Evan Eichler

Professor, University of Washington

It has been more than 20 years since scientists announced the completion of the Human Genome Project even though the $3 billion effort to sequence the 3 billion bases of human DNA was not, in fact, complete. Technological limitations meant that roughly 8 percent of the genome remained a mystery.

In April, the Telomere-to-Telomere Consortium closed nearly all the gaps, adding roughly 200 million bases of genetic information that codes for more than 1,900 genes.

This new treasure trove of data, detailed in six papers in Science, stands to advance autism research, says Evan Eichler, professor of genome sciences at the University of Washington in Seattle.

Spectrum spoke with Eichler, who was part of the Human Genome Project and the Telomere-to-Telomere Consortium, about what secrets may emerge from once-murky regions of the genome.

This interview has been edited for length and clarity.

Spectrum: How will having a more complete human genome affect autism research?

Evan Eichler: Because our reference genome was incomplete, some gene sequences were not correctly mapped to their place in the genome. So when we would find a variant in an autism genome that was missing from the reference genome, we didnt always know where it was or which gene or genes it affected. This new telomere-to-telomere draft improves mapping across the board. The sequences we gather from people with autism are now more likely to be mapped to the right place.

One phenomenon often associated with autism is the deletion or duplication of DNA, known as copy number variation (CNV). In our recent paper in Science, we analyzed the new telomere-to-telomere data and found that it was a better predictor of true copy number 9 times out of 10 when compared with the old reference. That means were in a much better position to assess CNVs, which we know to contribute to autism, than with the old reference that was full of holes.

S: How was this updated human genome sequence produced differently from previous ones?

EE: We typically sequence autism genomes with short reads, which are just a few hundred bases long. When we do this, were missing genetic variation that occur over long stretches of DNA, particularly structural variation such as large deletions, duplications and rearrangements of DNA. We have previously shown that about 75 percent of all structural variation in the human genome goes undetected if we rely only on short-read data. Roughly 10 percent of autism cases stem from known structural variation in DNA. If we can sequence the genomes of autism families with long reads, many thousands of bases long, we can explore the 75 percent of structural variation that was previously undetected and potentially find more genetic causes of autism.

S: Are there potentially new autism-linked genes in the more complete genome?

EE: About 500 genes have been mapped to complex regions of the new reference genome that were previously excluded from sequencing studies because our techniques didnt reliably map there. Among those genes are ones important for brain function, such as SRGAP2C. The number of copies of this gene influences where, how and when dendrites form during development, which influences the density and strength of synaptic connections. Its a gene incredibly important to brain function, whose duplicate copies we couldnt reliably detect with short reads.

Another gene, ARHGAP11B on chromosome 15, was previously found to be deleted in two people with autism and intellectual disability. Its known to increase neuronal stem cell division during development. That gene is typically not studied in autistic people because it was mapped to very repetitive regions of the genome that previous genome-sequencing techniques skipped over entirely.

S: What could we learn about autism from the dark regions of the human genome that do not code for proteins?

EE: DNA that makes up the short arms of human chromosomes, called acrocentric DNA, may be important in autism. Those stretches were only sequenced in the last year or so of the Telomere-to-Telomere project.

There are gene families in acrocentric DNA that encode rDNA, which helps form the ribosomes that produce proteins in cells. We know autism is often linked with having too many or too few copies of genes; acrocentric DNA is another category of DNA we can now analyze for the same problem. If we can compare the rDNA of people with autism with that of neurotypical individuals, any differences we see may help us understand the chances of developing autism.

S: Now that we have a new reference genome, will some autism studies need to be repeated?

EE: Yes, well need to run all autism genomes against this new, more complete reference genome. Im particularly interested in looking for variations in genes on the X chromosome, which is linked with sex. There are significant sex differences in boys versus girls when it comes to autism, with boys four times more likely to be autistic than girls. Now, with the new reference genome, we can detect copy number variations and other genetic variation better than before, including on the X chromosome.

