Tag Archives: DNA

On the brink of 3 parent IVF

the metro front page 4/6/2014
the METRO front page 4/6/2014

The Human Fertilisation and Embryology Authority have confirmed that mitochondrial transfer procedures are ‘potentially useful for a specified and defined group of patients’. In addition they have said that the techniques are not unsafe but there are some critical experiments still to take place before the method hits the clinics.

Continue reading On the brink of 3 parent IVF

Population Genetics: Methods and Findings (UCL Genetics Institute)

Yesterday I went to a talk at UCL. The evening was a “beer and pizza science evening” led by the UCL Genetics Institute in population genetics. Anyone with some sort of knowledge in this field would also realise that the beer and pizza would bring in a crowd despite the amount of not so popular statistics and modelling that can be involved. This was very true as the large gathering of people to the event somewhat dwindled after the half-time break. I however did stay until the end and was pleasantly surprised both at my ability to understand the talks and the actual content. Here I’ll summarise each one and give my own take on the topics.

Prof Mark Jobling was first and spoke about Y chromosome analysis. The Y chromosome is the smallest of the bunch and is somewhat neglected in sequencing projects and medical genetics. It is present in just males and in many instances it isn’t even included in higher organism genome releases purely because the subject chosen is female as this gives the added benefit of twice the amount of X chromosome for your money. However the potential in this little guy shouldn’t be underestimated.

The X chromosome next to the somewhat puny Y chromosome: small and mighty?
The X chromosome next to the somewhat puny Y chromosome: small and mighty?

The Y chromosome itself actually has very little sequence diversity and through custom sequencing of just this chromosome it is possible to map all the chunks of DNA across it and where they come from. The contents of these chunks and order of variation inside them can be called the haplotype. The novelty of comparing haplotypes across the Y chromosome with inherited surname shows that many men who think they are unrelated (despite actually having the same surname) are in fact descendants of common ancestors. In fact, a relatively rare version of the Y chromosome is common in almost all ‘Attenborough’ men that were sequenced! The idea behind all of this is that the Y chromosome appears to be under some strong purifying selection, although what that exactly is we can only guess (but most people believe it is some sexual/social advantage i.e. successful men have successful sons who have successful sons etc.). The personal gain from this talk was the confirmation that the methods behind this sequencing are very similar to mine and they are facing very similar problems to me. Woohoo, I am not alone!

Dr Simon Myers was the second speaker and he described his lab’s work on chromosome painting. When we inherit our chromosomes (one from mum, one from dad) they undergo recombination. That is bits from one chromosome in dad have crossed over and replaced the same bit from the paired chromosome in dad and therefore we get a mixture of both chromosomes from dad in just one chromosome. The same thing happens with the chromosome from mum and suddenly we realise that we have a mix of bits from all 4 grandparents in the 2 chromosomes. The image below goes might help explain that…


Now what his lab have done is trace these bits of chromosome back across many generations and painted all the differently inherited bits in different colours. Well they haven’t manually done this; they have a big fancy computer algorithm to do the maths. But from this information you can look at a modern day person and see how ‘African’ they are or how ‘East Asian’ they are based on their inherited chromosome segments. What’s then nice to do is show that these descriptions of modern populations follow patterns of ancient large-scale and more modern small scale human migration patterns. Plus there are lots of pretty colours to look at…

Dr Daniel Lawson was the first speaker after the beer and pizza break so had a smaller audience to contend with. The talk was a lot more maths/statistics/programming/algorithm stuff that often goes over my head but at least I understood the reasoning behind the concept. I often talk about sequencing and whole genomes but what can be difficult to comprehend is the enormity of this data. The total length of the human genome is over 3 billion base pairs, now multiply that by however many people you are sequencing and your computer can get really slow! Now the genome can supposedly be sequenced in its entirety for $1000 we are going to get a lot more data, but how do we handle this? The current algorithms and models can’t be scaled up easily as the estimates of important parameters actually get worse with more data! We have to look for analytics rather than models to generate our data. Now the rest of the talk was describing the specific algorithm Dr Lawson has been working on which seems to iteratively select a samples to estimate off of but I’d be lying if I said I understood any more. I have a lot of reading to go and do!

