Autism Vox

29 opinions for Autism Genes: Approaching a New Neurobiology

• laurentius-rex
  Jun 24, 2008 at 7:21 pm

  Still ain’t gonna work though, because the problem is in having decided what autism is before looking for a cause, rather than by looking from the ground up to see how genes actually work in constructing reified phenotypes that have little to do with biology at all.

• MAría Luján
  Jun 24, 2008 at 7:46 pm

  There are several problems with genes detected in ASD, because they are not only linked to ASD;

  “None of the genes linked to autism by year of publication are in fact, specific to autism. The most prevelant phenotype is mental retardation with a smaller subgroup having enough isolated (and non-specific) secondary symptoms to qualify for an ASD diagnosis.”
  from RAJ
  The same poster commenting here
  Link

• Emily
  Jun 24, 2008 at 9:15 pm

  Please investigate “Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder” on PubMed and related articles. CNVs (copy number variants, distinguished from what is likely what most people think of when they think of “genes” or “mutations”) are a promising avenue of investigation for linkage with an autism phenotype.

  And see associated publications from 2008, focusing specifically on “autism susceptibility genes.”

  Also, I don’t see why the presence of “mental retardation”–which itself may be an erroneous diagnosis–somehow precludes an association of a given correlated gene or mutation with autism, as well, given that the two are acknowledged frequently to occur together.

  Other 2008 PubMed references of potential interest:
  –Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder.

  –Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders.

  –Structural variation of chromosomes in autism spectrum disorder.

  –Gene expression changes in children with autism.

  –Strong association of de novo copy number mutations with autism. (this one’s 2007, not 2008, like the others)…

  And there are many more from 2007 and 2008 that are locus specific.

  On my blog, I’ve gone into the details of concepts like penetrance and expressivity (”You, as Gestalt”), but they’re probably not concepts that most people incorporate into their thinking about genetics. I am hoping that as more genomics and proteomics (and metabolomics! and other -omics!) data mining occurs that people start thinking with more complexity about genes, including epigenetic regulatory factors. That will take us into a better understanding of these new movements in neurobiology.

  N.B.–Speaking of movements, there is a movement afoot of several years’ standing to stop referring to people who participate in clinical and basic research studies as “subjects.” It’s considered condescending, at best, distancing, objectifying, etc. Many journals instruct authors to avoid it.

• MAría Luján
  Jun 24, 2008 at 9:59 pm

  Hi Emily
  The point is that epigenetics- beyond genetics- is being and should be more deeply researched
  Link

  Methylation of DNA not only serves to mediate repression of gene expression in imprinted domains, but also provides a mechanism through which environmental factors can have long-lasting effects on the genome. How imprinting or methylation-based regulation of gene expression contribute to the loci that confer autism susceptibility remains to be seen. Because the standard approaches used in genome mapping do not assay DNA methylation, a risk conferred by variation of an epiallele would not be detected by sequence-based strategies. Thus, as the field continues to progress, with refinement of the areas of recurrent linkage by increasing sample sizes and the application of high resolution SNP typing and HapMap strategies in study of the ASD, it will be prudent to keep in mind the importance of epigenetic modifications in the regions of interest and to develop high throughput approaches to screen samples of adequate size to definitively determine their role in ASD

  The model should not be limited to find the genes
  Heterogeneous dysregulation of microRNAs across the autism spectrum.
  Nat Rev Genet. 2008 Jul;9(7):527-40. Links
  Psychiatric genetics: progress amid controversy.Burmeister M, McInnis MG, Zöllner S.
  Molecular and Behavioral Neuroscience Institute, University of Michigan, 5061 BSRB, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200, USA. margit@umich.edu

  Several psychiatric disorders–such as bipolar disorder, schizophrenia and autism–are highly heritable, yet identifying their genetic basis has been challenging, with most discoveries failing to be replicated. However, inroads have been made by the incorporation of intermediate traits (endophenotypes) and of environmental factors into genetic analyses, and through the identification of rare inherited variants and novel structural mutations. Current efforts aim to increase sample sizes by gathering larger samples for case-control studies or through meta-analyses of such studies. More attention on unique families, rare variants, and on incorporating environment and the emerging knowledge of biological function and pathways into genetic analysis is warranted.