We would also like to look at unsolved cases of autism those not linked to any known rare genetic variants and those without high polygenic risk scores, which reflect common genetic variants associated with the condition. These unsolved cases account for a very large fraction of kids with autism. Maybe in the dark regions of the genome, or in genes not characterized before, we can find answers especially with long-read sequences of Mom, Dad and unaffected siblings to shed light on how these unsolved cases are genetically distinct or similar to their family members.

S: What about methylated DNA DNA with chemical tags called methyl groups on top. There is evidence that these epigenetic tags, which influence gene activity, play a role in autism.

EE: With new long-read sequencing techniques such as nanopore sequencing, we can distinguish methylated sequences without having to amplify or convert the DNA beforehand, as was necessary with prior techniques. There might be differences in epigenetic modifications of DNA between people with and without autism that we missed before, which could help address some of the unsolved cases of autism.

S: How feasible is it for researchers to conduct long-read sequencing, or for families to access it?

EE: The major limitation is the cost. Sequencing and assembling a genome well with long reads costs about $10,000, compared with about $1,000 with short reads. Most insurance companies are not going to pay for long-read sequencing. Theres also the issue of throughput. Since it started in 2016, the SPARK project has aimed to look at 50,000 families using exome sequences, which capture only the protein-coding regions of the genome. In that same time, we could look at just 50 families with long-read whole-genome sequencing. [SPARK is funded by the Simons Foundation,Spectrumsparent organization.]

But costs always come down with time. I think that long reads will replace short reads in 10 years. I think every family deserves to have their genomes fully sequenced and characterized, to help them make decisions such as what the best care for their children should be. We just have to get the technology to a cost-effective point.

S: The newly sequenced parts of the genome often contain highly repetitive DNA. Autism has been linked to the presence of such repetitive regions. What might these new regions tell us about autism?

EE: The short answer is we dont know yet. But there is evidence that those regions are very relevant to autism. Two common genetic causes of autism include duplications on chromosome 15q, which account for about 1.5 percent of autism cases, and deletions on 16p11.2, which account for just under 1 percent of autism cases. We know that repetitive regions are hotspots for chromosomal damage that can lead to deletions and duplications, but they werent precisely mapped. Now we can precisely map these regions of genomic instability and gain insights on how breaks occur there and potentially lead to autism.

S: Does anything else come to mind with this new work?

EE: One thing thats still a puzzle is that the same genetic variation strongly linked with autism can have very different outcomes in one kid versus another. Some children may be mildly affected, whereas others may be severely affected. I dont think the odyssey of this work ends with finding the primary genetic causes of autism. We need to understand the background in which these variations lie the way they interact with other genetic variation to understand their true outcome.

Another thing I have reflected on more recently is how most of the innovations we see with this new project were driven by scientists a full generation younger than me. I think that bodes well for the future, to have so many young people interested in solving these difficult problems. The future of human genetics research is in good hands.

Cite this article: https://doi.org/10.53053/GPXL5356

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Autism and the complete human genome: Q&A with Evan Eichler | Spectrum - Spectrum

Summary: Hypermutation in children may be linked to increased mutations in the sperm of the biological father, especially fathers who received certain forms of chemotherapy to treat cancer early in life.

Source: Wellcome Sanger Institute

Some rare cases of higher genetic mutation rates in children, known as hypermutation, could be linked to the father receiving certain chemotherapy treatments, new research has found.

Scientists from the Wellcome Sanger Institute and their collaborators analyzed over 20,000 familiesgenetic informationand identified 12childrenwith between two to seven times more mutations than the general population.

The team linked the majority of these to increased mutations in thespermof the biological father.

The research, published today inNature, shows that just under half of these fathers had been treated with certain types ofchemotherapyearlier in life, which could be linked to the increased number of mutations in theirsperm cells.

While these cases of hypermutation in children are rare, and in the vast majority of children will not lead to genetic disorders, hypermutation will increase the risk of a child having arare genetic disorder. It is important to investigate this further due to the implications it has for patients who receive chemotherapy and want to have children in the future.

If further research confirms an impact of chemotherapy, patients could be offered the opportunity to freeze their sperm before treatment.

