Idea: The “Autism-Asperger’s Spectrum” is just a convenient way to talk about many different conditions. Scientists studying autism say that this spectrum actually is a combination of many different conditions; each condition now appears t0 have a different genetic origin. See Is a ‘Spectrum’ the Best Way to Talk About Autism?
Idea: Autism usually isn’t caused by one mutation by itself. Many mutations increase the chances of some condition developing, but the condition is often due to the gene plus some other triggering factor, perhaps:
a) exposure to a pathogen or hormone during gestation
b) There are molecular switches on top of the genes, epigenes. Sometimes genes only have a significant effect if the epigenetic switches are engaged in one way; but otherwise that gene variation might have little noticeable effect.
Autism genetics, explained
by Nicholette Zeliadt, June 27, 2017
Spectrum. [Spectrum began in 2008 as the News & Opinion section of SFARI.org. Simons Foundation Autism Research Initiative (SFARI). In the summer of 2015, we spun off to create an independent online identity.
How do researchers know genes contribute to autism? Since the first autism twin study in 1977, several teams have compared autism rates in twins and shown that autism is highly heritable. When one identical twin has autism, there is about an 80 percent chance that the other twin has it too. The corresponding rate for fraternal twins is around 40 percent.
However, genetics clearly does not account for all autism risk. Environmental factors also contribute to the condition — although researchers disagree on the relative contributions of genes and environment. Some environmental risk factors for autism, such as exposure to a maternal immune response in the womb or complications during birth, may work with genetic factors to produce autism or intensify its features.
Is there such a thing as a [single] autism gene? Not really. There are several conditions associated with autism that stem from mutations in a single gene, including fragile X and Rett syndromes. But less than 1 percent of non-syndromic cases of autism stem from mutations in any single gene. So far, at least, there is no such thing as an ‘autism gene’ — meaning that no gene is consistently mutated in every person with autism. There also does not seem to be any gene that causes autism every time it is mutated.
Still, the list of genes implicated in autism is growing. Researchers have tallied 65 genes they consider strongly linked to autism, and more than 200 others that have weaker ties. Many of these genes are important for communication between neurons or control the expression of other genes.
How do these genes contribute to autism?
Changes, or mutations, in the DNA of these genes can lead to autism. Some mutations affect a single DNA base pair, or ‘letter.’ In fact, everyone has thousands of these genetic variants. A variant that is found in 1 percent or more of the population is considered ‘common’ and is called a single nucleotide polymorphism, or SNP.
Common variants typically have subtle effects and may work together to contribute to autism. ‘Rare’ variants, which are found in less than 1 percent of people, tend to have stronger effects. Many of the mutations linked to autism so far have been rare. It is significantly more difficult to find common variants for autism risk, although some studies are underway.
Other changes, known as copy number variations (CNVs), show up as deletions or duplications of long stretches of DNA and often include many genes.
But mutations that contribute to autism are probably not all in genes, which make up less than 2 percent of the genome. Researchers are trying to wade into the remaining 98 percent of the genome to look for irregularities associated with autism. So far, these regions are poorly understood.
Are all mutations equally harmful?
No. At the molecular level, the effects of mutations may differ, even among SNPs. Mutations can be either harmful or benign, depending on how much they alter the corresponding protein’s function. A missense mutation, for example, swaps one amino acid in the protein for another. If the substitution doesn’t significantly change the protein, it is likely to be benign. A nonsense mutation, on the other hand, inserts a ‘stop’ sign within a gene, causing protein production to halt prematurely. The resulting protein is too short and functions poorly, if at all.
How do people acquire mutations?
Most mutations are inherited from parents, and they can be common or rare. Mutations can also arise spontaneously in an egg or sperm, and so are found only in the child and not in her parents. Researchers can find these rare ‘de novo’ mutations by comparing the DNA sequences of people who have autism with those of their unaffected family members. Spontaneous mutations that arise after conception are usually ‘mosaic,’ meaning they affect only some of the cells in the body.
Can genetics explain why boys are more likely than girls to have autism?
Perhaps. Girls with autism seem to have more mutations than do boys with the condition. And boys with autism sometimes inherit their mutations from unaffected mothers. Together, these results suggest that girls may be somehow resistant to mutations that contribute to autism and need a bigger genetic hit to have the condition.
Is there a way to test for mutations before a child is born?
