The genetic line of inquiry: initial suspects

A small area of chromosome 11 contains genes whose malfunctioning is involved in autism. This is the principal conclusion reached by the Autism Genome Project (AGP), the largest international consortium ever formed to study the genetics of the condition. The next stage is to identify these genes and describe their role in the brain’s development.

© Image courtesy of the artist Sabina con chitarra © Image courtesy of the artist
© Image courtesy of the artist Sogno-Montagne dell’est e la laguna di Venezia ( © Image courtesy of the artist Born in Treviso (IT) in 1973, Lisa Perini has always drawn. She studied at the Venice Academy of Fine Art and launched her artistic career when she participated in the 50th Venice Biennale as part of the Brain Academy Apartment project. Since then she has never stopped exhibiting her works, often paying homage to Venice and female characters that she bathes in intense colour. One of her latest works, Veronica, earned her special prize at the Wanabee Gallery in Milan.

The vast majority of experts are now convinced that the origin of autism is to be found in the early malfunctioning of several genes. The figures provide the main supporting evidence. Depending on the study, the brothers and sisters of an autistic child have between 25 and 67 times the risk of having the same illness. Yet this is not enough in itself to confirm a genetic origin. Brothers and sisters have part of their genetic patrimony in common… but they also share that of their parents. In his 1943 landmark article the US psychiatrist Leo Kanner, although convinced that the disorder he was describing for the first time was largely innate, also stressed that the parents of these 11 young patients were stiff and cold, demonstrating little affection for the child.

This view of autism as caused largely by problems in the affective relationship with the parents, which was dominant in Europe until some 20 years ago, is difficult to reconcile with the results of studies on twins. The identical twin of an autistic child suffers from autism between 60% and 92% of cases, compared with less than 10% of cases for fraternal twins who have no more genes in common than any other brother or sister.

Searching for genes

These statistical studies, carried out in the 1970s and 1980s, did much to shift conceptions of the aetiology of the disease. From a model based on the relationship with the mother we moved to a view that stresses the role of genetic factors that predispose to the illness. However, until the late 1990s the tools available to geneticians were insufficient to investigate these mysterious genes that were suspected of existing but whose number, function and location on the chromosomes remained a mystery.

Success in sequencing the complete human genome gave their quest new impetus thanks to the development of linkage analyses. Rather like looking for a needle in a haystack, the task involves searching for areas on chromosomes that show systematic variations in autistic subjects and in autistic subjects alone. These areas are identified by the genetic markers that are distributed along the length of the genome. When the presence of certain markers is statistically “linked” (hence the term linkage analysis) to the illness, the geneticians deduce that this region contains genes that are involved in its aetiology and therefore warrant further investigation.

As they are based on statistical calculations, the chances of a result increase the greater the quantity on which the linkage analyses are carried out– preferably at least several dozen families with at least two members suffering from the condition. The strength of the Autism Genome Project lies in having brought together, in a single database, the families monitored by 50 geneticians from 50 laboratories in nine countries, in total nearly 8000 people from 1 496 families – a third of whom had never previously been studied – and of whom 1 181 were selected for genetic analysis. “A very large part of our work in phase 1 of the AGP was to standardise the data provided by the project partners in terms of diagnosing the illness and collecting and analysing DNA samples,” explains Anthony Monaco of the Wellcome Trust Centre for Human Genetics in Oxford (UK), which coordinated the study.

Initial clues

The first results were published last March in the journal Nature Genetics. By using DNA microchips, which make it possible to automate the search for 10 000 genetic markers for linkage analyses, researchers were able to show that variations in a single region of chromosome 11, whose role nobody had suspected, were associated systematically with the illness.

Were the regions identified by previous studies on chromosomes 2, 7, 15 or 17 artefacts due to statistical chance? Probably not. As Catalina Betancur, a researcher at the Institut national de la science et de la recherche médicale in Créteil (FR) who took part in the study, points out: “autism is not an illness with a single cause, but a behavioural disorder with many genetic causes and where the genes involved vary from one family to another.” In other words, the region identified by the AGP on chromosome 11 is the one most likely to be involved in all forms of autism… but other regions could play a role in certain forms or certain particular cases of autistic syndromes. In line with this interpretation, the AGP research has been able to identify chromosomic regions linked to the disease in families where only girls are affected.

Genes involved in the brain’s development

The difficulty therefore lies in identifying these many genes, about 20 at the most, in which changes increase the risk of developing the illness by several hundred percent. An added complication is that these genes could be present in an abnormal form in patients, resulting in the loss of the markers that make it possible to identify them in the linkage analyses. This is at least what is suggested by the discovery by the AGP study of the frequency, among autism sufferers, of local anomalies in the chromosome architecture that lead to deletions – or on the contrary repetitions – in the short fragment DNA.

“These anomalies are not in themselves pathological,” explains Anthony Monaco, as they are also found in healthy people. “Our approach was therefore to search for them systematically on the 23 chromosomes and to compare their frequency in families who have more than one autistic child with that of the average population.” These local chromosomic anomalies also proved to be particularly frequent in several genes that play a role in the brain’s development.

Establishing the link between the global anomalies, in terms of the chromosomes and genome, and the physiological malfunctionings that disturb the brain’s development in young autism sufferers is the task for phase 2 of the AGP study, which started a year ago. The chromosome 11 region identified as important in determining the illness includes many genes that are involved in glutamate metabolism. This molecule plays an essential role as neuromediator permitting communication between adult neurons as well as participating in the formation of developing synapses. Thanks to the AGP, it is now clear that the malfunctioning of certain genes involved in the brain’s development plays a role in the appearance of autistic syndromes. The first phase of the project made it possible to seek them out. What remains is to investigate further these suspect genes.

Nicolas Chevassus


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An unprecedented international effort

The Autism Genome Project was created in 2004 when four international consortia engaged in separate studies of the genetics of the condition decided to join forces. It received funding of 14,5 million euros for the next three years out of public and private funds, especially from the charity organisation Autism Speaks, which was at the origin of the grouping. The AGP is headed by two Oxford University researchers, Anthony Bailey and Anthony Monaco, who had previously coordinated the European project Autism MOLGEN that was financed by the Sixth Framework Programme between 2005 and 2008. Its 17 European laboratories had created a DNA databank based on samples collected from 425 families that later merged with those of the other AGP partners.