Prof Mark Thomas was the final speaker and he works on detecting signals of recent selection using ancient DNA data. Again, I’d like to brush over the statistics and modelling and talk more about the applications and ideas. There are a few aspects of modern humans that have so obviously been strongly selected for. A key one is lactase persistence – the ability to digest lactose from milk. It is a western thing really and you may even know many East Asian descendants who are lactose intolerant. Oddly enough there are many known (and unknown) mutations that lead to the persistence of the enzyme lactase into adulthood. This shows convergent evolution: different pathways have led to the same outcome. The benefit of being able to drink milk and eat dairy was, at some point in the past, so strong in Western Europe that people who couldn’t effectively died out! The map below shows lactase persistence (people who can digest lactose in adulthood) in red and lactose intolerance in blue.


It can be shown that this emergence of lactase persistence did not occur from natural genetic drift and was definitely the result of high selection pressure.The same effect can be seen in the blue eye pigmentation in Western Europe and the development of lighter skin. The question of ‘why?’ is one I don’t think we can ever answer for sure but a lot of people have their own theories. A strong case is put forward for the change from a fishing diet to an agricultural farming one where vitamin D and calcium deficiencies left people needing to be able to drink milk and use UVB rays from the sun to make a form of vitamin D in their skin. However this doesn’t explain the blue eyes part, at all. No one can. I’d speculate that the sudden emergence of a child with blue eyes would either be seen as an outsider or someone special so I wouldn’t be surprised if it just so happened that people with blue eyes simply looked hotter and preferentially reproduced with each other in some form of blue eyed revolution! But like I said, sexual/social selection can only be guessed, but it is fun to do so, I mean, look at this fitty:

Swarthy, blue-eyed caveman revealed using DNA from ancient tooth
Swarthy, blue-eyed caveman revealed using DNA from ancient tooth

Find the story in the guardian here.

Identically Different: why you can change your genes


First note: the title of this post is the name of a book by Professor Tim Spector. Just thought I’d get that in quick before anyone throws around accusations of plagiarism! And on that same note, this is a post about a talk I went to at my old university (King’s College London – thanks to KCLA for organising it!) by Prof Spector about that same topic his book is about: epigenetics.

Epigenetics is another biologically defined layer to who we are. It sits ‘above’ the genes so to speak and, similar to regulatory elements, can control the amount a gene is expressed without actually being a genetic code that is itself transcribed. The difference is that epigenetics isn’t a genetic code in the same way our DNA is, it is a layer of other changes to the DNA without changing the actual bases written in our genome. Two key examples of these changes are methylation and histone modification. Both are effectively ‘structural’ changes. It is believed that our ‘epigenetic code’ is heritable (although there is some debate over that of histone modifications) and this is where Prof Spector’s talk focussed it’s attention.

Professor Tim Spector works with twins, thousands of them. And what better way to understand heritability of things, stuff, everything to do with who we are! Monozygotic twins have exactly the same DNA but we can tell (once we’ve got past the identical appearances) who is who in a pair through anything from favourite colour to taste in a partner. So how can two people derived from the same egg, the same sperm, the same ‘stuff’ be different? Prof Spector believes that much of this missing heritability lies in our epigenetics. This extra layer of ‘code’ (I’m not keen on calling it code but will use this for now until I think of a better word. It is not code like our DNA is, it is not comprised of bases or chains of molecules) can be affected by our diet, exercise regime and even maternal care. However Prof Spector goes on to suggest that the diet, exercise regime and even maternal care of our parents or even grandparents could affect our epigenetic pattern (possibly a better word?). He also spoke about how our epigenetic pattern (yes a much better word) could be altered, reversed or added to. Surely epigenetics is therefore transient? I therefore feel slightly uneasy at the idea that nurture could alter what we think of as nature in the great debate of who we are and how we become ourselves if it isn’t permanent however Prof Spector put forward some good valid points about family patterns of inheritance not found in the genes.

One thing that has certainly been shown is that our epigenetics do change over time, with MZ twins diverging from one another, a reasonable explanation for differences in identical twins as they get older (1). This leaves me with two questions really, how much of this missing heritability can we attribute to epigenetics? I don’t want to blame my grandparents’ generation for our current obesity epidemic just yet…! and secondly, a question that I’ll have to just read into more probably, could it be possible for epigenetic changes to cause subtle permanent changes to our genome in a way we don’t yet understand and cause a whole new way of creating variation within the population? Just speculation for now, I’ll have a read round and see what I can find but a layer of information on top of the genome (although limited to the possible information within it) surely has plenty of potential?


1) Fraga, Mario F., et al. “Epigenetic differences arise during the lifetime of monozygotic twins.” Proceedings of the National Academy of Sciences of the United States of America 102.30 (2005): 10604-10609.

