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Tag: genes

Atlantic Cod Are Not Your Average Fish

Another month, another paper, and like with last month’s, I picked another genetics paper, this time covering an interesting quirk of immunology.

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This month’s paper from Nature talks about a species of fish that has made it to the dinner plates of many: the Atlantic Cod (Gadus morhua). The researchers applied shotgun sequencing techniques to look at the DNA of the Atlantic Cod. What they found about the Atlantic Cod’s immune system was very puzzling: animals with vertebra (so that includes fish, birds, reptiles, mammals, including humans!) tend to rely on proteins called Major Histocompatibility Complex (MHC) to trigger our adaptive immune systems. There tend to be two kinds of MHC proteins, conveniently called MHC I and MHC II:

    • MHC I is found on almost every cell in the body – they act like a snapshot X-ray of sorts for your cells, revealing what’s going on inside. If a cell has been infected by an intracellular pathogen like a virus, the MHC I complexes on the cell will reveal abnormal proteins (an abnormal snapshot X-ray), triggering an immune response to destroy the cell.
    • MHC II is found only on special cells called antigen-presenting cells. These cells are like advance scouts for your immune system – they roam your body searching for signs of infection. When they find it, they reveal these telltale abnormal proteins to the immune system, triggering an immune response to clear the infection.

The genome of the Atlantic cod, however, seemed to be completely lacking in genes for MHC II! In fact, when the researchers used computational methods to see how the Atlantic cod’s genome aligned with another fish species, the Stickleback (Gasterosteus aculeatus), it looked as if someone had simply cut the MHCII genes (highlighted in yellow) out! (see Supplemental Figure 17 below)

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Yet, despite not having MHC II, Atlantic cod do not appear to suffer any serious susceptibility to disease. How could this be if they’re lacking one entire arm of their disease detection?One possible answer: they seemed to have compensated for their lack of MHC II by beefing up on MHC I! By looking at the RNA (the “working copy” of the DNA that is edited and used to create proteins) from Atlantic cod, the researchers were able to see a diverse range of MHC I complexes, which you can see in how wide the “family tree” of MHCs in Atlantic cod is relative to other species (see figure 3B, below).

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Of course, that’s just a working theory – the researchers also found evidence of other adaptations on the part of Atlantic cod. The key question the authors don’t answer, presumably because they are fish genetics guys rather than fish immunologists, is how these adaptations work? Is it really an increase in MHC I diversity that helps the Atlantic cod compensate for the lack of MHC II? That sort of functional analysis rather than a purely genetic one would be very interesting to see.

The paper is definitely a testament to the interesting sorts of questions and investigations that genetic analysis can reveal and give a nice tantalizing clue to how alternative immune systems might work.

(Image credit – Atlantic Cod) (All figures from paper)

Paper: Star et al, “The Genome Sequence of Atlantic Cod Reveals a Unique Immune System.” Nature (Aug 2011). doi:10.1038/nature10342

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Its not just SNPs

Another month, another paper (although this one is almost two weeks overdue – sorry!)

In my life in venture capital, I’ve started more seriously looking at new bioinformatics technologies so I decided to dig into a topic that is right up that alley. This month’s paper from Nature Biotechnology covers the use of next-generation DNA sequencing technologies to look into something which had been previously extremely difficult to study with past sequencing technologies.

As the vast majority of human DNA is the same from person to person, one would expect that the areas of our genetic code which tend to vary the most from person to person, locations which are commonly known as Single Nucleotide Polymorphisms, or SNPs, would be the biggest driver of the variation we see in the human race (at least the variations that we can attribute to genes). This paper from researchers at the Beijing Genomics Institute (now the world’s largest sequencing facility – yes, its in China) adds another dimension to this – its not just SNPs that make us different from one another: humans also appear to have a wide range of variations on an individual level in the “structure” of our DNA, what are called Structural Variations, or SVs.

