sunday syndrome


Sunday syndrome #6: Welcome to life

This is another archival repost from the old blog — this one from january 2008.

This post is part six in a series. The series so far can be found here.

Cogito, ergo sum.

René Descartes, 1637.

I’ve given five posts and several thousand words over to introductions to principles in development, evolution and molecular biology. I won’t be dropping those topics altogether, but it’s time to explore new territories in the Sunday syndrome, including the philosophical and political. Things should be a little more digestible from here on. Chromosomal aberrations — that is, large scale mutations in which so much genetic material is deleted or duplicated that a difference is visible under the light microscope — have serious effects on development. We have discussed a few examples of syndromes which arise in individuals which carry these aberrations, but the individuals we see are the exceptions. In each case, I have given the frequency of the disease in terms of live births, but the frequencies are much higher in conceptions. The deletions that we see in live births are a relatively small proportion of the genome, and we rarely see live births in which both of the two copies of the genome are affected. More extreme deletions do occur, but the individuals carrying them never make it to birth. The rule is miscarriage.

Perhaps the most extreme syndrome that we see surviving to term is anencephaly. And yet, paradoxically, anencephaly has the smallest number of symptoms and directly affected organs of any of the syndromes that I have so far discussed. In most cases, physical development is largely normal, with the exception of one particular system: the nervous system. Anencephaly is classified as a neural tube defect, alongside spina bifida, and is caused by an error during the developmental process of neurulation.

Neurulation starts on day 18 of development, and is complete by day 30. The cells along the centre of the back fold in to form a grove, which then closes over to form the neural tube, the precursor of the central nervous system. With a frequency above one in every 500 births, closure of the neutral tube fails to complete. If this occurs towards the posterior,spina bifida arises, and the individual is physically disabled. When this occurs at the head, the skull does not form properly, and the amniotic fluid destroys the developing brain. Those individuals which survive to term are born without a brain. All will die within hours of birth. The reason anencephaly is the most extreme of our syndromes is because it affects those parts of us that are most uniquely human, and raises important questions about medical ethics, and the fuzzy boundaries of humanity.

This is one of the great social functions of science: to free people from superstition.

Steven Weinberg

Last year, a court case was brought in Ireland to determine whether a woman whose foetus had been diagnosed with anencephaly could travel to the UK for abortion. A French website exists solely to oppose the abortion of anencephalics . It is murder. Despite the fact that these individuals will never have a life. Never have a thought or feeling, either of pain or joy. Never know that they exist or will cease to exist. Never, no matter what the anti-abortionists may tell you, “know God”. There is no they.

I am not willing to believe that the anti-abortion movement is solely about the control of women — though that is undoubtedly a motivation for cynically manipulative church elders. Rather, it is about simple rules. When faced with difficult moral decisions some people are just too cowardly to give important decisions the time and thought that they deserve, and would rather follow an easy formula. Why take the time to make an informed and reasoned decision on an important issue, when you can have somebody else make an uninformed one for you? Why waste paper on a law library when there’s a handy single volume that never needs revising? Why test competing ideas when yours comes straight from the Lord? Why examine his world when his world is so stubbornly rebellious? Sweep aside the complicating details that five hundred years of discovery have burdened us with, and go for the simple answer.

Physiology, psychology and neuroscience, with a little help from physics and philosophy, have destroyed simple dualism. Developmental biology has destroyed the simple boundaries of life and consciousness. Evolutionary biology has destroyed the simple boundary between species. Biochemistry has destroyed the simple boundary between life and non-life. Astronomy has put us in our place and physics has overturned our understanding of that place. It’s time to stop pretending that there are simple rules.

https://joe.dunckley.me.uk/2007/05/science-and-sci-fi-biochemistry-on-your-pc/

Sunday syndrome #5: The anarchist that wasn’t

This is another archival repost from the old blog — this one from January 2008.  The post is part five in a series. The series so far can be found here.

