Category Archives: epigenetics

How going beyond genetics reveals more about autism

Autism spectrum disorder (autism for short) describes a heterogeneous set of conditions characterised by problems with social communication, social interaction and repetitive or restrictive behaviours. It effects approximately one in a hundred people and is four times more common in males than females, although it has been suggested that girls may “hide” their symptoms more than boys.

We do not know what causes autism, but we do know that brain development is different when compared to those without autism, known as ‘neurotypicals’. Recent reports have led us to believe that autism is a genetic disorder. But there is more to life than genetic sequence. We are physiological beings; our genetic instruments are played at different tempos in different individuals and are likely contributing to our individual differences in health and wellbeing.

Our best guess is that genetic sequence accounts for, on average, just over three quarters of each individual’s autism. My team studies the ‘epigenetic’ musicians that play the symphony of life on our genes. Such musicians, in reality tiny molecules, are essential for making each tissue in our body different, despite having identical genes. Epigenetic musicians can often be influenced by environment. As they are often sidelined by genetic researchers, we chose to review what we know about them and to see what came out of the wash.

We first chose to briefly review the hundreds of genes whose sequences have been linked with autism. Luckily, the Simons Foundation had done this for us. They had even ranked the genes based on accumulated evidence. Interestingly, of the sixteen genes that are most strongly associated with autism, half code for proteins that act as epigenetic musicians. Many of these genes also play a role in the brain’s development.

Leaving gene sequences behind, we started at the level of the ‘shop floor’ of the body. We asked what is known about the physiology of people with autism. Among other things, it turns out that their immune systems are more easily disrupted than those in neurotypicals. They are more likely to experience inflammation, both in the blood and the brain, and this may explain why immune suppressants have sometimes been shown to reduce autistic symptoms temporarily.

Moving back one step in the production line, we looked for studies that had measured gene activity in people with autism. Those genes most frequently played too loud or too quiet were associated with brain development and function, and again, with immune state in the blood and brain.

Finally, we focused most of my attention on the epigenetic musicians that play the genes. A few researchers had taken a guess at which genes weren’t being played very well. Looking mostly in the brain, they found four or five genes whose epigenetic musicians weren’t working properly. The clearest evidence was for a gene called the oxytocin receptor, for which two studies showed differences in the blood and brain of those with autism compared with neurotypicals. Oxytocin, often referred to as the ‘love hormone’, regulates many of the behaviours associated with autism, so this is a plausible candidate for causing some of its characteristic features.

However, with almost twenty thousand genes in the genome, the quickest way to find genes is to look everywhere in our genomes, and current technology is advanced enough to do this. So that’s where we went next. One of the problems with this approach is that different researchers use different technologies to search for epigenetic changes to genes, which meant that comparing studies was hard. But surely, any gene identified by two independent studies must be worthy of more attention? So we carefully read through three genome-wide epigenetic studies of the brain, three of blood and one of cheek cells. Again, you can see that researchers look in different places for clues about the causes of autism.

Yet again, genes involved in brain development and the immune system floated to the top. As for specific genes, four emerged for which two independent studies showed a disruption to the epigenetic musicians that played them. None had been indicated previously as strong autism candidates, which may be a surprise to some. For two, very little is known about what they do in the body. The other two are known but not previously associated with autism. The first of these is likely to play a role in the sense of smell. A common feature of autism is a lower sensory threshold – senses, including smelling, working overtime. The second gene codes for an epigenetic musician required for early development and has been shown to be affected in immune cells in children whose mothers had low levels of folate during pregnancy. Interestingly, low folate levels have been linked with autism risk in a small number of studies.

So, what does all this information tell us? Firstly, as Aristotle said may years ago “One swallow does not a summer make, nor one fine day”, which means that we need to gather a lot more evidence that epigenetic changes in such genes are truly associated with autism. Then of course such changes could result from autism rather than cause autism, an idea that also needs testing.

However, there are numerous research teams around the world that can start giving attention to these ‘candidates’ and to the physiological processes such as inflammation that have not been identified in purely genetic studies. Should we be thinking of ways to minimise inflammation during pregnancy to lower the risk of autism? Should we be focusing on raising our children in low inflammatory environments? There is currently not enough evidence available for us to answer these questions and clearly, more research is needed.

