Meet the world's newest lifeform: Syn 3.0

Every now and then, a piece of science is done that is truly ground-breaking and world changing. One such piece is:

Hutchison III CA et al. (2016) Design and synthesis of a minimal bacterial genome. Science 351(6280): aad6253-1. DOI: 10.1126/science.aad6253

Science has a summary here but it’s worth reading the whole paper. Syn 3.0 itself is pretty impressive, but what’s even more impressive is the approach taken to make it. In addition to using current knowledge of fundamental biological machinery, the Venter group used large-scale transposon mutagenesis and selection to identify additional genes that were either essential (i.e. no growth without them) or “quasi-essential”, where removal resulted in a major growth deficit.

They also had to overcome the problem of redundancy: even in a genome as reduced as the Mycoplasma species, there can sometimes be multiple genes that do the same thing. Removing one makes little difference but removing both is lethal - something hard to identify when knocking out single genes at a time. Whatever the Intelligent Design crowd would like to believe, biology is messy.

Of course, Syn 3.0 is just the start, as the goal was making a “minimal cell”:

“A minimal cell is usually defined as a cell in which all genes are essential. This definition is incomplete, because the genetic requirements for survival, and therefore the minimal genome size, depend on the environment in which the cell is grown. The work described here has been conducted in medium that supplies virtually all the small molecules required for life. A minimal genome determined under such permissive conditions should reveal a core set of environment-independent functions that are necessary and sufficient for life. Under less permissive conditions, we expect that additional genes will be required.”

Robust life will therefore need a lot more genes. It will be interesting to see how many are required for autotrophy - life that needs only inorganic chemicals and an energy source.

Even within the “minimal cell” concept, Syn 3.0 represents a somewhat arbitrary end-point. In identifying the “quasi-essential” genes, a judgement had to be made regarding what constitutes an acceptable growth rate*. Whittling down to 473 genes is impressive, but this number could no doubt be even smaller if slower growth rates were accepted. (Modern life is in competition with lots of other highly evolved organisms. Early life would have been able to get by with much lower growth rates, so this is not a “minimal cell” in that context.)

There is also a lot of exciting potential ahead for manually reducing the number of genes by true intelligent design. Fusing interacting gene products together, for example, might eliminate the need for so many genes contributing to core processes. (Looking for apparent protein fusion/fission events in evolution is a reasonably successful method for predicting protein-protein interactions.) With time, we might be able to “wind back the clock” and remove some of the unnecessary complexity that has probably crept into the system due to the underlying evolutionary process.

I also wonder how many of the current crop of genes of unknown function - a surprising 149 genes - can be replaced over time with genes of known function. (In other words, how many of them represent convergent evolution of functions we already know about but are not recognisable.) And how many of the rest are genome-/condition-specific?

Like all of the best science, this work opens the door to more questions than it answers! Some exciting times ahead, I think.

[*The important but oft-overlooked concept that any assessment of life is context- and environment-dependent exposes another flaw with Intelligent Design as a testable hypothesis: designed to do what? To assess how well-designed something is, one needs to know its purpose and/or the acceptable design traits. To hide from the fact that Intelligent Design is Creationism, supporters often make the argument that the identity of the designer (Creator) is not important - but without knowledge of the designer, how can one predict the motivation behind the design?]

Developments in high throughput sequencing (June 2015 Edition)

This is nearly a month old now but Keith Bradnam’s ACGT blog a while back drew my attention to the June 2015 edition of Lex Nederbragt’s Developments in high throughput sequencing in which he plots Gigabases* per run against (log) read length (*the human genome is about 3Gb):

I’m particularly excited by the two technologies on the right of this graph, which represent the latest single molecule “long read” sequencing technologies, both of which we now have access to through the Ramaciotti Centre for Genomics. In fact, we got our first data from the PacBio RS II (right) and it’s looking good! (More on that later.)

Despite being a bioinformatician with a background in genetics, I have been keeping my distance a bit from “next generation sequencing” as the technical challenges of dealing with short read data far eclipse the scientific interest. (For me, that is - the kinds of things that I am most interested in do not suit short read data.) The new long read technologies are a real game changer, and I see a lot more genomics in my (and this blog’s) future.

Best journal cover ever?

Courtesy of the Molecular Biology and Evolution Facebook page comes this awesome cover art:

According to the MBE Editor:

The author and artist info: The cover image depicts representative squamate species (lizards and snakes) playing poker, with the card and chip colors representing the sex-determining system most prevalent in each clade. The tabletop shows results from a comparative genomic analysis of squamate sex-determining mechanisms by Gamble et al in this issue. This study discovered that changes between sex-determining mechanisms in one clade, geckos, account for a half to two-thirds of the total transitions known in lizards and snakes. This remarkable frequency of transition is reflected in the illustration by the heightened activity at the gecko side of the table: the three gecko species in the foreground are cheating, implying that when it comes to sex determination, geckos do not play by the rules. The image was created by University of Minnesota biologist and artist Anna Minkina and pays homage to the Cassius M. Coolidge painting, “A Friend in Need”, part of the artist’s “Dogs Playing Poker” series.

h/t: James McInereny

Prof Bryan Clarke (1932-2014)

I was sad to read a post on the Evolution Directory (Evoldir) by my PhD supervisor, John Brookfield, that Professor Bryan Clarke died last month. Bryan founded the Genetics Department (later Institute and now Centre for Genetics and Genomics) at the University of Nottingham , where I did both my undergrad degree and PhD. He and retired when I was still an undergrad but, as Emeritus Professor, he was still heavily involved in the department for the rest of my time there.

Although I did not know Bryan well, he always had time for students and was an inspirational character - and that was before the Frozen Ark project was launched. I was particularly impressed by the way that he managed to combine ground-breaking basic science with regular visits to Pacific island paradise!

With permission, I have repeated John’s post below:

It is with great sadness that we have to report to the evolution community the death of Professor Bryan Clarke FRS on Thursday, the 27th February 2014.

Bryan Clarke was a leader in our understanding of the process of evolution for more than four decades. He made fundamental contributions, both empirical and theoretical, particularly in elucidating the forces that maintain genetic variation in populations, and in throwing light on the process of speciation.

Bryan was born on the 24th June 1932, and, following service in the Royal Air Force, was educated at Magdalen College Oxford, from where he received both his BA in 1956 and DPhil in 1961. From 1959 to 1971 he worked at the University of Edinburgh, starting as Assistant Lecturer and rising to a Readership. In 1971 he was the Foundation Professor at the new Department of Genetics at the University of Nottingham, and remained until 1997, when he became Professor Emeritus.

The Darwinian theory of evolution by natural selection identifies genetic differences in populations - polymorphisms, as the key to evolutionary change. It is of fundamental interest whether polymorphisms are affected by natural selection, or solely by genetic drift. Bryan’s research focussed on polymorphisms in snails, including members of the genus Cepaea, the shells of which vary greatly in colour and in their banding patterns. While some had naively suggested that this variation might have no effect on the organisms’ fitness, earlier experiments and observations, from Cain and Sheppard in particular, had demonstrated that these variants were indeed subject to natural selection. But, if there is selection operating on this genetic variation, why does the population not come to consist of only a single, best-adapted, type? The answer is that selection can, in some circumstances, maintain variation rather than destroying it. One mechanism for the maintenance of genetic variation is heterozygote advantage, which explains, for example, the high frequency of the allele causing sickle cell anaemia. Bryan knew that the patterns of inheritance of the polymorphisms in Cepaea could not be explained by heterozygote advantage. Rather, he was able to demonstrate that these are maintained by a different mechanism, frequency-dependent selection, in which the fitness of genetic types increases if their frequencies in the population diminish, thereby creating a stable equilibrium in which multiple genetic types are maintained. His studies of frequency-dependent selection were able to demonstrate the near-ubiquity of this phenomenon when visible polymorphisms are studied in wild populations, and also showed the selective agents which brought this about. The frequencies of polymorphic variants in snails can vary greatly in space, without any obvious environmental correlates. An important and influential step in the understanding of such “area effects” came from Bryan’s models of morph-ratio clines in his 1966 American Naturalist paper.