In the first installment of Sunday Syndrome I used the example of Prader-Willi Syndrome. This week we’ll bring in a very different disorder, Angelman’s Syndrome (OMIM:#105830), whose surprising connection to Prader-Willi gives us some interesting insights into how inheritance, evolution and development work — insights whose application to medicine includes everything from understanding cancer to developing stem-cell therapies. Angelman’s syndrome is also known as “Happy Puppet syndrome”, because of its symptoms: severe mental retardation with limited language ability and a habit of laughing; and abnormal movement, a little bit like the jerky movements of the puppets in Thunderbirds. The interesting thing about Angelman’s is how it is inherited: the most common culprit is a deletion of bands 11-13 in the long arm of chromosome 15 (15q11-q13): the same region as Prader-Willi.

But Angelman’s and Prader-Willi, if they are deletions of exactly the same piece of DNA, should surely be one syndrome, combining the symptoms of each and always co-occurring? And yet we only ever see one or the other, never both. The clue to why this should be comes from a closer inspection of the inheritance pattern. We inherit two copies of each of our chromosomes: one from each parent (with the exception of the sex-chromosomes). A deletion on the paternally inherited chromosome 15 causes Prader-Willi, but never causes Angelman’s. A deletion on the maternally inherited version causes Angelman’s, but never causes Prader-Willi. Actually, it’s not quite that simple: “uniparental inheritance”, in which one parent contributes two copies of a chromosome, while the other parent contributes none (an improbable coincidence of errors, but with some documented cases). Two copies from the father and the child has Angelman’s, two copies from the mother and the child has Prader-Willi. Conclusion: an intact paternally inherited copy of chromosome 15 is required to prevent the child developing Prader-Willi, and an intact maternally inherited version is required to prevent the child developing Angelman’s.

It can’t just be a coincidence that the syndromes correlate so perfectly with the parent in every one of the thousands of documented cases, nor can it be some simple historical accident: during gametogenesis (sperm and egg production) homologous chromosomes pair up and sections are shuffled between them. Therefore, Y chromosome aside, no chromosome follows an all male or an all female line: the relevant section of the paternal chromosome 15 may be a part of your grandmother’s chromosome 15, for example. Something must be being done to the chromosome duringgametogenesis , something that males and females do differently, but which is ubiquitous throughout the species. The solution to this riddle is a marvelous quirk of inheritance called “genomic imprinting”. During gametogenesis chemical modifications are made to a selection of genes. These modifications do not change the gene sequence, but they do alter gene expression (time, place, quantity, and so on) — sometimes effectively switching a gene off altogether.

This raises the question: why should such a mechanism arise? It could be purely the result of neutral evolutionary mechanisms, of course, but this seems unlikely: a layer of complexity that carries risks such as Prader-Willi and Angelman’s suggests something more complicated is going on. Deducing how and why something evolved is difficult — even when one has fossils or comparative genomics with which to test hypotheses. Still, we can make hypotheses, and we can build models to test their plausibility — so long as we don’t put too much weight on mere hypotheses and models. One of the more plausible and interesting models proposed for imprinting is Tom Moore and David Haig’s 1991 “parental conflict” model.[1] This model follows from the fact that mothers and fathers do not invest an equal amount of their resources in a child: the mother invests in the pregnancy, with a considerable risk of death, followed by protection of the child during vulnerable early life; the investment of the father depends on the species, but in all mammals it is less than the mother. An additional important fact is that mothers can be certain which children are their own, while it is possible for fathers to be deceived.

In such situations, mothers and fathers are predicted to evolve different strategies for maximising the survival of their genes. The mother’s strategy is to value her long term fertility above the survival of any one child. The father has less interest in his partner’s long-term fertility — after all, the relationship may not last — so he values a child’s survival above the ability of the mother to bear children in the future. These are not conscious strategies or values, of course, and for the purpose of this post, we are only interested in their physiological rather than behavioural manifestations. Moore and Haig’s model proposes that we should expect fathers to encourage maximum growth rate of the child in order to minimise the length of the most vulnerable stage of the child’s life, and to give the child a head-start against all those children of other fathers. The mother should fight back against this: rapid growth could damage her body and her chances of future offspring, or may put her other children in danger.