Research is likely to lead to the development of tests at birth, which may be able to help (i) predict the likelihood of a child developing autism, and ultimately (ii) develop better informed treatments and (iii) alleviate some of the symptoms of some of the most distressing cases of autism. Interventions that lessen the symptoms of autism are currently being trialled. And to link prediction with treatment would be a great outcome, although as this can be a sensitive area for some in the autism community, we must progress by engagement.

With many thanks to my co-authors Tony Hannan and Jane Loke and to Jeanette Purkis and Dennis Crowley for helpful advice and proofreading.


Blowing the trumpet: a year in review for Dr Chromo

This year, instead of posting disjointed highlights of Facebook, I’ve decided to go back to the old tradition of the “Round Robin” Christmas letter, upgraded to a blog. I still receive Round Robin letters along with Christmas cards from friends and relations and always enjoy reading so why not do something similar but different? Yes, they have been lampooned for being too long and uninteresting so I will keep mine short, and hopefully, interesting.

First up, some trumpet blowing for other people. A large toot for my wife Jane who ran 125 runs this year, most of them around an hour long. I ran the last  one with her this morning and I can tell you, she has definitely overtaken me in the fitness stakes. We’ve also been out to some great restaurants and can tell she has taken note by the standards of her home cooking.

urlNext, a salute to my parents, who  have remained active despite each going through health scares and coping with the loss of a daughter. It’s hard to imagine what they have been through. A further trumpet to my in-laws who are coping with their own troubles. It was nice to see both sets of parents in November.

A further parp for brother Rod in Canada for suggesting that we brothers swap answers to a Life Questionnaire – around thirty questions on who we are, what we are, what we have achieved and what we like. When our sister Sarah died last year, an outpouring of grief and praise came from her close friends and colleagues past and present and we were all deeply touched by that. Strangely, these people knew better as an adult than did the three of us, mainly because we are scattered to the four winds. A “Big-Up” also to Alex for getting into St Martin’s College in London. I enjoyed a brief visit and a drink or two or three to him in November; I vaguely remember getting my photo taken on King’s cross Station’s Platform Nine the Three Quarters by a pair of Japanese tourists. On the same trip I also met op with Brother-in-law Dfyed, a brilliant art teacher and with his amazing son Matthew, who now goes to high school, where he studies Minecraft among other things 😉 I also had a day out in Leeds (and a drink in Whitelocks) with Brother Jim, who’s also going great guns as a Community Arts Chaplain in Gateshead.

Art Show Will Challenge Perceptions Of Religion

Work trumpets go to my student, now turned Postdoc, Jane Loke, who graduated with a PhD this year. I had a great time at Graduation with Jane and her family. Sadly, I lost Linh Nguyen, to Singapore, and would like to thank her for her excellent work as a student and Research Assistant.  A Herald also for Theme Director Katie Allen and Institute Director Kathy North, for providing ways for me to top up my salary. I will repay in kind in 2015 when I have my whole salary covered, and hopefully beyond. Ana Yap was a great Honours student from MOnash Uni and I was impressed by the quality of all their students.

Next, what are my favourite movies and songs from 2014 (and 2013; sometimes I’m slow to catch on)? First, I filled in a few gaps in my favourite movie genre – time travel. Films I watched included FrequencyLooper, 12 Monkeys, About Time , all great in their own way, and finally the great but head-scratching  Predestination,  and the even more head-scratching and the low budget Primer. My overall favourite films of the year were the weird Under The Skin (filmed in Glasgow with Scarlett Johannsen in disguise) the brilliantly thrilling  Calvary, Read My Lips, and yes, the “Hollywood” but exhilarating Edge of Tomorrow. Other films worth a mention are Philomena, Boyhood and Lucy. Finally, a special mention to the movie Gabrielle, an uplifting drama/romance whose main characters (and most of the actors) all had intellectual impairments. I say “impairments” but the main character, having Williams Syndrome, was perceptive and super-friendly. Heart-warming.


