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Daniel MacArthur
Geneticist, personal genomics enthusiast, blogger
Geneticist, personal genomics enthusiast, blogger

Daniel's posts

Peeps in Cambridge MA: any tips on home internet plans? I just want a stable, moderately fast internet connection (mainly just for browsing, some file transfers). I don't need TV or phone. Is Comcast my only option?

I've tried to extract useful information from Comcast, but their website makes me want to stab myself in the face.

Had to share this thought-provoking email:

Deer Daniel MacArthur,

I am [deleted],an undergraduate form [Chinese university].I have read your latest paper published on Science days before,which about LoF Variants in Human Protein-Codin Genes.
Time and time again the life show me its complex and magical,and this time should be another "again".
However,I still prefer to trust that the Nature should not make this big joke.For the discovery of true number of human genes after "HGP" have shocked everybody around the world,we now draw a conclusion that some high rate of Lof were magically happend,which is more or less mysterious to explain,even though researchers have found so much complex mechanism more or less compensate the gene number.
So my childish sense is that,the "Lof" happend before which can be called "Still none function",while much have got new function,some haven't.And many "Lof"s have relation with desease while about 20 still have goodness can support this.
When we consider the "Time" factors,we may realize that God should not give us a "small" number of genes,and let some luxurious "loss".

If this is actually happening,the God must first make sure the others(not be lossed)have more effective ways to achieve the total "work".Maybe there will be some new pattern appears,and this is what we,as human, have experienced.

Best whishes and many thanks for your attention.

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Interesting job opportunity for computational biology types - a position in Iain MacCallum's group at the Broad Institute, working on improved algorithms for stitching together genome sequence. An important project, and based in one of the best scientific environments in the world...

No direct link, but search the Broad careers site (below) for requisition number 704.

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Good to see +Keith Grimaldi beat me to this. This is a result we should be celebrating - yet I can guarantee any coverage of the paper will continue to be along the "family history beats genetic testing" line.
Tweets from Daniel MacArthur

@dgmacarthur"genetic tests as effective, but not more effective, as family/personal history in assessing disease risk"


@dgmacarthur I find it astonishing that genetic testing, in its infancy, is ALREADY as good as family history. Still, cue negative headlines...

The headline is "Scripps Finds Genotyping No More Useful than Family, Personal History in Assessing Disease Risk"

Why negative? The glass is not even half-full, it is full! Genetics AS GOOD AS family history and traditional risk factors... but the article goes on to say:

"Based on these findings, Bloss and colleagues concluded that such genetic tests are as effective — but not more effective — as family and personal history in assessing disease risk, and that these services may be medically useful to consumers only when information about traditional disease risk factors, such as family history, is not available."

Why "useful only when"? Why should it be one or the other anyway?

Genetics = cheap, reliable, one off test, ready at birth
Family history = hard to assemble, imprecise and unreliable
Trad risk factors = already ill

So, let's wait until I have I risk factors before taking any action. thanks doc.

Interesting unadvertised fact about family history is that it has yet to be proven by clinical trial - so far it has performed quite badly. Yet it is strongly touted by those who urge people to ignore genetic testing until it has been proven by clinical trial. see the CDC blog and discussion

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"The genome of each individual is a temporary assemblage of DNA segments brought together for a single generation by a combination of chance, ancestry, recombination and natural selection." An eloquent review of human genetic history by my office-mates at Sanger.

Sadly, subscription required for access.

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Follow-up on the "sequencing old people" project by Complete Genomics, and a new entrant in the genome interpretation space
Some interesting tidbits on the Complete Genomics deal with Scripps to sequence 1,000 healthy elderly people (I can't bring myself to use the term "wellderly" in any context other than an ironic one).

Firstly, from an email exchange with Complete Genomics publicist Lisa Osborne. I was puzzled by the decision by Complete to do this sequencing free of charge, so I asked:

Will the company be charging academic researchers for access to the data? If not, what is the goal of this project from a commercial perspective?

The reply:

By providing Scripps with this sequencing data at no charge, we are enabling them to allocate their resources towards further analysis and annotation of the data via Cypher Genomics. Complete Genomics will then provide this annotated data to the genomics community through a new service offering – the Wellderly Genomics Reference Resource.

