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How reliable are genetic ancestry tests?

How reliable are genetic ancestry tests/genealogical DNA testing?

Ancestry report 23andme family

Sample report from 23AndMe


What is the technology?


Why would people want to do this?

Learn about family history

Learn about susceptibility to diseases (Parkinson’s, Cancer)

Predicting Side Effects of Pharmaceuticals

Are we really of only the heritage that we think we are from?

If you’re black, DNA ancestry results can reveal an awkward truth, Splinter News, 2016

What companies are offering these tests?

  • 23andMe, personal genomics and biotechnology company, Mountain View, CA

  • Affymetrix

  • AncestryDNA

  • Family Tree DNA

  • MyHeritageDNA

Ethical issues


genetic counseling

Example: Tay Sachs

Five Things to Know about Direct-to-Consumer Genetic Tests. Johns Hopkins Medicine.

Alzheimer’s Society’s view on genetic testing

How reliable is the interpretation of the data?

Intro tba

How DNA Testing Botched My Family’s Heritage, and Probably Yours, Too, Gizmodo, 2018

How Accurate Are Online DNA Tests? Scientific American

Genetic tests are everywhere, but how reliable are they? Boston Globe

Pulling Back the Curtain on DNA Ancestry Tests. Tufts University

What genetic tests from 23andMe, Veritas and Genos really told me about my health. Science News

What I actually learned about my family after trying 5 DNA ancestry tests. Results Vary Wildly. Science News

Articles from scientific journals

False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Nature, 2018

How is genetic testing evaluated? A systematic review of the literature. European Journal of Human Genetics, 2018

Why is the interpretation of the data often wrong?

The accuracy of the interpretations will get better over time. But for now they are not great. Why not?

Kristen V. Brown writes:

Four tests, four very different answers about where my DNA comes from—including some results that contradicted family history I felt confident was fact. What gives?

There are a few different factors at play here. Genetics is inherently a comparative science: Data about your genes is determined by comparing them to the genes of other people.

As Adam Rutherford, a British geneticist and author of the excellent book “A Brief History of Everyone Who Ever Lived,” explained to me, we’ve got a fundamental misunderstanding of what an ancestry DNA test even does.

“They’re not telling you where your DNA comes from in the past,” he told me, “They’re telling you where on Earth your DNA is from today.”

Ancestry, for example, had determined that my Aunt Cat was 30 percent Italian by comparing her genes to other people in its database of more than six million people, and finding presumably that her genes had a lot of things in common with the present-day people of Italy.

Heritage DNA tests are more accurate for some groups of people than others, depending how many people with similar DNA to yours have already taken their test. Ancestry and 23andMe have actually both published papers about how their statistical modeling works.

As Ancestry puts it: “When considering AncestryDNA estimates of genetic ethnicity it is important to remember that our estimates are, in fact, estimates. The estimates are variable and depend on the method applied, the reference panel used, and the other customer samples included during estimation.”

That the data sets are primarily made up of paying customers also skews demographics. If there’s only a small number of Middle Eastern DNA samples that your DNA has been matched against, it’s less likely you’ll get a strong Middle Eastern match.

from gizmodo How-dna-testing-botched-my-familys-heritage-and-probably yours, 2018

Further reading

Understanding genetic testing: U.S. National Library of Medicine


Learning Standards

HS-LS1-1. Construct a model of transcription and translation to explain the roles of DNA and RNA that code for proteins that regulate and carry out essential functions of life.

HS-LS3-1. Develop and use a model to show how DNA in the form of chromosomes is passed from parents to offspring through the processes of meiosis and fertilization in sexual reproduction.

HS-LS3-2. Make and defend a claim based on evidence that genetic variations (alleles) may result from (a) new genetic combinations via the processes of crossing over and random segregation of chromosomes during meiosis, (b) mutations that occur during replication, and/or (c) mutations caused by environmental factors. Recognize that mutations that occur in gametes can be passed to offspring.

HS-LS3-3. Apply concepts of probability to represent possible genotype and phenotype combinations in offspring caused by different types of Mendelian inheritance patterns.

HS-LS3-4(MA). Use scientific information to illustrate that many traits of individuals, and the presence of specific alleles in a population, are due to interactions of genetic factors
and environmental factors.




