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I'm working on a project in malaria genetics this summer, and I was shocked to find out that the entire analysis toolkit is entirely based on math and statistics (and some non-trivial stuff too, e.g. hidden Markov models to predict CNV). Genotype likelihoods throw an extra wrench into the process, since even basic stuff like predicting allele frequencies requires a maximum likelihood estimator instead of simple counting. This whole area was quite eye-opening, and I'm still amazed that reading billions of base-pairs in DNA sequencing reliably works.

Also gotta shout out to these incredible molecular animations by WEHI: https://www.youtube.com/watch?v=7Hk9jct2ozY

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All one needs to do is look at the Claude Science thread here last week and note how many comments were surprised that it appeared to be a statistical/analysis tool.
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Just a couple days ago I argued with an HN poster who quipped that biology is stamp collecting. A non-negligible number of "mathy" engineer types (not actual mathematicians, those usually understand the complexity of biology and even gladly contribute to the field) seem to think all biologists are quirky eccentrics dedicating 30 years to a single protein or a species of ants in the Kalahari desert. (Not that these don't exist or aren't worthy of respect, but they don't score high in the sophomoric 'hardness scale' of fields that these mathy types still subscribe to)
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The rub is of course it is actually far harder to work on your rare species of ant than to do something more "noble" like human genetics. You may have to build the reference genome yourself working on your ant before you can begin with other work. Collecting your ant samples and processing them eventually into raw sequence reads. You may have to optimize this library preparation process yourself if you are really in uncharted territory here.

Meanwhile human geneticist doesn't even need to collect any data. Reference genomes are always being improved. People dump their data into public repositories (at least public for other credentialed researchers). A couple emails and filling of approval forms and you too can have access to 10,000 patient samples of some human disease already sequenced for you to an acceptable depth. Of course you will still need to pay for downstream compute needs in money and your time crafting the analysis to suit your reasoning, but still, half the battle is already won when you work on these well trodden paths. So much necessary groundwork has been performed by others for you already.

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Biology is often an intensely statistics-heavy field. A remarkably large part of statistics was developed to study issues in biology, particularly dealing with evolution and ecology.
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And the foundations of those statistical approaches are built on heuristics and shortcuts.

For example, sequencing instruments include base quality strings in the output. Base qualities are estimates how likely the instrument got each sequenced base right. But most people don't want to store that much noise, especially when the actual data is highly compressible. So the base qualities get quantized using more or less principled methods that seem to work well empirically.

Read aligners make similar estimates of how likely they got the correct alignment for each read. Those estimates are typically based on simplistic models and a number of assumptions. There are two main components in the estimate. One is based on comparing the primary alignment the aligner chose to the secondary alignments it also found. Another is an estimate that the aligner didn't find the correct alignment, because that part of the sequenced genome is too different from the reference. The latter is obviously handwavy. And the aligner cheats in the former. Because people don't want to wait 10x or 100x longer for better results, the aligner gives up early and estimates how good secondary alignments it might have found if it had actually done the work.

And then there is variant calling. At some point, the state-of-the-art callers were statistical. But then people got better results with neural networks. Or at least the results were empirically better.

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To expand this a bit, most sequencing methods are exact, and have a low error rate (except nanopores).

But they produce short reads, and because DNA is full of repetitive fragments, it's not always clear where the read came from.

We also have two copies of genes, which also further complicates matters.

The first startup where I worked, developed synthetic long reads on top of Illumina's hardware. We could stitch together 50kbp reads, which really helped with de-novo sequencing.

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