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Archive September 2009

What good is a genome anyway? Hilary Miller Sep 30

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I read an interesting post by Olivia Judson at the New York Times blog a few weeks ago, which asked if you could sequence any genome, what would you choose?  Olivia’s choice was the coelacanth- a worthy choice, given that the coelacanth may represent the ancestor of all tetrapods (the amphibians, reptiles, birds and mammals).  No prizes for guessing what my choice would be…

Anyway, this got me thinking.  What good is a genome sequence?  What is it going to tell us about our favourite organism that good old-fashioned biological enquiry and lab work hasn’t been able to tell us so far?  Whenever the idea of sequencing the tuatara genome is discussed, one of the major questions that comes back (especially from non-geneticists) is “why?  Even though genome sequencing is getting faster and cheaper by the day, it still requires huge resources of time and money and it’s not always obvious why its worth going to the effort.  

By now you may be wondering what sequencing a genome actually means.  The genome of an organism refers to all the DNA that makes up one set of its chromosomes – this includes all the genes, and all the pieces of DNA in between the genes.  DNA is made up of 4 nucleotides, or bases – Adenine (A), Guanine (G), Cytosine (C) and Thymine (T).  So sequencing a genome means determining the entire sequence of As, Gs, Cs and Ts for all of the chromosomes.  Because genomes are so large (most mammalian genomes are a few billion bases long), they have to be sequenced in pieces (usually of a few hundred bases each) then put back together.  Sequencing all the pieces is quick and easy, but putting them together takes huge amounts of computing power – like doing one giant jigsaw puzzle with several million pieces. 

DNA packaged into chromosomes makes up the genome. (Source: Wikimedia commons http://commons.wikimedia.org/wiki/File:Genome.jpg)

DNA packaged into chromosomes makes up the genome. (Source: http://commons.wikimedia.org/wiki/File:Genome.jpg)

Having the DNA sequence is only just the beginning, however.  The DNA sequence itself is meaningless until it is annotated – this involves figuring out which bits are the genes, what these genes are and eventually, what the genes do and how they interact.  Annotation can take years and require huge amounts of bioinformatics manpower (and computer power).  To give you some idea of what we’re talking about here, the cow genome sequence was finished a few months ago and involved more than 300 researchers in 25 countries, including 15 analysis teams to turn the raw data into meaningful knowledge. 

So what do we get out of all this investment of time and money?  Once we have an annotated whole genome sequence we theoretically know all the genes an organism has, and where they are found on the chromosomes in relation to each other.  And even if our genome sequence is only partially annotated, we still have a huge head start on finding the genes we are interested in.  Most of the power in a genome sequence comes with being able to compare its structure with other genomes already sequenced, enabling us to work on a much larger scale than was previously possible and without having to “guess” which genes may be important to investigate in advance. 

This kind of scaling up has revolutionised evolutionary biology, enabling us to spot patterns in genome evolution that wouldn’t be apparent if we were only studying individual genes.  For instance, we can identify parts of the genome that are conserved across distantly related species – these may have some important functional role which means their DNA sequence hasn’t changed much over millions of years, and may even be regions of the genome previously regarded as “junk” or nonfunctional DNA.  We can also study how genes are formed and lost, or identify genes that appear to have evolved faster or taken on a new function in a particular species.  Genome sequences can also help us understand how species and populations are related to each other.  Instead of just having a handful of genes or markers available to build phylogenetic trees we now have literally thousands of markers at our fingertips, enabling more powerful comparisons to be made. 

Whole genome sequences can also facilitate research where we only want to look at individual genes or particular regions of the genome to understand a particular biological trait, for instance resistance to a particular disease.  For this type of more traditional genetics research having a whole genome is unnecessary, but it does provide a very convenient shortcut.  Finding a particular gene or region of a chromosome and then sequencing it can be a laborious task requiring many hours in the lab.  With genome sequencing becoming faster and cheaper by the day, it is fast becoming more cost-effective to sequence an entire genome upfront than to pick off small pieces of it to sequence as individual projects.  