The following intro comes from – Biology 110H Basic Concepts, Stephen,  haeffer; Variation in Dominance, Multiple Alleles, Epistasis, Pleiotropy, and Polygenic Inheritance, Penn State.

Sometimes a gene at one location on a chromosome can affect the expression of a gene at a second location (epistasis). A good example of epistasis is the genetic interactions that produce coat color in horses and other mammals.

In horses, brown coat color (B) is dominant over tan (b).

Gene expression is dependent on a second gene that controls the deposition of pigment in hair.

The dominant gene (C) codes for the presence of pigment in hair, whereas the recessive gene (c) codes for the absence of pigment.

If a horse is homozygous recessive for the second gene (cc), it will have a white coat regardless of the genetically programmed coat color (B gene) because pigment is not deposited in the hair.epistasis in horse punnett square

The figure above demonstrates this scenario. Several of the white horses have genotypes for brown or tan coat color in the first gene, but are completely white because they are homozygous recessive for the gene controlling pigment deposition.


Great resource here – “The term epistasis describes a certain relationship between genes, where an allele of one gene (e.g., ‘spread’) hides or masks the visible output, or phenotype, of another gene (e.g., pattern). Epistasis is entirely different from dominant and recessive, which are terms that apply to different alleles of the same gene (e.g., ‘bar’ is dominant to ‘barless’ and recessive to ‘check’).”

Click Epistasis, Genetic Science Learning Center, Univ of Utah

Epistasis: Gene Interaction and Phenotype Effects
By: Ilona Miko, Nature Education 1(1):197

Epistasis: Gene Interaction and Phenotype Effects. Nature education.

Modeling DNA with Legos

Modeling DNA with Legos

Students learn best when they develop mental models. For many students this is almost automatic – they see diagrams and can internally translate them into… TBA

But for many other students … TBA

One great solution is to physically create models of molecules… TBA

Strengths and limitations of using Legos TBA

(article to be written)

Legos DNA purines pyrimidines 1

In this next image we see (TBA)

Legos DNA purines pyrimidines 4


Learning Expectations

2016 Massachusetts Science and Technology/Engineering Curriculum Framework

8.MS-PS1-1. Develop a model to describe that (a) atoms combine in a multitude of ways to produce pure substances which make up all of the living and nonliving things that we encounter.

HS-LS1-1. Construct a model of transcription and translation to explain the roles of DNA and RNA that code for proteins that regulate and carry out essential functions of life.

HS-LS1-6. Construct an explanation based on evidence that organic molecules are primarily composed of six elements, where carbon, hydrogen, and oxygen atoms may combine with nitrogen, sulfur, and phosphorus to form monomers that can further combine to form large carbon-based macromolecules.

College Board Standards for College Success: Science

LSM-PE.5.2.2 Construct a representation of DNA replication, showing how the helical DNA molecule unzips and how nucleotide bases pair with the DNA template to form a duplicate of the DNA molecule.

Benchmarks for Science Literacy, AAAS

The information passed from parents to offspring is coded in DNA molecules, long chains linking just four kinds of smaller molecules, whose precise sequence encodes genetic information. 5B/H3*

Genes are segments of DNA molecules. Inserting, deleting, or substituting segments of DNA molecules can alter genes. An altered gene may be passed on to every cell that develops from it. The resulting features may help, harm, or have little or no effect on the offspring’s success in its environment. 5B/H4*

Did Watson and Crick really steal Rosalind Franklin’s data?

Sexism in science: did Watson and Crick really steal Rosalind Franklin’s data?

The race to uncover the structure of DNA reveals fascinating insights into how Franklin’s data was key to the double helix model, but the ‘stealing’ myth stems from Watson’s memoir and attitude rather than facts.

Photo 51 DNA Diffraction pattern

X-ray diffraction image of the double helix structure of the DNA molecule, taken 1952 by Raymond Gosling, commonly referred to as “Photo 51”, during work by Rosalind Franklin on the structure of DNA (text Wikipedia)

Matthew Cobb, The Guardian, 6/23/15

The wave of protest that followed Sir Tim Hunt’s stupid comments about ‘girls’ in laboratories highlighted many examples of sexism in science. One claim was that during the race to uncover the structure of DNA, Jim Watson and Francis Crick either stole Rosalind Franklin’s data, or ‘forgot’ to credit her. Neither suggestion is true.