Genomes are copied with a very low error rate when they are passed from one generation to the next. Nevertheless, as thehuman genomecontains three billion letters, random mutations in the sperm and the egg are inevitable and pass from the parent to the child. This means that typically every child has around 60 to 70 new mutations that their biological parents dont have.

These mutations are responsible for genetic variation along with many genetic diseases. Around 75 percent of these random mutationscome from the father.

Most genetic disorders only occur when both copies of an important gene are damaged, resulting in what is known as a recessive disease. If only one copy is damaged, for example, by a new mutation, the remaining functioning copy of the gene will be able to prevent disease.

However, a minority of genetic disorders, known as dominant disorders, occur when only one copy of a gene is damaged. It is these dominant disorders that can be caused by a single, random mutation.

One of the main factors influencing mutation rate is the age of the parents, with mutations increasing by 1.3 mutations per year in the fathers and0.4 mutations per year in mothers. If there is a higher number of germline mutations, there is a higher risk of a child being born with a dominant disorder.

However, hypermutation in children does not always mean they will have a dominant disorder.

In new research, from the Wellcome Sanger Institute and collaborators, scientists used genetic data and family health histories from existing databases to identify children that had unusually high mutation rates, between two and seven times higher than average, to investigate where these might have originated from.

The team analyzed data from over 20,000 UK families with children with suspected genetic conditions participating in the Deciphering Developmental Disorders and 100,000 Genomes projects.

They found that children with hypermutation were rare among these families. As the number of children with hypermutations was only 12 out of around 20,000, these rates of increased mutations could not have been caused by common exposures, such as smoking, pollution, or commongenetic variation.

For eight of these children the excess mutations could be linked to their fathers sperm. It was possible to investigate in detail seven of the families, where the excess mutations came from the biological father. Two of the fathers had rare recessive genetic variants that impaired DNA repair mechanisms.

The other five men had all previously been treated with chemotherapy before conceiving a child. Three of these children had a pattern of mutations characteristic of chemotherapy using platinum-based drugs and the fathers of the other two children had both received chemotherapy with mustard-derived alkylating agents.

However, by linking the genetic data to anonymized health data, it could be shown that most fathers and all mothers who had received chemotherapy prior to conceiving a child did not have children with a notable excess of mutations.

This study exemplifies the value of linking nationwide genetic data and routine clinical records in secure, anonymized and trustworthy ways to provide unique insights into unanticipated, but important, questions.

Through the efforts of Health Data Research UK and its partners, these kinds of responsible analyses of potential clinical relevance will be easier to perform in the future.

While chemotherapy is one of the most effective treatments for cancer, it is widely recognized that it can have disruptive and debilitating side effects. Clinicians take these into account when prescribing this treatment.

If these types of chemotherapy were shown to impact sperm in some patients, this could have clinical implications on treatment plans and family planning.

Further research is required to investigate this at a deeper level before changing treatment for cancer in men. It is currently unclear why these types of chemotherapies seem to impact the sperm more than the egg cells.

Dr. Joanna Kaplanis, first author and Post-Doctoral Fellow at the Wellcome Sanger Institute, said: Hypermutation in children, where they have between two and seven times more random mutations than the general population, is rare and therefore cannot be caused by common carcinogens or exposures.

Our research analyses over 20,000 families and highlights new causes of these mutations, linking them back to germline mutations in the fathers sperm as well as identifying a new mutational signature.

Understanding the impact of these germline mutations in the sperm could help us uncover why some people are more likely to have children with these high rates ofrandom mutations, and help protect against these if they cause disease.

John Danesh, Director of HDR UK Cambridge, who supported the research, said, Hypermutation in children is an uncommon but important phenomenon that increases the risk of life-altering genetic diseases. By bringing together genetic data at scale, and linking this with routine clinical data like the hospital records of parents, the team has identified new risk factors that may influence future healthcare decisions.

This work elegantly demonstrates how work in Health Data Research UKs Understanding the Causes of Disease Programme is helping to link nationwidegenetic dataand clinical records in secure, anonymised and trustworthy ways that provide unique insights into unanticipated, but important questions.

Sir Mark Caulfield, from Queen Mary University of London, and former Chief Scientist at Genomics England, said: These findings were only possible due to access to whole genomes and linked health record data on the family members from the 100,000 Genomes Project. These findings could really help people with cancer consider family planning.

