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Cheetah genetic diversity revisited Hilary Miller Feb 04

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ResearchBlogging.org

Another chapter has been added to the story of genetic variation in the cheetah, with a paper out in next month’s Molecular Biology and Evolution journal giving a detailed description of variation at key immune genes in the species.  I first became familiar with the cheetah story as a PhD student when I was studying genetic diversity in the black robin.  At the time the cheetah was something of a poster child for the perils of low genetic variation, but this most recent paper suggests that their immune system is not as genetically invariant as first thought, and they may not be so vulnerable to disease after all.

Back in 1985, Stephen O’Brien and colleagues at the National Cancer Institute in Maryland reported extremely low levels of genetic variation in cheetahs - so low in fact, that skin grafts from one animal were not rejected by another, a sign that their immune systems are genetically identical.  This lack of genetic variation was attributed to a decline in population numbers at end of last ice age, plus more recent declines that have led to inbreeding.  The species appeared to be highly susceptible to feline infectious peritonitis (FIP), a disease which had decimated some captive populations, and attempts to breed cheetahs in captivity were hampered by poor reproductive success and apparently high levels of sperm defects.  O’Brien and colleagues attributed these problems to their extremely low levels of genetic variation, and the species quickly became a classic example of the perils of inbreeding. 

The cheetah (Acinonyx jubatus) is found mainly in southern and eastern Africa

However, in the early 1990’s, field studies questioned whether the cheetah’s survival in the wild was being compromised by their lack of genetic variation.  In a commentary in Science in 1994, Caro and Laurenson pointed out that disease susceptibility and breeding problems only appeared to be an issue for captive cheetahs, and that predation of cubs, habitat destruction and persecution by humans were greater threats to the species.

Still, a lack of variation at immune genes is still an important potential threat to any species, as shown by the case of the Tasmanian devil, where low variation at Major Histocompatibility Complex, or MHC genes, has allowed Devil Facial Tumour Disease to spread unchecked throughout the population.  MHC genes are key part of the immune system in vertebrates as they code for the molecules that distinguish self from non-self, and instruct the immune system to respond when foreign proteins (i.e. from a pathogen) are detected.  High diversity at MHC genes plays an important role in protecting populations from disease epidemics as it allows wide array of foreign pathogens to be resisted, and means that some individuals are likely to be more resistant to new diseases than others (instead of all individuals being equally susceptible).  

The skin graft experiments of the mid-1980s indicated that cheetahs have virtually no MHC variation, because of the absence of an immune response when skin from one cheetah was grafted onto another.  However the disease susceptibility seen in captive cheetahs doesn’t seem to extend to cheetahs in the wild – a recent study on wild cheetahs in Namibia  found that the population was generally in good health, and that many individuals carried antibodies to a range of diseases (suggesting they had been exposed to those diseases) but no clinical symptoms of acute disease.  These results suggest that wild cheetahs may have more MHC diversity than the captive population, and that their immune systems work just fine. 

Somewhat surprisingly, only a couple of studies in the 26 years since the skin-graft study was published have actually attempted to quantify cheetah MHC diversity.  These studies found low diversity and seemed to corroborate the skin-graft results, but either used low resolution methods to measure MHC diversity or had small sample sizes, so weren’t particularly conclusive.

This latest study, by Aines Castro-Prieto, Simone Sommer and colleagues at the Leibniz Institute for Zoo and Wildlife Research in Berlin, takes a much more comprehensive approach to measuring genetic variation.  Castro-Prieto and colleagues determined how many different alleles are present at two types of MHC genes in 149 Namibian cheetahs.  They found more variation than was previously described for the first type (Class I MHC), but not for the second type of gene (Class II MHC).  The number of different MHC alleles counted in the Namibian cheetahs is still quite low compared with what is seen in other big cat populations, so it appears that cheetahs have lost a fair amount of variation as their numbers have declined.  However, the amount of DNA sequence variation among the alleles is fairly high – that is the different alleles code for proteins that are quite different from one another in their sequence, so overall they can probably recognise a wide array of foreign proteins. 

Castro-Prieto and colleagues also found hallmarks of selection on the MHC sequences, and speculate that selection, driven by exposure to a range of pathogens over thousands of generations, has led to highly divergent alleles being retained.  However, they point out that although wild cheetahs appear to have enough MHC variation to respond to common infectious diseases, they may still be at risk from new emerging diseases, as the few remaining alleles might not be sufficient to be able to recognise and ward off an entirely new pathogen.   