Studies of visible polymorphisms were augmented, from the 1960s, by the study of polymorphisms in the amino acid sequences in proteins, investigated initially through electrophoretic detection of differences in the electric change on enzyme molecules. As with the visual polymorphisms in Cepaea, some assumed that the changes were invisible to natural selection. Bryan Clarke advocated the view that a large proportion of the changes were indeed subject to natural selection and demonstrated experimental support for this view, particularly for variants in the enzyme alcohol dehydrogenase in Drosophila melanogaster. The study of selection acting on polymorphic differences in amino acid sequences is a direct way to obtain evidence about whether the long-term evolution of the amino acid sequences of proteins is shaped by natural selection. Some believe that protein evolution is almost completely dominated by random forces in which the successful variants were so not because of the advantages they gave to their bearers, but as a result of genetic drift. Bryan Clarke was one of the main advocates of the view that a large part of the evolutionary changes in the amino acid sequences of proteins were indeed driven by Darwinian natural selection, a view that results from large-scale DNA sequencing are confirming in many species.

Bryan Clarke also played a large part in developing our understanding of the process through which species form. He carried out a long-term study of species of the land snail Partula on the South Pacific island of Moorea and neighbouring islands. He appreciated that, in the early stages of speciation, matings between members of populations undergoing speciation do not stop instantly- some hybridisation persists. Species stay distinct notwithstanding there being some gene flow between them. Thus, selectively important genetic differences between species, such as those determining form, colour and behaviour, are maintained as distinct and recognisable features, while the low levels of gene flow resulting from hybridisation allow genetic differences which are not selectively important to randomise themselves between the hybridising forms. These phenomena have been documented in Partula, where less important differences have been shown to be shared between species which live in the same geographic location. The ability to study these early events results from the choice of the Partula species, where speciation has been “caught in the act”. Increasingly, similar phenomena are now being documented in patterns of DNA sequence diversity in other species studied at these early stages.

Through these diverse achievements at the cutting-edge of understanding of the process of evolutionary change, Bryan Clarke was a great mentor and role-model for younger scientists in evolutionary genetics, and supervised more than thirty research students, at least six of whom are now professors. He was a co-founder of the very successful Population Genetics Group, a meeting for population geneticists from the UK and Europe that has been running for almost fifty years.

He was co-founder and trustee of the charity “The Frozen Ark”, which preserves, in the form of DNA and cell lines, the genetic material of endangered animals, to allow future scientific study.

Honours and awards for Professor Clarke reflected his outstanding role in modern evolutionary genetics. He was elected a Fellow of the Royal Society in 1982, became an International Member of the American Philosophical Society in 2003, and a Foreign Honorary Member of the American Academy of Arts and Sciences in 2004. Medals and awards include the Linnean Medal for Zoology in 2003, the Darwin-Wallace Medal of the Linnean Society in 2008, and the Royal Society’s Darwin Medal in 2010.

Bryan leaves his wife Ann, his son Peter and daughter Alex.

Picture from Bryan Clark's obituary in The Telegraph.

The $1000 genome is here... Kind of...

I’m not an avid follower of tech news but something that popped up on my radar this week seemed worthy of a blog post. As Bio-IT World reports in What You Need to Know About Illumina’s New Sequencers, Illumina have announced the first sub-$1000 human genome:

Sequencing costs have been coming down steadily and dramatically since the invention of “Next Generation” techniques and the “$1000 genome” - a full human genome for under $1000 - has long been one of the holy grail targets of cheap sequencing. The cost-per-genome that Illumina quote does indeed represent a substantial drop:

This is not for everyone, as you need to buy at least ten machines as a “HighSeq X^TM Ten package at $1 million a piece.

According to the Illumina press release:

The HiSeq X Ten is the world’s first platform to deliver full coverage human genomes for less than $1,000, inclusive of typical instrument depreciation, DNA extraction, library preparation, and estimated labor. Purpose-built for population-scale human whole genome sequencing, the HiSeq X Ten is an ideal platform for scientists and institutions focused on the discovery of genotypic variation to enable a deeper understanding of human biology and genetic disease. It can sequence tens of thousands of samples annually with high-quality, high-coverage sequencing, delivering a comprehensive catalog of human variation within and outside coding regions.

The $1000 price tag only applies “when used at this scale” and it doesn’t say anything about computational costs - storing and processing the vast quantities of data coming of the machine. For many sequencing applications, the computational cost now exceeds the sequencing cost, although I suspect that genome re-sequencing is at the cheaper/easier end of the processing spectrum. Which brings me to the other aspect of my “kind of…” qualifier: the HighSeq X^TM still only produces 150bp reads, and at 30x coverage. This is ample for certain applications and will enable you to re-sequence (i.e. use an existing genome sequence as a scaffold to map the short reads onto) most of a “normal” human genome. It will probably struggle, however, when looking at repetitive sequences. Sequencing a genome de novo (i.e. without a template for assembly) will not be possible at the sub-$1000 price tag. Likewise, samples with heterogeneity, such as cancer genomes, need much more that 30x coverage.

As a bioinformatician, announcements like this fill me with a mixture of excitement and dread. Don’t get me wrong: being able to generate so much more data is great. The problem is, we need to be able to do something with all that data. Short 150bp read data is, ultimately, quite limiting: you need loads of it to get decent coverage/assembly and you are always going to be stuck where greater lengths are required to discriminate between repeats etc. Processing, quality-controlling, filtering and assembly these short reads remain a bioinformatic headache. This is definitely progress but, personally, I am still waiting for long-read single molecule sequencing before I get too excited.

RIP Fred Sanger (1918-2013)

I opened my email this morning to the news that Fred Sanger had died. This was not entirely surprising, given that he was 95, but still sad. Although I have never met him, I think it is fair to say that I am one of many scientists whose careers have been shaped and influenced by the work of this great scientist.

I still remember sitting in lectures as an undergraduate and discovering how “Sanger” sequencing worked - like many of the ideas that change the world, it was gloriously simple and yet spectacularly clever. And, I think it is fair to say, it changed the face of biology forever.

Indeed, that was back in 1977, and Sanger sequencing is still used all over the world today, even in the face of stiff competition from “Next Generation” methods. It was the sequencing method (albeit in a much tweaked and automated version) that got us the Human Genome and one of the world’s leading sequencing centres - the Wellcome Trust Sanger Institute at Hinxton, outside Cambridge - still bears his name.

The centre has a press release about the “remarkable man”, which has been written by greater wordsmiths than I:

“Fred Sanger, who died on Tuesday 19 November 2013, aged 95, was the quiet giant of genomics, the father of an area of science that we will explore for decades to come.

His achievements rank alongside those of Francis Crick, James Watson and Rosalind Franklin in discovering the structure of DNA. We are proud that he graciously agreed to allow our Institute to be named after him.

In research marked by two Nobel Prizes, he developed methods that allow us to determine the order of the building blocks of DNA and of proteins. This technique allowed the languages of life to be read.

Because of Fred’s work we have been able to interpret those languages and to use that knowledge for good.”

There is more, including quotes and links out to other resources about his work, at the site.