Professor Matthew Hurles, senior author and Head of Human Genetics at the Wellcome Sanger Institute, said: Chemotherapy is an incredibly effective treatment for many cancers, but unfortunately it can have some damaging side effects. Our research found a plausible link between two types of chemotherapy and their impact on sperm in a very small number of men.

These results require further systematic studies to see if there is acausal linkbetween chemotherapy and spermmutations, and if there is a way of identifying individuals at risk prior to treatment so they could takefamily planningmeasures, such as freezing their sperm prior to treatment.

I would also like to thank the families that donated their genetic and health information to make this research possible.

Author: Press OfficeSource: Wellcome Sanger InsituteContact: Press Office Wellcome Sanger InstituteImage: The image is in the public domain

Original Research: Open access.Genetic and chemotherapeutic influences on germline hypermutation by Matthew Hurles et al. Nature

Abstract

Genetic and chemotherapeutic influences on germline hypermutation

Mutations in the germline generates all evolutionary genetic variation and is a cause of genetic disease. Parental age is the primary determinant of the number of new germline mutations in an individuals genome.

Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 individuals with a hypermutated genome with between two and seven times more de novo single-nucleotide variants than expected. In most families (9 out of 12), the excess mutations came from the father.

Two families had genetic drivers of germline hypermutation, with fathers carrying damaging genetic variation in DNA-repair genes. For five of the families, paternal exposure to chemotherapeutic agents before conception was probably a key driver of hypermutation.

Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare, the number of excessmutations is relatively modest and most individuals with a hypermutated genome will not have a genetic disease.

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Increased Mutations in Children Can Be Traced Back to Mistakes in Father's Sperm - Neuroscience News

In 1996, Dolly the sheep made headlines around the world after becoming the first mammal to be successfully cloned from an adult cell. Many commentators thought this would catalyze a golden age of cloning, with numerous voices speculating that the first human clone must surely be just a few years away.

Some people suggested that human clones could play a role in eradicating genetic diseases, while others considered that the cloning process could, eventually, eliminate birth defects (despite research by a group of French scientists in 1999 finding that cloning may actually increase the risk of birth defects).

There have been various claims all unfounded, it is important to add of successful human cloning progams since the success of Dolly. In 2002, Brigitte Boisselier, a French chemist and devout supporter of Ralism a UFO religion based on the idea that aliens created humanity claimed that she and a team of scientists had successfully delivered the first cloned human, whom she named Eve.

However, Boisselier was unwilling or indeed unable to provide any evidence, and so it is widely believed to be a hoax.

So why, almost 30 years on from Dolly, haven't humans been cloned yet? Is it primarily for ethical reasons, are there technological barriers, or is it simply not worth doing?

Related: What are the alternatives to animal testing?

"Cloning" is a broad term, given it can be used to describe a range of processes and approaches, but the aim is always to produce "genetically identical copies of a biological entity," according to the National Human Genome Research Institute (NHGRI).

Any attempted human cloning would most likely utilize "reproductive cloning" techniques an approach in which a "mature somatic cell," most probably a skin cell, would be used, according to NHGRI. The DNA extracted from this cell would be placed into the egg cell of a donor that has "had its own DNA-containing nucleus removed."

The egg would then begin to develop in a test tube before being "implanted into the womb of an adult female," according to NHGRI.

However, while scientists have cloned many mammals, including cattle, goats, rabbits and cats, humans have not made the list.

"I think there is no good reason to make [human] clones," Hank Greely, a professor of law and genetics at Stanford University who specializes in ethical, legal and social issues arising from advances in the biosciences, told Live Science in an email.

"Human cloning is a particularly dramatic action, and was one of the topics that helped launch American bioethics," Greely added.

The ethical concerns around human cloning are many and varied. According to Britannica, the potential issues encompass "psychological, social and physiological risks." These include the idea that cloning could lead to a "very high likelihood" of loss of life, as well as concerns around cloning being used by supporters of eugenics. Furthermore, according to Britannica, cloning could be deemed to violate "principles of human dignity, freedom and equality."