• daedalus2u
  Jun 24, 2008 at 10:07 pm

  Emily, so what is the final common pathway of all of those different genetic difficulties? Why do so many different genetic problems lead to autism and only to autism?

  Why does social deprivation such as observed in the Romanian orphanages also lead to symptoms that are strikingly like autism?

  I think the final common pathway is low NO. Any kind of metabolic stress, such as caused by difficulties like loss of MeCP2, is going to lead to low NO.

• Emily
  Jun 24, 2008 at 10:14 pm

  I don’t mean more recognition of epigenetics among scientists, I mean among laypeople. I think people will rant less about some single cause or etiology when they have a better grasp of the complexities of genetics. I can’t begin to tell you how familiar I am myself with all of this literature. Really. Nondisclosure agreements prevent my doing so. ;-)

• Kristina Chew, PhD
  Jun 24, 2008 at 10:23 pm

  Just saw this about epigenetics research at Johns Hopkins University and published June 25 in JAMA:

  http://www.news-medical.net/?id=39447

  Researchers at Johns Hopkins have found that epigenetic marks on DNA-chemical marks other than the DNA sequence-do indeed change over a person’s lifetime, and that the degree of change is similar among family members.

  Reporting in the June 25 issue of the Journal of the American Medical Association, the team suggests that overall genome health is heritable and that epigenetic changes occurring over one’s lifetime may explain why disease susceptibility increases with age.

  “We’re beginning to see that epigenetics stands at the center of modern medicine because epigenetic changes, unlike DNA sequence which is the same in every cell, can occur as a result of dietary and other environmental exposure,” says Andrew P. Feinberg, M.D., M.P.H, a professor of molecular biology and genetics and director of the Epigenetics Center at the Johns Hopkins School of Medicine. “Epigenetics might very well play a role in diseases like diabetes, autism and cancer.”

  Here’s the JAMA link:

  http://jama.ama-assn.org/cgi/content/short/299/24/2877

• Emily
  Jun 24, 2008 at 10:29 pm

  There are fascinating studies of identical twins that show that because of these chemical markers accumulated (or not) on the DNA over a lifetime, identical twins gradually become more and more different with age, one likely explanation for some differences in disease susceptibility, etc., between people who are otherwise genetically identical. It’s not just a matter of whether or not you have a gene. Genes aren’t binary factors, either on or off, there or not. There’s much much more involved.

  Again, it’s just another aspect of the complexities of genetics, and I wish there were greater common recognition of some of these things.

• laurentius-rex
  Jun 25, 2008 at 3:39 am

  Nobody in this blog world gets it yet do they?

  Autism is as heterogeneous as Arthritis, it is only a term that has been applied to a set of symptoms and as is does not stand up to any kind of rigour as an explanation of process in itself, it is only the interest of researchers that has made it so.

  It’s like trying to determine Scottishness or Jewishness genetically, well actually it is a lot less certain than that.

• Regan
  Jun 25, 2008 at 5:52 am

  and just to complicate it more, identical twins are not necessarily identical,
  http://www.sciam.com/article.cfm?id=identical-twins-genes-are-not-identical

• Regan
  Jun 25, 2008 at 6:00 am

  Emily, thanks for the leads to look at.

  FWIW, I don’t think that a common pathway is necessary at all–simply by observation of the heterogeneity, it seems that there are multiple potential paths.

  The DSM is really quite a blunt tool, and assessment tools have dependence on the observer, observer skills and conditions. What we seem to be currently better at is ruling out specific conditions that might be otherwise diagnosed as “autism”.