Whatever the reasons for imprinting having evolved, the process itself need not have been especially complicated: the mechanisms for heritable modification of gene expression are not used for imprinting alone, and are likely far more ancient than imprinting. The steps involved in setting up an imbalance in imprinting may be relatively small, and once initiated could canalise evolution into reinforcing the imbalance (and I may elaborate on that topic another day). Imprinting is just one of several examples of epigenetics: the heritable (either in terms of parent to child, or in terms of cell division within an individual) modification of gene expression. One of the most important mechanisms of epigenetics is chromatin modification. Chromatin is a protein structure associated with DNA, and which can control access to genes by tightly packing the DNA and preventing it associating with the transcription machinery. Some of the other roles of epigenetics include X-inactivation, the process by which the extra X chromosome is silenced in females, in order to equalise gene expression with males, who have a single X; the silencing of some of the junk DNA in the genome, such as pseudogenes and parasitic DNA acquired from viruses; and most interestingly, with the differentiation of cells into their specialised roles.

This latter function, sometimes described as “cellular memory”, brings us back to our tale of development. Development is to a large extent about cells taking specialised jobs in different tissues, organs and systems. To do this, cells remodel their genome by changing the pattern of repression by chromatin in response to external signals (such as the concentration gradients discussed at the end of the last entry). Differentiation by chromatin remodeling of the genome allows different cells to produce unique sets of metabolic enzymes, receptors and cellular structures, and to respond differently to events outside of the cell. Not all such modifications are permanent, however, and chromatin remodeling goes on throughout the life of the cell — in response to external events, or in order to control cell division, for example — as a contributor to short- and medium-term control of gene expression. It is tempting to think of chromatin as being in control of genes because of this role it plays. Yet the opposite is just as true: the way in which chromatin remodeling responds to signals is just as much a product of genes, and ultimately evolution.

Just as the genome is vulnerable to damage, leading to diseases, so the epigenome is vulnerable to damage. Cancers, for example, occur when there is a loss of regulation of the cell cycle. We talk of tumour suppressor genes (which slow down the cell cycle) and oncogenes (which speed up the cell cycle) picking up a mutation that jams them in an always-on or always-off state. But the genes themselves need not be mutated: abnormal control of transcription will have the same outcome, and we commonly see cancers in whichepigenetic abnormalities lead to an over- or under-expression of important genes.[2] Additionally, our knowledge of epigenetics is enabling the development of cancer drugs which target those genes which have become jammed, whether by epigenetic or genetic mutation. Epigenetics has another important medical application: induced pluripotent stem cells (IPS), which were the big science news of November, when the first human IPS cells were produced. The production of IPS cells essentially involves the de-differentiation of an adult cell into a mimic of early embryonic stem cells, which have the potential to develop into any other adult cell. An important part of this process is to reverse all of those changes in chromatin structure that have been made during development. This, it turns out, can be done by switching on a few specialised genes which have already evolved to do that job.[3]

With such a diverse range of important applications epigenetics is set to be a newsworthy field. This leads on to my final point about epigenetics. As the youthful epigenetics begins to break through to the mainstream it has begun also to pick up quacks and cranks. The religious-in-crisis, afraid of the advances that are explaining consciousness, have cited epigenetics as the source of free will. Faith healers and quacks jump on epigenetics as the mechanism by which one can alter gene expression with “mind energy” (which also has something to do with quantum physics, I’m told).[4] Others cite imprinting as a mechanism for the inheritance of acquired characteristics.[5] Epigenetics is important and exciting, but it is not the revolution that these groups have been so desperately seeking. Epigenetics does not break up the rules of biology, and it does not mean that any old failed ideas suddenly become true; it does not support the claims of alternative medicine practitioners or eastern mysticists any more than quantum mechanics does (that is: not at all). Epigenetics fits comfortably in mainstream biology: it is no less a product of evolution than any other aspect of our heredity; and in common with the rest of molecular biology, it is a product of and a servant to genetics, not just a master over it.

Note: I tried a variety of titles for this post, and didn’t like any of them. A prize for anyone who can come up with a good title.

The author reserves the right not to award any prizes.