I remember thinking in those lectures back in Nottingham how I wished that one day I might have an idea as good as Sanger sequencing. I doubt that I ever will; instead, I will just have to settle for trying to do the best I can with all of the amazing sequence data that now exists as a result.

New(ish) Zooniverse Project: Worm Watch Lab

This post is actually about a month out of date but I was reminded of it after some “citizen science” on Dara O’Briain’s Science Club this week. Back in January, I posted about mapping Mars with Planet Four (also following a Dara O’Briain show!) and the Zooniverse team behind it brought out a new project last month, classifying videos of tiny nematode worms in Worm Watch Lab.

I have a bit of a soft spot for the little nematode species, Caenorhabditis elegans, which is used in labs around the world as a model organism. Not only is it cool in its own right - it was the first animal to have its genome sequenced and has had the entirety of its developmental cell lineages mapped - it was the basis of one of my first collaborative projects in Southampton as well as my only joint publication with my wife. As a well characterised model organism with (perhaps) surprising genetic and biochemical similarities to humans, C. elegans worms are a big part of the 3R’s effort in animal research (replacement, refinement and reduction) across British life science.

Worm Watch Lab constitutes one such project in association with the Medical Research Project:

We need the public’s help in observing the behaviour of tiny nematode worms. When you classify on wormwatchlab.org you’re shown a video of a worm wriggling around. The aim of the game is to watch and wait for the worm to lay eggs, and to hit the ‘z’ key when they do. It’s very simple and strangely addictive. By watching these worms lay eggs, you’re helping to collect valuable data about genetics that will assist medical research.

With your classifications we can understand how the brain works and how genes affect behaviour. The idea is that if a gene is involved in a visible behaviour, then mutations that break that gene might lead to detectable behavioural changes. The type of change gives us a hint about what the affected gene might be doing. Although it is small and has far fewer cells than we do, the worm used in these studies (called C. elegans) has almost as many genes as we do! We share a common ancestor with these worms, so many of their genes are closely related to human genes. This presents us with the opportunity to study the function of genes that are important for human brain function in an animal that is easier to handle, great for microscopy and genetics, and has a generation time of only a few days. It’s all quite amazing!

To get started visit www.wormwatchlab.org and follow the tutorial.

I’ve had a little play and it is quite fun. Not an awful lot of egg-laying but its interesting watching them move as there are clearly behavioural differences between the videos. (I wonder if they will start recording reversals etc. in future.)

The Ehux genome is here and it looks epic!

In addition to my main research on Short Linear Motifs, I have a number of collaborations with environmental scientists looking at how various organisms, such as corals, might be affected by rising CO₂ levels.

One of the more fun collaborations has been with Bethan Jones (now at Oregon State University) and Debora Iglesias-rodriguez (now at UC Santa Barbara), working on the marine phytoplankton Emiliania huxleyi. Along with Paul Skipp at Southampton, I was involved with with proteomic analysis of this small but important organism. This was challenging because, at the time, their was no annotated genome available - hence the need for some bioinformatics help. (The second paper from this came out in April but my planned blog post was postponed after the Boston marathon bombing and is now sitting on my To Do list.)

Happily, the genome is now out! As reported in the KQED blog post, Opening the Gene Box of a Key Ocean Species:

“This week in the journal Nature, a worldwide team of 75 scientists revealed the genetic blueprint of the one-celled alga Emiliania huxleyi, which may be the most important species you’ve never heard of. The genomes of the domestic dog and cat are interesting, but the E. huxleyi genome is a much bigger story. Some day this organism may become another of our partner species, as vital to us as yeast.”

Even more happily, Bethan and Debora are both authors on the paper (as part of the Emiliania huxleyi Annotation Consortium), Pan genome of the phytoplankton Emiliania underpins its global distribution, which reports “sequences from 13 additional isolates” in addition to the genome of the reference strain CCMP1516. Many years in the making, it’s a bit of an epic, and I look forward to learning some more of Ehux’s secrets.

h/t: Bethan. [Picture from KQED] Citation: Read et al. (2013). Nature doi:10.1038/nature12221.

Happy DNA Day!

It's 60 years to the day since the trio of Nature papers about the structure of DNA were published, including the famous 1953 Watson & Crick paper. The double helix has to be one of the most elegant and beautiful of all natural phenomena. The Exploratorium website has an annotated version of the Watson and Crick paper if you fancy a read. It's pretty short and contains one (or two) of the biggest understatements in biological history:

"This structure has novel features which are of considerable biological interest. ... It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material."

Indeed!

Nature launches "pastcasts" with 1953 DNA papers - and unsung hero of the story, Raymond Gosling

The Nature Podcast has added a new series: the Nature Pastcast, which revisits key papers from the Nature archives. The first episode looks at the famous 1953 Watson & Crick paper and the other two DNA papers from the same issue.

Watson and Crick are rightly famous for the discovery of the structure of DNA. Maurice Wilkins, who was senior authors on one of the other papers in the issue and showed Watson the famous X-Ray diffraction image of "B DNA" ("Photograph 51" [image, above right, from Wikipedia]) shared the Nobel prize with Watson and Crick.

Everyone also seems to know about Rosalind Franklin, whose group took the X-Ray image (but did not appreciate its significance) and many people was cheated of a Nobel prize because it is not awarded posthumously. There was another key player that I had never heard of until today, though, Raymond Gosling.

Having listened to the podcast, if anyone should have shared the glory of the discovery it was Gosling. It was he who took the famous Photograph 51 and he who gave it to Wilkins, who in turn showed it to Watson. Franklin, it seems, was primarily interested in solving the "A" form of DNA, of which this was not an image. You can hear more of his story in his own words in a Nature Podcast Extra interview. Interesting stuff.

Geek architecture at Cold Spring Harbor Laboratory

As well as the geeky sculptures, the Cold Spring Harbor Laboratory has some good geeky architecture. The tower of the Beckman Laboratory (above) stood out to me as a geneticist, with the four nucleotide abbreviations (g, a, t, c) on its four faces. There was a bit of a missed opportunity with the staircase in the middle, though, which is just a spiral up a central column rather than a double helix (right). Oh well.

As it happens, the conference was too engaging to do much exploration, so I'm not sure if it's a repeating theme across campus. If I get to go back, I will have to find out. Even if there isn't, though, it's a charming place to wander about. Apparently, it used to be a whaling station and many of the labs are in what look like large colonial houses, such as the Luke Building (below).

Prominent anti-GM campaigner becomes GM defender after looking into the science

I don't like to name-and-shame on my blog (attack the idea, not the person) but I don't mind giving a positive shout out to those deserving of praise and I think one such person is Mark Lynas. Mark is an author, journalist and environmental activist. He has written a lot about climate change (in a pro-science, myth-busting way) but was also a very active anti-GM campaigner.

The corner of Twitter that I follow is alight with the fact that, last week, he delivered a frank admission that his anti-GM stance was wrong to an Oxford Farming Conference. I've not watched the video but the transcript on his website makes an interesting and inspiring read. The first three paragraphs are particularly hard-hitting:

"I want to start with some apologies. For the record, here and upfront, I apologise for having spent several years ripping up GM crops. I am also sorry that I helped to start the anti-GM movement back in the mid 1990s, and that I thereby assisted in demonising an important technological option which can be used to benefit the environment.

As an environmentalist, and someone who believes that everyone in this world has a right to a healthy and nutritious diet of their choosing, I could not have chosen a more counter-productive path. I now regret it completely.

So I guess you’ll be wondering – what happened between 1995 and now that made me not only change my mind but come here and admit it? Well, the answer is fairly simple: I discovered science, and in the process I hope I became a better environmentalist."