• daedalus2u
  Jun 25, 2008 at 6:56 am

  Just to remind everyone, the only difference between a nerve cell and a muscel cell and a liver cell is epigenetic programming. The DNA in all the cells is the same. The difference is in how it is programmed.

• Emily
  Jun 25, 2008 at 8:33 am

  And it’s also our dose-response mechanism as females for turning off an X chromosome–or some of one, anyway. And without appropriate paternal and maternal genomic imprinting, you don’t get to be you.

  Regan, that twin study mentions exactly the kinds of CNVs I was talking about.

  @l-rex: “Nobody in this blog world gets it yet do they? Autism is as heterogeneous as Arthritis, it is only a term that has been applied to a set of symptoms and as is does not stand up to any kind of rigour as an explanation of process in itself, it is only the interest of researchers that has made it so.

  It’s like trying to determine Scottishness or Jewishness genetically, well actually it is a lot less certain than that.”
  Don’t know what you’re basing your inference on here. I don’t see anyone around here with any sense claiming a single etiology or mechanism for autism or even that it is a single entity. I thought that was rather a given at this point among those who are paying attention. It’s been made clear that it accompanies obviously genetic disorders like tuberous sclerosis and that there also for others are multiple susceptibility genes and CNVs and on and on. What people are talking about here is a suite of markers, but that doesn’t mean that every single person with autism is expected to have the same member of the suite or even any member of the suite. There are probably tens if not hundreds of genes as candidates for any one individual. That’s why genomics data mining is so useful here.

• Kristina Chew, PhD
  Jun 25, 2008 at 9:30 am

  @Emily,
  The more I’ve read, the more I think that one reason the vaccine-autism theory has had such (and too) long a life because it’s so simple and seemingly obvious. Whereas, in reading about genetics, one reads so many terms and acronyms and scientific-Latin sounding words—-what’s a good genetics article/essay/text for the general (if not generally clueless) audience? (something by yourself?)

• passionlessDrone
  Jun 25, 2008 at 10:48 am

  Hi Kristina -

  The more I’ve read, the more I think that one reason the vaccine-autism theory has had such (and too) long a life because it’s so simple and seemingly obvious.

  99.99% of the discussions on the genetic association to autism are just as simpleminded as those about vaccines; it’s the genes and nothing else; children were just born that way, my childs father is quirky so it isn’t surprizing his child can’t speak, ‘I know’ vaccines (and therefore nothing else in the environment) had nothing to do with autism, ect.

  This discussion, it seems, is the outlier, which is quite nice. I saw a fascinating Nova a while ago now on epigenetic manipulation of genetic information and the changes that could result, a large segment included information on the changes to twins genetic makeups over time mentioned by Emily.

  I would recommend it to anyone interested in this discussion.

  http://www.pbs.org/wgbh/nova/sciencenow/3411/02.html

  Hey Emily -

  Here’s a question for you. My memory tells me that as twins aged; the staining / resonance pictures (?) of their gene expression gradually changed [they showed differences between children, adults, and seniors as examples]. What I didn’t see, or am having trouble envisioning, is would we get a similar picture of the differences in genetic expression from different samples if the problems were based on DNA structure (i.e., CNVs), as opposed to environmental alterations on how the gene operated.

  What I’m struggling with is a mechanism by which a CNV occurring anytime long after conception could be responsible for more or less global impacts that we might see as twins age; or for that matter, for differences we see in autism biology. With however many trillion copies of DNA, if one gets CNV, why is that more important than the others that didn’t or got a different CNV? Or is the idea that CNVs very early on propogate out and thus are able to have an impact.

  Make sense?

  - pD
  - pD

• Kristina Chew, PhD
  Jun 25, 2008 at 2:02 pm

  @pD, I think the discussions are simplistic because of a lack of understanding and education about the issues and about genetic research. Readers get stuck about terms like “mutation” and, for instance, assume that such a word means something (something negative, in particular).