My favourite albums of the year were “Our Love” by Caribou – brilliant Canadian  electronic artist and very catchy tunes; “Partly Fiction” by Harry Dean Stanton,  such a sweet voice from the veteran actor; “The Island of Dr Electrico” by The Bombay Royale, a great debut album by the Melbourne band with a hot Indian flavour. And a special mention for “All I ever wanted – The Anthology” by the late, great Kirsty MacColl.  So sad that such a talent has been lost.


I am finishing with my personal achievements of the year, as, someone once said “if you can’t blow your own trumpet, no-one else will”.  In the garden, I have tended every square metre, with failures and successes, the latter in potatoes, chillies (including the World’s hottest),  silverbeet, lettuce, carrots, zucchinis including the amazing Tromboncino.

After dabbling in slightly cushioned trainers and hurting my ankle, I returned to “barefoot” running with the minimalist Vibram 5 fingers. Despite some controversy as to their effectiveness,  I have been injury free since wearing them, I’ve run a half marathon in them and hope to run a full one in 2015. It was also joy to run again after a few months off due to deep vein thrombosis in late 2013. This year I’ve gone further and run totally barefoot on some great Autralian beaches: Ocean Grove, Rainbow Beach, Noosa, Apollo Bay and Sandy Point.


Highlights at work this year have included having lunch with a princess on behalf on the Australian Twin Registry,  of which I was appointed Deputy Director. I was also elected to the Board of the International Society of twin Studies. at the twins conference in Budapest.

As a Chief Investigator,  I was awarded eight research grants of various sizes, the largest being the five-year NHMRC Centre for Research Excellence in twin Research (Chief Investigator B)  and an NHMRC Project grant asking whether we can predict long-term outcomes of preterm birth, and two that give me great pride:  new studies of epigenetic differences within identical twins discordant  for autism or cerebral palsy. Both are collaborations with hospital clinician teams. I now have the best team I have ever had, with whom I am sure I can at least match  our achievements from 2014.

In 2015 I am looking to secure my own salary in the form of an NHMRC Fellowship; hopefully third time lucky; it’s tough.


In 2014 I published 11 peer-reviewed papers, a short chapter about DNA in a crowd-funded book, two articles on twins for the Raising Children Network, and, with colleague Don Newgreen, “Why so many domestic mammals have floppy ears” for The Conversation which, via secondary sites such as IFL Science, was read by over 300,000 people. a year of blogging, I have written 15 posts, each one read on average over a thousand times  and posted over 2,500 Tweets in my first year on Twitter as @DrChromo and a few hundred for the Society for the Developmental Origins of Health and Disease Australia and New Zealand and the Murdoch Childrens Research Institute . Social media is getting the message out about medical research quicker than ever, to more people and those researchers who don’t use social media will quickly become dinosaurs. There is also an amazing thrill when you Tweet at a conference as part of a group of Tweeters and get feedback from outside the conference including overseas. Try it.

I’ve had fun trying to get the message across to Uni students and “the public” about epigenetics, twins, the early life origins of chronic disease and medical research in general. This is an obligation for all medical researchers, so why not enjoy it. I lectured (unpaid) in the courses: Genetics; Poetics of The Body; Genetics, Health and Society; Societal Issues and Personal Genomics, all at Melbourne Uni; Nutrition and Dietetics and Monash Uni, and in courses at Victoria and Deakin Universities. I went as far afield as Brisbane and Warrnambool to give talks to GPs and in the latter, discovered a little gem of a place in the South West of Victoria.

I also went out and about to talk to Rotary, GPs, teachers, school kids, an, with colleague Richard Saffery, was filmed for a documentary about twins, recently aired in Canada and got to meet Dr Feelgood on radio station 3AW. Talking of radio, I continued in my role as a monthly panelist on community radio 3RRR’s Einstein A Go-Go science show. I also started listening to an excellent request show – Centrelinked – on community radio station NorthWest FM and even went on as a guest co-presenter on a hair-themed to coincide with shaving all my hair off for the Leukaemia Foundation’s World’s Greatest Shave. And coming soon you will get to see the results of the >30 blogs to be published on the new MCRI web site early in the New Year. I commissioned these from MCRI staff and students and interestingly, found that in general, the younger the writer, the better the quality of blog. These are the small mammals that will soon take over the territory of the dinosaurs when the social media meteor really hits. However, for an example of a well-written blog by a seasoned researcher, see Dr Jenny Martin’s blog Espresso Science.