Whereas SNPs represent changes at the individual DNA code level (for instance, turning a C into a T), SVs are examples where DNA is moved (i.e., between chromosomes), repeated, inverted (i.e., large stretches of DNA reversed in sequence), or subject to deletions/insertions (i.e., where a stretch of DNA is removed or inserted into the original code). Yes, at the end of the day, these are changes to the underlying genetic code, but because of the nature of these changes, they are more difficult to detect with “old school” sequencing technologies which rely on starting at one position in the DNA and “reading” a stretch of DNA from that point onward. Take the example of a stretch of DNA that is moved – unless you start your “reading” right before or right at the end of where the new DNA has been moved to, you’d never know as the DNA would read normally everywhere else and in the middle of the DNA fragment.

What the researchers figured out is that new sequencing technologies let you tackle the problem of detecting SVs in a very different way. Instead of approaching each SV separately (trying to structure your reading strategy to catch these modifications), why not use the fact that so-called “next generation sequencing” is far faster and cheaper to read an individual’s entire genome and then look at the overall structure that way?

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And that’s exactly what they did (see figures 1b and 1c above). They applied their sequencing technologies to the genomes of an African individual (1c) and an Asian individual (1b) and compared them to some of the genomes we have on file. The circles above map out the chromosomes for each of the individuals on the outer-most ring. On the inside, the lines show spots where DNA was moved or copied from place to place. The blue histogram shows where all the insertions are located, and the red histogram does the same thing with deletions. All in all: there looks to be a ton of structural variation between individuals. The two individuals had 80-90,000 insertions, 50-60,000 deletions, 20-30 inversions, and 500-800 copy/moves.

The key question that the authors don’t answer (mainly because the paper was about explaining how they did this approach, which I heavily glossed over here partly because I’m no expert, and how they know this approach is a valid one) is what sort of effect do these structural variations have on us biologically? The authors did a little hand-waving to show, with the limited data that they have, that humans seem to have more rare structural variations than we do rare SNPs – in other words, that you and I are more likely to have different SVs than different SNPs: a weak, but intriguing argument that structural variations drive a lot of the genetic-related individual variations between people. But that remains to be validated.

Suffice to say, this was an interesting technique with a very cool “million dollar figure” and I’m looking forward to seeing further research in this field as well as new uses that researchers and doctors dig up for the new DNA sequencing technology that is coming our way.

(All figures from paper)

Paper: Li et al., “Structural Variation in Two Human Genomes Mapped at Single-Nucleotide Resolution by Whole Genome Assembly.” Nature Biotechnology 29 (Jul 2011) — doi:10.1038/nbt.1904

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Do you have the guts for nori?

The paper I will talk about this month is from April of this year and highlights the diversity of our “gut flora” (a pleasant way to describe the many bacteria which live in our digestive tract and help us digest the food we eat). Specifically, this paper highlights how a particular bacteria in the digestive tracts of some Japanese individuals has picked up a unique ability to digest certain certain sugars which are common in marine plants (e.g., Porphyra, the seaweed used to make sushi) but not in terrestrial plants.

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Interestingly, the researchers weren’t originally focused on how gut flora at all, but in understanding how marine bacteria digested marine plants. They started by studying a particular marine bacteria, Z. galactanivorans which was known for its ability to digest certain types of algae. Scanning the genome of Z., the researchers were able to identify a few genes which were similar enough to known sugar-digesting enzymes but didn’t seem to have the ability to act on the “usual plant sugars”.

Two of the identified genes, which they called PorA and PorB, were found to be very selective in the type of plant sugar they digested. In the chart below (from Figure 1), 3 different plants are characterized along a spectrum showing if they have more LA (4-linked 3,6-anhydro-a-L-galactopyranose) chemical groups (red) or L6S (4-linked a-L-galactopyranose-6-sulphate) groups (yellow). Panel b on the right shows the H1-NMR spectrum associated with these different sugar mixes and is a chemical technique to verify what sort of sugar groups are present.