• daedalus2u
  Jun 25, 2008 at 3:55 pm

  PD, you are right, many of the talks I have been to on genetics are just as simple minded about the “cause” being solely due to genetics. This is coming from very senior researchers working on the genetics. When confronted with the fact that identical twins are sometimes discordant, they hem and haw and say they both have the broader phenotype. No appreciation that there has to be non-genetic stuff going on (that means environment).

  There is a lot of naïveté on the part of people working on genetics as to how much looking at the DNA can “explain”. Most of the genome (more than 95%) isn’t genes, and for most of it, there is no generally accepted idea of what it actually does, if anything.

  Breathtaking naïveté is sometimes exhibited by the most senior of genome researchers. I am reminded of a quote from the researcher who headed the consortium that sequenced the honey bee genome, a consortium of ~150 researchers. He was asked what the most surprising thing he found; his response was that he didn’t learn much about the social behaviors of bees by looking at their genome.

  To expect that emergent social properties of bees would be apparent by looking at their genome when the properties of a single nerve cell are not apparent from a genome is (in my opinion) breathtakingly naïve. People don’t appreciate how complicated things are outside their own specialty.

  I come across that all the time. When I talk to autism researchers about NO, some of them tell me that “it can’t be that simple”. There is nothing about thousands of coupled non-linear pathways that is simple. A system of even a handful of coupled non-linear parameters is inherently chaotic and is cannot be modeled long term.

• Emily
  Jun 25, 2008 at 4:54 pm

  CNVs are assumed to be present at the beginning of development. One doesn’t usually “get” a CNV necessarily, one inherits it or develops with it from conception as a de novo mutation. You’ll find a good 2007 commentary on CNVs if you google “Major changes in our DNA lead to major changes in our thinking.”

  It’s just another kind of mutation, really, but not the sort people really think of when they think “mutation.” Mutations are just changes from what existed before. They can be good, bad, or indifferent, depending on the environment. These mutations at the chromosome level–duplications of sequences, deletions of sequences, inversions of sequences–have long been known, but only relatively recently have we started tracking them down in relation to pathology or disorders or even human diversity.

  The deletions have been easier to identify, I think, but we’re also now managing to tease apart differences that might arise from having copy number polymorphisms, i.e., having two or three or four copies of a sequence and what effect each copy number might have, respectively, in the organism.

  So we’ve moved beyond just looking at a gene sequence, determining what’s “normal,” and then looking for little changes in that sequence, like substitutions of a single nucleotide (SNPs). Maybe having several “normal” sequences in a row is meaningful, or maybe having two in a row is meaningless, but three does something important. This is not entirely a new concept; tuberous sclerosis, fragile X, and Huntington’s are three examples I can think of off the top of my head of this concept on a smaller scale of repeats–trinucleotide repeats (three nucleotides in a row). The greater the number of repeats, the worse the disorder or the earlier it manifests, or both. One generation may not even show symptoms, but with the expansion of the number of repeats, the next generation will.

  I’m afraid I may have misled by talking about CNVs and then launching right after that into a promotion of increased layperson understanding of epigenetic regulation. These large structural-level changes in DNA, such as CNVs, that have organismal effects are present at conception or certainly shortly thereafter, and are not epigenetic. Structural changes in DNA that occur later, if they manifest as disease, underlie disorders like cancer. Epigenetic alterations that end up making identical twins different over a lifetime (there are also epigenetic patterns related to appropriate development) accumulate over time and are not structural changes, per se, but regulation above the level of the gene using chemical tags.

  Daedalus, I’ve ALWAYS wondered why it is that geneticists become so fixated on the gene alone (although I think I can answer that: it’s, um, their fixation). It’s never made sense to me, and it’s always seemed so narrow in conception. As I’ve said here and elsewhere repeatedly, no gene is an island. I like my science to have a bit of a sense of gestalt.

