How personal genomics solved a family's tragic health mystery




Similar story here : Hunting my son's killer

.... We live in interesting times.

Does knowing make it easier for these parents? I guess our human tendancy is to blame ourselves for something we imagine we might have done when we don't know.

The costs of these genome analysis just keep dropping so we are rapidly getting to a point where we can help couples make informed choices about risks even before they have kids. Amazing work.

I wonder how good the tools are getting at searching out the mutated chromosomes. Perhaps when the accuracy rates of the exome sequencing drops (and/or full genomic sequencing eventually) and the costs drop to zero (its on the way!) will we really start to see revolutions in medicine.


It just goes to show how little the Human Genome Project and Hap Map have yielded that it's still a huge puzzle to track down a disease caused by a single gene. These projects were supposed to let us solve complex multigene diseases. While it's nice to have the fancy hardware that can do the DNA profile for this poor family, the HGP probably did not contribute much. And this is done using trio data (parents and offspring), so it's not like the HGP and HapMap data at all. In fact those projects were supposed to make trio studies obsolete.


BTW, they concluded that the problem is an autosomal recessive lethal mutation and both parents are carriers. They said it was a 1 in 64 chance of three children in a row getting it (which implies the twins were fraternal), which would be 0.25*0.25*0.25=0.0156. Although that seems like a bit a stretch, it's also the odds of flipping a coin and having it come up heads six times in a row


That simply isn't true.

The HGP was certainly overhyped in its day, but I don't think any serious medical or scientific expert honestly believed that a single, crude composite genome sequence would answer most (or even many) of life's mysteries. What it has undeniably done is offer a valuable framework - a lay of the land against which other genome sequences can be organized and understood and compared. Every new set of genome sequence data is composed of zillions of short 100 to 300 nucleotide 'excerpts' that are meaningless unless scientists have a clear sense of their proper coordinates in the genome. HGP and HapMap also gave starting points for understanding sites and combinations of common variation, but by definition rare diseases are RARE, and will therefore need a family-based trio sequence analysis.

TL;DR version: Without the expensive, first-of-its-kind work done in the HGP (and the parallel efforts from Venter et al.), there would be no personal genomics - just like there had to be a Sputnik before there could be an International Space Station or GPS satellites.


The bioinformatics community certainly "believed" it in a sort of group make-believe that ignored variation in chromosome size and copy number. The cytogeneticists knew this, but the statistics folks were doing their usual scoffing at the very notion of empirical knowledge. We ended up with a repeat of how microarrays were going to be the answer (that statisticians all promised), and that was about the same time we were being told that massive NMR would prove protein form predicted function ( well that lasted about 3 months), and there's a couple more that will occur to me.

All of these supposedly transformational technologies are driven by the need for large hardware vendors to get the government to splurge on billions of dollars of hardware and reagents. And before anyone realizes it's 95% hype, we've moved onto the next fad.


Every shiny new technology goes through a hype cycle, but it's silly to follow the backlash all the way back the other way and devalue what those technologies have actually delivered. These are in fact transformational tools, and just because Time and Newsweek (and ok, maybe occasionally Nature) promised us jetpacks doesn't mean we aren't reaping real benefits in terms of disease diagnostics and our understanding human biology. Much as it pains me to quote Rumsfeld, there will always be "unknown unknowns". If you're clever enough to look past the hype, then you shouldn't be disappointed when things turn out to be a bit more complicated.

Sequencing IS in hospitals, and being used to guide patient care (see for example Baylor and UMichigan, or Foundation Medicine's cancer platform). Microarrays are in fact routinely used for patient diagnostics and identifying new disease genes. All these new technologies and reagents? They're still being used, not rotting in an alley. Read the Methods section of any journal article - lots of equipment and tools from 10 years ago is still routinely used. I don't understand the need to piss on these kinds of concrete advances just because we're not living in Star Trek yet. It reminds me of that Louis CK routine about how everything's terrific but nobody's happy.


How about Francis Collins?

The people who can surf these waves of hype are extremely happy, the people whose research programs got slashed so administrators could buy expensive toys, not so much.

The vision was a factory style research culture where scientists were obsolete. The pharmaceutical industry lost the better part of a decade after slashing and burning their research units. They ended up with empty drug pipelines. They had to turn back to working with academic scientists who still knew things, like Irish monks who rode out the Dark Ages on remote islands.


Do you have a particular quote you'd like to cite? Even the experts can be loudly wrong about their own area of expertise, like that famous chestnut about Thomas Watson thought the world only needs five personal computers at most.

And people aren't getting their research programs slashed so that they can buy a new machine from Illumina. They're getting their funding slashed because of an ignorant Congress that doesn't value scientific research and squabbles like children over every single budget negotiation. Again, please provide quotes about this "vision" - smacks of a strawman to me.

Regardless, my point still stands. Maybe you don't like the hype, but that doesn't mean that geneticists and biologists haven't made amazing progress with those very tools.

EDIT AT 12:12p: I would respond further in this discussion, but because I'm a n00b to the board I'm restricted to three replies per post. But in parting: there's no logical fallacy in my post - if there was no money poured into the HGP and (to a lesser degree) HapMap, then yes, we would absolutely be considerably more ignorant about human biology and genetics, and would lack the skills, knowledge and technology to move medicine forward. Was everything as efficient as I would like it to have been? Hell no. What big program (public/private/academic/nonprofit) is? Was it worth the money? Hell yes.

Missed your edit about the HapMap commentary, will look into that - but again, these research efforts were all valuable building blocks even if they weren't universal solutions. I'm not here to champion Collins or say he never put his foot in his mouth. I'm making a bigger point about the value of the technology once you get past the hype.

The fact is, academic scientists who are 'saving the day' (per your post above) from 'dumb pharmas' who wasted their money are among the biggest champions and early adopters of these genomics technologies and the big corporations that are reluctant to move into this area. What do you think these academic scientists are doing, sequencing DNA by hand? Figuring out protein structures with a pencil and paper? I worked in an academic bio lab in the 90s - trust me, I would have killed for a modern genome sequencing platform, and so would every single person in my department.


I'de refer you to Terwilligers & Hiekkalinna ."An utter refutation of the "fundamental theorem of the HapMap"" ( ).

When Collins wrote the paper wrapping up the hapmap he promised to answer these criticisms in his paper, and then he didn't.

There was supposed to be a fixed framework that was going to apply to everyone - this is what was sold to the politicians, and the scientific community knew it was bs. The statisticians filled their usual role of claiming that whatever the data looked like they'd be able to fix it with some sort of opaque mathematical voodoo. and anyone that doubted them must be dumb.

You've constructed some sort of logical fallacy there - that nearly 20 years and billions of dollars would have produced nothing had it not been poured into the HGP and HapMaps.


You probably want to pick a better example.


I'm not being a Luddite about the technology - I'm criticizing the idea that scientists would be largely redundant in an era where science would consist mostly of vendors dealing with administrators.

And why didn't your department have sequencers? because people would have been sequencing stuff that directly interested them instead of following the lead of the HGP committees. They got to act as gatekeepers.

Oh, the other fad that ended with a thud was ontologies, which are sort of still around, but they gave up on the formal magical definition of "ontologies" and are now really talking about controlled vocaularies, which they used to ridicule.


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