The year in review
The ten notable papers picked by SFARI staff describe superb contributions that span the breadth of autism research from molecules to behavior. We recognize that ten other articles might have been selected without loss of enthusiasm or excitement. It has indeed been an extraordinary year and we invite your comments on our selections.
I would like to thank the SFARI staff — writers, editors, research directors and research administrators. Together with the National Institutes of Health and non-profit organizations such as Autism Speaks, the Nancy Lurie Marks Family Foundation and the Autism Science Foundation, they have helped move the field forward at an unprecedented pace. Few of the advances described in our annual review would have been possible just a few years ago.
The notable papers describe new findings in human genetics, gene and protein networks, stem cell biology, potential therapeutics, epidemiology and clinical description of the autism spectrum.
Here are a few thoughts.
It is now clear that certain copy number variants (CNVs) are autism risk factors. Each one is rare, but together they account for a significant fraction of ‘idiopathic’ (non-syndromic) autism. This is a still-unfolding story as techniques for CNV detection evolve from comparative genomic hybridization to DNA sequencing.
We will know more in the coming year about the genetic landscape of autism spectrum disorders. More than 300 genes may be involved, so it is essential to develop sophisticated analyses of gene and protein networks that may bring some order to these vast amounts of data.
Arrows already point to proteins that may regulate the balance between synaptic excitation and inhibition, and also to proteins that influence the expression of synaptic plasticity, the ability of synapses — the junctions between neurons — to modulate their strength in response to experience. It will be important to document how these changes contribute to the function of neural circuits that mediate components of social cognition and behavior.
The elegant study of fragile X syndrome and tuberous sclerosis complex by Auerbach, Osterweil and Bear offers important lessons regarding potential therapeutics. The two disorders share aspects of intellectual disability and autism-like behaviors. Both are associated with changes in protein synthesis in dendrites and changes in long-term synaptic depression. Both are regulated by mGluR5, a receptor that mediates excitatory signaling. It seemed plausible that an effective therapy in one condition would have a positive effect on the other.
No such luck. On close examination, the TSC2 gene and the FMR1 gene were found to have opposite effects on dendritic mRNA and protein levels and on long-term depression. What’s more, drugs that enhance the action of mGluR5 have opposite effects on dendritic mRNA and protein levels in TSC and FMR1 mouse models. Opposite effects are also seen with mGluR5 antagonists.
This means that a useful therapy in one condition would likely exacerbate the deficit in the other. There are double negatives (inhibition of inhibitors) and triple negatives in this story, but it is worth the effort. Basically, FMR1 serves as a brake on mRNA and TSC1/2 stimulates mRNA production. Genetic variants lead to the opposite effects. Both effects are regulated in part by mGluR5.
The implications for idiopathic autism are clear. Biomarkers must be discovered that can stratify the population. Potential therapies that only benefit a subset of individuals in the heterogeneous autism population should not be discarded.
The past year illustrates once again how fundamental neuroscience and clinical research converge to the great benefit of those on the autism spectrum.
In the coming year, I hope that we will move closer to the identification of specific protein targets, specific neural circuits, and specific times in development that are particularly vulnerable to the action of autism risk factors.
Comments
The most important paper published in 2011 may have been one that hasn't made the top ten lists of SFARI or Autism Speaks which has also not included this study in their Top Ten list This study comes not from the narrow field of autism research but rather from the field of evolutionary biology. One of the most important questions that are becoming increasingly asked is 'Why hasn't autism become extinct? and 'Why is increased risk associated with advancing parental age?
Molina et al (2011) studied sperm mutations in healthy male volunteer donors focusing on three mutations identified in individuals with a genetic syndrome that also have high ASD risk. The three sperm mutations that were specifically examined were: 7q11.23 (Williams Syndrome), 15q11-13 (Prader-Willi Syndrome), Di George/velo-cardio-facial (22q11 deletion syndrom) and most genetic and epigenetic cases of Williams Syndrome, Prader-Willi Syndrome and 22q11 deletion Syndrome are de novo mutations in contrast to being inherited events. All three sperm mutations (deletions and duplications) were sporadically found in the sperm of all the volunteer donors. One marked difference between the human male and female is that there are many more germ
line cell divisions in the life history of a sperm relative to that of an egg. Furthermore, the frequency of sperm mutation may increase with the age at which the sperm is produced. Sperm or egg mutations is explanatory of why monozygotic twins (MZ) are concordant and dizygotic (DZ) twins are discordant in Rett Syndrome and Downs Syndrome. These sperm (or egg)mutations are random events that can strike any family at any time without any discernible
reason other than pure chance (Molina et al 2011 ) ( Thomas et al 2006 ) ( Crow 2000 ) (Kinney et al 2010 ) ( Geschwind 2008 ) ( Ellegren 2007).
REFERENCE
Molina et al (2011). Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions and duplications: a FISH approach. Hum Genet. 2011 Jan;129(1):35-44. Epub 2010 Oct 8.
This is an open access paper and the full text is available at the following link:
http://www.ncbi.nlm.nih.gov/pubmed/20931230
Thanks RAJensen.
This is indeed an interesting paper. Studies that search for genetic variants in blood cells in order to identify risk factors for brain disorders, must assume that the variant has arisen in germ cells. But I was not aware of direct studies of sperm cells as reported by Molina et al. Is it time to consider testing sperm for variants before accepting donors at sperm banks?