  (Apologize for any typos; I’m blind as a bat right now from pupil dilation for an eye exam.)

• daedalus2u
  Jun 25, 2008 at 6:02 pm

  Here is a link to where he was quoted.

  http://www.nature.com/nature/journal/v443/n7114/full/7114xiiib.html

  I don’t think he appreciated how breathtakingly naïve his idea was, that social aspects of bees would be apparent from their genome.

  There is a great deal of naïveté like that in science when people are working outside their specialty, even inside specialties, people can get so caught up in conventional wisdom that they accept it without thinking.

  Autism is a lot like that. No NT is expert enough in autism to actually understand it.

• laurentius-rex
  Jun 25, 2008 at 6:06 pm

  Actually there is more than genetics and epigenetics, there is the underlying physics that governs what can and does happen, and that is a long way from being understood, Hadron colliders notwithstanding.

  Indeed even though mathematics of chaos may have some interesting pointers into the way the brain (and the rest of the body) assembles itself, that mathematics may well be so difficult partly because it is in itself and artefact of our current embodied being, and if we were some other kind of intelligence we might be able to model it with a clarity borne of another system we are cognitively designed never to be able to understand, only to have glimpses at through the fuzzy logic of our imperfect reasoning.

  I take my hat off to people like Roger Penrose who piddle in these waters.

• passionlessDrone
  Jun 25, 2008 at 9:57 pm

  Hello friends -

  I spent some more time thinking about the problems with the simplicity argument some more.

  What strikes me about how a lot of the discussion on genetics impact autism is that once an area of genetic association is found there is frequently an ‘Aha!’ style declaration; ‘You see, yet another way in which genes cause autism! The environment hypothesis sure is simplistic!’ (and wrong)

  [Usually this is in regards to a vaccine, or vaccine preservative argument, but most environmental insult style arguments suffer the same fate, they are just argued less frequently for whatever reason.]

  The failure in this is that it ignores the fact that all the genes define is a way in which biological processes interact; and there is more than one way to get to a point of ‘abnormal’ biological process interaction.

  By way of example, there were the neurexins studies from last year; deletions in genes known to modify proteins critical in neuronal formation, and glutamate transport were found to be more frequent in people with autism.

  Google: “”Tiny Genetic Variations Raise Autism Risk” glutamate” (submitting links was causing wordpress to puke out)

  It makes good sense; glutamate levels have been found to be abnormally skewed in autism; excessive glutatmate is known to be neurotoxic, and genes involved with glutamate metabolism have been found mutated with greater frequency in autism. Great.

  But what is almost always lost is the fact that there is more than one way to skew glutamate transport; another way, for example, is to introduce mercury into the system.

  Pubmed for: “Methylmercury increases glutamate extracellular levels in frontal cortex of awake rats.” [there are many others re: mercury and glutamate processing]

  From a glutamate homeostasis perspective, what might be the effect of introducing mercury to an individual that already had glutamate processing issues as a result of neurexin related deletions? Might you consider a person with existing neurexin deletions more succeptible to mercury than someone without such a deletion; a member of a so called ’suceptible population’ in terms of maintaining optimal levesl of glutamate?

  Such a person might not have autism ’caused’ by mercury; but that doesn’t mean their metabolism will react in the same way to the same amount of mercury as someone else.

  I’m using a common boogey man here, but for the record I’d like to state I’m sure there are plenty of environmental ways to module glutamate levels, calcium influx into neurons, or other genetic ’causes’ of autism; it just seems that frequently this distinction is lost everytime a new ‘genetic cause’ of autism is declared.

  Thoughts?

  - pD

  ps - kristina - I double posted removing links in this one. Please nuke the first post if two go through. Thanks. (pD)

• Kristina Chew, PhD
  Jun 25, 2008 at 10:07 pm

  @pD, thanks!

  Perhaps the lesson (or one lesson) to be learned is to be wary of the over-simplifications of any scientific topic in the media—in what’s presented to the general reader.

