Thursday, November 27, 2008

The DNA Network

The DNA Network

GWAS of metabolite profiles [Yann Klimentidis' Weblog]

Posted: 27 Nov 2008 07:09 PM CST

This is great, and somewhat appropriate for Thanksgiving.

An important issue in deciphering the genetic basis for traits is appropriate phenotype definition. In this study, they look at the association between metabolic by-products in individuals and their genetic profile. These metabolites represent a better phenotype since they are more proximal to the genetic/biochemical pathways that happen within cells, compared to the clinically assessed symptoms of a "disease." Not only does this give us a more appropriate and well-defined phenotype, it's also a phenotype that can be measured on a continuous scale.

The subjects are from Germany and they briefly dismiss the possibility of population stratification: "Also, recent experimental assessment has found little population stratification to exist within and across Germany [33]". Ironically, the latest European genetic structure study, see my last blog post, showed some stratification within Germany - granted, probably not too big of a deal for this study, but it's just funny

Blood samples were obtained in the morning after overnight fasting. In the future, I can imagine collecting samples after feeding of some sugary or fatty meal to get even better measures of metabolic variation.

Genetics Meets Metabolomics: A Genome-Wide Association Study of Metabolite Profiles in Human Serum.
Gieger C, Geistlinger L, Altmaier E, Hrabe´ de Angelis M, Kronenberg F, et al.
PLoS Genet (2008)4(11): e1000282. doi:10.1371/journal.pgen.1000282
Abstract: The rapidly evolving field of metabolomics aims at comprehensive measurement of ideally all endogenous metabolites in a cell or body fluid. It thereby provides a functional readout of the physiological state of the human body. Genetic variants that associate with changes in the homeostasis of key lipids, carbohydrates, or amino acids are not only expected to display much larger effect sizes due to their direct involvement in metabolite conversion modification, but should also provide access to the biochemical context of such variations, in particular when enzyme coding genes are concerned. To test this hypothesis, we conducted what is, to the best of our knowledge, the first GWA study with metabolomics based on the quantitative measurement of 363 metabolites in serum of 284 male participants of the KORA study. We found associations of frequent single nucleotide polymorphisms (SNPs) with considerable differences in the metabolic homeostasis of the human body, explaining up to 12% of the observed variance. Using ratios of certain metabolite concentrations as a proxy for enzymatic activity, up to 28% of the variance can be explained (p-values 10216 to 10221). We identified four genetic variants in genes coding for enzymes (FADS1, LIPC, SCAD, MCAD) where the corresponding metabolic phenotype (metabotype) clearly matches the biochemical pathways in which these enzymes are active. Our results suggest that common genetic polymorphisms induce major differentiations in the metabolic make-up of the human population. This may lead to a novel approach to personalized health care based on a combination of genotyping and metabolic characterization. These genetically determined metabotypes may subscribe the risk for a certain medical phenotype, the response to a given drug treatment, or the reaction to a nutritional intervention or environmental challenge.

Cooking a turkey in an egg [Discovering Biology in a Digital World]

Posted: 27 Nov 2008 06:50 PM CST

Thanksgiving is a holiday (in the U.S. at least) when we're all reminded about the things we're thankful for. At our house, we're thankful for the opportunity to cook all day and share a meal with friends and young adults.

And, even though I haven't given my turkey an IP address, this is still a meal that deserves some documentation.

Here's the turkey soaking in brine. That large pink tongue belongs to our dog.

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Call for Submissions! [Bayblab]

Posted: 27 Nov 2008 04:01 PM CST

It's that time of the month again - dig up your best posts about cancer, or hit the keyboard and write something new for the Cancer Research Blog Carnival. You have a week to get your submissions in here. And if you have a blog and want to host a future edition, be sure to contact us!

Farewell! Thou art too dear for my possessing* [Tomorrow's Table]

Posted: 27 Nov 2008 02:53 PM CST

"A thing of beauty is a joy for ever;
Its loveliness increases: it will never
Pass into nothingness; but still will keep
A bower quiet for us, and a sleep
Full of sweet dreams, and health, and quiet breathing."

(Keats, "A thing of beauty")

Imagine the choices. You have successfully had two children using in vitro fertilization (mixing eggs and sperm in the laboratory), but there are 10 embryos left over. When faced with such an overabundance, what would you do? Do you attempt to have more children, discard the embryos, or donate them to embryonic stem cell research?

This choice is faced by thousands of parents every year, because, for every successful in vitro fertilization, more embryos are created than can be implanted into a womb.

If you choose research, scientists will harvest the inner mass of cells from your embryos and transfer them into a plastic laboratory culture dish. After six months or more, the original 30 cells of the inner cell mass will proliferate, yielding millions of embryonic stem cells.