So there are a couple of good reasons to sequence whole genomes.  Genome sequences allow researchers to work on a much larger scale than was previously possible to answer some fundamental questions about evolution; and circumvent the need for a whole lot of laborious labwork to isolate specific genes or genomic regions.  So perhaps the question should be ”which genome should you sequence?”  That might have to be a topic for another post…

Something funny for a Friday afternoon Hilary Miller Sep 25

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Irish comedian Dara O’Briain talking about science, journalistic “balance”, homeopathy and other things

Thanks to Open Parachute for posting this and making me laugh on a slow friday afternoon.

Pesky reptiles confuse palaeontologists Hilary Miller Sep 17

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This from a letter to Nature, in the latest edition:

Could Nature have been unknowingly publishing papers for the past 80 years about crocodilian gastroliths (stomach stones) instead of stones concluded to be 2.5-million-year-old hominid tools? This possibility could cast doubt, for example, on the nature of the Oldowan specimens described by Michael Haslam and colleagues in their Review of primate archaeology (Nature 460, 339—344; 2009).

…Identification of the Oldowan specimens as tools is based on the fact that the soft relict sands of Olduvai Gorge contain no natural stones of their own, so any stone found there must have been moved from distant river beds by some unknown animal transporter – concluded by high science to be Homo habilis. But crocodiles have the curious habit of swallowing rocks: these account for 1% of their body weight, so for a 1-tonne crocodile that’s 10 kg of stones in its stomach at all times. Surprisingly, science has never even considered the crocodile as transporter.

Read the full version here

Warrior genes and the disease of being a scientist Hilary Miller Sep 15

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The past few days, headlines like ’Maori don’t have warrior gene’ and ’Maori warrior gene debunked’ have been all over the media. This has left me with a sinking feeling in the pit of my stomach, and thinking that this sounds a lot like media hype/oversimplification of what is a very complex area of research.  To recap…

Back in 2006, Rod Lea gave a presentation at the 11th International Congress of Human Genetics showing that Maori have a higher frequency of a particular variant of the Monoamine Oxidase-A (MAO-A) gene.  In some studies, this particular variant has been linked with aggression and antisocial behaviour, and one study back in 2004 dubbed it ’the warrior gene’.  The media picked this story up, and bandied around headlines like ’Warrior gene blamed for Maori violence’, making statements claiming that “New Zealand Maori carry a “warriorgene which makes them more prone to violence, criminal acts and risky behaviour’.  This is not what Lea and colleagues claim in their original study at all — I’ll talk more about that below.

Anyway, now according to media reports this claim has been “debunked by science”.  When I read this my initial thought was that someone has done another study of Maori MAO-A allele frequencies, and found conflicting results.  But actually this is not the case at all.  The ’scientific study’ that debunks this claim is actually just a review by Maori academic Dr Gary Hook, published in Mai Review — a peer-reviewed journal of Maori and Indigenous development, but not a scientific journal.  Hook makes some good points, which I’ll talk more about in a minute, but presents no new data and much of his review of the scientific controversy has already been covered in a previous article.

So what is monoamine oxidase, and what did Lea and colleagues actually find in their study? Monoamine oxidase enzymes break down neurotransmitters like serotonin and dopamine, and are therefore capable of affecting mood.  These proteins and the genes that code for them come in two forms — A and B — it is the A form that is the subject of their study.  This gene contains a number of variants, one of which contains a 30 bp repeat (MAO-A30bp-rpt) in the promoter region of the gene.  The number of times this 30bp sequence is repeated affects how active the gene is and therefore how much MAO-A enzyme is produced.  The 3-repeat form (or allele) in particular results a lower level of MAO-A activity and higher dopamine levels.  Several genetic association studies have linked this low activity variant with antisocial behaviour and increased aggression, but the results are rather complex.  The three largest studies have all found that there is actually no relationship between this variant and antisocial behaviour when this is analysed in isolation, but that this allele is associated with behaviour when environmental factors are taken into account.  For example, a study of Dunedin children found that those who who were abused and neglected in childhood were more likely to show antisocial behaviour later in life if they had the low activity form.  It is important to note that the studies that found this effect were all on caucasian males, and studies of other ethnic groups found no such effect. 