References

  1. ^ Moore, T. and Haig , D. 1991. Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet 7(2), pp. 45-49. doi
  2. ^ See e.g., Kim TY, Bang YJ, Robertson KD (2006) Histone deacetylase inhibitors for cancer therapy. Epigenetics 1(1):14-23.
  3. ^ Nimet Maherali, Rupa Sridharan, Wei Xie, Jochen Utikal, Sarah Eminli, Katrin Arnold, Matthias Stadtfeld, Robin Yachechko, Jason Tchieu, Rudolf Jaenisch, Kathrin Plath, and Konrad Hochedlinger (2007) Directly Reprogrammed Fibroblasts Show Global Epigenetic Remodeling and Widespread Tissue Contribution. Cell Stem Cell 1:55-70. doi
  4. ^ I also spotted Dawson Church’s book The Genie in Your Genes: Epigenetic Medicine and the New Biology of Intention, which looks like it is making similar claims, though I’ve only seen the blurb so I can’t really comment on that.
  5. ^ Eva Jablonka and Marion J. Lamb are supposedly proponents of this, but my only knowledge of their work is second hand, so I can’t be sure that I’m not getting the garbled accounts of those trying to misuse their work.

Sunday syndrome #4: Concentrate!

This is another archival repost from the old blog — this time from Nov 2007.  The post is part four in a series. The series so far can be found here.

So far in the Sunday syndrome column, we’ve been talking in terms of the all-or-nothing loss (or gain) of a gene. This is biological development that we’re talking about, though. Development is an incredibly complicated process, and to understand why many syndromes occur, we have to understand a little more about just how complicated it is. Previously in the series, I’ve looked at gene-gene interaction, and gene-environment interaction, and begun introducing the idea that various elements cooperate to run developmental programs. This week’s element is quantity. Chemical concentrations, relative proportions of gene products, and other such measures, all contain data from the point of view of the developmental program. Syndromes may arise when a gene is deleted, even if there is an identical copy of the gene on the homologous chromosome. Other syndromes arise when there is an additional identical copy of a gene: the trisomies (extreme cases, where there is an extra copy of an entire chromosome), for example, cause Down’s, Edwards’, Patau’s and Klinefelter’s syndromes. In such cases, no gene has been entirely lost, and no novel genes have been introduced; the only difference is in quantities.

This week’s syndrome is Attention-Deficit Hyperactivity Disorder (ADHD).[1] ADHD is heritable: carrying certain gene variants predisposes one to ADHD. But none of those alleles has been shown to be either necessary or sufficient to explain the disorder. We are therefore looking at an issue with a developmental program, complete with its diverse collection of variable and non-variable influences. ADHD is, of course, characterised by a short attention span, and a disinclination to sitting still. This is the result of delayed neurological development: slow overall development means delayed or incomplete development of the controls that we put on impulsive behaviour. Because there are so many interacting influences, there are many subtle variations in the manifestation of ADHD, which in turn means that the cellular and molecular details of ADHD are difficult to determine. One thing that does appear to be relatively consistent, though, is the involvement of dopamine, a neurotransmitter that is known to influence many aspects of behaviour and cognitive activity. In ADHD, dopamine signalling tends to be reduced, but the situation is not as simple as saying that a particular gene has been lost. Common candidates for involvement in ADHD are dopamine transporters, which move dopamine across cell membranes; dopamine receptors, which mediate the cell’s responses to changes in dopamine levels; and enzymes which make chemical modifications to dopamine itself, thus altering its ability to interact with receptors and transporters. In some cases, the genes for these receptors, transporters, and enzymes may indeed be missing, but more commonly they carry a mutation which reduces their efficiency.

Take dopamine receptor D4 (DRD4), a gene which produces a protein whose job it is to sit in the membrane of neurons at synapses (places where two neurons communicate) and initiate activity inside the cell whenever it encounters dopamine outside of the cell. The internal activity of the cell will not amount to anything significant until the concentration of dopamine outside of the cell crosses a threshold: the continuous variation in dopamine concentration is translated into all-or-nothing effects. The most common allele of DRD4 includes a sequence of 48 base pairs which is repeated four times. Mutations are particularly common in repetitive sequences as “replication slippage” occurs when the DNA is duplicated during cell division; the daughter strand ends up with an incorrect number of repeats, which the copy-editing mechanism fails to correct. DRD4 alleles have therefore been observed with anything from two to eleven repeats of that 48 base pair sequence. The seven-repeat allele (DRD4 7R) is common enough for its association with ADHD to have been noticed. The additional copies of the repeating sequence in the DRD4 7R gene mean that the resulting protein has a slightly different structure, and has difficulty interacting with dopamine.[2] The result is that higher concentrations of dopamine are required to activate that activity inside of the cell: the DRD4 7R allele could be said to mimic dopamine deficiency in that situation. A similar variety of mutation in the dopamine transporter 1 (DAT1) gene — whose function is completely different from DRD4 — also reduces its efficiency, again mimicking dopamine deficiency.