Ultimately, in many ways I have had a good year and wish you all the best for 2015.

This immortal coil

DNA, they say, is the molecule of life. Its long threads can be found in almost every cell of your body. Every minute of every day, the many genes it contains are put through production lines to produce the bounty of proteins that are built into each cell type, from eye lenses to heart muscles.

But where did that DNA come from? Let’s take a trip back in time. Before every cell divides, it replicates every one of its 46 molecules of DNA, or chromosomes. When egg met sperm at the moment you came into being, two sets of chromosome came together, one from Mum, one from Dad. As your parents reproductive cells developed, your grandmother’s and grandfather’s chromosomes came together and for the only time during your parents’ lifespans, they swapped genetic information. The chromosomes then divided twice, again for the only time, to produce sex cells with only 23 chromosomes. The earlier shuffling meant that each chromosome wasn’t just Grandfather’s or Grandmother’s; it was a bit of both. This genetic shuffling has increased genetic diversity and has provided grist for the mill of natural selection.

Gaining reverse speed, going further back in time, this division and shuffling has happened as humans have evolved from less complex organisms such as fish-like creatures, multicellular organisms and single cell organisms. Where it all began is still a mystery, but the message is that molecules of DNA have been passed down all this way to you. Sure, they have been shuffled a lot on the way but they are effectively immortal. How will they continue to evolve? Who will they inhabit? Time will tell.

Richard Dawkins wrote a book on evolution he called “The Selfish Gene”. Although he regrets the title because some have interpreted it as giving genes a sense of purpose, he meant that the gene was at the centre of evolution and not the organism or social group. Dawkins suggested that in the beginning, a DNA molecule he calls the “replicator”, managed to reproduce itself and thus gain in number. He proposed that somewhere along the line, it gained the protection of a cell around it; a survival capsule. As the cell’s environment changed, DNA molecules needed to adapt to these changes or the organism would die and it would lose its protection. So it kept mutating until one version of itself helped the cell adapt to its new home and start dividing again.

Sometimes in their rapid charges to survive, genes survive but organisms don’t. Think about the species of spiders in which the male is eaten by his mate just after mating and passing on his genes. It has been argued that only recently tables have turned. We can now choose birth control and end its billion year life in your body when you die.

So maybe those of us who choose not to have children should give quiet thanks to our DNA and those that mourn for us when we go, should mourn for our DNA too, for it will have lost its immortality.


Epigenetics 201: the four ‘R’s

Want to know a little more about epigenetic marks; what they are and how they come about? Read on.

Epigenetic marks are all small molecules, some examples being the methyl group (-CH3) and the acetyl group (-COH3). Many different marks can bind to histones – the proteins that are responsible for packaging DNA into the two metres of genetic information found in every nucleus. Histones are shaped like commas and most epigenetic marks bind to the tail of the comma. However, only a single mark – the methyl group – binds to DNA and only then, to one specific sequence – cytosine-guanine (CG) – often referred to as CpG, the ‘p’ denoting the phosphate ‘backbone’ of the DNA double helix. Together with other packaging molecules and RNA, they make a substance called chromatin. Chromatin can come in many flavours depending on how tight it is packed, from ‘open for business’ to ‘closed for the season’ and states in between. At any particular gene, combinations of different epigenetic marks combine to influence its structure and function. Generally speaking, when regions regulating gene activity contain DNA with CpG methylation, the gene is inactive. Conversely, if the CpG methylation is removed, the gene may be activated. This is, however, a very simplistic interpretation because it ignores all the other epigenetic marks but it fits most situations.


How do epigenetic marks get added and removed from our genes? This is when the ‘four Rs’ come in: epigenetic Recruiters, wRiters, Readers and eRasers. In the figure below, a strand of DNA located at a gene’s control region is illustrated with, for clarity, only four groups of histones.

JC1The first stage of epigenetic change involves the addition of sequence-specific Recruiter proteins or RNA, illustrated by the coloured symbols.