In April 1953, the scientific journal Nature published three back-to-back articles on the structure of DNA, the material our genes are made of. Together, they constituted one of the most important scientific discoveries in history.

The first, purely theoretical, article was written by Watson and Crick from the University of Cambridge. Immediately following this article were two data-rich papers by researchers from King’s College London: one by Maurice Wilkins and two colleagues, the other by Franklin and a PhD student, Ray Gosling.

Rosalind Franklin

Credit: Vittoria Luzzati/NPG

The model the Cambridge duo put forward did not simply describe the DNA molecule as a double helix. It was extremely precise, based on complex measurements of the angles formed by different chemical bonds, underpinned by some extremely powerful mathematics and based on interpretations that Crick had recently developed as part of his PhD thesis. The historical whodunnit, and the claims of data theft, turn on the origin of those measurements.

The four protagonists would make good characters in a novel – Watson was young, brash, and obsessed with finding the structure of DNA; Crick was brilliant with a magpie mind, and had struck up a friendship with Wilkins, who was shy and diffident. Franklin, an expert in X-ray crystallography, had been recruited to King’s in late 1950. Wilkins expected she would work with him, but the head of the King’s group, John Randall, led her to believe she would be independent.

From the outset, Franklin and Wilkins simply did not get on. Wilkins was quiet and hated arguments; Franklin was forceful and thrived on intellectual debate. Her friend Norma Sutherland recalled: “Her manner was brusque and at times confrontational – she aroused quite a lot of hostility among the people she talked to, and she seemed quite insensitive to this.”

Watson and Crick’s first foray into trying to crack the structure of DNA took place in 1952. It was a disaster. Their three-stranded, inside-out model was hopelessly wrong and was dismissed at a glance by Franklin. Following complaints from the King’s group that Watson and Crick were treading on their toes, Sir Lawrence Bragg, the head of their lab in Cambridge told them to cease all work on DNA.

However, at the beginning of 1953, a US competitor, Linus Pauling, became interested in the structure of DNA, so Bragg decided to set Watson and Crick on the problem once more.

At the end of January 1953, Watson visited King’s, where Wilkins showed him an X-ray photo that was subsequently used in Franklin’s Nature article. This image, often called ‘Photo 51’, had been made by Raymond Gosling, a PhD student who had originally worked with Wilkins, had then been transferred to Franklin (without Wilkins knowing), and was now once more being supervised by Wilkins, as Franklin prepared to leave the terrible atmosphere at King’s and abandon her work on DNA.

Watson recalled that when he saw the photo – which was far clearer than any other he had seen – ‘my mouth fell open and my pulse began to race.’ According to Watson, photo 51 provided the vital clue to the double helix. But despite the excitement that Watson felt, all the main issues, such as the number of strands and above all the precise chemical organisation of the molecule, remained a mystery. A glance at photo 51 could not shed any light on those details.

What Watson and Crick needed was far more than the idea of a helix – they needed precise observations from X-ray crystallography. Those numbers were unwittingly provided by Franklin herself, included in a brief informal report that was given to Max Perutz of Cambridge University.

In February 1953, Perutz passed the report to Bragg, and thence to Watson and Crick.

Crick now had the material he needed to do his calculations. Those numbers, which included the relative distances of the repetitive elements in the DNA molecule, and the dimensions of what is called the monoclinic unit cell – which indicated that the molecule was in two matching parts, running in opposite directions – were decisive.

The report was not confidential, and there is no question that the Cambridge duo acquired the data dishonestly. However, they did not tell anyone at King’s what they were doing, and they did not ask Franklin for permission to interpret her data (something she was particularly prickly about).

Their behaviour was cavalier, to say the least, but there is no evidence that it was driven by sexist disdain: Perutz, Bragg, Watson and Crick would have undoubtedly behaved the same way had the data been produced by Maurice Wilkins.

Ironically, the data provided by Franklin to the MRC were virtually identical to those she presented at a small seminar in King’s in autumn 1951, when Jim Watson was in the audience. Had Watson bothered to take notes during her talk, instead of idly musing about her dress sense and her looks, he would have provided Crick with the vital numerical evidence 15 months before the breakthrough finally came.