In addition, the cloning of mammals has historically resulted in extremely high rates of death and developmental abnormalities in the clones, Live Science previously reported.

Another core issue with human cloning is that, rather than creating a carbon copy of the original person, it would produce an individual with their own thoughts and opinions.

"We've all known clones identical twins are clones of each other and thus we all know that clones aren't the same person," Greely explained.

A human clone, Greely continued, would only have the same genetic makeup as someone else they would not share other things such as personality, morals or sense of humor: these would be unique to both parties.

People are, as we well know, far more than simply a product of their DNA. While it is possible to reproduce genetic material, it is not possible to exactly replicate living environments, create an identical upbringing, or have two people encounter the same life experiences.

So, if scientists were to clone a human, would there be any benefits, scientific or otherwise?

"There are none that we should be willing to consider," Greely said, emphasizing that the ethical concerns would be impossible to overlook.

However, if moral considerations were removed entirely from the equation, then "one theoretical benefit would be to create genetically identical humans for research purposes," Greely said, though he was keen to reaffirm his view that this should be thought of as "an ethical non-starter."

Greely also stated that, regardless of his own personal opinion, some of the potential benefits associated with cloning humans have, to a certain degree, been made redundant by other scientific developments.

"The idea of using cloned embryos for purposes other than making babies, for example producing human embryonic stem cells identical to a donor's cells, was widely discussed in the early 2000s," he said, but this line of research became irrelevant and has subsequently not been expanded upon post-2006, the year so-called induced pluripotent stem cells (iPSCs) were discovered. These are "adult" cells that have been reprogrammed to resemble cells in early development.

Shinya Yamanaka, a Japanese stem cell researcher and 2012 Nobel Prize winner, made the discovery when he "worked out how to return adult mouse cells to an embryonic-like state using just four genetic factors," according to an article in Nature. The following year, Yamanaka, alongside renowned American biologist James Thompson, managed to do the same with human cells.

When iPSCs are "reprogrammed back into an embryonic-like pluripotent state," they enable the "development of an unlimited source of any type of human cell needed for therapeutic purposes," according to the Center of Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles.

Therefore, instead of using embryos, "we can effectively do the same thing with skin cells," Greely said.

This development in iPSC technology essentially rendered the concept of using cloned embryos both unnecessary and scientifically inferior.

Related: What is the most genetically diverse species?

Nowadays, iPSCs can be used for research in disease modeling, medicinal drug discovery and regenerative medicine, according to a 2015 paper published in the journal Frontiers in Cell and Developmental Biology.

Additionally, Greely also suggested that human cloning may simply no longer be a "sexy" area of scientific study, which could also explain why it has seen very little development in recent years.

He pointed out that human germline genome editing is now a more interesting topic in the public's mind, with many curious about the concept of creating "super babies," for example. Germline editing, or germline engineering, is a process, or series of processes, that create permanent changes to an individuals genome. These alterations, when introduced effectively, become heritable, meaning they will be handed down from parent to child.

Such editing is controversial and yet to be fully understood. In 2018, the Council of Europe Committee on Bioethics, which represents 47 European states, released a statement saying that "ethics and human rights must guide any use of genome editing technologies in human beings," adding that "the application of genome editing technologies to human embryos raises many ethical, social and safety issues, particularly from any modification of the human genome which could be passed on to future generations."

However, the council also noted that there is "strong support" for using such engineering and editing technologies to better understand "the causes of diseases and their future treatment," noting that they offer "considerable potential for research in this field and to improve human health."

George Church, a geneticist and molecular engineer at Harvard University, supports Greely's assertion that germline editing is likely to garner more scientific interest in the future, especially when compared with "conventional" cloning.

"Cloning-based germline editing is typically more precise, can involve more genes, and has more efficient delivery to all cells than somatic genome editing," he told Live Science.

However, Church was keen to urge caution, and admitted that such editing has not yet been mastered.

"Potential drawbacks to address include safety, efficacy and equitable access for all," he concluded.

Originally published on Live Science.

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Why haven't we cloned a human yet? - Livescience.com