This study provides some much-needed data on immune variation in cheetahs, and it seems that the idea of the cheetah being a classic case of disease vulnerability associated with low genetic diversity is looking a little shaky.  As Castro-Prieto et al point out, “the long term survival of free-ranging cheetahs in Namibia seems more likely to depend on human-induced rather than genetic factors”.

Reference: Castro-Prieto A, Wachter B, & Sommer S (2010). Cheetah paradigm revisited: MHC diversity in the world’s largest free-ranging population. Molecular biology and evolution PMID: 21183613

Further reading:

For an excellent write-up on why genetic diversity is important (and more stuff about cheetahs), see this (fairly old) post on Mauka to Makai .

O’Brien SJ, Roelke ME, Marker L, Newman A, Winkler CA, Meltzer D, Colly L, Evermann JF, Bush M, Wildt DE (1985) Genetic basis for species vulnerability in the cheetah. Science 227: 1428-1434

Caro TM, Laurenson MK (1994) Ecological and genetic factors in conservation: a cautionary tale. Science 263: 485-486.

Thalwitzer S, Wachter B, Robert N, Wibbelt G, Muller T, Lonzer J, Meli ML, Bay G, Hofer H, Lutz H (2010) Seroprevalences to Viral Pathogens in Free-Ranging and Captive Cheetahs (Acinonyx jubatus) on Namibian Farmland. Clin. Vaccine Immunol. 17: 232-238.

A simple change determines male vs female organ development in flowers Hilary Miller Oct 30

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ResearchBlogging.org Gene duplication is a  major source of genomic novelty for evolution to work on.  When genes duplicate, the extra copy of the gene is often redundant – it might degrade and become a pseudogene or take on a completely new function.  Alternatively, the function of the original gene might become partitioned between the two duplicates in a process known as subfunctionalization.  An excellent example of this has recently been reported in the genes that control male and female organ development in the flower, and it’s (almost) all down to a single amino acid change between the duplicate genes.

Development of male and female reproductive organs in flowers is controlled largely by a group of genes called MADS-box transcription factors. Different versions of these transcription factors (known as A, B or C function genes) are expressed in different parts of the developing flower, acting either alone or together to produce sepals, petals, stamens (male) or carpels (female)*.

Much of what we know about flower development comes from studies on two “model” plants – Arabidopsis (rockcress) and Antirrhinum (snapdragon).  In these species, and in many other flowering plants, the MADs-box C-function gene that controls the production of carpels vs stamens has duplicated. In Arabidopsis, one of the copies (called AG) makes both male and female organs, but the other copy has taken on the completely new function of making seed pods shatter (and is appropriately called SHATTERPROOF).  However, in Antirrhinum both copies still play a role in sex organ development: one copy (called FAR) makes only male parts, while the other copy (PLE) makes mainly female parts but also has a small role in making male parts.

Thus in Antirrhinum, the function of the original gene (making both male and female parts) has almost been split between the two duplicate copies.  In a study published online in PNAS last week, researchers at the University of Leeds, led by Professor Brendan Davies,  found a surprisingly simple difference in the two copies has led to their profoundly different roles.

Davies and colleagues created chimeric versions of PLE and FAR, swapping domains between the proteins to determine exactly what parts of the different proteins are responsible for their differing function.  They narrowed down the difference between the two genes to a single amino acid that is present in FAR but not in PLE. When this amino acid was removed from FAR, the gene switched to making both female and male parts.  FAR and PLE are estimated to have duplicated around 120 million years ago, and the researchers estimate that the mutation responsible for inserting the extra amino acid into FAR happened around 20 million years after the duplication.

Duplicated genes often take on new functions because changes in their regulatory regions change how and where they are expressed.  Thus, finding an example such as this one, where a simple change in the protein coding sequence causes a profound change in function is somewhat unusual.  However, these proteins don’t act in isolation – they are just one part of a network of genes that must work together to control sex organ development.  Davies and colleagues found that the single amino acid change alters the ability of the protein to interact with other proteins in this network.

The additional amino acid in FAR is found in the part of the protein that interacts with other types of MADs-box proteins called SEP proteins.  C-function genes without the additional amino acid (like PLE) can interact with 3 different SEP proteins (SEP1, SEP2 and SEP3), but proteins with the additional amino acid (like FAR) can only interact with SEP3.  The SEP3 gene is not expressed in the first whorl of the flower, where female parts are produced, so FAR doesn’t have anything to interact with in this whorl and therefore doesn’t produce female parts.

Davies describes this as “an excellent example of how a chance imperfection sparks evolutionary change”.  It is also a nice example of subfunctionalization in action, where a simple amino acid change provides a means of separating the functions of the duplicate copies by causing a change in how the protein operates in a larger regulatory network.