By chance, Franklin’s data chimed completely with what Crick had been working on for months: the type of monoclinic unit cell found in DNA was also present in the horse haemoglobin he had been studying for his PhD. This meant that DNA was in two parts or chains, each matching the other. Crick’s expertise explains why he quickly realised the significance of these facts, whereas it took Franklin months to get to the same point.

While Watson and Crick were working feverishly in Cambridge, fearful that Pauling might scoop them, Franklin was finishing up her work on DNA before leaving the lab. The progress she made on her own, increasingly isolated and without the benefit of anyone to exchange ideas with, was simply remarkable.

Franklin’s laboratory notebooks reveal that she initially found it difficult to interpret the outcome of the complex mathematics – like Crick, she was working with nothing more than a slide rule and a pencil – but by 24 February, she had realised that DNA had a double helix structure and that the way the component nucleotides or bases on each strand were connected meant that the two strands were complementary, enabling the molecule to replicate.

Above all, Franklin noted that ‘an infinite variety of nucleotide sequences would be possible to explain the biological specificity of DNA’, thereby showing that she had glimpsed the most decisive secret of DNA: the sequence of bases contains the genetic code.

To prove her point, she would have to convert this insight into a precise, mathematically and chemically rigorous model. She did not get the chance to do this, because Watson and Crick had already crossed the finishing line – the Cambridge duo had rapidly interpreted the double helix structure in terms of precise spatial relationships and chemical bonds, through the construction of a physical model.

In the middle of March 1953, Wilkins and Franklin were invited to Cambridge to see the model, and they immediately agreed it must be right. It was agreed that the model would be published solely as the work of Watson and Crick, while the supporting data would be published by Wilkins and Franklin – separately, of course. On 25 April there was a party at King’s to celebrate the publication of the three articles in Nature. Franklin did not attend. She was now at Birkbeck and had stopped working on DNA.

Franklin died of ovarian cancer in 1958, four years before the Nobel prize was awarded to Watson, Crick and Wilkins for their work on DNA structure. She never learned the full extent to which Watson and Crick had relied on her data to make their model; if she suspected, she did not express any bitterness or frustration, and in subsequent years she became very friendly with Crick and his wife, Odile.

Our picture of how the structure of DNA was discovered, and the myth about Watson and Crick stealing Franklin’s data, is almost entirely framed by Jim Watson’s powerful and influential memoir, The Double Helix. Watson included frank descriptions of his own appalling attitude towards Franklin, whom he tended to dismiss, even down to calling her ‘Rosy’ in the pages of his book – a nickname she never used (her name was pronounced ‘Ros-lind’). The epilogue to the book, which is often overlooked in criticism of Watson’s attitude to Franklin, contains a generous and fair description by Watson of Franklin’s vital contribution and a recognition of his own failures with respect to her – including using her proper name.

It is clear that, had Franklin lived, the Nobel prize committee ought to have awarded her a Nobel prize, too – her conceptual understanding of the structure of the DNA molecule and its significance was on a par with that of Watson and Crick, while her crystallographic data were as good as, if not better, than those of Wilkins. The simple expedient would have been to award Watson and Crick the prize for Physiology or Medicine, while Franklin and Watkins received the prize for Chemistry.

Whether the committee would have been able to recognise Franklin’s contribution is another matter. As the Tim Hunt affair showed, sexist attitudes are ingrained in science, as in the rest of our culture.

By Matthew Cobb


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Epigenetics is the study of biological mechanisms that switch genes on and off. Epigenetics affects how genes are read by cells, and thus how they produce proteins. Here are a few important points:

  • Epigenetics Controls Genes. Certain circumstances in life can cause genes to be silenced or expressed over time. In other words, they can be turned off (becoming dormant) or turned on (becoming active).

  • Epigenetics Is Everywhere. What you eat, where you live, who you interact with, when you sleep, how you exercise, even aging – all of these can eventually cause chemical modifications around the genes that will turn those genes on or off over time.

    Additionally, in certain diseases such as cancer or Alzheimer’s, various genes will be switched into the opposite state, away from the normal/healthy state.

  • Epigenetics Makes Us Unique. Even though we are all human, why do some of us have blonde hair or darker skin? Why do some of us hate the taste of mushrooms or eggplants? Why are some of us more sociable than others? The different combinations of genes that are turned on or off is what makes each one of us unique. Furthermore, there have been indications that some epigenetic changes can be inherited.