These mixes were subjected to PorA and PorB as well as AgaA (a sugar-digesting enzyme which works mainly on LA-type sugars like agarose). The bar charts in the middle show how active the respective enzymes were (as indicated by the amount of digested sugar that came out):

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As you can see, PorA and PorB are only effective on L6S-type sugar groups, and not LA-type sugar groups. The researchers wondered if they had discovered the key class of enzyme responsible for allowing marine life to digest marine plant sugars and scanned other genomes for other enzymes similar to PorA and PorB. What they found was very interesting (see below, from Figure 3):

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What you see above is an evolutionary family tree for PorA/PorB-like genes. The red and blue boxes represent PorA/PorB-like genes which target “usual plant sugars”, but the yellow show the enzymes which specifically target the sugars found in nori (Porphyra, hence the enzymes are called porhyranases). All the enzymes marked with solid diamonds are actually found in Z. galactanivorans (and were henced dubbed PorC, PorD, and PorE – clearly not the most imaginative naming convention). The other identified genes, however, all belonged to marine bacteria… with the notable exception of Bateroides plebeius, marked with a open circle. And Bacteroides plebeius (at least to the knowledge of the researchers at the time of this publication) has only been found in the guts of certain Japanese people!

The researchers scanned the Bacteroides plebeius genome and found that the bacteria actually had a sizable chunk of genetic material which were a much better match for marine bacteria than other similar Bacteroides strains. The researchers concluded that the best explanation for this is that the Bacteroides plebeius picked up its unique ability to digest marine plants not on its own, but from marine bacteria (in a process called Horizontal Gene Transfer or HGT), most probably from bacteria that were present on dietary seaweed. Or, to put it more simply: your gut bacteria have the ability to “steal” genes/abilities from bacteria on the food we eat!

Cool! While this is a conclusion which we can probably never truly *prove* (its an informed hypothesis based on genetic evidence), this finding does make you wonder if a similar genetic screening process could identify if our gut flora have picked up any other genes from “dietary bacteria.”

(Image credit – Nori rolls) (Figures from paper)

Paper: Hehemann et al, “Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota.” Nature 464: 908-912 (Apr 2010) – doi:10.1038/nature08937

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United States of Amoeba

Another month, another paper to read and blog about.

Most people know that viruses are notoriously tricky disease-causing pathogens to tackle. Unlike bacteria which are completely separate organisms, viruses are parasites which use a host cell’s own DNA-and-RNA-and-protein producing mechanisms to reproduce. As a result, most viruses are extremely small, as they need to find a way into a cell to hijack the cell’s  machinery, and, in fact, are oftentimes too small for light microscopes to see as beams of light have wavelengths that are too large to resolve them.

However, just because most viruses are small, doesn’t mean all viruses are. In fact, giant Mimiviruses, Mamaviruses, and Marseillesviruses have been found which are larger than many bacteria. The Mimivirus (pictured below), for instance, was so large it was actually identified incorrectly as a bacteria at first glance!

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Little concrete detail is known about these giant viruses, and there has been some debate about whether or not these viruses constitute a new “kingdom” of life (the way that bacteria and archaebacteria are), but one thing these megaviruses have in common is that they are all found within amoeba!

This month’s paper (HT: Anthony) looks into the genome of the Marseillesvirus to try to get a better understanding of the genetic origins of these giant viruses. The left-hand-side panel of picture below is an electron micrograph of an amoeba phagocytosing Marseillesvirus (amoeba, in the search for food, will engulf almost anything smaller than they are) and the right-hand-side panel shows the virus creating viral factories (“VF”, the very dark dots) within the amoeba’s cytoplasm. If you were to zoom in even further, you’d be able to see viral particles in different stages of viral assembly!

