Researchers have developed a new method to precisely and rapidly correct genetic alterations in cultured patient cells.
The genetically corrected stem cells are produced from a 2–3 mm skin biopsy taken from patients with different genetic diseases. The corrected stem cells are essential in the research and for the development of new therapies for the diseases in question.
The scientists based the new method on previous groundbreaking research in the fields of stem cells and gene editing; the first technique is the invention of induced pluripotent stem cells, iPSCs from differentiated cells, which won the Nobel in 2012. The other technique is the CRISPR-Cas9 ‘gene scissors’, which got the prize in 2020. The new method combines these techniques to correct gene alterations that cause inherited diseases, creating fully functional new stem cells.
The researchers aim to eventually produce autologous cells with therapeutic properties. The use of the patient’s own corrected cells could help in avoiding the immunological challenges hampering the organ and tissue transplantation from a donor. The new method was developed by PhD student Sami Jalil and is published in Stem Cell Reports.
More than 6000 inherited diseases are known to exist, which are caused by various gene alterations. Currently, some are treated with a cell or organ transplant from a healthy donor, if available.
“Our new system is much faster and more precise than the older methods in correcting the DNA errors, and the speed makes it easier and diminishes also the risk of unwanted changes,” commented adjunct professor Kirmo Wartiovaara, who supervised the work.
“In perfect conditions, we have reached up to 100 percent efficacy, although one has to remember that the correction of cultured cells is still far away from proven therapeutic applications. But it is a very positive start” Prof Wartiovaara added.
Researchers have uncovered differences in immune pathway activation to influenza infection between individuals of European and African genetic ancestry, according to a study published in Science. Many of the genes that were associated with these immune response differences to influenza are also enriched among genes associated with COVID disease severity.
“The lab has been interested in understanding how individuals from diverse populations respond differently to infectious diseases,” said first author Haley Randolph, a graduate student at the University of Chicago. “In this study, we wanted to look at the differences in how various cell types respond to viral infection.”
The researchers examined gene expression patterns in peripheral mononuclear blood cells, a diverse set of specialised immune cells that play important roles in the body’s response to infection. These cells were gathered from men of European and African ancestry and then exposed the cells to flu in a laboratory setting. This let the team examine the gene signatures of a variety of immune cell types, and observe how the flu virus affected each cell type’s gene expression.
The results showed that individuals of European ancestry showed an increase in type I interferon pathway activity during early influenza infection.
“Interferons are proteins that are critical for fighting viral infections,” said senior author Luis Barreiro, PhD, Associate Professor of Medicine at UChicago. “In COVID-19, for example, the type I interferon response has been associated with differences in the severity of the disease.”
This increased pathway activation hindered the replication of the virus more and limited viral replication later on. “Inducing a strong type I interferon pathway response early upon infection stops the virus from replicating and may therefore have a direct impact on the body’s ability to control the virus,” said Barreiro. “Unexpectedly, this central pathway to our defense against viruses appears to be amongst the most divergent between individuals from African and European ancestry.”
The researchers saw a variety of differences in gene expression across different cell types, suggesting a constellation of cells that work together to fight disease.
Such a difference in immune pathway activation could explain influenza outcome disparities between different racial groups; Non-Hispanic Black Americans are more likely to be hospitalised due to the flu than any other racial group.
However, these results are not evidence for genetic differences in disease susceptibility, the researchers point out. Rather, possible differences in environmental and lifestyle between racial groups could be influencing gene expression, and affecting the immune response.
“There’s a strong relationship between the interferon response and the proportion of the genome that is of African ancestry, which might make you think it’s genetic, but it’s not that simple,” said Barreiro. “Genetic ancestry also correlates with environmental differences. A lot of what we’re capturing could be the result of other disparities in our society, such as systemic racism and healthcare inequities. Although some of the differences we show in the paper can be linked to specific genetic variation, showing that genetics do play some role, such genetic differences are not enough to fully explain the differences in the interferon response.”