It's a pretty courageous admission to make, I think, especially given the later paragraph that gives some truth to what a lot of us in favour of a balanced approach to GM food have long suspected:

"This was also explicitly an anti-science movement. We employed a lot of imagery about scientists in their labs cackling demonically as they tinkered with the very building blocks of life. Hence the Frankenstein food tag – this absolutely was about deep-seated fears of scientific powers being used secretly for unnatural ends. What we didn’t realise at the time was that the real Frankenstein’s monster was not GM technology, but our reaction against it."

What changed Mark's mind?

"So I did some reading. And I discovered that one by one my cherished beliefs about GM turned out to be little more than green urban myths.

I’d assumed that it would increase the use of chemicals. It turned out that pest-resistant cotton and maize needed less insecticide.

I’d assumed that GM benefited only the big companies. It turned out that billions of dollars of benefits were accruing to farmers needing fewer inputs.

I’d assumed that Terminator Technology was robbing farmers of the right to save seed. It turned out that hybrids did that long ago, and that Terminator never happened.

I’d assumed that no-one wanted GM. Actually what happened was that Bt cotton was pirated into India and roundup ready soya into Brazil because farmers were so eager to use them.

I’d assumed that GM was dangerous. It turned out that it was safer and more precise than conventional breeding using mutagenesis for example; GM just moves a couple of genes, whereas conventional breeding mucks about with the entire genome in a trial and error way."

What's worse, is not so much the myths themselves but the unwanted consequence of perpetuating those myths:

"Before [Norman] Borlaug died in 2009 he spent many years campaigning against those who for political and ideological reasons oppose modern innovation in agriculture. To quote: “If the naysayers do manage to stop agricultural biotechnology, they might actually precipitate the famines and the crisis of global biodiversity they have been predicting for nearly 40 years.”

And, thanks to supposedly environmental campaigns spread from affluent countries, we are perilously close to this position now. Biotechnology has not been stopped, but it has been made prohibitively expensive to all but the very biggest corporations.
...
There is a depressing irony here that the anti-biotech campaigners complain about GM crops only being marketed by big corporations when this is a situation they have done more than anyone to help bring about."

There's a lot in there dispelling some of the myths about the benefits of organic food too but, being a geneticist, I'm more interested in the Genetic Modification angle. I've already given some of my own views on (Standing up for Genetic Modification) so I won't repeat them here. I was not quite aware, however, just how much the anti-GM movement had stood in the way of progress, including the Golden Rice project that I mentioned in my previous post:

"The second example comes from China, where Greenpeace managed to trigger a national media panic by claiming that two dozen children had been used as human guinea pigs in a trial of GM golden rice. They gave no consideration to the fact that this rice is healthier, and could save thousands of children from vitamin A deficiency-related blindness and death each year.

What happened was that the three Chinese scientists named in the Greenpeace press release were publicly hounded and have since lost their jobs, and in an autocratic country like China they are at serious personal risk. Internationally because of over-regulation golden rice has already been on the shelf for over a decade, and thanks to the activities of groups like Greenpeace it may never become available to vitamin-deficient poor people.

This to my mind is immoral and inhumane, depriving the needy of something that would help them and their children because of the aesthetic preferences of rich people far away who are in no danger from Vitamin A shortage. Greenpeace is a $100-million a year multinational, and as such it has moral responsibilities just like any other large company.

The fact that golden rice was developed in the public sector and for public benefit cuts no ice with the antis. Take Rothamsted Research, whose director Maurice Moloney is speaking tomorrow. Last year Rothamsted began a trial of an aphid-resistant GM wheat which would need no pesticides to combat this serious pest.

Because it is GM the antis were determined to destroy it. They failed because of the courage of Professor John Pickett and his team, who took to YouTube and the media to tell the important story of why their research mattered and why it should not be trashed. They gathered thousands of signatures on a petition when the antis could only manage a couple of hundred, and the attempted destruction was a damp squib."

He also draws attention to another case that, having lived in Ireland for six years, was of particular interest to me:

"One final example is the sad story of the GM blight-resistant potato. This was being developed by both the Sainsbury Lab and Teagasc, a publicly-funded institute in Ireland – but the Irish Green Party, whose leader often attends this very conference, was so opposed that they even took out a court case against it.

This is despite the fact that the blight-resistant potato would save farmers from doing 15 fungicide sprays per season, that pollen transfer is not an issue because potatoes are clonally propagated and that the offending gene came from a wild relative of the potato.

There would have been a nice historical resonance to having a blight-resistant potato developed in Ireland, given the million or more who died due to the potato famine in the mid 19th century. It would have been a wonderful thing for Ireland to be the country that defeated blight. But thanks to the Irish Green Party, this is not to be."

There's a lot more in the post and I think that the lecture itself has more still, so I encourage you to go and read and/or listen to the post on Mark's website if you are even slightly convinced that blanket opposition to GM is a good thing. (The Science Museum has a fairly balanced intro to some of the pros and cons here. It is important to stress that GM is not always good nor is it the only solution to food security but it is a vital weapon in our arsenal against the duel threat of climate change and global over-population.)

The end is pretty hard-hitting too:

"So I challenge all of you today to question your beliefs in this area and to see whether they stand up to rational examination. Always ask for evidence, as the campaigning group Sense About Science advises, and make sure you go beyond the self-referential reports of campaigning NGOs.

But most important of all, farmers should be free to choose what kind of technologies they want to adopt. If you think the old ways are the best, that’s fine. You have that right.

What you don’t have the right to do is to stand in the way of others who hope and strive for ways of doing things differently, and hopefully better. Farmers who understand the pressures of a growing population and a warming world. Who understand that yields per hectare are the most important environmental metric. And who understand that technology never stops developing, and that even the fridge and the humble potato were new and scary once.

So my message to the anti-GM lobby, from the ranks of the British aristocrats and celebrity chefs to the US foodies to the peasant groups of India is this. You are entitled to your views. But you must know by now that they are not supported by science. We are coming to a crunch point, and for the sake of both people and the planet, now is the time for you to get out of the way and let the rest of us get on with feeding the world sustainably."

I think the message here goes well beyond the GM debate too. There are a lot of worthy causes to campaign for but it is always important to periodically re-visit and re-evaluate the evidence for and against any given position. (It is very rare for something to be all-good or all-bad.) Most important of all, one should always be willing and able to admit that one was wrong, as Mark Lynas has done.

h/t: Simon Singh. [Golden Rice Picture taken from the Genetic Literacy Project. (Although based on a Google search, the anti-GM lobby have all the good pictures!)]

More genomes than you can shake a bamboo stick at

I remember when the first eukaryotic genome - that of yeast - was sequenced in 1996. I was still an undergraduate student, studying Genetics. At the time, it felt like it was the golden age of genetics, with the excitement of the ongoing Human Genome Project. The original human genome took over 10 years and cost around 3 billion dollars - approximately one dollar per base pair. (Nowadays, it's less than $10k per genome.)

It is sometimes easy to forget how far we have come in the decade or so since the first human genome was finished but in case you need a reminder, you need look no further than the latest issue of Nature Reviews Genetics, which features the sequenced genomes of sweet oranges, mandarins, pummelos, watermelons and 34 giant pandas. (2% of all the wild giant pandas!)

I like the last paragraph of the editorial too:

"We do not have to just believe in the process of evolution by natural selection. We can see mutation and selection produce varieties and species of crop plants. We can see the process at work in the wild and admire the way it creates and shapes species and populations of animals and plants. And, the most wonderful thing of all is that you can test the predictions of the idea with your own experiments, with your own eyes."