Information about Professor Tim Spector’s book is found here.

Mind the gaps

I’m a new PhD student at the National Institute for Medical Research. I’m fresh out of university having graduated from King’s College London this summer. I’m in the systems biology department and have a research focus on conserved non-coding elements. To me, this makes sense. However to a lot of people they look at me like I’m crazy. Not because I’ve decided to do a PhD in research science and that in itself may result in some form of psychological breakdown but because, once I’ve explained a bit more about what exactly CNEs are, they realise I’m ‘just looking in the gaps between genes’.

It’s one of the easiest ways to explain what regulatory elements are, bits in the gaps. But that doesn’t mean they’re any less important than the bits either side of the gap – the genes themselves. Someone tried telling me that statistically I would never find anything or the chances of me finding anything were so low that I wouldn’t have any results by the time I’m 30, let alone in the 4 years I have to complete my PhD, because “pretty much all the disease mutations we’ve found so far have been in the genes”. Aside from the fact I realised I’d only be 3 years away from being 30 by the time I finish my PhD (and subsequently scared myself rigid into making a life plan including a tight schedule for engagement, marriage and children) I also replied with what I find a glaringly obvious answer: that’s because we’ve only looked in the genes so far anyway. Track back to before we developed sequencing technologies and most of the diseases we knew were because of poor diet, the environment and cleanliness (or lack thereof) so why bother looking in the genes? Now we’ve moved on, discovered many mendelian and non-mendelian disease causing genes and mutations, hundreds of them. However, by looking at just the coding regions of the genome we are missing out around 98.5% of the DNA sequence in humans. When the human genome was first sequenced, the surprise that its millions of bases only held around 20,000 genes led to the labelling of much of the ‘gaps’ as ‘junk’. Why is it then that some of this ‘junk’ is so highly conserved over millions of years in evolution?

That’s kind of the idea behind everything I’m doing. There’s a set of CNEs that are conserved in vertebrates, so highly so that we can compare those in zebrafish, humans, pufferfish and mice and they’re the same. If a sequence doesn’t change over that sort of evolutionary time and distance surely it is important? We already know that there is more behind the ‘junk’ DNA so surely discrepancies, insertions, deletions and mutations in these regions could have phenotypic effects? Albeit uncovering the extent of these variations’ effects on disorders and anomalies would be trickier than how a single base change in a coding region could cause a genetic disorder as we are yet to uncover the code, grammar and spelling of these non-coding regulatory regions (if only it was as simple as the base triplet into amino acid version seen in coding regions…). The principle thought behind the theory would say that in a region as highly conserved as the ones we’re investigating, a single base pair could make a dramatic difference as it’s not seen in wild type organisms (the same with insertions and deletions). However we need to prove this. We need to decode the non-coding areas. We need to find a disease-causing mutation in these conserved CNEs. We need to prove this through a functional assay. We need a PhD student to sequence cohorts of hundreds of people with developmental disorders and anomalies and then analyse the data to find these, oh wait… When we find these (because we will, others already have and I’m a bright eyed bushy tailed new PhD student who believes I’ll have some form of answer in the next 4 years, let alone by the time I’m 30…) hopefully it will slowly start steering the balance of research from 99% exome sequencing to a more equal balance between exome and regulome searching. Our genes are crucial to who we are, but we can’t just ignore all the ‘gaps’ in between. They’re full of lots of important stuff too!


  1. Alexander, R. P., Fang, G., Rozowsky, J., Snyder, M. & Gerstein, M. B. Annotating non-coding regions of the genome. Nature reviews. Genetics 11, 559-571, doi:10.1038/nrg2814 (2010).
  2. Epstein, D. J. Cis-regulatory mutations in human disease. Briefings in functional genomics & proteomics 8, 310-316, doi:10.1093/bfgp/elp021 (2009).
  3. Nelson, A. C. & Wardle, F. C. Conserved non-coding elements and cis regulation: actions speak louder than words. Development 140, 1385-1395, doi:10.1242/dev.084459 (2013).
  4. Woolfe, A. et al. CONDOR: a database resource of developmentally associated conserved non-coding elements. BMC Developmental Biology 7, 100, doi:10.1186/1471-213x-7-100 (2007).
  5. http://scienceblogs.com/evolgen/wp-content/blogs.dir/296/files/2012/04/i-9e2a23088c9980f92d903a97e602c0af-noncoding_dna.jpg from https://www.sciencenews.org//node/21410 (image)