JC2Next, epigenetic wRiters, often called transferases, attracted by the recruiters, add an epigenetic mark, for example, acetyl (Ac), methyl (Me) and phosphoryl (P). Note that the first three marks are added to histones and the final, methyl mark, is added to DNA.

JC3Next, a combination of epigenetic Readers specific for each epigenetic mark bind in tandem in a way analogous to a key in a lock. Each gene or group of genes can have its own specific combination of marks, writers and readers.

JC4This ‘opening of a lock’ is akin to opening up the structure of the gene for it to be expressed.

JC5To reverse this process, a set of molecular eRasers specific for each mark can strip the mark off. An example of such an eraser is the deacteylase group of proteins.

JC6Which, when all marks have been stripped off, brings the gene back to square one.

JC7Further links and a more basic description of epigenetics can be found in my Blog “Epigenetics: from Greeks to geeks and leaks”

Epigenetics: from Greeks to geeks and leaks

Epigenetics, a word that seems to have stirred up disagreement between scientists for so long, is currently experiencing a rebirth and may have applications for the prevention of many different human diseases.

Starting at the beginning, the word ‘epigenesis’ was coined by the Greek philosopher Aristotle over 2,200 years ago because he was sick of the theory current at the time that we all start out as microscopic versions of our adult selves. He believed that all complex creatures grow from a simple fertilised egg or seed though to a mature organism through stages of development and differentiation: out of the simple comes the complex. This idea is widely accepted as true today.

Aristotle Jump forward just over 2,100 years and we come across a man with possibly the longest name in scientific history: Jean-Baptiste Pierre Antoine de Monet, Chevalier de Lamarck. Let’s just call him Lamarck. He proposed that the way an organism adapted to its environment would somehow be passed down the generations. Two generations later, Charles Darwin liked Lamarck’s idea and went further, proposing an idea of his own – ‘gemmules’ – minute granules that are ‘thrown off’ by our tissues. Gemmules, he proposed, could multiply and travel to our eggs or sperm sex cells through which they could be passed on to future generations.


 Step forward another 75 years and followers of Darwin thought they knew it all – evolution occurs by natural selection through random changes in our DNA that have enabled us evolve and adapt over millennia. And that’s that. Then Conrad ‘Hal’ Waddington came along and stirred things up by turning ‘epigenesis’ to ‘epigenetics’, which he used to describe the way in which our genes interact with their environment to make us what we are. In this sense, epigenetics means literally ‘the factors on top of our genes’. Waddington was a man before his time.  Between then and now, arguments have raged about whether nature (genes) or nurture (environment) are more likely to influence our health and behaviour. The truth, exemplified by a recent book by Matt Ridley entitled ‘Nature via Nurture: Genes, experience and what makes us human’ is, like Waddington suggested, a combination of the two.

waddington2Today, epigenetics now describes the set of small molecules that sit ‘on top of our genes’ and choreograph when and how they act. This in turn directs our development from the zygote to the grave. Epigenetic molecules can be encoded by our DNA and they can be added or removed in response to our environment. Nature via nurture. Another way of looking at it is that in the symphony of life, epigenetic molecules are the musicians that play the genes as instruments and together they make up a huge orchestra of thousands of working genes. Alone, genes are silent; they need musicians to play them.

orchestraHowever, controversy still exists about what we can actually label as ‘epigenetic’. Some say that epigenetic changes need to be long-term, lasting for many cell generations, while others have shown that some epigenetic marks can change within a single cell’s lifetime. Some geeks say that the epigenetics should be tightly linked with its molecular definition and others that it should be loosely applied to how an organism adapts to its environment.

Arguments aside, epigenetic changes are most likely lie behind a recently recognised phenomenon call the Developmental Origins of Health and Disease. Known in short as ‘DOHaD’, the idea is that our experiences in the womb and early childhood can ‘program’ our future health. It is likely that epigenetics is part of the programming language involved. An oft-cited example of this in humans is that sixty-year-olds who were in their mother’s womb at the time of the Dutch Famine in the Second World War, not only had poorer heart health than their siblings but also had an epigenetic imprint of this experience stamped on a handful of their genes.