These differences in viral susceptibility may not be confined to just influenza. Comparing a list of genes associated with differences in COVID severity, the researchers found that many of the same genes showed significant differences in their expression after flu infection between individuals of African and European ancestry.
“We didn’t study COVID patient samples as part of this study, but the overlap between these gene sets suggests that there may be some underlying biological differences, influenced by genetic ancestry and environmental effects, that might explain the disparities we see in COVID outcomes,” said Barreiro.
As they explore this further, the researchers hope to figure out which factors contribute to the differences in the interferon response, and immune responses more broadly, to better predict individual disease risk.
Patients with this unusual combination of conditions were referred to Mehul Dattani (UCL), and affected individuals were found to carry the same homozygous mutation in the PRDM13 gene, which encodes a chromatin modifying factor that contributes to regulating cell fate. Intriguingly, an unaffected heterozygous carrier of this mutation was identified by screening 42 unaffected individuals in the Maltese population, suggesting that this mutation is present at low levels in the population.
The researchers set out to model this condition and identify the underlying causes using a PRDM13-deficient mouse model. The researchers found evidence that both the cerebellar hypoplasia and reproductive phenotypes resulted from defects in the specification of specific populations of GABAergic neuronal progenitors in the developing cerebellum and hypothalamus, respectively.
The results indicate that this condition results from abnormal cell fate specification during development. Consequently, the hypoplastic cerebellum is deficient in molecular layer interneurons, which play critical roles in regulating cerebellar circuits. In the hypothalamus, fewer Kisspeptin neurons, which are important regulators of gonadotropin releasing hormone and puberty, were present in PRDM13 mutant mice.
Together, these findings identify PRDM13 as a critical regulator of neuronal cell fate in the cerebellum and hypothalamus, providing a mechanistic explanation for the co-occurrence of hypogonadism and cerebellar hypoplasia in this syndrome.
Earlier this year, UCT professor Ambroise Wonkam published the Three Million African Genomes (3MAG) project in Nature, which he said started with a “crazy idea”. Now, it looks like his vision is starting to take shape.
The idea of creating a huge library of genetic information about the population of Africa emerged from his work on how genetic mutations among Africans contribute to conditions like sickle-cell disease and hearing impairments.
African genes contain great genetic variation, more than that seen outside of Africa. As he explained, “We are all African but only a small fraction of Africans moved out of Africa about 20–40 000 years ago and settled in Europe and in Asia.”
Another concern for Prof Wonkam is equity, saying: “Too little of the knowledge and applications from genomics have benefited the global south because of inequalities in health-care systems, a small local research workforce and lack of funding.”
Thus far only about 2% of genomes mapped are African, a good proportion of which are African American. This stes from a lack of prioritising funding, policies and training infrastructure, he says, but it also means the understanding of genetic medicine as a whole is lopsided. By studying African genomes, injustics can be corrected, such as finding that genetic risk profiles based on Europeans could be misleading for those of African descent.
To address these disparities, Prof Wonkam and other scientists are speaking to governments, companies and professional bodies across Africa and internationally, in order to build up capacity over the next decade to make the vision a reality.
He expects three million is the number needed to accurately map genetic variations across Africa. The project will take a decade, he says, costing around $450m per year, with industry already showing interest.
Biotech firms welcome prospects of new data The Centre for Proteomic and Genomic Research (CPGR) in Cape Town works with biotech firm Artisan Biomed on a variety of diagnostic tests. Gaps in the applicability of genetic data to the local population are a challenge for the firm, it said.
A genetic mutation in someone could be found but it would be uncertain if that variation is associated with a disease, especially as a marker for that particular population.
“The more information you have at that level, the better the diagnosis, treatment and eventually care can be for any individual, regardless of your ethnicity,” said Dr Lindsay Petersen, the company’s chief operations officer.
Artisan Biomed says the data it collects feeds back into CPGR’s research – allowing them to design a better diagnostic toolkit that is better suited to African populations, for instance.
Dr Judith Hornby Cuff said that the 3MAG project would help streamline processes and improve research, and one day could provide cheaper, more effective and more accessible health care, particularly in the strained South African system.