Reference: Airoldi CA, Bergonzi S, & Davies B (2010). Single amino acid change alters the ability to specify male or female organ identity. Proceedings of the National Academy of Sciences of the United States of America PMID: 20956314

*For more on the ABC model of plant development, see here or here.

When is a gene really an allele? Hilary Miller May 18

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The way some sections of the media use the word “gene” has become a bit of a pet peeve of mine.  Here’s an example from ScienceDaily:

Tibetans Developed Genes to Help Them Adapt to Life at High Elevations

Researchers have long wondered why the people of the Tibetan Highlands can live at elevations that cause some humans to become life-threateningly ill — and a new study answers that mystery, in part, by showing that through thousands of years of natural selection, those hardy inhabitants of south-central Asia evolved 10 unique oxygen-processing genes that help them live in higher climes.

Closer inspection of this research, which was published in Science last week, reveals that Tibetans don’t actually have 10 genes that are missing in the rest of humanity, what they have are different variants of the same genes.  These variants are called alleles, or haplotypes (there is a subtle difference between these two terms which I won’t go into here – but they both basically refer to different forms of the same gene or chromosomal region).  When geneticists refer to genetic variation in a species or population they are referring to the changes in the DNA sequence that results in multiple variant forms (alleles) of any given gene, the stuff that natural selection works on.

This study found that the Tibetan population have DNA changes in 10 genes that appear to be the result of natural selection.  Two of these genes, EGLN1 and PPARA have haplotypes that are significantly associated with the “decreased hemoglobin phenotype”, which is thought to be an adaptation to high altitude living.  These haplotypes appear to be selected for in the Tibetan population.  We all have EGLN1 and PPARA, but the Tibetan populations have unique haplotypes of these genes that help them live in higher climes.

This sort of incorrect usage of the word gene is pervasive in the popular media.  The phrase ’the gene for’ seems to be everywhere — the gene for breast cancer, the gene for schizophrenia, the gene for diabetes etc etc.  This gives the wrong impression of what these studies actually show, and is just plain incorrect.  What is actually being referred to in these studies is an allele or haplotype of a gene that we all have, and usually it is an allele that is correlated with a slightly higher incidence of the disease, not necessarily one that causes the disease.  Perhaps its time for for biologists to be more clear about what they mean by the word “gene”, and for journalists to incorporate the word “allele” or even just “genetic variant” into their vernacular.

If you want to read more about the Tibetans, the original paper is here, and an excellent summary of it by Razib Khan at Discover Magazine is here.

Mammoth hemoglobin back from the dead Hilary Miller May 05

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While we’re on the subject of extinct species, Prof Kevin Campbell and colleagues in Canada and Australia have reported resurrecting mammoth hemoglobin in a paper out this week in Nature Genetics.  This won’t help at all with cloning a mammoth, but provides a fascinating insight into mammoth physiology and evolution.

Hemoglobin is the protein which transports oxygen in the blood.  It is made up of two subunits, alpha and beta globin, which are coded for by two different genes.  Campbell and colleagues used fairly basic molecular biology techniques to isolate these genes from mammoth remains and express the protein in bacterial cells.  Firstly, they amplified both elephant and mammoth hemoglobin genes using PCR and compared their sequences, finding that mammoth beta-globin protein differs from the elephant protein at three amino acid sites.

They then inserted the elephant hemoglobin genes into a bacterial carrier molecule called a plasmid, which had previously been designed to express human hemoglobin.  This carrier molecule basically contains the elephant hemoglobin genes and a bacterial promoter – a little sequence of DNA which is recognized by bacterial proteins that switch on the genes to produce the hemoglobin protein.  Producing mammoth hemoglobin was slightly more complicated because the mammoth DNA was degraded so the hemoglobin genes had to be isolated in pieces.  This meant they couldn’t insert the genes directly into the plasmid, so instead they recreated the mammoth sequence by modifying the elephant construct at the sites where it differs from mammoths.

Once they had the expressed hemoglobin, they then compared the oxygen-binding properties of the elephant and mammoth proteins using standard physiological tests and chemical modelling.  The changes in the amino acid sequence of the mammoth hemoglobin protein, when compared with elephants, appear to be important for cold tolerance, as they allow the mammoth blood to deliver oxygen to cells even at very low temperatures.

“This is true paleobiology, as we can study and measure how these animals functioned as if they were alive today” says Professor Alan Cooper, Director of the Australian Centre for Ancient DNA (ACAD) at the University of Adelaide, where the mammoth hemoglobin sequences were determined.  You can hear more about this research from Alan Cooper on Radio New Zealand here.

