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{
The Genomic Revolution; How Sequencing Anythingand Everything Is Changing the Way We Do Science
C. Titus Brown
Reed College, BA in Mathematics Caltech, PhD and post-doctoral fellow in
Biology; Michigan State University, Assistant
Professor in Biology and Computer Science.
My background
I’m still confused by almost everything, but in some cases I have a lot more detail to be confused about.
So if you ask questions, I may say “I don’t know!” (but may then guess).
Please! Ask questions!
On “Expertise”
First, genetic investigation of fetuses in utero;
Second, tracking hospital infections;
Third, investigating global nutrient cycling.
Three stories:
Genome sequencing!!
The ability to cheaply sequence DNA is an
extremely exciting and fairly new technique; all three
stories used this extensively.
Why these stories?
1. DNA, genomes, and sequencing;2. Story 1: genetics of unborn fetuses3. Story 2: staph transmission in hospitals4. Story 3: global nutrient cycling in the
oceans5. My research, briefly!
Outline
A C G T
DNA.
AGTCCA is different from CCAAGT!
DNA is combinatorial.
This means that for a string of 10 DNA bases, there are over 1
million combinations!
AAAAAAAAATAAAAAAAATAAAAAAAATAA
…
DNA is combinatorial.
This combinatorial property matters because it means that DNA is an alphabet and can be used as a language – you can build “words” and “sentences” in it.
(Just in case you’re wondering, we still don’t really understand the language in detail, although we know a lot about it.)
DNA is a language.
Every cell in your body contains about 6 billion bases of DNA, in a particular order.
This is your genome.
Almost every one of your cells contains the same 6 billion bases of DNA.
…and it’s what you pass on to your children.
DNA underlies heredity
Since your genome has 6 billion bases of DNA, it would take up about 1.5 million pages in a book --
This book would be the architectural plans for you!
DNA is a language.
Sequencing your genome is the same thing as digitizing it – putting the sequences of bases into a format that computers can read.
Analogy: scanning in old photos.
Important side note: just because you can digitize it, doesn’t mean you understand it!
“Sequencing” the genome.
You can look for known words and sentences, to diagnose disease susceptibility.
You can compare with other genomes, to find out what words and sentences might be responsible for disease.
Why is it useful to sequence your genome?
The first human genome cost between $300m and $3bn dollars. That was in ~2002.
Today, you can sequence your genome for under $5000!
This decrease in cost lets us look at a lot more genomes!
…and the price is dropping fast.
How much does it cost?!
Knowing a particular genome sequence lets us look for known disease susceptibility, as well as helping us find “words” associated with unknown diseases.
We can do this for around $5000 per person.
Summary of DNA:
Questions at this point?
Inheritance of traits.
You have two near-copies of each string of DNA, or “chromosome”.
Inheritance of traits.
These two copies are a bit different.
Inheritance of traits.
One copy may carry a particular trait – say, albinism, or wet earwax.
Inheritance of traits.
This trait may not show up if you have only one copy (albinism).
Non-albino
Inheritance traits.
But if it’s on both copies, it may have an effect.
Albino
Albinism occurs only with two copies of albino trait.
Non-albino Albino
…many diseases work the same way.
OK Very badly ill
Can we diagnose fetuses?
OK Very badly ill
Amniocentisis is invasive.
http://www.reproduccionasistida.org/evitar-amniocentesis/
Mother’s genome Father’s genome
Child’s genome
Heredity and crossover.
Thomas Hunt Morgan, 1916
Mother’s genome Father’s genome
Children’s genomes
(Only 1 in 4 will have trait.)
Sequence plasma, mother, and father – then count.
Pregnant mother
+ Father
* Complication: between 1/10 and ½ of cells are fetal.
(+ Fetal cells)
Good accuracy!Fan et al., 2012
So, it’s now possible (if not yet really cheap!) to non-invasively figure out the genotype of a fetus, by sampling parents + blood.
Instead of one genome, sequence three!
DNA sequencing shows a lot of promise for diagnosing rare diseases.
http://www.forbes.com/sites/matthewherper/2011/01/05/the-first-child-saved-by-dna-sequencing/
Questions?
Methicillin-resistant Staph (“MRSA”)
Wikipedia
Staph tends to attack soft tissue in people who are already ill.
Correlation between staph infections and hospitals/assisted care.
Staph infections are a problem!
Hypothesis 1: broad transmission
Hypothesis 2: deep transmission
Does it spread within facilities?
or
Does it spread between facilities?
How does staph spread?
Sequence staph strains from within hospitals.
If transmission is within hospital, all the strains will look alike.
If transmission is mainly from outside, strains will be spread across hospitals.
Approach:
Tracking transmission by mutations in the genome
AncestorPresent strains
Do staph strains cluster by hospital?
Prosperi et al., 2013. Nature.
Hospitals:
Strain relatedness
Do staph strains cluster by hospital? No!
Prosperi et al., 2013. Nature.
Hospitals:
Strain relatedness
More than 80% of staph infections were newly acquired from non-patients!
Implications for prevention: focus on isolation from outsiders, not just patients.
Conclusions: mostly from outside.
Questions?
Exploring the microbial unknown!
The Great Plate Count Anomaly: most microbes cannot be studied in the lab
http://schaechter.asmblog.org/schaechter/2010/07/the-uncultured-bacteria.html
Distribution of microbial archaea off of Hawaii; why so many, so deep?
Depth
Location
Karner et al., Nature, 2001.
Distribution of microbial archaea off of Hawaii; why so many, so deep?
Measurements + extrapolation suggest:
1/3 of cells in ocean are archaeal;2/3 of cells in ocean are bacterial.
Approximately 20% of cells are from one group of archaea.
Hints came from just sequencing “seawater” in 2004:
“an ammonium monooxygenase gene was found on an archaeal-associated” section of genome.
What are all these archaea doing!?
Venter et al., 2004. Science.
“Primary pump” – CO2 sequestration in deep ocean
Wikipedia
Current theory is that a majority of the nitrification in the ocean (a driver of this CO2 sequestration pump) occurs via these archaeal cells.
What are all these archaea doing!?
More emphasis on analysis rather than just data gathering.
More exploration – “just sequence it”. More unexpected results!
How is cheap sequencing changing research?
We can generate a lot of data quite easily.
How do we interpret the data correctly, and efficiently? How do we correlate between data sets?
How can we do good biology in the face of these technical challenges?
My research is:
Great Prairie Grand Challenge --SAMPLING
LOCATIONS
2008
Sea lamprey in the Great Lakes
Non-native Parasite of
medium to large fishes
Caused populations of host fishes to crash
Li Lab / Y-W C-D
Tail loss and notochord genes
a) M. oculata b) hybrid (occulta egg x oculata sperm) c) M. occultaNotochord cells in orange Swalla, B. et al. Science, Vol 274, Issue 5290, 1205-1208 , 15 November 1996
You do!
Via:National Science Foundation (NSF);National Institutes of Health (NIH);
US Department of Agriculture (USDA);US Department of Energy (DOE)
Who funds all this research (including mine)?
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