  • Epigenetics Is Reversible. With 20,000+ genes, what will be the result of the different combinations of genes being turned on or off? The possible arrangements are enormous! But if we could map every single cause and effect of the different combinations, and if we could reverse the gene’s state to keep the good while eliminating the bad… then we could theoretically* cure cancer, slow aging, stop obesity, and so much more.

This introduction has been excerpted from WhatIsEpigenetics.com

How does this happen?

We currently know of three systems that attach to genes, and turn them on or off. More systems may be discovered!

DNA methylation

histone modification

non-coding RNA (ncRNA)-associated gene silencing



More content TBA

Example 1

gene environment interactions in human obesity

From The importance of gene–environment interactions in human obesity, Hudson Reddon, Jean-Louis Guéant, David Meyre, Clinical Science Aug 08, 2016, 130

Learning Standards



Detecting genetic disorders with 3d face scans

Detecting genetic disorders with 3d face scans

Johan at the Phineas Gage Fan Club writes:

Following on from last week’s post on smile measuring software, The Scotsman (via Gizmodo) reports on the work by Hammond and colleagues at UCL, who are developing 3d face scans as a quick, inexpensive alternative to genetic testing. This is not as crazy as it sounds at first since it is known that in a number of congenital conditions, the hallmark behavioural, physiological or cognitive deficits are also (conveniently) accompanied by characteristic appearances. The classic example of this is Down syndrome, which you need no software to recognise. More examples appear in the figure above, where you can compare the characteristic appearances of various conditions to the unaffected face in the middle.

Hammond’s software can be used to identify 30 congenital conditions, ranging from Williams syndrome (a sure topic of a future post) to Autism,


Face scan Williams syndrome

Face scan Fragile X and Jacobson


Diagnostically relevant facial gestalt information from ordinary photos

Rare genetic disorders affect around 8% of people, many of whom live with symptoms that greatly reduce their quality of life. Genetic diagnoses can provide doctors with information that cannot be obtained by assessing clinical symptoms, and this allows them to select more suitable treatments for patients. However, only a minority of patients currently receive a genetic diagnosis.

Alterations in the face and skull are present in 30–40% of genetic disorders, and these alterations can help doctors to identify certain disorders, such as Down’s syndrome or Fragile X.

Extending this approach, Ferry et al. trained a computer-based model to identify the patterns of facial abnormalities associated with different genetic disorders. The model compares data extracted from a photograph of the patient’s face with data on the facial characteristics of 91 disorders, and then provides a list of the most likely diagnoses for that individual. The model used 36 points to describe the space, including 7 for the jaw, 6 for the mouth, 7 for the nose, 8 for the eyes and 8 for the brow.

This approach of Ferry et al. has three advantages. First, it provides clinicians with information that can aid their diagnosis of a rare genetic disorder. Second, it can narrow down the range of possible disorders for patients who have the same ultra-rare disorder, even if that disorder is currently unknown. Third, it can identify groups of patients who can have their genomes sequenced in order to identify the genetic variants that are associated with specific disorders.


Quentin Ferry et al, eLife 2014;3:e02020


This App Uses Facial Recognition Software to Help Identify Genetic Conditions

A geneticist uploads a photo of a patient’s face, and Face2Gene gathers data and generates a list of possible syndromes

… Face2Gene, the tool Abdul-Rahman used, was created by the Boston startup, FDNA. The company uses facial recognition software to aid clinical diagnoses of thousands of genetic conditions, such as Sotos syndrome (cerebral gigantism), Kabuki syndrome (a complicated disorder that features developmental delay, intellectual disability and more) and Down syndrome.

This App Uses Facial Recognition Software to Help Identify Genetic Conditions, Smithsonian Magazine


Related resources

How phenotypes lead to genotypes (infographic?)

Scientific journal articles

Detecting Genetic Association of Common Human Facial Morphological Variation Using High Density 3D Image Registration
Shouneng Peng et al, PLoS Comput Biol. 2013 Dec; 9(12)


Causes of autism

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/

See The genetics of autism


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
Author Affiliations
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

Charlotte Schubert

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

Also see



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

DOI 10.1016/j.neuron.2011.05.015

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