Other types of mutation may have no affect on interactions with dopamine, but affect the lifespan of the gene product. Over time, all proteins accumulate damage, affecting their performance; the cell therefore has a system for clearing up old proteins. The products of some alleles, though efficient at their job, look to the cleaners like old wrecks, while others may be more susceptible to damage, and prematurely age. If production does not keep up with the cleanup operation, concentration will be lower than normal, and there will therefore be abnormal downstream effects. There are plenty of other examples, but the point is: there is more to molecular biology than gene sequences, and development is a web of variables. This is perhaps illustrated best by the suggestion that expression of dopamine receptor D2 (DRD2) is correlated with marital stability, and may mediate an effect of family environment on ADHD.[3]

That concentrations and proportions contain information would be a minor curiosity if it were restricted to a few specific examples, like dopamine in development of the nervous system. But cascades of concentration gradients and switches made of chemical proportions are the very stuff of development. Concentration gradients in the egg determine the body’s head-tail and front-back axis, and go on to set up further concentration gradients, which put cells onto a path of differentiation into their specialised jobs.[4] Other embryonic cells amplify random fluctuations in chemical proportions into the signals that tell organs where to develop.[5] Throwing such gradients and switches out of balance can be done with something far smaller than the loss of a gene, and have far greater implications than the loss of a gene in an insignificant system. We have approximately 25,000 genes: far fewer than the estimates, and a figure only widely accepted upon completion of the human genome project. The reason: genes are versatile and variable. That’s a theme I’ll return to in the next installment.

References

  1. ^ OMIM:#143465
  2. ^ Swanson JM, Flodman P, Kennedy J, et al. 2000. “Dopamine Genes and ADD.” Neurosci Biobehav Rev. 24(1):21–5
  3. ^ Waldman ID. 2007. Gene-environment interactions reexamined: Does mother’s marital stability interact with the dopamine receptor D2 gene in the etiology of childhood attention-deficit/hyperactivity disorder? Dev Psychopathol. 19(4):1117-28
  4. ^ See any introduction to development, e.g. Wolpert et al 2001. Particular favourite examples include the HOX genes and SSH/BMP in neurulation.
  5. ^ ibid. See e.g. Notch/Delta and Ephrins.

Sunday syndrome #3: Fight of the century

This is another archival repost from the old blog, this time from november 2007. The post is part three in a series. The series so far can be found here.

Some causes of disease are heritable genetic aberrations. Others are diet, pathogens, trauma, and similar environmental factors. One might get the impression from this that diseases themselves can be classified as “nature” or “nurture”; and from there, it’s a short step to partitioning normal developmental processes. The nature/nurture dichotomy has haunted development — especially of the brain and behaviour — for a century or more. When interviewing scientists about a disease or behaviour, it is in most journalists’ priority category of questions: nature or nurture? Even more depressing is that many scientists, to varying degrees, either still think this way themselves, or they play along and propagate the idea: in his recent semi-apology to the world, James Watson talked of the “relative importance” of nature and nurture in determining mental ability.[1]

This week’s syndrome is Tourette’s syndrome (OMIM:#137580), a neurological disorder. The most famous symptom ofTourette’s is involuntary swearing (“coprolalia”), though this is actually seen in less than ten percent of Tourette’s. Involuntary movements and grunts are more common, many involuntarily repeat words they hear (“echolalia “), and individuals frequently harm themselves by accident. Another interesting syndrome, thought to be related, is the Jumping Frenchmen of Maine (OMIM:244100), who have an exaggerated startle reflex, and therefore react rapidly to sudden sensory input. When told to hit somebody nearby, they do so immediately and involuntarily. Tourette’s clearly runs in families, but there is no obvious chromosomal aberration behind it, as there are in the two other syndromes we have looked at so far. Some correlation has been reported between a particular mutation of the SLITRK1 gene, on the long arm of chromosome 13 (13q31), and Tourette’s; but the situation can not be so simple. Another study failed to find any such correlation, but did find an effect of a mutation on the short arm of chromosome two in many cases.[2]