Perhaps the craziest things of all is that sequencing technology is still improving and still getting cheaper. As a bioinformatician, this is both exciting and scary, as data storage and analysis struggles to keep up with data generation. In fact, I wonder whether 2013 will be the year when sequencing itself becomes like the intermediate stage of a laboratory experiment and people will stop storing the raw data once it's been processed - it's probably cheaper just to repeat the sequencing than to store and backup the raw data!

Differential survival, (inclusive) fitness, selection and evolution

In my last post about Multi-level selection and The Selfish Gene, I neglected probably the most famous and important aspect of the "Group Selection" debate: "inclusive fitness", which (along with its specific form, "kin selection") can potentially give rise to counter-intuitive adaptive behaviours such as altruism and self-sacrifice. To understand inclusive fitness and how/why (a) it works, and (b) it is important, we have to revisit the importance and meaning of heritability in selection.

The key point is that "fitness" and selection are about more than just differential survival. Differential survival is sufficient for evolution - the population will change with time - but without the heritability aspect, this is not selection and there can be no adaptation.

It's easiest to think about this in terms of purely random events. Imagine two populations of beetle (there sure are a lot of beetles!) living in two trees who, by chance founder effects have different frequencies of an allele that causes melanism (a dark colour morph). Now imagine that one of those trees experiences a rare catastrophic event - perhaps a meteor-strike, or it is on a cliff-top and collapses into the sea - that wipes out its entire beetle population. The frequency of melanic colour morphs in the beetle population has changed - there has been differential survival - but because it was totally unrelated to the causal reason for the differential survival, this is not selection.

Evolution without selection happens all the time and can easily lead to certain traits becoming fixed in a population, even if they have no direct (or only a very weak) fitness effect on those with the trait relative to those without. (Fitness is always relative.) Most changes at the molecular level, for example, are neutral changes occurring through random genetic drift. This is still evolution, it is just not selection - it will not give rise to adaptation. (Although a change of environment - and the environment for genes is never static - could render a previously neutral trait as good or bad.)

So where does kin selection and inclusive fitness come in? Well, a key - and sometimes confusing - point about fitness and selection is that the individuals expressing the heritable trait and the individuals benefiting from the heritable trait do not have to be the same individuals. This is critical because it reinforces the special place that genes have in multi-level selection.

In the last post, I wrote:

Yes, selection can potentially act at some of these different levels - the collective properties of the family, tribe, species or ecosystem can affect the fitness of the genes therein - but only the genes make copies of themselves. Only the genetic information is passed on - all of the physical aspects - the DNA, the chromosomes, the cells, the bodies, the tribes, the ecosystems - are transient vehicles for this information. Only if this genetic information gives rise (in an appropriate background) to the trait that influences fitness - whatever the level that fitness is manifest - will that trait be heritable and selection happen.

This is the difference between "replicators" (in Dawkins parlance) and mere reproducers. The crucial thing about genes is that they make copies of themselves, which are then carried by different members of the population. A particular genetic variant will increase in frequency if the sum total of all its effects is to the collective benefit of carriers of that genetic variant, even if some of its effects are detrimental to some of its carriers. Hence altruism can still spread if it has a genetic basis and the net product is increased survival/reproduction of carriers of the altruism "gene(s)".

There are two more important points about inclusive fitness:

1. Kin recognition is not required. Crucially, there does not need to be a conscious awareness by the altruistic individual; it does not need to be able to recognises its kin or fellow gene-carriers. (Although, clearly, if it can then it will be even more successful.)

2. All fitness is inclusive fitness. Inclusive fitness is one of the few unifying principles of biology that, as far as I can tell at least, applies across the board. Whether you are talking about Artificial or Natural Selection, Individual or Group Selection, it all comes down to inclusive fitness. Even when all of the phenotypic effects of gene are limited to its carrier - pure "Individual Selection" - inclusive fitness comes in to play: as long as it benefits more individuals than it impairs, it will still spread. (The same gene can have different effects in different individuals.)

The nice thing about inclusive fitness is that it works irrespective of the nature by which the sum total of its effects benefit its carriers. These effects can occur at any level of biological organisation and may, indeed, have effects at multiple levels; thanks to inclusive fitness, far from being in conflict, multi-level selection and The Selfish Gene are one and the same.

Multi-level selection and The Selfish Gene

Yesterday, I attended a seminar run by the University's Institute for Complex Systems Simulation by Samir Okasha, a Professor of Philosophy of Science from the University of Bristol and author of the book "Evolution and the Levels of Selection" (among others). The talk was entitled 'Individuals versus Groups in Evolutionary Biology' and Prof. Okasha gave a very interesting presentation about some of the history and issues surrounding the discussions (and sometimes arguments) about "Group Selection" and its modern incarnation, "multi-level" selection.

It looks like an interesting book too and is on my ever-growing reading list. I'd particularly like to ponder some more his thoughts on emergent group properties - something I do not currently have the time, space or philosophical nonce to explore further in this post.

There was one key aspect of the debate that, in the interests of time, was not covered in detail in his talk: the issue of heritability and what that means for "Units of Selection". The more I think about it, the more I think it is a real barrier for people understanding the problem and, in my opinion, leads to all sorts of confusion about how evolution and selection work.

This is a quote from an Amazon review of his book that sums up the key issue quite nicely:

So often we are bombarded with 'scientists' giving us their metaphysical views as if they were 'scientific fact'. It is therefore refreshing to find a philosopher looking at a science and seeking to clarify the various concepts in that science.

Okasha observes that the various life forms are arranged in a hierarchy:
Ecosystems
Species
Colonies
Organisms
Cells
Chromosomes
Genes.

Generally reproduction occurs at the same level in the hierarchy: organisms reproduce to give organisms; chromosomes divide to give chromosomes; colonies divide to give colonies, and so on. According to the logical formulation of the theory of `natural selection' a) variation, b) differential fitness (different rates of survival and reproduction) and c)heritability (parent - offspring correlation) are required to produce evolutionary change. All these may be present at each of the levels in the hierarchy so there is nothing that necessarily restricts selection to any one level, say at the level of the gene. To claim that selection always occurs at the level of the gene is to confuse the result of selection (the proportion of the various genes in the gene pool) with the process of selection (where in the hierarchy the winnowing actually occurs). [My emphasis]

This is an argument that I have come across a few times on internet forums and like - often by non-biologists. (I'm not sure why the reviewer puts quotes around 'scientists' - perhaps this is an unfair dig at Dawkins. When these arguments appear, they are often accompanied by a barrage of anti-Dawkins nonsense about dogmas and how our old, flawed understanding of evolution is being overthrown etc. At best, this is a gross exaggeration. In my opinion, it is utter hogwash.)

Quite simply, I don't think this argument works because it overlooks something very important. I have highlighted the key phrases in bold. This review has the matter utterly backwards. To say that selection is occurring at a level other than the gene and not the gene (and "gene" in this context must have the correct evolutionary meaning not the biochemical meaning) is to confuse the agent of selection, which can be gene, cell, organism, family, whatever, and the target of selection - the "gene". This is because, for selection to work, there has to be heritability and this heritability is not simply "parent - offspring correlation".

(At this point, I would like to make it clear that I do not think Samir Okasha makes this mistake. I've not read his book yet but in his talk he was very clear to make the distinction between causality in selection - what we call direct and indirection selection, which correspond to causal and correlative changes in gene frequency. He also pointed out that there is no conflict with multi-level selection and "The Selfish Gene".)