Reference:  Campbell KL, Roberts JEE, Watson LN, et al. Substitutions in woolly mammoth hemoglobin confer biochemical properties adaptive for cold tolerance. Nature Genetics doi:10.1038/ng.574

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Tasmanian devil facial tumour disease: too good a match for the immune system Hilary Miller Apr 13

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ResearchBlogging.org
A central premise in conservation genetics is that high genetic diversity is good for a species’ continued survival, and low genetic diversity is bad. This seems intuitively obvious (after all, we all know that you shouldn’t marry your cousin) but actually finding examples in nature where we can say for sure that low genetic diversity has contributed to a population’s demise is difficult.   

However, the recent decline of tasmanian devil populations due to disease provides an excellent example of the perils of low genetic diversity.  Wild devil populations in eastern Tasmania have been decimated in recent years by devil facial tumour disease (DFTD).  This nasty disease is a transmissible cancer spread by biting, and causes large tumours to form around the mouth, interferring with feeding and eventually causing death.  Kathy Belov’s group at the University of Sydney has been studying the genetic basis of DFTD susceptibility in devils and has found that a lack of variation in immune system genes is responsible for the spread of the cancer in some populations.    

Tasmanian devil with facial tumour disease (photo: Menna Jones)

Belov’s group has been studying the genes of the Major Histocompatibility Complex, or MHC.  MHC molecules are a crucial part of the immune system in vertebrates, as they are responsible for recognising foreign invaders and mounting an immune response.  MHC molecules are also an important part of the process of self/non-self recognition that prevents the immune system attacking the body’s own cells.  MHC genes are normally highly variable in populations, with a large number of different alleles (or variants) for each gene.  This variability allows for a wide array of foreign pathogens to be resisted and accounts for differences in disease resistance among individuals.  Thus, populations with low or no variation at MHC genes are potentially susceptible to disease epidemics, as all individuals in the population will be equally susceptible to novel diseases.   

Devil populations in eastern Tasmania have low levels of genetic diversity due to reductions in population size over the last 150 years.  DFTD is so virulent in these populations because the tumours have the same MHC type as healthy devil cells.  Being an infectious cancer, transmission of DFTD between individuals is a bit like a skin graft or organ transplant. If the tissue’s MHC type matches, the transplant is accepted, if not it is rejected.  Because the MHC types of the tumour and the devil match, DFTD cells are not recognised as foreign so no immune response is mounted.  And because of the low genetic diversity, all devils in the population have similar MHC types meaning the disease can easily spread from one individual to another. 

DFTD has spread rapidly throughout eastern Tasmanian populations, causing a 90% decline in total devil numbers.  However, a population at West Pencil Pine in northwestern Tasmania has much lower prevalence of DFTD, suggesting this population harbours animals that are resistant to the disease.  New research by Belov’s lab published in Proceedings of the Royal Society of London last month shows that these populations have differences in their MHC makeup that appear to allow them to resist the disease. 

Here the story gets a little (more) complicated: Tasmanian devils have multiple MHC genes (up to 7 genes each), which fall into two groups on the basis of their DNA sequence.  The tumour cells have both group 1 and group 2 variants, as do the individuals from the susceptible eastern populations.  However the northwestern populations harbour a greater diversity of MHC types, and many individuals from these populations have MHC types which have only either group 1 or group 2 sequences.  None of these individuals have succumbed to DFTD, suggesting they are resistant to the disease.  Belov’s group proposes that in individuals with only group 1 sequences, the immune system will recognise the group 2 sequences on the tumour as foreign and resist it (and vice versa for individuals with only group 2 sequences).   This has yet to be tested in practice, as it is obviously difficult to get permission to infect an endangered species with a deadly disease.  However, these findings are promising for the continued survival of the species and may have a significant impact on their conservation management.

Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ, Pyecroft S, Woods GM, & Belov K (2007). Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. Proceedings of the National Academy of Sciences of the United States of America, 104 (41), 16221-6 PMID: 17911263

Siddle, H., Marzec, J., Cheng, Y., Jones, M., & Belov, K. (2010). MHC gene copy number variation in Tasmanian devils: implications for the spread of a contagious cancer Proceedings of the Royal Society B: Biological Sciences DOI: 10.1098/rspb.2009.2362

The complicated genetics of human eye colour inheritance Hilary Miller Feb 01

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I’ll be taking a break from blogging over the next month as the “egg” (or is that the chicken?) will be hatching.  As you do, when about to have a baby, I’ve been thinking a bit about inheritance lately – what colour eyes or hair will my baby have, how tall, who will he/she take after? The questions are endless really (and no we DONT know the sex!). 