The reason is that development is not a simple series of gene expression events. Development involves complex programs of gene expression, in which genes cross-reference with many others (see part 2); their behaviour is altered in response to the other concurrently active genes; and they are affected by a variety of environmental conditions. Similar symptoms may therefore be caused by errors in any one of the many genes involved in that program, or by abnormal environmental input into the program. Genetic and environmental inputs are present in every trait. People tend to think of development as a series of inputs building something, but one can also look at it from the (just as useful and just as flawed) view of constraining possibility. Start with infinite possibility and cut away, starting with the laws of physics and chemistry, followed by genes inherited and environmental conditions. When one looks at development from this point of view, one sees that every trait is limited in its possibility by both genes and environment. It looks silly to then ask “yes, but which one is more important?” One may as well ask whether the ingredients or the cooking instructions are more “important” when making the cake; is it the algorithm or data that determines the outcome of a calculation.

The reason nature vs nurture thinking remains popular is that for many traits, one or the other class of inputs may not be very interesting, because it does not play a major role in determining the variation between individuals. In computing, it is the data and not the algorithm that varies, and thus determines variation in the computer’s behaviour; while different statistical tests may apply different algorithms to the same set of data, giving a variety of results. The difference between pancakes and Yorkshire pudding depends on the cooking instructions, but without the recipe, neither can be made. Similarly, eye colour is described as “genetically determined” because variation in eye colour is caused by variation in genetics and not by variation in the environment (the environmental variation is usually small enough to be tolerated by the genetic program). We think of our native language as environmentally determined — we learn the language of our parents and peers, and most of us have little difficulty doing so — yet languages themselves depend on genetic constraints on the types of sounds we can produce, and the way we think. Our behavioural traits are therefore the result of a variety of interacting genetic and environmental constraints on possibility. There is no reason to think thatTourette’s must be the result of a single gene defect: 13q31 and 2p might both be involved. There may be multiple exclusive routes by whichTourette’s may develop; or, it may depend on multiple abnormal variables occurring together.

“Nature versus nurture” is therefore of no use in describing the origin of traits, but it is sometimes of use when looking for the origin of variation in traits, so long as we are aware of the caveats. James Watson no doubt knows all this, and was using the “nature versus nurture” terminology as shorthand in the quote above. Shorthand and metaphor, though, are supposed to aid communication and understanding. “Nature versus nurture” merely aids misunderstanding. This aspect of development will be of particular relevance in future posts where we look at the ambiguous boundary between abnormal “syndromes” and normal human variation; where we look at “treatment” of developmental syndromes; where we look at how our knowledge of development applies to the day-to-day running of the body; and where we ask how, if at all, development produces free will.

References

  1. ^ James Watson (2007) “To question genetic intelligence is not racism“, The Independent, 19 October 2007.
  2. ^ Tourett’e Syndrome Association International Consortium for Genetics (2007) Genome scan for Tourette disorder in affected-sibling-pair and multigenerational families. Am. J. Hum. Genet. 80: 265-272.


Sunday syndrome #2: The gene for low set ears

This is another archival repost, this time from oct 2007. The post is part two in a series. The series so far can be found here.

Knowing how and why things go wrong tells us a lot about how and why things work when they go right. Indeed, this is such an important principle in basic and medical research that the Nobel prize for physiology or medicine was awarded for discoveries of mechanisms which can be used to artificially switch off genes, in both 2006 (RNA interference) and 2007 (gene targeting). Similarly, developmental disorders give us clues about how normal development occurs. This week’s syndrome is Cri du chat (OMIM:#123450). Cri du chat is caused by deletions in the short arm of chromosome 5. The deletion may be as small as a single gene, though larger deletions, involving more genes, have more severe effects. Symptoms include low birth weights, poor muscle tone at birth, and slow growth; unusual facial characteristics, such as a round face, widely spaced eyes, small chin, and low set ears; severe psychomotor and mental retardation, due to abnormal brain architecture; and the characteristic “cat cry” sound of the newborn, caused by abnormal larynx development.