For selection to work, there has to be a causal link between the heritable trait and differential fitness. Mere correlation is not enough. It is enough for evolution - there will be a change over time - but it is not enough for natural selection. And this is where genes are special. Yes, selection can potentially act at some of these different levels - the collective properties of the family, tribe, species or ecosystem can affect the fitness of the genes therein - but only the genes make copies of themselves. Only the genetic information is passed on - all of the physical aspects - the DNA, the chromosomes, the cells, the bodies, the tribes, the ecosystems - are transient vehicles for this information. Only if this genetic information gives rise (in an appropriate background) to the trait that influences fitness - whatever the level that fitness is manifest - will that trait be heritable and selection happen. Reproduction in the important sense - heredity - does not occur "at the same level in the hierarchy".

Has anyone actually demonstrated non-genetic inheritance of any higher-level trait? I'm not aware of any and whenever I have raised this in online discussions, I am normally just met with a barrage of anti-Dawkins nonsense or some vague notions about epigenetics, behaviour and "emergent" properties (which I advocate in general, by the way,) without any specific demonstration or model as to how these higher levels reproduce and pass on their traits to the next generation. Crucially, you have to do more that demonstrate that it could work mathematically or in a computer simulation - you have to demonstrate that there is a corresponding biological reality.

Which brings me to another important point. I would also question the notion of "fitness" at some of these higher levels. Ecosystems do not reproduce at all. There can be competition between groups of organisms, certainly, and long-term differential survival, which will result in evolution - just as random events such as floods and meteor strikes can influence long-term evolution through differential survival. But this is not selection. The ecosystem is changing because of individual success or otherwise and individual success is being influenced by the environment - the changing ecosystem - but an ecosystem is not directly spawning a new ecosystem that inherits its properties and goes off into the world to compete with different ecosystems. (It seems to me that there is one higher level entity capable of non-genetic inheritance - something championed by Dawkins himself. The cultural replicator, or "meme". This is not what multi-level selection is about, though, as far as I can tell.)

A final problem for non-genetic multi-level selection is that many of these "levels" don't really exist in a fashion that makes selection possible - they are part of continua rather than discrete entities. An ecosystem, for example, does not really mean anything specific. I am an ecosystem from the perspective of my gut microbes. The whole planet is an ecosystem. It is useful to drawn the boundaries at different points for specific study but we should remember that these distinctions are arbitrary. Even an "individual" is a woolly concept thanks to symbiosis - and we are probably all symbionts at the end of the day.

The only thing that is absolute is that you can break everything down to genes (genetic information) and their environment. The flow of information is one way. Genetic information is modulated - but not created - by the environment. (Even accounting for epigenetics, which modulates the environment but not the genotype, though this is for another post.) The Selfish Gene (and its Extended Phenotype) still wins.

Or does it...?

There is one problem that remains for the "Selfish Gene" and it is the same one that plagues almost all of biology. Just like all the levels above it, a "gene" (in the evolutionary sense) is just a mirage. In many ways, there is no such thing as a gene. There is just genetic information. We like to talk about a "gene for X" but really what we mean is "heritable genetic information that has a causal but environment-dependent tendency to produce X". This is just a problem of conception and language, though, not the underlying mechanism and theory. Selection is still ultimately acting on genetic information, and it is still selection at this level that gives rise to adaptations, but how you package this genetic material up into genes is, again, context-dependent and (thanks to recombination and mutation) can be complicated.

It fascinates me how we love to try and split continua - life, species, development, genes - into discrete packets even when no such packets exist and then tie ourselves up in knots because we can't let go of those arbitrary (and false) divisions we have made. Ultimately, I think the issue of Individual versus Group Selection might just be this problem, taken to another level.

Standing up for Genetic Modification

It's my 300th blog post and so I wanted to try and post about something that captured the essence of the blog, hence the delay! What could be better than to combine food, science and The Cabbages of Doom?

Actually, The Cabbages of Doom is a bit of a red herring for this post. Just in case there is any confusion, The Cabbages of Doom is not a negative reference about Genetically Modified (GM) foods. (It's a surreal science fiction story about some marauding cabbages from another direction invading Swansea. And only 99p! Review here.)

In fact, I could not be much further away from an anti-GM position. For me, the success of the anti-GM lobby in the UK and across Europe in the late nineties represents one of the biggest scientific, political and media disasters of the modern age. A well-organised and probably well-intentioned but horribly misinformed group of scaremongers managed to hijack the public debate over use of one of the most promising technologies ever to be developed in the history of mankind.

Let's make one thing clear from the outset: there is nothing inherently unnatural about Genetically Modified Organisms (GMO). For a start, many GMO just involve targeted mutations within a strain or introduction of genetic variants from related species. These could potentially be achieved by conventional breeding and artificial selection at much greater expense of time and money (and death). The more advanced GMO involve taking DNA from one organism and inserting it in another. Even these GMO are not really unnatural, even if the techniques used to create them are: although it is rare in multicellular plants and animals, "Horizontal Transfer" of genetic material between organisms - including eukaryotes - does occur in nature. (See Keeling & Palmer (2008) Horizontal gene transfer in eukaryotic evolution. Nature Reviews Genetics 9:605-18 for some examples and discussion.)

It is true that the level of modification desired is unlikely to be achieved by natural mechanisms within the lifetimes of the scientists involved. This, though, is one of the key benefits of GM: it greatly speeds up our ability to generate and evaluate possible genetic solutions to environmental problems. We don't need to wait around just trying to get lucky.

Furthermore, far from being inherently dangerous, many GMO are probably safer to the environment than non-GM alternatives. Why? GM is far more precise and targeted than "traditional" methods of creating mutants for screening, which involve chemicals or radiation and produce something much less predictable. The more we understand the nature of the modification, the easier it is to both predict possible risks and also detect or mitigate them. You only have to look at the problems of "invasive species" to realise that entirely "natural" organisms in the wrong place can be an environmental calamity. By eliminating the ability to customise and refine appropriate native organisms through GM, inappropriate introduced species might be used instead. (Often it is not clear what the problems might be until they are released.) The other reason is that, done right, a GMO can permit reductions in uses of chemical fertilisers, pesticides and herbicides.

Food safety is more of a concern but the solution here is not a blanket ban nor even a blanket hysteria, it is adequate food testing and common sense. If a gene has simply been removed from an organism or repressed, as in the "Flavr Savr" tomato, it is no more dangerous than a new hybrid from natural breeding - DNA is digested when we eat food, so if the product itself is not toxic, there is no obvious risk. If, on the other hand, the GMO is producing something like Bt toxin, one obviously needs to be more careful. Even here, though, it is not obviously the case that using chemicals, or even "organic" alternatives (all GMO are organic!) like spraying Bt strains of bacteria, would be any safer. Preferably, all new foods would undergo appropriate toxicity and allergy testing, whether they were the product of conventional breeding or GM. If there is a genuine problem, clearly that specific GM food should be withdrawn, just as one would do with anything containing, or grown with, new bacteria or chemicals.

So, what went wrong? One of the big problems was the old chestnut of "balanced reporting" in the media. All too often, this seems to equate to equal air time for both sides, no matter how uneven the evidence supporting the two sides was. A calm and cautious (and often already pretty balanced) scientist is paired up with a volatile and definitely one-sided activist. Clearly, this is going to end up biased towards the activist even if their position is weaker and founded on misunderstanding and/or misrepresentation of the science. Worse, the journalists chairing the whole thing often fail to interject when one side is just plain wrong about their facts.

The second problem was education. I don't think it would be such a big problem today because DNA and genomics is in the news so much more but, at the time, a scary proportion of the British public did not think that a non-GM tomato had any DNA in it, for example. (At Nottingham, we had a public debate on the issue and a someone had to be removed because they just kept shouting "I don't want to eat DNA!" and would not stop to have it explained that he was eating DNA in all his regular food.)