Due to the constraints of the Wellderly Project participant consent forms, Complete Genomics cannot make this genomic data publicly available. Any customer who is provided access to this data will also have to agree to a number of privacy and legal restrictions in order to be able to use it.

We plan to make the Wellderly Genomic Reference Resource available to our customers as a genomic information service. Specific pricing to access this resource has yet to be determined. Customers will be provided with different tiers of service depending on the type of institution they represent (not for profit vs. for profit, for example) and the type of data they need to access. We anticipate having more details to share around the data access model and related fee structure by the end of Q4.

Well, that answers that question. As a kind of "hyper-control" group, this cohort may well have some value to academic and biotech researchers, although whether they'll be prepared to pay fees that make Complete's investment worthwhile remains to be seen. (It's worth noting that attempts to make money by generating genetic data do not have a good track record in the profitability stakes, but that doesn't mean it's impossible, or indeed that this is Complete's primary goal with this project.)

Osborne's answer raises a second question: who or what are Cypher Genomics? Turns out I missed this paragraph in the Scripps/Complete press release:

Another valuable aspect of the Reference Resource will be the addition of Cypher Genomics clinical annotations to the sequencing datasets. Cypher Genomics is a project headed by Drs. Schork and Topol, as well as STSI faculty member Dr. Ali Torkamani and STSI industry liaison Dr. Ashley Van Zeeland. STSI has developed and plans to commercialize this software suite for annotating genomic variant lists with clinically relevant pathway and disease prediction information.

Very interesting - yet another new entrant to the genome interpretation space, just a couple of week's after the launch of Stanford-based Personalis. The Cypher website contains no useful information yet, so we'll have to wait and see what emerges about this company over the next few months.

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Great story by +Erika Check Hayden on the ongoing ethical debate about returning genetic results to research participants, based on several sessions at the CSHL Personal Genomes meeting (which I also attended).

This story from Gholson Lyon was one of the most compelling cases I've yet heard for getting our collective act together on this issue, and fast:

"Lyon knew from his study that the mother carried the mutation. But he was not allowed to tell her, because the analysis had not been performed in a laboratory that was certified under the Clinical Laboratory Improvement Amendments, which aim to ensure that clinical tests are accurate and reliable.

The baby was eventually born with the disease — called Ogden syndrome — and later died, in the same week that Lyon's paper on the causative mutation was published"

Lyon's suggested solution - that all clinical research sequencing needs to be done in CLIA-certified labs - won't go down well with a lot of researchers, but it's hard to see a better solution. Despite the backlash from the more paternalistic brand of ethicists like Ellen Clayton (who also featured at the meeting and is mentioned in Hayden's piece), the moral case for returning research data is becoming increasingly more compelling.

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A few initial thoughts on 23andMe's new $999 exome product:

1. The company steers clear of the FDA's baleful gaze by (at least initially) offering raw data only with no analysis.

2. This is for hardcore beta testers only. A raw exome sequence with no interpretation requires some serious data-wrangling to extract useful data from. Even existing open-access interpretation tools like Promethease will provide fairly overwhelming data.

3. The offer is open only to existing customers. That has two benefits: the one they emphasise on their site is that it selects for people with at least some experience in looking at genetic data. A more important (but unstated) benefit is that the customers' chip data will provide a comparison data-set for exome quality control.

4. We shouldn't forget that Knome has been offering both genome and exome sequencing DTC (along with interpretation) for a long time. However, my sense is that they've attracted relatively few customers. I suspect 23andMe will be able to rope in a substantially larger customer base even at a comparable price point, leveraging their marketing and community-building strengths.

5. Still, no question that the number of people willing to fork out $999 for a non-clinical-grade exome is pretty small.

6. At Genomes Unzipped we'll be looking to get hold of at least one of these exomes, as well as providing some suggestions on ways in which the raw data can be used. Exciting times for those of us who've spent the last few years working with sequence data...

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This is a real taste of the way that next-gen sequencing is transforming rare disease genetics. The authors did exome sequencing in members of 136 consanguineous families (i.e. marriages between related individuals), mostly from Iran, where at least one family member suffered from intellectual disability. The result: 23 novel mutations in known cognitive disease-causing genes, and 50 likely causal mutations in completely novel genes.

Just a decade ago a group could labour for years to track down a single novel disease gene - now a single study is churning out fifty. Sure is a good time to be a human geneticist...
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