Future experiments with your embryonic stem cells could lead to partial or complete cures for Parkinson's disease, Lou Gehrig's Disease, and type I diabetes. They may even be useful for repairing heart muscle damaged from a heart attack.

If you choose to implant the embryos into your womb (or into that of your wife or a stranger's) they will most likely grow into a child that will be loved.

If you choose to discard the embryos, they will pass into nothingness-- no research will be carried out and no additional children will be created.

I think about the donors of these gametes. Some of these couples may have wanted a child for years. Some may have lost pregnancies through repeated miscarriages. I know one woman who lost her only child to a sudden heart attack on the high school football field; a weak heart that had gone undetected. These parents are beyond ecstatic when the in vitro approach is successful. I expect that it cannot be an easy decision for them to discard "surplus" embryos. After all, can one separate the concept of a child from that of an embryo?

What would I do? Would I donate the embryos to stem cell research so people like my father-in-law could one day have new bone marrow cells that would mitigate his leukemia? Or would it be too difficult to give up the idea of more children.

I think of the physical characteristics of my own boy and girl: the dimples of my son that he shares with his father and grandfather; the blue eyes that I envied in my handsome brothers, now his. My daughter's dark, thick lashes that have no precedent in recent family history. And then the complex behaviors- the calm, easygoing son who asks, puzzled, "mommy why do some people get mad so easily?" The daughter who does. The picture-perfect handwriting of one, the illegible scrawl of the other that is so closely related to my own. The team player and the rebel. I cannot help but wonder what our other children would have been like if we had had more.

And I would want more. After all, I was never was one to stop with one cookie. So sweet, so satisfying, seemingly simple. But I also know reaching for too many can bring indigestion. Before deciding to have more children, I would need to consider the possible stress it would bring. Would more children disrupt the delicate balance of family harmony we have occasionally achieved?

President-elect Obama has indicated that he will lift the current administration's ban on the federal funding of research on embryonic stem cell lines created after August 9,2001. That means that parents who donate their embryos will enhance the ability of some of the best scientists in the nation to develop cures to some of the most dreadful diseases. And they may be successful in our lifetime.

I imagine that faced with the choices of donate, discard or raise more children, that I would choose donation. A simple act of generosity, perhaps, but one made with regret and sadness for the children that I would never embrace.

* from Shakepeare's Sonnet 87

The Health Thing to Do This Thanksgiving [The Gene Sherpa: Personalized Medicine and You]

Posted: 27 Nov 2008 12:32 PM CST

In the US, today is Thanksgiving. A day where family and friends come together and appreciate what we have. We consume massive amounts of food, drink, some smoke, and not surprisingly get admitted to...

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Fun experiments for Thanksgiving [Discovering Biology in a Digital World]

Posted: 27 Nov 2008 12:20 PM CST

If you're not cooking today, why not experiment? Here's something fun you can do with Mentos and Diet Coke - and for those of you who think these experiments are too messy, you can still watch the movie.

Enjoy the music in the video, then go outside, and enjoy the show. Later, go to and learn about the science behind the fountain effect.

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Cooking on Thanksgiving? [Discovering Biology in a Digital World]

Posted: 27 Nov 2008 09:00 AM CST

Our household is very excited about Thanksgiving.

That's because this Thanksgiving, my husband is cooking a turkey in an egg. A big green egg. green_egg.gif

Check back later today, about 5:30 pm, Pacific Standard Time, to see a picture of the turkey. In the meantime, here are some other items that were cooked in the egg.

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What scientists should be thankful for ... [The Tree of Life]

Posted: 27 Nov 2008 03:32 AM CST

Well, it is Thanksgiving. I am up late as usual catching up on email. On this day, there is something I have been meaning to post for a few years. I think scientists should take a breath today and give thanks to those who have helped them along the way. I have some specific postings about this in terms of who I want to thanks, but I wanted to make a list here of the types of things scientists should be thankful for. So here goes.