Clinicians routinely screen the chromosomes of a developing baby to identify large chromosomal abnormalities, including CNVs. There are prenatal genetic tests for some syndromes associated with autism, such as fragile X syndrome. But even if a developing baby has these rare mutations, there is no way to know for sure whether he will later be diagnosed with autism.
Article source https://spectrumnews.org/news/autism-genetics-explained/
Most Autism Cases Can Be Explained by Faulty Genes, New Research Confirms: We understand it better than ever. By Mike Mcrae, Sept 27, 2017.
A fresh look at data from earlier research has reaffirmed what many researchers had thought – autism is primarily in the genes.
Other studies have shown autism spectrum disorder (ASD) tends to cluster in families and is associated with particular genes, but nailing down the risks with precision is a complex task. This new research has put a figure on the chances, claiming 83 percent of autism cases are inherited.
The study led by researchers from the Ichan School of Medicine in New York reanalysed a Swedish longitudinal study that involved over 2.6 million pairs of siblings, 37,570 pairs of twins, and just under a million half-sibling pairs.
Of these, 14,516 children had an ASD diagnosis.
Autism and its associated spectrum of conditions is a rather complex disorder, distinguished by difficulties in communicating and engaging in social interactions.
The signs usually aren’t all that clear until a child might be expected to develop advanced communication skills, around age 2 to 3, making it hard to untangle genetic and environmental causes.
In fact, as recently as just half a century ago, physicians thought it could be the result of a lack of maternal love and affection.
Studies that have focussed on finding links between family relationships have come up with a variety of figures on the genetics of ASD.
Twin studies have suggested as many as 9 out of 10 children with autism inherited the condition through their combination of genes, though other studies have also put a more conservative estimate down towards 60 percent.
One study published in 2011 conducted by researchers from Stanford University in California put the chances of genetic heritability at around 38 percent for ASD.
An analysis conducted in 2014 also calculated a lower number, nearer to just 50 percent.
Which of these numbers are more accurate?
The researchers were skeptical of how the 50 percent figure was determined, suspecting that by taking into account the precise timing of the autism diagnosis, the estimate was being distorted.
So the researchers took the same massive data-set on Swedish children and used another method that had previously proven itself in the field, identifying a model that fitted best.
Their conclusion of 83 percent is closer to the 90 percent determined by earlier twin studies than the 38 percent of the California research, and was estimated with higher precision.
“Like earlier twin studies, shared environmental factors contributed minimally to the risk of ASD,” write the researchers.
While we can be confident that genes play a key role in the development of the traits associated with ASD, we can also be sure that this won’t be the final word on the matter.
For one thing, just one in 68 children is diagnosed with the disorder. While not extraordinarily rare, it’s uncommon enough to make it hard to find a large enough sample size for precise predictions.
The condition isn’t cut and dried, either, with the spectrum covering a range of behaviours and functions. It affects just 1 in 189 girls, while 1 in 42 boys are diagnosed.
Progress is being made in determining which genes are responsible for the neurological variations that give rise to autism-like functions, but it’s slow going.
New research suggests a small fraction of the genes responsible might not be present in parents at all.
A recent study published in the American Journal of Human Genetics reported on the systematic analysis of genetic mutations among 2,300 families who had a single child affected by autism.
They found genetic changes that occur after conception – called postzygotic mosaic mutations – could be responsible for autism in around 2 percent of the individuals in their sample.
“This initial finding told us that, generally, these mosaic mutations are much more common than previously believed. We thought this might be the tip of a genetic iceberg waiting to be explored,” says researcher Brian O’Roak from Oregon Health & Science University.
We’re still a long way off mapping and understanding the role genes play in how our brains interact socially. And for all of this research, the environment can’t be ruled out completely. The more we discover, however, the clearer it is that ASD isn’t a condition we can easily prevent by simply making the right choices as a parent.
This research was published in JAMA. Source: https://www.sciencealert.com/researchers-find-most-autism-cases-can-be-explained-by-faulty-genes
Primary source: Research Letter. September 26, 2017
The Heritability of Autism Spectrum Disorder
Sven Sandin, PhD1; Paul Lichtenstein, PhD2; Ralf Kuja-Halkola, PhD2; et al Christina Hultman, PhD2; Henrik Larsson, PhD3; Abraham Reichenberg, PhD1
JAMA. 2017;318(12):1182-1184. doi:10.1001/jama.2017.12141
Half of all autism cases trace to rare gene-disabling mutations
Researchers identify short list of high-impact genetic causes of autism; see potential to guide personalized treatments
New research suggests that, in at least half of cases, autism traces to one of roughly 200 gene-disabling mutations found in the child but neither parent.