  For us, it just makes sense to see Charlie as he is, as the product of us—-not just ‘cuz of a shot.

• laurentius-rex
  Jun 26, 2008 at 4:57 am

  Well you might say that genes “probably” determine the very basic hardwear of the brain, what you start out with, rather like the components on the motherboard of a computer before an engineer starts connecting them to each other.

  The way things connect is like the way an artist paints from a particular pallete, essentially the artist can’t use any more materials than are there, but there is going to be a strict mathematical formula of immense complexity that will determine the probabilities of each paint stroke and colour mix.

  The properties of those colours, or components or whatever other analogy are going to be governed by physical properties inherent to there atomic structure at a pre molecular level.

  That is what I mean by complexity. Silicon acts the way it does not because it is chosen to make computer chips from, but because of the properties inherent to silicon. Copper shows a green spectrum not because it is used in the paint box to signify green, but because that is what copper does.

  Genes can’t determine ultimately what happens, they can only set a few switches, and the rest procedes because of the physical properties of the outcome of that, and the complexity of the interaction of everything else.

  That is why the genetics of autism is no less complex than the genetics that insures that no too people are ever entirely alike. There are genes no doubt that predispose to a good banjo player, but without a banjo who would ever know?

• passionlessDrone
  Jun 26, 2008 at 8:14 am

  Hi LR -

  That is why the genetics of autism is no less complex than the genetics that insures that no too people are ever entirely alike. There are genes no doubt that predispose to a good banjo player, but without a banjo who would ever know?

  Hehe

  - pD

• RAJ
  Jun 26, 2008 at 11:37 am

  “Daedalus, I’ve ALWAYS wondered why it is that geneticists become so fixated on the gene alone”

  ‘Autism’ has always come under the domain of child psychiatry. Kanner was heavily influenced by the psychiatric opinion of his day which embraced Feudian theory and psychodynamics leading to the concept of the refrigerator mother.

  Psychiatry has abandoned this belief at least with respect to the study of ‘autism’. The discovery of DNA and the human genome brought about a change in current thinking in psychiatry and the new opinion has embraced behavioral genetics as the Rosetta Stone that once it is decoded will lead to the understanding of all human behaviors. The leading proponents of the polygenic model are all on record as stating they just don’t see an environmental component.

  Autism is no more complicated under current beliefs in behavioral genetics than it was under the psychodynamic beliefs of 40 years ago

• Dysregulation of MicroRNAs and Autism
  Jun 26, 2008 at 3:51 pm

  […] complex disease,” researchers considered whether dysregulation of miRNA expression might play a role in autism. Specifically, the new study found that miRNAs can bind to longer RNA sequences and prevent them […]

• daedalus2u
  Jun 26, 2008 at 4:43 pm

  When your only tool is a hammer, every problem looks like a nail.

  Genetics is so complicated and so new, that if you look hard enough, you can find genetic differences between any two individuals, even identical twins.

  It is not possible to tell if the differences you observe are cause, effect or unrelated to any phenotype differences between those identical twins.

  It isn’t just autism that has complicated genetics. Diabetes, obesity, heart disease, hypertension, etc. all have “complex” genetics.

  To me, traits resulting from “complex” genetics have to be “complex” and under “complex” control to do “complex” things. I think it is likely that some of those “complex” things might be good and some might be bad depending on the “complex” environment the “complex” organism develops in. Because physiology is inherently non-linear and coupled, it is inherently chaotic and very complex results can occur due to very simple and modest changes.

• Children of the Stars: Autism in China
  Jun 27, 2008 at 2:32 am

  […] been learning a lot from a recent discussion here about autism genetics. My own interest in the topic arises from what it reveals about how Charlie is linked to us, to our […]

• More on Genetics and Autism
  Jun 27, 2008 at 1:47 pm

  […] we’re stumbling through a wilderness of possible causes; am glad to have some guides along the […]

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