How can such a diverse range of symptoms arise from such a small loss of data? Surely we should expect a change in one or two genes to correspond to a change in one or two features? This is the impression one might get from media coverage of genetics. The coverage seems to be improving, but we are still regularly treated to stories about the discovery of the gene “for” characteristic X. One of the genes lost in cri du chat could be described as “for” high ear position, since its absence causes low set ears. Another[1] could be described as “for” normal speech without cat-like cries. The reality for the majority of genes is that it is impossible to connect them directly to any physical or mental characteristic. Take the three genes that are most commonly involved in cri du chat. One of the genes is called TERT, short for telomerase reverse transcriptase, and it produces part of an enzyme (a piece of molecular machinery) called telomerase. During cell division, a duplicate of the genome is produced: for each of the chromosomes, a set of machinery clamps on, and moves along producing a copy. However, this machinery can not copy the first few letters at the very tip of the chromosome — it has to clamp on there, and so it gets in the way of itself! — so, over time, the chromosomes reduce in length, and eventually the genes become at risk. The most immediate purpose of telomerase is to produce some gibberish DNA with which to cap the chromosome, and thus protect the genes at the ends of chromosomes. Expression of TERT is activated at several stages in development, and in response to certain events. Notably, from the point of view of cri du chat, it appears to be used early in the development of the nervous system, and to a lesser extent in the survival of neurons. However, those aren’t its only roles: it is also known to be involved in maintaining the immortality of stem cells, and in cells’ responses to external signals, such as the hormone estrogen and cytokines, both of which are in turn involved in a range of functions, including regulating cell division and programmed cell death. Indeed, you may already have heard of telomerase, because it is the subject of research in aging and cancer.[2] Another gene involved in cri du chat is Semaphorin F (also known as Sema4C). The product of this gene is a protein which sits on the surface of the growing neuron, helping to guide it to the cells with which it should interact. However, it may also moonlight in the immune system, and bone development. The third gene is delta-catenin, whose product sits on the surface of dendrites — the branches of the neuron — and interact with another protein on neighbouring cells to keep the neurons together and communicating.[3]

These genes, then, can not be described as directly responsible for anything, except the proteins that they produce. They may directly map to a molecular phenotype, but they only indirectly map to visible anatomical, physiological and mental phenotypes, and may have a hand in many diverse systems throughout the body. At the level of anatomical structures and psychological circuits, so many genes must be involved to produce and fine tune even the smallest components that it often becomes difficult to determine their specific roles, or to visualise how the complexity of the macro emerges from the micro-world. Genes, therefore, can not be described as being “for” anything other than the molecule that they encode. What we have learnt about development from what happens when things go wrong therefore also shows us that there are limitations to what we can learn from these situations. Those who use RNA interference and gene targeting to “switch off” genes must treat their findings with caution: there are so many variables confusing the situation that it is difficult to draw concrete conclusions about anything above the molecular level. And we must bear it in mind throughout this series: when the situation appears to be simple, it probably is not. Next week, we’ll invite in environmental variables, and make the situation an order of magnitude more complicated again.

References

  1. ^ Or perhaps the same one
  2. ^ Mattson MP, Fu W, Zhang P (2001) Emerging roles for telomerase in regulating cell differentiation and survival: a neuroscientist’s perspective. Mech. Ageing Dev. 122 (7): 659-71.
  3. ^ I. Israely, R. M. Costa, C. w. Xie, A. J. Silva, K. S. Kosik and X. Liu. (2004) Deletion of the neuron-specific protein delta-catenin leads to severe cognitive and synaptic dysfunction. Current Biology 14:1657-63.

Sunday syndrome #1: Oh God, that’s just morbidly obese!

This is another archival repost from the old blog, originally from oct 2007.