Many of these “high-impact” mutations, the investigators found, completely disable genes crucial to early brain development. In addition, they appear to be more common among people who are severely disabled by autism versus those only mildly affected.
The study, by scientists at Cold Spring Harbor Laboratory, New York, appears this week in the Proceedings of the National Academy of Sciences. (Download the full paper here.)
The DNA analysis of 1,866 families affected by autism looked at the growing list of more than 500 gene changes known to increase autism risk. It identified 239 genes with the greatest likelihood of causing autism if any one of them was disabled by a mutation.
The study’s findings also run counter to the commonly held idea that autism almost always results from a complex interplay of common and subtle gene changes and environmental influences – none of which would cause autism by itself.
This shortened “priority list” may prove particularly helpful to doctors and geneticists using genetic screens to guide diagnosis and personalized treatment, comments Mathew Pletcher, head of Autism Speaks’ genomic discovery program. Dr. Pletcher was not involved in the research.
“These findings argue strongly that genetics can provide meaningful answers for a significant portion of individuals with autism,” Dr. Pletcher explains. “From this extends the idea we can provide better care and support by deepening our understanding of the health risks that arise from each person’s specific genetic disruption.”
Most of the high-impact mutations identified in the new study occurred in the child but neither parent. Such newly arising, or de novo, mutations first occur in the mother’s egg, the father’s sperm or early in embryo development.
Some of the first research out of the Autism Speaks MSSNG project implicated de novo mutations in the higher rates of autism seen among children of older parents. With age, a woman’s eggs and a man’s sperm-producing cells tend to accumulate these mutations. And one potential source of these accumulating mutations, Dr. Pletcher notes, is lifetime exposure to environmental “insults” such as radiation and toxic chemicals (naturally occurring or otherwise).
Scientific paper: Low load for disruptive mutations in autism genes and
their biased transmission. Authors: Ivan Iossifova, Dan Levya… and Michael Wiglera.
PNAS 2015 October, 112 (41) E5600-E5607.
Fathers bequeath more mutations as they age
Genome study may explain links between paternal age and conditions such as autism.
Ewen Callaway, 22 August 2012
In the 1930s, the pioneering geneticist J. B. S. Haldane noticed a peculiar inheritance pattern in families with long histories of haemophilia. The faulty mutation responsible for the blood-clotting disorder tended to arise on the X chromosomes that fathers passed to their daughters, rather than on those that mothers passed down. Haldane subsequently proposed1 that children inherit more mutations from their fathers than their mothers, although he acknowledged that “it is difficult to see how this could be proved or disproved for many years to come”.
That year has finally arrived: whole-genome sequencing of dozens of Icelandic families has at last provided the evidence that eluded Haldane. Moreover, a study published in Nature finds that the age at which a father sires children determines how many mutations those offspring inherit2. By starting families in their thirties, forties and beyond, men could be increasing the chances that their children will develop autism, schizophrenia and other diseases often linked to new mutations. “The older we are as fathers, the more likely we will pass on our mutations,” says lead author Kári Stefánsson, chief executive of deCODE Genetics in Reykjavik. “The more mutations we pass on, the more likely that one of them is going to be deleterious.”
Haldane, working years before the structure of DNA was determined, was also correct about why fathers pass on more mutations. Sperm is continually being generated by dividing precursor cells, which acquire new mutations with each division. By contrast, women are born with their lifelong complement of egg cells.
Stefánsson, whose company maintains genetic information on most Icelanders, compared the whole-genome sequences of 78 trios of a mother, father and child. The team searched for mutations in the child that were not present in either parent and that must therefore have arisen spontaneously in the egg, sperm or embryo. The paper reports the largest such study of nuclear families so far.
Fathers passed on nearly four times as many new mutations as mothers: on average, 55 versus 14. The father’s age also accounted for nearly all of the variation in the number of new mutations in a child’s genome, with the number of new mutations being passed on rising exponentially with paternal age. A 36-year-old will pass on twice as many mutations to his child as a man of 20, and a 70-year-old eight times as many, Stefánsson’s team estimates.
The researchers estimate that an Icelandic child born in 2011 will harbour 70 new mutations, compared with 60 for a child born in 1980; the average age of fatherhood rose from 28 to 33 over that time.