The final nail was economics. The anti-GM campaign was good enough at scaremongering that public confidence was weakened, despite (inadequate?) attempts by the scientific community to set the record straight. Supermarkets perceived that they would lose enough custom to warrant pulling the plug and so they did. GM has been largely vilified in the public domain ever since, although I think the EU has now relaxed its zero-tolerance stance. After all, if a supermarket is advertising itself as "GM free" as a good thing, GM must be bad. Right? (Obviously, the consumer desires of someone like me, who would rather eat the cheaper, tastier, less wasteful GM tomatoes, are not so important.)

GMO are not universally good and I am sure there have been situations where big corporations have used GM just to make more money or to increase herbicide resistance and thus use more herbicide, which is bad for the environment. Like any technology, the applications need to be considered on a case-by-case basis.

That said, there are some clear situations where GMO can be a force for good, such as the Golden Rice Project, which seeks to use "biofortified rice as a contribution to the alleviation of life-threatening micronutrient deficiencies in developing countries". Drought- and salt-tolerance maize and other such crops could also be important in our changing world.

The sad irony is that, by resisting the development of government-funded GM crops in academic institutions, the anti-GM lobby have actually driven it all into the hands of large corporations that can get round legislation by doing tests overseas and are far more likely to create the kind of GMO that we don't actually want. (Or, even more scary, unregulated amateur biohackers.)

Whether you think it's man-made or not (it is), Climate Change is a big problem and the more we ignore it, the worse it's going to get. This is a problem so big that we need to throw every weapon in our arsenal at tackling it head-on, and that includes taking a chance here and there. There is a reason that food security is one of the major focuses of UK science funding. We have to feed a growing population on dwindling resources. It's not rocket science. (And I haven't even mentioned biofuels.) Genetically modified organisms represent one of the best - possibly the only - chance we have, short of a massive reduction in the global population. (Population crashes and extinction are natural responses to Climate Change - let's make no mistake here, "natural" is not always good.) It's time to let the genie back out of the bottle and let it be a force for good.

Is evolution random?

In a recent perusal of The Blogosphere, my eye was caught by a post at A Tippling Philosopher entitled Far from random, evolution follows a predictable genetic pattern, Princeton researchers find. As I suspect most evolutionary biologists would, I got rather annoyed by this title. I should point out, however, that the Tippling Philosopher is not to blame - this is the title of the original Princeton press release.

Unfortunately, my VPN is playing up so I cannot access the original article (Zhen Y, Aardema ML, Medina EM, Schumer M & Andolfatto P (2012). Parallel molecular evolution in an herbivore community. Science 37(6102):1634-7) but I am a bit short of time anyway and don't want to do an in depth study. I suspect the press release actually does a fairly good job of summarising the main points as does the abstract:

Numerous insects have independently evolved the ability to feed on plants that produce toxic secondary compounds called cardenolides and can sequester these compounds for use in their defense. We surveyed the protein target for cardenolides, the alpha subunit of the sodium pump, Na+,K+-ATPase (ATPα), in 14 species that feed on cardenolide-producing plants and 15 outgroups spanning three insect orders. Despite the large number of potential targets for modulating cardenolide sensitivity, amino acid substitutions associated with host-plant specialization are highly clustered, with many parallel substitutions. Additionally, we document four independent duplications of ATPα with convergent tissue-specific expression patterns. We find that unique substitutions are disproportionately associated with recent duplications relative to parallel substitutions. Together, these findings support the hypothesis that adaptation tends to take evolutionary paths that minimize negative pleiotropy.

This is all very interesting and very cool - the power of evolution by Natural Selection demonstrated in replicate. The thing that irked me, though - and the focus of this (probably too hasty) post - is the title and the first paragraph of the Princeton press release:

Far from random, evolution follows a predictable genetic pattern, Princeton researchers find

Evolution, often perceived as a series of random changes, might in fact be driven by a simple and repeated genetic solution to an environmental pressure that a broad range of species happen to share, according to new research.

Evolution is not a series of random changes. At least, adaptive evolution, which is the subject of this paper, is not. Neutral evolution largely is random but that's only one part of evolution as a whole and to imply otherwise is rather misleading. The raw material for evolution is indeed random mutation but this is not the full picture. There was a clever chap who realised that heritable random variation in a trait, if it produced differential survival and/or reproduction, could result in the non-random change of that trait. Good ("fit") traits would increase in frequency and eventually dominate the population, while bad traits would be removed. He realised this over 150 years ago and called it Natural Selection. His name was Charles Darwin and his book is free on Kindle if you want to read it. (Yes, I know, this is a gross simplification of history!)

This is compounded by the title: "Far from being random, evolution follows a predictable genetic pattern, Princeton researchers find". Well, yes, sometimes it does (and in this case) but we've also known that for years. The argument about the predictability of evolution is one that has been going on for a long time. (Read Gould's "A Wonderful Life", for example.) If you were to rewind the clock and let evolution run again, how much would history repeat itself? We know the answer is not "always" and we know the answer is not "never" but we do not know where on the continuum between "always" and "never" reality lies. (Major catastrophic events notwithstanding. These are another role of chance but somewhat different to the one determining evolutionary trajectory.)

In evolution, the opposite of "predictable" is not completely "random". One has to be clear that even if we cannot predict a precise evolutionary trajectory due to the complexity (and, yes, randomness) in the system, trajectories that give rise to exquisite adaptations always have a large non-random component (selection). This may seem like a trivial thing but it's not, for this is the kind of language that feeds the misconceptions spread my advocates of Intelligent Design and other forms of Creationism. (Of course, this study also nicely blows such nonsense out of the water.) If it is "often perceived as a series of random changes", it is only because of misconceptions like this being repeated.

For me, it is the last line of the abstract that is most intriguing and possibly the big discovery:

"Together, these findings support the hypothesis that adaptation tends to take evolutionary paths that minimize negative pleiotropy."

The authors cite "the large number of potential targets for modulating cardenolide sensitivity". It seems that they think that the other possible target genes are more prone to affect other systems as well in a bad way. (I am not sure how they rule out the possibility that the selective advantage of changes in this particular pump are just much, much greater than the other genes and its just driven by the probability and rates of positive selection.) If this turns out to be a widespread phenomenon, it could indeed have implications for the predictability of future adaptation, which could be useful in our changing world!

This is just one example, of course. Another recent paper on parallel and convergent evolution in Proc. R. Soc. B (free this time), "The probability of genetic parallelism and convergence in natural populations" by Gina Conte, Matthew Arnegard, Catherine Peichel and Dolph Schluter, looked at a bunch of studies and concluded that "estimates [of the probability of gene reuse in parallel and convergent phenotypic evolution in nature] using data from published studies. The estimates are surprisingly high, with mean probabilities of 0.32 for genetic mapping studies and 0.55 for candidate gene studies".

I'm sure there's a bit of ascertainment bias towards traits under strong selection (as these are more obvious and thus more studied) but it confirms the Andolfatto study that in the right circumstances convergent evolution can make use of the same gene(s). (They also cite counter-examples, so be quite clear that this is not universal.) It's not a surprise that it happens but given the amount of diversity between genomes - and numbers of genes affecting many traits - the level is possibly surprising. To be honest, I can't decide if I am surprised or not as it is so hard to generate a reasonable a priori expectation.

I still don't think that all this means that evolution in general is predictable (we still need more studies) but it certainly does hammer yet another nail in the coffin of the old Creationist chestnut about evolution being random. Natural Selection is NOT random - that's the whole point!