It’s not healthy to bottle up your worries and stress. That’s why all the best comedy throughout the ages has dealt with the tough issues that worry us. It’s why doctors make jokes about diseases and pathologists laugh at unpleasant deaths. Its why the “Darwin Awards” are such a successful concept. We have a collective fascination with death and disease: what happens when our bodies and minds go wrong tells us things about what we are. I am therefore initiating a “Sunday syndrome” column for the discussion of developmental abnormalities that tell us interesting things about ourselves and our world. For this first post, I’ll introduce a serious of ides which I’ll discuss in depth in later posts; and in each post I will introduce a new example syndrome. As this introduction suggests, the posts will at times be light-hearted, and using a Peter Griffin quote as a headline is not meant to insensitive.

Our first syndrome is Prader-Willi Syndrome (OMIM:#176270), and the first question we need to ask is: “what is a syndrome?” A syndrome is merely an association of several symptoms — that is, abnormal states — occurring in multiple individuals. In Prader-Willi, the main symptoms are mild mental retardation (if the politically incorrect choice of words grabbed your attention, there will be more about those in a later post) and a difficulty controlling eating, leading to obesity. It is tempting to use the word “syndrome” as a synonym for “disease”, but disease implies impairment and distress (literally, lack of ease), which though common, are not necessary conditions of “syndrome”. Some symptoms may be hard to objectively categorise: one man’s “impairment” may be another man’s “healthy variation in human aptitudes.” Generally, a disease will have the same or similar causes and development (aetiologies) in all individuals, which is not always the case for syndromes. The syndromes we will be looking at are all caused by genetic aberrations, leading to developmental abnormalities; but often, one syndrome can be caused by any of several genetic aberrations, and this will be the subject of a later post. Perhaps our best objective measure of what is “disease” is to look at its effect on life expectancy, and using this measure, we will include many of our syndromes. “Syndrome” and “disease” therefore overlap, but are not synonyms. Another concept intimately linked to “disease” is the pursuit of a “cure”. This obviously can not apply to abnormalities of development, but it is, to varying extents, appropriate to talk of “intervention” and “treatment”, as I will discuss in a later post.

Prader-Willi has a frequency of around one in 25,000-30,000 live births.[1][2] It’s not easy to visualise what large numbers like these really mean, but we can predict, for example, that around 25 people will be born with Prader-Willi in the UK each year — a much more manageable number for the imagination.[3] Prader-Willi is caused by the deletion of a small section of one of the two copies of chromosome 15 (in the twelfth section of the long arm, to be precise), resulting in the loss of a handful of genes — typically seven. Deletions are one of several errors that may occur during the production of gametes (sperm and eggs), and these syndromes therefore help us understand the molecular details of sexual reproduction and evolution (the topics of later posts). Prader -Willi has both physical symptoms — short stature; poor muscle tone at birth; small hands and feet; and distinctive facial characteristics — and mental symptoms, resulting from abnormal brain development — low IQ (most individuals in the 40-80 range[4]), but with good visual processing, reading and vocabulary; and extreme, insatiable appetite. Such seemingly random combinations of physical and mental symptoms are common in syndromes resulting from the deletion of small numbers of genes. This phenomenon indicates the complexity of developmental programmes, and the problem with the simplistic picture of genes as being “for” a particular phenotype. This complexity of development also hints at the problems with the “nature vs nurture” dichotomy, which still haunts discussions of genetics and development; and the clear effect of genetics on mental aptitude in abnormal states, brings up the tough question of the general effects of genetics on mental aptitude in the general population. These topics will be the subjects of the next two editions of this column.

References

  1. ^ J E Whittingtona, A J Hollanda, T Webbb, J Butlera, D Clarkec, H Boer, 2001. Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in one UK Health Region. J Med Genet 38:792-798 Full Text
  2. ^ A Smith, J Egan, G Ridley, E Haan, P Montgomery, K Williams, E Elliott, 2003. Birth prevalence of Prader-Willi syndrome in Australia. Archives of Disease in Childhood 88:263-264. Full Text.
  3. ^ A quick and dirty estimate based on the registration of births in England and Wales (PDF).
  4. ^ Cassidy S.B. 1997. Prader Willi Syndrome. Journal of Medical Genetics 34:917-23.