Most such mutations are harmless, but Stefánsson’s team identified some that studies have linked to conditions such as autism and schizophrenia. The study does not prove that older fathers are more likely than younger ones to pass on disease-associated or other deleterious genes, but that is the strong implication, Stefánsson and other geneticists say.
Previous studies have shown that a child’s risk of being diagnosed with autism increases with the father’s age. And a trio of papers3–5 published this year identified dozens of new mutations implicated in autism and found that the mutations were four times more likely to originate on the father’s side than the mother’s.
The results might help to explain the apparent rise in autism spectrum disorder: this year, the US Centers for Disease Control and Prevention in Atlanta, Georgia, reported that one in every 88 American children has now been diagnosed with autism spectrum disorder, a 78% increase since 2007. Better and more inclusive autism diagnoses explain some of this increase, but new mutations are probably also a factor, says Daniel Geschwind, a neurobiologist at the University of California, Los Angeles. “I think we will find, in places where there are really old dads, higher prevalence of autism.”
However, Mark Daly, a geneticist at Massachusetts General Hospital in Boston who studies autism, says that increasing paternal age is unlikely to account for all of the rise in autism prevalence. He notes that autism is highly heritable, but that most cases are not caused by a single new mutation — so there must be predisposing factors that are inherited from parents but are distinct from the new mutations occurring in sperm.
Historical evidence suggests that older fathers are unlikely to augur a genetic meltdown. Throughout the seventeenth and eighteenth centuries, Icelandic men fathered children at much higher ages than they do today, averaging between 34 and 38. Moreover, genetic mutations are the basis for natural selection, Stefánsson points out. “You could argue what is bad for the next generation is good for the future of our species,” he says.
Nature 488, 439 (23 August 2012) doi:10.1038/488439a
Male biological clock possibly linked to autism, other disorders
Nature Medicine 14, 1170 (2008) doi:10.1038/nm1108-1170a
Over the last few years, epidemiological evidence has suggested that as men age their odds of having a child with autism, schizophrenia or bipolar disorder might increase. The findings, along with more recent genetic data have led researchers to ask whether the mutations that accumulate in sperm DNA with age might underlie this observed association. âIf this paternal age effect has something to do with mutations, then that opens up all sorts of interesting and sort of scary possibilities,â says Jonathan Sebat, a human geneticist at Cold Spring Harbor Laboratory in New York State. He says it is conceivable that the trend of delaying fatherhood might contribute to an increased incidence of mutations in the population that can give rise to neuropsychiatric disorders. In a study of more than 100,000 people, along with records about their parentsâ ages, Avi Reichenberg at Kingâs College London and his colleagues found that 33 out of every 10,000 offspring of men 40 years or older had autism spectrum disorderâa 475% increase compared to offspring of men younger than 30, who fathered afflicted children at a rate of 6 per 10,000 (Arch. Gen. Psychiatry 63, 1026â 1032; 2006). This association is now being tested in a larger study, says Reichenberg. A study this September showed a similar but less pronounced association of parental age with bipolar disorder (Arch. Gen. Psychiatry 65,1034â1040; 2008). Spontaneous mutations can arise in both sperm and eggs. As women age, for example, they have an increased risk of delivering a child with Downâs syndrome and other disorders caused by large-scale chromosome problems in eggs, such as trisomy. But unlike eggs, sperm arise from stem cells that continuously divideâabout 840 times by the time a man is 50 years old (Cytogenet. Genome Res. 111, 213â228; 2005). The theory is that the chances of mutations increase with each round of DNA replicationâa process that could underlie estimates that the mutation rate in males is about five times that in females (Nature 416, 624â626; 2002). âAny mutation you can think of occurs more frequently in the sperm of older men,â says Sebat. Meanwhile, recent genetic surveys of people with autism and other neuropsychiatric disorders have bolstered this controversialâ and still tenuousâhypothesis. The DNA studies have suggested that âspontaneousâ mutations contribute to schizophrenia and autism. This type of mutation can arise in the sperm or egg of the parents.
Sebat and his colleagues, for instance, looked at spontaneous deletions and duplications measuring about 100,000 DNA base pairs and longerâa length that often contain dozens of genesâin the genome of people with of autism spectrum disorders (Science 316, 445â449; 2007).
Such spontaneous mutations occurred in only 1% of unaffected people, but they occurred in about 10% of subjects with sporadic forms of the disorder, meaning they had no family history. The researchers’ methods only pick up a fraction of mutations, so the effect of sporadic mutations is probably substantially larger, says Sebat.