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Ok, so we can see them. But just what makes them so big? What the heck is inside? Well, because you asked so nicely:

    • ~368000-base pairs of DNA
        • This constitutes an estimated 457 genes
        • This is much larger than the ~5000 base pair genome of SV40, a popular lab virus, the ~10000 base pairs in HIV, the ~49000 in lambda phage (another scientifically famous lab virus), but is comparable to the genome sizes of some of the smaller bacterium
        • This is smaller than the ~1 million-base pair genome of the Mimivirus, the ~4.6 million of E. coli and the ~3.2 billion in humans
    • 49 proteins were identified in the viral particles, including:
        • Structural proteins
        • Transcription factors (helps regulate gene activity)
        • Protein kinases (primarily found in eukaryotic cells because they play a major role in cellular signaling networks)
        • Glutaredoxins and thioredoxins (usually only found in plant and bacterial cells to help fight off chemical stressors)
        • Ubiquitin system proteins (primarily in eukaryotic cells as they control which proteins are sent to a cell’s “garbage collector”)
        • Histone-like proteins (primarily in eukaryotic cells to pack a cell’s DNA into the nucelus)

As you can see, there are a whole lot of proteins which you would only expect to see in a “full-fledged” cell, not a virus. This begs the question, why do these giant viruses have so many extra genes and proteins that you wouldn’t have expected?

To answer this, the researchers ran a genetic analysis on the Marseillesvirus’s DNA, trying to identify not only which proteins were encoded in the DNA but also where those protein-encoding genes seem to come from (by identifying which species has the most similar gene structure). A high-level overview of the results of the analysis is shown in the circular map below:

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The outermost orange bands in the circle correspond to the proteins that were identified in the virus itself using mass spectrometry. The second row of red and blue bands represents protein-coding genes that are predicted to exist (but have yet to be detected in the virus; its possible they don’t make up the virus’s “body” and are only made while inside the amoeba, or even that they are not expressed at all). The gray ring with colored bands represents the researchers’ best guess as to what a predicted protein-coding gene codes for (based on seeing if the gene sequence is similar to other known proteins; the legend is below-right) whereas the colored bands just outside of the central pie chart represents a computer’s best determination of what species the gene seems to have come from (based on seeing if the gene sequence is similar to/the same as another specie’s; the legend is below-left).

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Of the 188 genes that a computational database identified as matching a previously characterized gene (~40% of all the predicted protein-coding genes), at least 108 come from sources outside of the giant viruses “evolutionary family”. The sources of these “misplaced” genes include bacteria, bacteria-infecting viruses called bacteriophages, amoeba, and even other eukaryotes! In other words, these giant viruses were genetic chimeras, mixed with DNA from all sorts of creatures in a way that you’d normally only expect in a genetically modified organism.

As many viruses are known to be able to “borrow” DNA from their hosts and from other viruses (a process called horizontal gene transfer), the researchers concluded that, like the immigrant’s conception of the United States of America, amoebas are giant genetic melting pots where genetic “immigrants” like bacteria and viruses comingle and share DNA (pictured below). In the case of the ancestors to the giant viruses, this resulted in viruses which kept gaining more and more genetic material from their amoeboid hosts and the abundance of bacterial and virus parasites living within.

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This finding is very interesting, as it suggests that amoeba may have played a crucial role in the early evolution of life. In the same way that a cultural “melting pot” like the US allows the combination of ideas from different cultures and walks of life, early amoeba “melting pots” may have helped kickstart evolutionary jumps by letting eukaryotes, bacteria, and viruses to co-exist and share DNA far more rapidly than “regular” natural selection could allow.

Of course, the flip side of this is that amoeba could also very well be allowing super-viruses and super-bacteria which could one day wipe out the human race to breed… but, maybe I’m just being paranoid. 🙂

Paper: Boyer, Mickael et al. “Giant Marseillevirus highlights the role of amoebae
as a melting pot in emergence of chimeric microorganisms.” PNAS 106, 21848-21853 (22 Dec 2009) – doi:10.1073/pnas.0911354106

(Image Credit – Mimivirus – Wikipedia) (Figures 1, 2, and 5 from paper)

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