Prof Wonkam acknowledged that while the costs are huge, the project will “improve capacity in a whole range of biomedical disciplines that will equip Africa to tackle public-health challenges more equitably”.
“We have to be ambitious when we are in Africa. You have so many challenges you cannot see small, you have to see big – and really big,” he said.
By Orlando Scott Goff – Heritage Auctions, Public Domain, https://commons.wikimedia.org/w/index.php?curid=27530348
A team of researchers led by the University of Cambridge has proven a man’s claim to be the great-grandson of legendary Native American leader Sitting Bull has been confirmed using DNA extracted from Sitting Bull’s scalp lock. This is the first time ancient DNA has been used to confirm a familial relationship between living and historical individuals.
The researchers used a new method to analyse family lineages using ancient DNA fragments, which searches for ‘autosomal DNA’ in the genetic fragments extracted from a body sample. Since half of our autosomal DNA is inherited from the father and half from the mother, this means genetic matches can be checked regardless of whether an ancestor is on the father or mother’s side of the family.
Autosomal DNA from Lakota Sioux leader Sitting Bull’s scalp lock was compared to DNA samples from Ernie Lapointe and other Lakota Sioux. The resulting match confirms that Lapointe is Sitting Bull’s great-grandson, and his closest living descendant.
“Autosomal DNA is our non-gender-specific DNA. We managed to locate sufficient amounts of autosomal DNA in Sitting Bull’s hair sample, and compare it to the DNA sample from Ernie Lapointe and other Lakota Sioux – and were delighted to find that it matched,” said senior author of the study, Professor Eske Willerslev in the University of Cambridge’s Department of Zoology and Lundbeck Foundation GeoGenetics Centre, who also developed the new DNA analysis technique.
Lapointe said: “over the years, many people have tried to question the relationship that I and my sisters have to Sitting Bull.”
Lapointe believes that Sitting Bull’s bones currently lie at a site in Mobridge, South Dakota, in a place that has no significant connection to Sitting Bull and the culture he represented. He also has concerns about the care of the gravesite. There are two official burial sites for Sitting Bull – at Fort Yates, North Dakota and Mobridge – and both receive visitors.
Lapointe, with the help of the DNA evidence confirming his heritage, now hopes to rebury the great Native American leader’s bones in a more appropriate location.
The new technique can be used when very limited genetic data are available, as was the case in this study. This could be used to match up long-dead historical figures and their living descendants.
The technique could also be used on old human DNA that might previously have been considered too degraded to analyse – for example in forensic investigations.
“In principle, you could investigate whoever you want – from outlaws like Jesse James to the Russian tsar’s family, the Romanovs. If there is access to old DNA – typically extracted from bones, hair or teeth, they can be examined in the same way,” said Willerslev, who is a Fellow of St John’s College, Cambridge.
It took the scientists 14 years to find a way of extracting useable DNA from the 5-6cm piece of Sitting Bull’s hair, which was extremely degraded, having been stored for over a century at room temperature in a museum before it was returned to Lapointe and his sisters in 2007.
In traditional DNA analysis, which searches for a genetic match between specific DNA in the Y chromosome passed down the male line, or, in females, specific DNA in the mitochondria passed from a mother to her offspring. Neither are particularly reliable, and in this case neither could be used as Lapointe claimed to be related to Sitting Bull on his mother’s side.
Tatanka-Iyotanka, better known as the Native American leader and military leader Sitting Bull (1831–1890), led 1,500 Lakota warriors at the Battle of the Little Bighorn in 1876 and wiped out US General Custer and five companies of soldiers.
“Sitting Bull has always been my hero, ever since I was a boy. I admire his courage and his drive. That’s why I almost choked on my coffee when I read in a magazine in 2007 that the Smithsonian Museum had decided to return Sitting Bull’s hair to Ernie Lapointe and his three sisters, in accordance with new US legislation on the repatriation of museum objects,” said Willerslev.