In response to the media storm created by their intial findings, Rod Lea and Geoff Chambers presented a brief outline of their work in the New Zealand Medical Journal in 2007.  I haven’t seen the full study published in a peer reviewed journal, but I suspect it may be in the works.  Anyway, their report from 2007 states that they genotyped 46 Maori males, and found that the low activity allele was present at a frequency of 56% – significantly higher than the frequency found in caucasian males.  They also claim evidence for positive selection on the MAO-A gene, implying that the low activity variant conferred an advantage at some point in Maori evolutionary history.  They suggest that this variant “may have conferred some selective advantage during the canoe voyages and inter-tribal wars that occurred during the Polynesian migrations”.  Their evidence for selection comes from a much smaller sample size of only 17 individuals (as individuals without 8 Maori great-grandparents were excluded to reduce the effect of European genes) and it is hard to evaluate from the information given in the NZMJ article.  It is possible that a larger sample would show different results, or that a genetic bottleneck associated with the colonisation of NZ would result in the same pattern as a result of chance sampling of alleles.

The work on MAO-A by Lea and colleagues was part of a study aimed at analysing the MAO-A gene as a genetic marker for alcohol and tobacco response traits in New Zealanders.  An important part of these types of studies is identifying whether there is any ethnic variation in MAO-A allele frequencies that can confound the results.  Thus their motivation was not to find a “gene” for aggression in Maori, and at no point do they claim that high frequencies of the MAO-A low activity variant cause increased violence and antisocial behaviour in Maori.  This is not what they tested, and in fact no other study has tested this either.  In their NZMJ article, they state:

It is important that the incidental formation of this ’warrior gene hypothesis’ is interpreted for what it is–a retrospective, yet scientifically plausible explanation of the evolutionary forces that have shaped the unique MAO-A gene patterns that our empirical data are indicating for the Māori population.
As alluded to by Merriman and Cameron, the extrapolation and negative twisting of this notion by journalists or politicians to try and explain non-medical antisocial issues like criminality need to be recognised as having no scientific support whatsoever and should be ignored.

The way Lea and Colleagues framed their study did not help their cause though.  They stated that the MAO-A variant has been strongly associated with aggression and risk taking, without adding the qualifiers that this is only in some ethnic groups, and only when previous environmental factors are taken into account.  This, in addition to referring to the MAO-A variant as the ’warrior gene’, was bound to get misinterpreted by the media. 

Gary Hook’s article is largely concerned with the cultural issues around branding Maori with a ’warrior gene’.  This is an opinion article, not a scientific study, and much of the scientific “debunking” of the warrior gene hypothesis is simply a review of conclusions already presented by Merriman and Cameron in the NZMJ.  Hook’s main point (which I think is good one) is that labelling maori with a “warrior gene” is akin to labelling them with a disease, and that propagating the idea that maori are intrinsically violent is dangerous and unhelpful.  He rightly states

the implications that follow from the “warrior” gene hypothesis should it become fact in the minds of the general public are horrendous

The media attention given to this article will go a long way towards ensuring that this hypothesis does not become fact in the minds of the general public, so in that sense it has served its purpose.