The issue of embryonic lethality raised by the discordance between the frequency of sperm deletions and the frequency of the associated syndrome in the population is important as we search for relevant developmental mechanisms.
Thanks for your response Dr.Fishbach.
Several studies have been published in the field of evolutionary biology that tested the hypothesis that advancing paternal age may be associated with increased frequency of sperm mutations in healthy volunteer donors. Bosch et al (2003) did indeed find that the frequency of chromosome 9 sperm mutations does increase with advancing age in healthy volunteer sperm donors. Sloter et al (2007) found that structural aberrations in chromosome 1 significantly increases with advancing paternal age in healthy volunteer sperm donors.
These studies appear to have solved several problems that has vexed autism researchers for many years. First, the genetic syndromes, excluding Fragile X, are almost always cause by a de novo mutation (Williams Syndrome, Angelmans Syndrome, Prader-Willi Syndrome, 22q.11 deletion syndrome, Klinefelter Sydrome etc.). Individuals diagnosed with these devastating genetic syndromes seldom reproduce and these studies may have answered the oft asked question ‘Why haven’t the genetic syndromes associated with high rates of autism not become extinct?. Second, these studies demonstrate that all males generate sperm mutations throughout their lifetimes and the frequency of the sperm mutations increases with advancing paternal age.
This research design strategy should be of significant interest by the autism research community as it will most certainly advance the understanding of the biology of autism. The most important problem that remains to be solved is what are the complex mechanisms underlying the sperm mutations that are generated in all males.
As far as your question about testing sperm donors is concerned, there would be no sperm donors as all males generate sperm mutations throughout their lifetimes. The rate of sperm mutations in fertility bank volunteer donors is likely to be no greater than the rate of sperm mutations in the general population.
References
Bosch et al (2003). Linear increase of structural and numerical chromosome 9 abnormalities in human sperm regarding age. European Journal of Human Genetics (2003) 11, 754–759. doi:10.1038/sj.ejhg.5201049
Full open access is available at:
http://www.ncbi.nlm.nih.gov/pubmed/14512965
Sloter ED et al (2007). Frequency of human sperm carrying structural aberrations of chromosome 1 increases with advancing age. Fertil Steril. 2007 May;87(5):1077-86. Epub 2007 Apr 11.
http://www.ncbi.nlm.nih.gov/pubmed/17433321 (Abstract only)
Hopefully, you'll be able to start talking openly about serious cannabinoid medicines for us autistic people.
Enough of us already do, why do we have to go to a gangster to get our medicine? I'd prefer to get mine from a doctor. The conversation is often more stimulating.
cannabisforautism.wordpress.com
Final thoughts. With respect to screening sperm bank donors, here are the screening standards employed by most sperm banks:
http://www.cryolab.com/
Klinefelter Syndrome is one of the most common mutations effecting 1 in 500-1,000 boys. The Klinefelter mutation is caused by a de novo mutation and is not inherited. Klinfelter Syndrome is associated with autism and may involve the neurexin–neuroligin genes (Bishop & Scerif 2011).
Lowe et al (2001) examined the sperm of 38 fathers of Klinefelters boys (FISH) and found the frequency of the XY sperm mutation is increased with advancing paternal age.
Aside from Fragile X Syndrome, most, and in some genetic disorders, almost all cases are caused by de novo mutations as contrasted to being inherited events.
References
Bishop & Scerif (2011). Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin–neurexin hypothesis. Acta Pediatr. 2011 June 100(6):903-907 ( PUBMED)
Lowe et al (2001). Frequency of XY Sperm Increases with Age in Fathers of Boys with Klinefelter Syndrome. American Journal of Human Genetics 69(5) Nov 2001 1046-1054. (PUBMED).
NIH Genetics Reference Table: (Klinefelter Syndrome ) : http://ghr.nlm.nih.gov/condition/klinefelter-syndrome
An important study was published a few months ago that examined the frequency of sperm mutations in workers at a benzene manufacturing plant in China. The study recruited 30 workers who had worked at the benzene manufacturing plant for more than a year and divided the workers into three groups, a low exposure group, a moderate exposure group and a high exposure group. The study included a control group of 11 unexposed workers from the same town.
Every participant in all four groups was found to have de novo sperm mutations including 1p36 sperm mutations. The frequency of the sperm mutations was lowest, but present, in the unexposed group, higher in the low exposed group, higher still in the moderate exposed group and highest in the high exposed group. The 1p36 deletion syndrome is present in 1 in 5,000 to 10,000 newborns:
http://ghr.nlm.nih.gov/condition/1p36-deletion-syndrome
The 1p36 deletion syndrome is also associated with co-occurring autism:
http://174.79.186.155/GeneDetail/MTHFR
This is the first study that has demonstrated a direct connection between a specific de novo sperm mutation (1p36 deletion), a specific severe genetic syndrome (1p36 deletion syndrome) and a specific environmental pathogen (benzene). Benzene, because of its high octane number, is an important component in the production of refined gasoline and diesel fuels.
Marchetti F, Eskanazi B, Weldon RH et al (2011). Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environ Health Perspect
Doi:10.1289/ehp.1103921.
http://ehp03.niehs.nih.gov/article/info:doi/10.1289/ehp.1103921
What can SFARI researchers learn from evolutionary biology? First, all males generate de novo sperm mutations throughout their lifetimes, second, the frequency of de novo sperm mutations increases with advancing age and third, environmental factors have to be considered as being central to understanding the mechanisms involved in the generation of de novo sperm mutations.