10 things scientists should be thankful for
  1. Teachers. Scientists had to learn science at some point. And most of us have had some stellar science teachers, or teachers of science-related things like math, along the way. We should give thanks to these people.
  2. Inspirers. Similar to #1 except in many cases we have been inspired to become scientists by someone who may not have been a teacher of ours. Perhaps it was a famous scientist, or even a fictional one. Or even someone we knew. It is that inspiration that frequently gets one through the tough times.
  3. Benefactors In general, scientists have a pretty nice life. We get paid (sometimes well, sometimes poorly) and are given research funds, to unlock the secrets of the universe. How cool is that? We should therefore be very thankful for the immediate source of our funds - such as the institutes where we work and the agencies that provide us funds.
  4. Taxpayers. Unless one is funded by private foundations, taxpayers are the ultimate source of those funds mentioned in #3. This source of funds is frequently overlooked but should never be forgotten. Don't forget - we take money people from people that in theory they could have gotten to keep if their taxes were lower. We should thank these taxpayers..
  5. Research personnel (including student researchers, post docs, technicians, etc). Most of the time, scientists get credit for some work that was in a large part actually done by people in our labs. They deserve our eternal gratitude.
  6. Students we teach. Overall, for those scientists who teach, though it may be a required part of our jobs, it is also a great way to learn and to become a better scientist.
  7. Staff at publishers. An important part of communicating science is of course publishing. And though I am a big fan of new ways to disseminate information, let us not forget that there are many many people who aid and abet this dissemination by working for publishers. These folks deserve our thanks.
  8. Study subjects or objects. Whether one studies organisms, rocks, molecules, planets, forces, or whatever, we should all be thankful that there is interesting stuff out there to study. And for those who study living things, if one disturbs them along the way, we should
  9. Librarians and library staff. Access to information is critical for both learning to become a scientist and being a scientist. And libraries play a key role in providing this access.
  10. Family and friends. Late nights at the lab? Working on a grant over the weekend? Writing papers all the time? In school for years and years? All of this takes a toll on friends and family. And we owe them some props.
I am sure there are more categories. But these are some that came to me on this Thanksgiving. Any categories I missed?

The role of neutral mutations in the evolution of phenotypes [The Seven Stones]

Posted: 25 Nov 2008 05:16 PM CST

Research highlight by Pedro Beltrao, University of California, San Francisco

MSB Research HighlightsIn a recent opinion piece, Andreas Wagner tries to reconcile the tension between proponents of neutral evolution and selectionism (Wagner 2008). He argues that "neutral mutations prepare the ground for later evolutionary innovation". Wagner illustrates this point using a network model of genotype-phenotype relationships (Wagner 2005). In a so-called 'neutral network', nodes correspond to distinct genotypes associated with the same phenotype and are connected by an edge if the respective genotypes differ only by a single mutation event (eg point mutation). Examples of neutral networks include different genotypes coding for RNA or protein structures. In this representation, highly connected networks correspond to robust phenotypes that are not very sensitive to changes in genotype. Wagner notes the zinc finger fold as an impressive example of a highly connected neutral network as its structure remains essentially the same even after mutating all but seven of its 26 residues to alanine.

Using this model, Wagner describes how highly robust phenotypes can lead to faster exploration of the genotype space. He further proposes that evolution of innovation occurs via cycles of exploration of nearly neutral spaces (dubbed neutralist regime) followed by a reduction in diversity once a new phenotype of higher fitness is discovered (selectionist regime).

Although these models and ideas were mostly developed using models of sequence to structure relationships, Wagner cites several examples suggesting that these concepts are equally valid for cellular phenotypes that depend on molecular interactions (ex. gene expression patterns).

As Wagner points out, in order to understand the evolution of innovation we must fully understand the mapping between genotypes to phenotypes. This is why it is important to continue to develop richer evolutionary models to link changes at the DNA level with changes in molecular structures, interactions and ultimately phenotypes with a quantifiable impact on fitness. This is an area where systems biology should play an important role.

Models of RNA and protein structure stability upon mutation have existed now for some time (Hofacker et al. 1994, Guerois et al. 2002). More recently the study of large amounts of genomic information and/or systematic interactions studies are providing us with accurate models for different types of molecular interactions (Berger et al. 2008, Burger & van Nimwegen 2008, Chen et al. 2008). In parallel to these, theoretical analysis has been use to aid in the understanding of cellular phenotypes (i.e. cell-cycle, signaling pathways etc) (Tyson et al. 2003). Connecting these different layers of abstraction is an important challenge that will allow us to better understand the origins of biological innovation.

Berger MF et al. (2008). Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133:1266-76

Burger L & van Nimwegen E (2008). Accurate prediction of protein-protein interactions from sequence alignments using a Bayesian method. Mol Syst Biol 4:165

Chen JR et al. (2008). Predicting PDZ domain-peptide interactions from primary sequences. Nat Biotechnol 26:1041-5

Guerois R, Nielsen JE & Serrano L (2002). Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 320:369-87

Hofacker IL et al. (1994). Fast folding and comparison of RNA secondary structures. Monatshefte für Chemie / Chemical Monthly 125:167-188

Tyson JJ, Chen KC & Novak B (2003). Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol 15:221-31

Wagner A (2005). Robustness and Evolvability in Living Systems. Princeton University Press

Wagner A (2008). Neutralism and selectionism: a network-based reconciliation. Nat Rev Genet 9:965-974

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