinski @MKrzywinski
My Science Advances cover that encodes sequence onto hypercubes (volume 9, issue 1, 6 January 2023). (more)

Kijima, Y. et al. A universal sequencing read interpreter (2023) Science Advances 9

Browse my gallery of cover designs.

Martin Krzywinski @MKrzywinski
A catalogue of my journal and magazine cover designs. (more)

Regression modeling of time-to-event data with censoring

Mon 21-11-2022

If you sit on the sofa for your entire life, you’re running a higher risk of getting heart disease and cancer. —Alex Honnold, American rock climber

In a follow-up to our Survival analysis — time-to-event data and censoring article, we look at how regression can be used to account for additional risk factors in survival analysis.

We explore accelerated failure time regression (AFTR) and the Cox Proportional Hazards model (Cox PH).

Martin Krzywinski @MKrzywinski
Nature Methods Points of Significance column: Regression modeling of time-to-event data with censoring. (read)

Dey, T., Lipsitz, S.R., Cooper, Z., Trinh, Q., Krzywinski, M & Altman, N. (2022) Points of significance: Regression modeling of time-to-event data with censoring. Nature Methods 19.

Music video for Max Cooper's Ascent

Tue 25-10-2022

My 5-dimensional animation sets the visual stage for Max Cooper's Ascent from the album Unspoken Words. I have previously collaborated with Max on telling a story about infinity for his Yearning for the Infinite album.

I provide a walkthrough the video, describe the animation system I created to generate the frames, and show you all the keyframes

Martin Krzywinski @MKrzywinski
Frame 4897 from the music video of Max Cooper's Asent.

The video recently premiered on YouTube.

Renders of the full scene are available as NFTs.

Gene Cultures exhibit — art at the MIT Museum

Tue 25-10-2022

I am more than my genome and my genome is more than me.

The MIT Museum reopened at its new location on 2nd October 2022. The new Gene Cultures exhibit featured my visualization of the human genome, which walks through the size and organization of the genome and some of the important structures.

Martin Krzywinski @MKrzywinski
My art at the MIT Museum Gene Cultures exhibit tells shows the scale and structure of the human genome. Pay no attention to the pink chicken.

© 1999–2023 Martin Krzywinski | contact | Canada's Michael Smith Genome Sciences CentreBC Cancer Research CenterBC CancerPHSA