Being a geneticist, I figured the answers to at least some of these questions must be relatively well worked out.  Eye colour for starters – we all know brown eyes are dominant to blue, right?  And if you google “eye colour inheritance” you can find any number of “eye colour calculators” that will work out the likely eye colour of your offspring.  I tried to use one of these and immediately ran into a problem – even the most sophisticated one I could find only allowed brown, blue or green as eye colours.  Well, my eyes are hazel (grey/green with a brown ring around the pupil).  Does this count as green? And my partners eyes are not exactly blue or green, they are kind of greyish-greenish-blueish with a tendency to change colour depending on his clothes and the light.  So having fallen at the first hurdle, I began to suspect that eye colour might be a whole lot more complicated than what you learn at school. 

And it turns out that it is – eye colour is a polygenic trait, which means there are multiple genes that interact to produce the colour.  How many genes there are, where they are and what they do exactly is only partially known. 

Eye colour is determined by the amount and distribution of melanin in the iris.  Brown eyes contain more melanin than green eyes, while blue eyes have very little melanin.  The old textbook explanation that brown is dominant to green and both are dominant to blue does generally hold true, but not always, and is too simplistic to explain the multitude of variations on grey, blue, green and brown.  Geneticists have been modelling the inheritance of eye colour since the late 19th century, but originally described inheritance along the simple Mendelian dominant/recessive lines I described above.  It didn’t take long for exceptions to this rule to become apparent (like two blue eyed parents having a brown eyed child) and it became obvious that there must be more than one gene involved. 

In the 1980s chromosome mapping techniques were developed which enabled researchers to identify particular chromosomal regions (or loci) that are associated with inheritance of particular traits.  A locus associated with green eye colour (named Gey) was mapped to chromosome 19, and a locus associated with brown/blue eye eye colour (named Bey) was mapped to chromosome 15.  These “loci” are not genes as such, but they are regions of the chromosome that contain the genes likely to play a role in eye colour.  Many of the textbook explanations (and online calculators) for eye colour will tell you that there are 2 variants (alleles) for each of these loci - a green (dominant) and blue (recessive) allele at Gey, and a brown (dominant) and blue (recessive) allele at Bey.  This is a useful model for demonstrating how inheritance of a polygenic trait works, and in the case of eye colour it does explain some common patterns of inheritance.  But there are clearly additional alleles and additional genes at work that are only now beginning to be identified. 

The Bey locus has now been identified as a gene called OCA2.  This gene codes for a protein that stimulates the melanin-producing cells in the eye to mature and well, produce melanin.  OCA2 now looks to be the major determinant of eye colour, with some recent research estimating that this gene alone is responsible for about 74% of the variation in human eye colour.  There are far more than just two variant forms of this gene – dozens of alleles have now been identified, many differing by only a few changes in their DNA sequence.  A 2006 study found that some of these changes are highly diagnostic for particular eye colours – in fact, eye colour can be predicted reasonably well (but not entirely) from a person’s genotype at OCA2.  With the availability of human genome sequences, more new genes associated with eye colour are being discovered, but how these genes interact with OCA2, and exactly how much they contribute to eye colour is yet to be determined.   

So what colour will my baby’s eyes be?  After all my research I’m really no closer to an answer, but I’m guessing probably some variation on green.  I’ll be sure to let you know.

References (these appear to be free to access):

Sturm RA and Larsson M (2009) Genetics of human iris colour and patterns. Pigment Cell and Melanoma Research 22: 544-562. DOI: j.1755-148X.2009.00606.x

Duffy DL, Montgomery GW, Chen W, Zhao ZZ, Le L, James MR, Hayward NK, Martin NG, Sturm RA (2006).  A three single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. American Journal of Human Genetics 80: 241-52. DOI: 10.1086/510885

 

So what is a gene, exactly? Hilary Miller Dec 13

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Ever wondered just what a “gene” is, exactly? Well turns out that even geneticists are wondering the same thing these days, as they learn more about the genome and find that the concept of what comprises a gene is becoming more and more vague.

This months BioScience journal has an interesting (open-access) article on how the definition of a gene is changing. 

With the discovery that nearly all of the genome is transcribed, the definition of a ’gene’ needs another revision.

The article describes how the old definitions based around protein function (genes are units of DNA that code for proteins) have had to be expanded with the discovery that a large portion of the genome is transcribed into RNAs that don’t go on to make proteins, but have an important functional role themselves.

Citation:  Hopkins, K (2009). The Evolving Definition of a Gene. BioScience 59(11):928-931. doi: 10.1525/bio.2009.59.11.3

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…

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)

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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