Similar studies this year have shown that people with nonfamilial forms of schizophrenia also have a higher rate of spontaneous duplications and deletions, and Sebat says his unpublished data show a similar association in bipolar disorder. But whether the mutations that arise spontaneously in neuropsychiatric disorders come mainly from mom or dad is still unclear, as is their association with parental age. Sebat says larger studies underway should help clarify these questions. And researchers caution that they have very little idea how the disrupted genes in eggs and sperm might potentially give rise to neuropsychiatric disease. âIt is not established, and it can put a class of individuals in a negative light, says Rita Cantor, a human geneticist at the University of California, Los Angeles. Moreover, other, even more tenuous explanations could underlie the parental age effect – such as the idea that fathers who delay parenthood somehow have genes that affect their social behavior and make their offspring more prone to neuropsychiatric disorders.
Says Cantor, âI think itâs a delicate subject.â Charlotte Schubert, Washington, DC 1170 volume 14 | number 11 | novmeber 2008 nature medicine Male biological clock possibly linked to autism, other disorders New techniques preserve fertility hope for women For a man battling cancer, preserving the option to have children later in life is simple: store samples of semen. Even a single ejaculate contains millions of sperm that can later be used to fertilize an egg. A woman facing cancer, on the other hand, has far fewer choices, which depend on her age, how much time she has before treatment must begin and the availability of a partner who can provide sperm. Oocytes, or eggs, are particularly vulnerable to chemotherapy and radiation, leaving many women infertile after being treated for cancer. The most successful option for a woman of child-bearing age is to create embryos through in vitro fertilization and freeze them. (Even if the womanâs ovaries are removed, her uterus can still carry a transplanted embryo to term.) Doctors have turned to this method for over two decades, with a success rate of up to 40%. âThatâs a procedure that doesnât need improvement,â says Kutluk Oktay, director of reproductive medicine and infertility at New York Medical College. Women who donât have a partner can try to freeze unfertilized eggs. But, unlike hardy embryos, eggs are sensitive to chilling. Hundreds of babies have been born with this technique, but the success rate overall hovers around 3%.
above text from https://dokumen.tips/documents/male-biological-clock-possibly-linked-to-autism-other-disorders.html
Strong Association of De Novo Copy Number Mutations with Autism
Authors: Jonathan Sebat, B. Lakshmi… and Michael Wigler
Science 15 Mar 2007: DOI: 10.1126/science.1138659
We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping.
Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders
Authors: Dan Levy, Michael Ronemus, … and Michael Wigler
Neuron 70, 886–897, June 9, 2011
To explore the genetic contribution to autistic spectrum disorders (ASDs), we have studied genomic copy-number variation in a large cohort of families with a single affected child and at least one unaffected sibling. We confirm a major contribution from de novo deletions and duplications but also find evidence of a role for inherited ‘‘ultrarare’’ duplications. Our results show that, relative to males, females have greater resistance to autism from genetic causes, which raises the question of the fate of female carriers. By analysis of the proportion and number of recurrent loci, we set a lower bound for distinct target loci at several hundred. We find many new candidate regions, adding substantially to the list of potential gene targets, and confirm several loci previously observed. The functions of the genes in the regions of de novo variation point to a great diversity of genetic causes but also suggest functional convergence.
Autism spectrum disorder: Genetics Home Reference
Many of the genes associated with ASD are involved in the development of the brain. The proteins produced from these genes affect multiple aspects of brain development, including production, growth, and organization of nerve cells (neurons). Some affect the number of neurons that are produced, while others are involved in the development or function of the connections between neurons (synapses) where cell-to-cell communication takes place, or of the cell projections (dendrites) that carry signals received at the synapses to the body of the neuron. Many affect development by controlling (regulating) the activity of other genes or proteins.
The specific ways that changes in these and other genes relate to the development of ASD are unknown. However, studies indicate that during brain development, some people with ASD have more neurons than normal and overgrowth in parts of the outer surface of the brain (the cortex). In addition, there are often patchy areas where the normal structure of the layers of the cortex is disturbed. Normally the cortex has six layers, which are established during development before birth, and each layer has specialized neurons and different patterns of neural connection. The neuron and brain abnormalities occur in the frontal and temporal lobes of the cortex, which are involved in emotions, social behavior, and language. These abnormalities are thought to underlie the differences in socialization, communication, and cognitive functioning characteristic of ASD.
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See our article on issues relating to Asperger syndrome and Autism