Animal studies reveal a similar story. In rats, a mother’s licking and grooming behaviour influenced subsequent stress levels in the offspring, mediated by an epigenetic change to a gene involved in stress response. Newborn rat pups whose mothers spend time licking and grooming them grow into calmer adults, whilst pups who receive little maternal attention tended to grow into more anxious adults. Grooming altered the pattern of epigenetic marks, which in turn altered gene activity of the stress regulator gene. Critically, when neglected rats were treated with a drug that alters these epigenetic marks, both their anxiety and the accompanying epigenetic changes could be reversed.

Such findings have huge implications for medicine, the largest being that if we can reliably detect epigenetic changes that in early childhood signal a risk for diseases such as cancer, heart disease, autism or diabetes, we can start to prevent these diseases by intervening early. This is the area I find most exciting, but we have a long way to go to the clinic for most of these. However, we can take heart from cancer research, which has already supplied a small number of epigenetic tests that can predict severity or response to treatment in some cancers.

Finally, it seems that in principle, Lamarck and Darwin may also have been on the right track after all. There is accumulating evidence that the environment our mothers and even our fathers encountered before we were a twinkling in their eye may be passed onto us in the form of a risk for conditions such as obesity, diabetes or anxiety. Studies of a remote Swedish village have shown that food abundance in grandparents correlate with the health of their grandchildren. Another found that sons of men who smoked just before puberty were more likely to become obese. However, neither of these has yet been linked with an epigenetic change. Could it be that epigenetic marks can ‘leak though’ to us via eggs and sperm? There is recent evidence that this can happen in animals that has people in some very high places invoking Lamarck.

NN lamarckWe still need to discover how such factors could pass into the eggs and sperm and how these changes would survive two major life stages at which the epigenetic ‘whiteboard’ is wiped almost clean. This usually occurs just after fertilisation when a newly-formed zygote wants to shed its sexual origins and become a new human being and when the opposite happens, when a group of cells early on in development want to put on the sexual cloak and become eggs and sperm. However, I said ‘almost clean’, which leaves the door open in principle for these barriers to be breached. An attractive, emerging idea borrowed originally from plants is that small epigenetic molecules, in form of the “messenger” genetic material – ribonucleic acid (RNA) – can be shuttled into eggs or sperm and be inherited by the next generation, and survive the epigenetic cleaning. Watch this space.


Epigenetics resources

Web sites

Epigenetics Genetic Science Learning Center, University of Utah

The Nova documentary on epigenetics originally aired in 2007

Instant expert: epigenetics’ from New Scientist magazine

Epigenetics explained‘ by Scientific American

Awesome animations and short documentaries

The epigenome at a glance‘from the Epigenetics Genetic Science Learning Center, University of Utah (01:46)

Lick your rats‘ interactive game from the Epigenetics Genetic Science Learning Center, University of Utah (takes about 5 mins to lick a couple of rats)

Insights from identical twins‘ from the Epigenetics Genetic Science Learning Center, University of Utah (04:41)

‘X inactivation and Epigenetics’ by Etsuko Uno and Drew Berry from WEHI TV (11:04)

Epigenetics Overview‘ by Cell Signaling Technologies (02:14)

Epigenetics: what makes us who we are?‘ from Begin before Birth (04:10)

What happens in the womb can last a lifetime‘ from Begin before Birth (02:24)

Epigenetics‘ – a short documentary from the Science Show on DNATube (09:26)

Resverlogix movie about epigenetic drug RVX-208 (03:32)

Charlie’s Story – can we improve crime rates by supporting vulnerable women during pregnancy and the first 2 years of their baby’s life?‘ from Begin before Birth

Articles – basic

Epigenetics’ by Brona McVittie (2006)

‘Evolution, Epigenetics, and Maternal Nutrition’ by Asim K. Duttaroy (2006)

‘Why Your DNA isn’t your destiny’ from Time Magazine (2010)

Epigenetics: promising field delivers (2013)

Articles aimed more at undergraduates

Epigenetics: the sins of the father’ from Nature magazine (2006)

‘Taking a chance on epigenetics’ (2014)


epigenetics revolutionorigins2genome generationidenitcally different

Further learning

Marnie Blewitt’s Coursera online course on epigenetics

Epigenetics 201: the four Rs