I think Hook does science a disservice though.  In the introduction he states

 It was proposed that the high criminality of Māori was due to the expression of a “warrior” gene that rendered Māori “more prone to violence, criminal acts, and risky behaviour.”

citing both a news article and Lea and Chambers’ NZMJ article.  The media may have claimed this, but Lea and Chamber’s article certainly didn’t.   He also unfairly states

It is one thing for newspapers to promote their fetishes but it is another for scientists to be the source of speculation and fantasy about the nature of Māori

 when the speculation and fantasy came from the media, not the scientists. 

The associated media coverage of this report does nothing for understanding the science, and contributes to the “scientists always get things wrong” attitude that seems to be prevalent out there.   To present the science in this case as a series of black and white facts – first we think they have a warrior gene, and now we think they don’t – is extremely misleading and only adds to the misunderstandings surrounding the original study.

 References:

 Hook, G.R. (2009). “Warrior genes” and the disease of being Maori. Mai Review, 2, Target article.

 Lea, R., & Chambers, G. (2007). Monoamine oxidase, addiction, and the “warrior” gene hypothesis. Journal of the New Zealand Medical Association 120(1250)

 Merriman, T., & Cameron, V. (2007). Risk-taking: behind the warrior gene story. Journal of the New Zealand Medical Association 120(1250)

Bird sex gene identified Hilary Miller Sep 11

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ResearchBlogging.org In mammals, sex is determined by genes contained on sex chromosomes — males have an X and a Y chromosome, and females have two X chromosomes.  In birds things are quite different, as it is the male that has two of the same type of sex chromosome.  Male birds have two Z chromosomes and female birds have a Z and a W chromosome.  In mammals, the Y chromosome contains a gene called SRY, which ’switches on’ the male sex determining pathway.  So if you have the SRY gene you develop testes, and if you don’t you develop ovaries.

Until now, the identity of the master sex-determining gene in birds has been a mystery.  The Z and W chromosomes of birds are not related to the X and Y chromosomes of mammals, and birds do not have an SRY gene.  Research published in Nature yesterday appears to have solved this mystery, with evidence that the DMRT1 gene, located on the Z chromosome, is the bird sex determining gene.

baby chickensDMRT1 has long been suggested as a good candidate for the ’master switch’ gene in birds, but until now this has been difficult to prove due to the technical difficulty in knocking out expression of genes in large, yolky bird eggs.  Craig Smith, Andrew Sinclair and colleagues from the University of Melbourne have now succeeded in silencing expression of DMRT1 in chicken embryos using a method called RNA interference.  They found that in genetically male chicken embryos where levels of the DMRT1 protein were reduced by RNAi, the gonads developed into ovaries rather than testes, suggesting that DMRT1 is required for testes development.  These embryos also showed reduced expression of a male marker gene SOX9, but levels of a female marker gene aromatase (which is not present in normal male embryos) increased.  Reducing DMRT1 expression had no effect on genetically female embryos - their gonads developed into ovaries as usual.

These results suggest that DMRT1 alone can determine whether an embryo becomes male or female.  However, unlike in mammals, where sex is determined by presence or absence of SRY, DMRT1 appears to act in a dosage-dependent manner.  Male birds have two copies of the gene (one on each Z chromosome) so produce twice as much DMRT1 protein as female birds.  The results of Smith and colleagues suggest that DMRT1 levels need to reach a certain threshold before the male developmental pathway is switched on, and this level can only be reached by birds with two Z chromosomes.

Unfortunately, Smith and Colleagues were unable to conduct the converse experiment to test whether you can turn genetically female embryos into males by overexpressing DMRT1.  This is because their experiments resulted in overexpression of DMRT1 in all tissues, not just the gonad, which is lethal to the developing embryo.  Future refinements of their method should enable them to direct expression to the gonad only, mimicking what would happen in a genetically male embryo and confirming the role of DMRT1 as the master sex switch.

This study fills a large hole in our understanding of sex determination in vertebrates.  DMRT1 appears to be involved in sex determination across a variety of vertebrates, suggesting it has an ancient role.   This is backed up by the fact that early mammalian lineages and some reptiles have sex chromosomes related to the ZW system of birds, not the XY system of later mammals, suggesting that SRY is only a recent arrival on the sex determination scene.

