Causes Mom: Which one is the mommy chicken? The mom Narrator: Scientist still haven’t found the exact cause of autism Open that box but they do know that genes are involved put the ball in the hole and give me the key one clue is the increased incidence observed in siblings Geswind: If you have one child that is born with autism, what’s the chance to each successive child that’s born? And what we find there is, it’s about, it’s about 15%, maybe even a little higher if it’s a boy, maybe even close to 20% and an even greater incidence is found if the child is an identical twin Lajonchere: What we see is that among identical twins where one child has autism, 90% of the time, the co-twin will either have autism or be somewhere in the spectrum. That really suggests that is a highly heritable disorder. The other part of that is 90% isn’t 100%, so there’s something else there. So autism is not purely just a genetic disorder, but genetics does play a large part Narrator: Humans have about 25,000 genes and they exist in nearly every cell of the body. Genes are made of linear sequences of four nucleotides, represented by the letters A, C, G, and T, arranged in long strands of DNA. These sequences act like instructions that are read like blueprint plans, to make different proteins with different functions. Some define different characteristics like eye and hair color Some help with the biological processes like metabolize the food we eat, and some regulate the neural networks in our brain One such gene callde the FMR1 gene is located on the x-chromosome It makes a protein that helps build connections between neurons Fragile-X syndrome, a common form of inherited intellectual disability can be traced to a mutation of this one gene. It is called a single gene disorder. But there is no single gene that causes autism Over the last decade researchers have discovered that more and more genes are associated with autism. Now hundreds of genes have been identified but the evidence for these candidate genes varies with only a handful considered syndromic or strong candidates. When mutations occur in any of these genes, the regular production of their proteins and corresponding functions can become faulty. The length of a mutation can vary greatly. Sometimes just a single incorrect nucleotide in the DNA sequence can cause problems. Other times, longer segments of the genome are deleted, duplicated, or rearranged. These are called copy number variations and range in length to several million in base pairs Some genetic mutations are inherited. If a mutation exist in the parents DNA, it can be passed to the child. But there is another type of mutation that has recently caught the attention of many researchers, a denovo mutation. This kind of mutation is one that does not exist in the regular DNA sequence of the parent, rather, it appears anew in the DNA sequence of the child. It might occur in the generation of a sperm or egg cell, or it might occur over the time of fertilization. We have known for a while now that parental age is a causal factor. Older fathers are more likely to have a child with autism. The reason is, the cell’s that create sperm continue to divide over their lifetime, leading to increased chances of a mutation appearing. Geshwind: As cells divide, DNA mutates, and one thing that we’ve known is, for example, sperm, as men get older. If you look at 70 year old man and 60 year old men and 50 year old men versus 20 year old men, there are more mutations accumulating in the older sperm. It’s kind of like, you can think of it this way, that as you get older, thing’s just don’t heal as well If you hurt your knee it takes longer to heal, etc. Your skin cut, etc.Same thing with DNA repair. DNA is always being replicated and in dividing cells and mistakes occur and sometimes it’s not repaired well and that’s essentially what’s happening Parental age is just one of many environmental factors researchers are looking at. These factors not only include the air and water around us, but a wider range of elements. Dawson: Now, we are still learning what environmental factors might contribute to autism and the research is casting a very broad net. We do believe that these factors would have affected the very early development of the child so we’re interested in the prenatal environment. This could be everything from what the mother ate during pregnancy, whether the mother had a, an infection, and also whether the child was born prematurely. What happens during the birth process? And then right after birth, also during that early post-naval environment, was the child exposed to toxins? So many potential factors that could be contributing to risk for autism Lajonchere: What is the relationship between the environmental factors and the genetics? What is the interplay between them? How is it that these factors can change or modify the way that genes are expressed? One of the main epigenetic mechanisms is the coiling and uncoiling of different regions of the DNA strand. When the DNA is uncoiled, in an open state, it is exposed to transcription machinery which can then find its correct binding site, and initiate expression of a gene. This is “turning the gene on”. The gene can be “silenced” by a number of chemical changes that make the DNA strand coil up in many successive layers into a highly compact form known as “chromatin”. The genes in this area cannot be expressed, as their binding sites are physically hidden from the transcription machinery. The genes are effectively “turned off”. Levitt: You can change when genes are turned on and off, when they’re used, where they’re used. What’s happened over the past 20 or 30 years has been both a genetic and a neurobiological, neuroscience revolution in terms of our understanding. The first 25 years of autism research, I think, was characterization of the disorder, mostly on the psychology side, and then a lot of studies saying what it isn’t? And to a parent, saying what it isn’t is not very helpful. It’s not immunization. Okay, what is it? .. and then the sentence stops. So I would say, the more that we say what it is, the more we embrace this idea that it’s a complex interaction between genes and environment, we are getting closer to understanding what those interactions might be, and working more rapidly towards things that we can do right now, in terms of intervention. The more the relationship and the strength we’ll build between families and clinicians and between scientists. And I think, that’s where advances are going to take place in a more rapid pace than they are taking place now.