Footnote: I must concede that in writing this post I realised that explaining the role (and meaning) of "random" in the context of evolution is not quite as simple as I thought. "Random" commonly does mean a lack of predictability but I maintain that it is not helpful to use this language for evolution without some serious explanation of what you mean by random. Random mutation plus Selection means that we are talking about a lack of determinism, not a lack of direction. (This was also supposed to be a quick/short post!)

h/t: A Tippling Philosopher and WEIT

There's nothing scary about the Spice Kittens

It's Biology Week, so what better excuse to spend some quality time watching kittens! Thanks to felid-fancier Jerry Coyne at WEIT, I was alerted today to the presence of the Spice Kittens Live Webcam. Worry not, for though there is a ginger one, this has nothing to do with the Spice Girls:

Rosemary, a stray, gave birth to her kittens October 5th. She is estimated to be two years old. The two orange boys are Basil & Mace. The buff boy is Sage. The B&W girl is Nutmeg.

Cat coat genetics are actually quite complicated but we would know that Rosemary was (almost certainly) a dam (a lady cat) even if she had not given birth to kittens because she is calico. Calico cats are an interesting (and pretty) example of what is known as X-inactivation.

Cats, like all mammals (including us) have genetic sex determination. (Not all animals do. For some it is temperature dependent or they can even change sex during their lives - see "Finding Nemo's sex-changing father", for example.) Genetic sex determination does not necessarily need sex chromosomes (yeast manage with a single mating type locus (gene)) but in cats (and humans) it is determined by a pair of sex chromosomes. (A single pair of sex chromosomes is normal. The platypus has five pairs!) These are the famous "X" and "Y" chromosomes, pictured right. (Human ones but cats are probably quite similar.) As you can see, the Y (right) is a runty little thing compare to the elegant and well-formed X - and this is where X-inactivation comes in.

The problem is that, with the exception of some short regions at each end, the Y chromosome is missing most of the genes that sit on the X chromosome. This means that a female (XX) has two copies of these genes and males (XY) have only one. This in turn would mean that a female cell would produce approximately twice as much of the products of these genes. Gene dosage is often important: rather than the absolute level of something, it is often the ratio between two things that is important. To compensate for having two copies, therefore, the cells of female mammals switch off one of the copies. This is "X-inactivation".

Because it is random which X chromosome gets switched off, this can lead to some interesting chimeric patterns, including that of the calico cat coat. This in turn is because one of the main coat colour genes - the "ginger gene" - is on the X chromosome. The parts of the calico cat that have a functional ginger gene are like a ginger cat and the parts that inactivate this copy but instead have the recessive "black and white" variant are like a black and white cat. (An extra complication is the status of additional genes that determine how much white patterning there is.)

This also explains why two of the male kittens are ginger - they have inherited their Y chromosome from their father (no ginger genes) plus a random X chromosome from their mother - the ginger one in the case of Basil and Mace. I cannot quite work out whether Sage also has the ginger gene but it has been "diluted" by another coat gene, or whether he is a different colour variant. (The girl, Nutmeg, is a more simple black and white.) The other complicating factor with kitties is that different kittens in a litter can actually have different fathers, so the variety of coat colours within a little can exceed all the possible combinations of one tom and one dam. (It also means that I don't think we can use the colours of the Spice litter to work out what colour the fathers were, except that Nutmeg's father was not ginger.)

Anyway, I am pretty sure that watching kittens is good for your mental health (and you can't catch Toxoplasma gondii online) so do have a little look when you have a spare moment and ponder X-inactivation, study animal behaviour, or just admire their kittie cuteness! (I'm not sure how long the live stream will be up but I will try to remember to update this post if it disappears.) [Edit: The girl kitten now seems to be called Pepper.]

h/t WEIT.

The Life Scientific of Richard Dawkins

Richard Dawkins is one of my personal heroes. Although I do not always agree with everything he says, I usually agree with most of it and he has been a source of inspiration at many points in my life. Reading his classic book on gene-centric evolution, The Selfish Gene, was like having a light switched on. I was fascinated in evolution and genetics before then - I was in the first year of a degree in Genetics at the time - but suddenly it all just made sense. It's still a book I recommend.

Another one of my favourite books of all time is The God Delusion. It sums up the position of a rational agnostic atheist incredibly well. A lot of people argue against it, and vilify Dawkins because of it, but I have never actually seen a good argument against what he writes. (Usually, people are arguing against something that he didn't write. I sometimes wonder whether any of the anti-Dawkins crowd have actually read anything by him.)

If you are one of those people - or a fan, like me - then I strongly recommend downloading this week's episode of The Life Scientific and listening to his half hour interview with presenter Jim Al-Khalili. I am always impressed about how calm and rational he is, and not at all strident as his detractors proclaim in ignorance. This is a man who clearly loves nature - the magic of reality - and loves science - the "poetry of reality". Another great BBC podcast.

ENCODE: highlighting the best and worst of science in the modern world

A massive ENCODE publication release was made yesterday, including 30 papers, an iPad App (downloaded and looking good) and a Virtual Machine full of data. I'm not going to give my opinions on the findings here because, frankly, there's too much to digest. Instead, I recommend reading Ed Yong's summary and the thoughts of Ewan Birney. [Image pinched from Ed Yong.]

ENCODE is an amazing example of what humanity can achieve it is puts time, effort and resources into a coordinated scientific endeavour - and also a reminder (should we need one) of how much more there is to learn about our genome. My mind is blown just thinking about reading all the papers and trying to make sense of them. (I wish I could clear my diary for a few days but deadlines loom!)

ENCODE is also a stark reminder of what it means to do science in the 21st Century world of bloggers, tweeter and general bitchers who just like to take quotes and soundbites out of context and then moan about them. The ability of some folk to digest 30 data-dense papers in a few hours (or minutes) and then have an informed opinion about them - and why they are wrong - is astounding.

So, my second recommendation is this: ignore the hype and all the nonsense flying around about what Ewan Birney meant by "functional" (he explains if you bother to read) and what this means for "junk" DNA. (Probably not much - I am sure it still exists, there just might be quite a lot more functional bits and long-range interactions than we thought - but let's let science and investigation answer that one.) Ignore all this and read the papers (if you're a scientist or committed lay person) or wait for the dust to settle for some reasoned, rational responses (if you are lacking the time/capacity/inclination to tackle 30 papers plus extras). Concentrate on the content and not the language. (I suspect a lot of it comes down to your definition of "junk" and "functional". I don't think I would choose the definitions that they have but, as the authors, it is their prerogative to define their terms and the serious reader's responsibility to make sense of the articles in that context.)

It's going to be years before we make sense of all this new data and work out how much of it is important. Years of wonderful, real science, not soundbites and speculations. As any ground-breaking study is likely to do, ENCODE has raised far more questions than answers - what (if anything) are all these DNA elements doing? Get excited by those questions and start thinking about how we can answer them. Keep your mind open to the possibilities and don't just shoot them down because they make you - or your future discourse with Creationists - uncomfortable.

So, could Ed and Ewan been more careful about the "80% functional" quote? Yes. Should they have been? I'm not so sure. Creationists are having a field day with it but so what? Whatever the finding, Creationists will try to twist it to their goals. That's one of their defining characteristics. If we change how we do or report science to pander to that particular bunch of deluded crackpots, we hand them victory. (Ewan explains his choice and, whether you agree or not, it was his choice to make. Our choice, is how we interpret the quote and whether we bother to find out what he actually meant before slagging it off.)

As a final footnote, I had the pleasure of meeting Ewan Birney once at a conference in Hinxton and the man is phenomenal. As with all great scientists, he is not going to be 100% right 100% of the time but ignore or scoff at him at your peril.