Smith, C., Roeszler, K., Ohnesorg, T., Cummins, D., Farlie, P., Doran, T., & Sinclair, A. (2009). The avian Z-linked gene DMRT1 is required for male sex determination in the chicken Nature, 461 (7261), 267-271 DOI: 10.1038/nature08298

Protected minke whales from unreported bycatch sold on Japanese markets Hilary Miller Sep 06

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ResearchBlogging.org Japan kills over a hundred minke whales each year under the guise of ’scientific whaling’, and much of the meat ends up in the commercial markets destined for Japanese dinner plates.  Now a study just published in Animal Conservation indicates that a similar number of whales are killed as ’bycatch’ in Japanese coastal waters, and much of this catch is unregulated and goes unreported.

Scott Baker (University of Auckland and Oregon State University) and colleagues from New Zealand, Australia, USA and Japan used some genetic detective work to sample the whale meat sold on Japanese markets and found that 46% of the meat sold was of the protected ’J stock’.  Minke whales form 2 distinct groups that can be distinguished by their genetic makeup: the O stocks are found in offshore Pacific waters, and are the target of scientific whaling; and the J stocks are primarily found in coastal waters in the Sea of Japan and are largely killed as fisheries bycatch.  The J stocks were depleted as the result of intense whaling by Korea and Japan between 1962 and 1986 and have been protected since 1986.

Whales that are killed incidentally in fishing nets are reported by most member nations of the International Whaling Commission (IWC).  However, Japan and Korea are the only countries that allow the sale of these whales. In Japan, whale meat originating from bycatch was originally only allowed to be sold locally, but in 2001 a law change allowed fishers to legally kill, distribute and sell these whales.  Between 1997 and 2000 an average of 25 whales a year were reported as bycatch, but once the regulations were changed to allow their commercial sale, the reported bycatch suddenly increased about 4-5 fold to over 100 whales per year.

Baker and colleagues sampled meat from markets across Japan between 1997 and 2004.  Using mitochondrial DNA markers they were able to determine which species the meat came from, and for minke whales to determine whether the meat was from O or J stock whales.  They were also able to determine how many individual whales the samples represented by using a suite of microsatellite markers which are highly variable between individuals.

Baker and colleagues determined that the number of J stock animals sold on Japanese markets was fairly constant over the 1997-2004 period.  The estimated true take of J stocks from bycatch is more than 100 whales per year in Japanese waters alone.  This is at odds with the number reported as bycatch, particularly in the years before 2001 when only 19-29 animals per year were recorded, suggesting that a large amount of fisheries bycatch goes unreported.

Speaking after the scientific meeting of the IWC in June, Baker commented that the sheer number of whales represented by whale-meat products on the Japanese and Korean market suggests that both countries have an inordinate amount of bycatch.

’The sale of bycatch alone supports a lucrative trade in whale meat at markets in some Korean coastal cities, where the wholesale price of an adult minke whale can reach as high as $100,000,’ Baker said. ’Given these financial incentives, you have to wonder how many of these whales are, in fact, killed intentionally.’

Footnote: Much of the lab work for this study and others by Baker’s group is done using ’portable’ lab equipment which can be set up in Japanese hotel rooms. This gets around the problem of sending CITES-listed whale tissue overseas for analysis.  As an MSc student at Auckland University in the mid 1990s I remember hearing about this work and thinking it made molecular ecology seem all very James Bond and exciting.

Lukoschek, V., Funahashi, N., Lavery, S., Dalebout, M., Cipriano, F., & Baker, C. (2009). High proportion of protected minke whales sold on Japanese markets is due to illegal, unreported or unregulated exploitation Animal Conservation DOI: 10.1111/j.1469-1795.2009.00302.x
(Additional material from Science Daily)

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