He added: “I wrote to Lapointe and explained that I specialised in the analysis of ancient DNA, and that I was an admirer of Sitting Bull, and I would consider it a great honour if I could be allowed to compare the DNA of Ernie and his sisters with the DNA of the Native American leader’s hair when it was returned to them.”
Until this study, the familial relationship between LaPointe and Sitting Bull was based on birth and death certificates, a family tree, and a review of historical records. This new genetic analysis lends further credence to his claims. Before the remain can be reburied, they will have to be analysed in the same to ensure a genetic match to Sitting Bull.
Before the remains from the Mobridge burial site can be reburied elsewhere, they will have to be analysed in a similar way to the hair sample to ensure a genetic match to Sitting Bull.
While cannabis use may impact some autism-linked genes in men’s sperm, briefly quitting cannabis over time may significantly lower many of those effects, according to a new study.
This study, published online in Environmental Epigenetics, followed several other studies at Duke University that linked cannabis use to epigenetic changes (alteration of expression without changing genes) present in sperm, including genes in early development.
This new study aimed to find out if cannabis abstinence could reduce such epigenetic changes. The results showed marijuana users who stopped using cannabis for 77 days produced sperm lacking most of the significant changes found when the men were actively using cannabis. Study author Susan Murphy, PhD, associate professor in the Department of Obstetrics & Gynecology at Duke University School of Medicine, said the results may suggest that marijuana abstinence could result in washout of sperm with the drug’s epigenetic effects. More research is needed for lingering epigenetic effects after abstinence, but there are immediate implications for some.
“Stopping cannabis use for as long as possible – at least for a 74-day period before trying to conceive – would be a good idea,” she said. “If someone is really serious about that, I would say to stop cannabis use for as long as possible prior to conception – meaning multiple spermatogenic cycles.”
“Is it going to fix everything? Probably not,” Prof Murphy said. “We know there are other epigenetic changes that emerged in the ‘after’ sample that we don’t understand yet – and some of those changes are troubling, like an enrichment of other genes related to autism. But it does appear that the things that were the most severely affected in the ‘before’ sample seem to be mitigated by the abstinence period in the ‘after’ samples.”
The study took a baseline sperm sample from marijuana users and non-marijuana users, then followed both groups as the marijuana-using group abstained from cannabis for 77 days – a period spanning the average time it takes for a sperm to mature, which is 74 days. Researchers collected a second sample from both groups after the 77-day period.
During baseline tests, the marijuana-consuming group produced sperm with changes in line with previous studies, which showed altered epigenetic information, including changes in genes linked to early development and neurodevelopmental disorders. With a 77-day abstinence period, this same group was able to produce sperm that had far less altered epigenetic information at the same genes.
The post-abstinence sample was also much more in line with the samples produced by the non-cannabis-using control group.
Prof Murphy says further research is needed to see if the remaining epigenetic changes observed in the sperm of cannabis consumers, when they abstain, carry over into development after fertilisation.
“We don’t know yet whether the alterations that we’re seeing are at genes that have a stable characteristic,” she said, “or if they are in genes that get reprogrammed and really are going to be of no consequence to the child.”
In any case, Prof Murphy says this work is not about legalisation, rather about giving people the power to make informed decisions for themselves.
“I think that we deserve to know what the biological consequences are so that if you are planning to have a child, or even for your own health, you can make an informed decision about whether you want to use it and when, and that’s not really an option right now because we don’t know what it does,” Prof Murphy said.
Ball-and-stick model of the testosterone molecule, C19H28O2, as found in the crystal structure of testosterone monohydrate. Credit: Ben Mills, Wikimedia Commons.
With the Olympics underway, testosterone is again in the spotlight over its role in enhancing physical performance, with rules about its natural level being once again debated. It has also been popularly thought to be involved in success in other endeavours – but its importance in this regard may be overrated.
New research has found little evidence that testosterone exerts a meaningful influence on successes in life for men or women. The study in fact suggests that testosterone’s importance outside of physical endeavours could be even less important than previously believed.
In men, it is known that testosterone is linked to socioeconomic position, such as income or educational qualifications. Researchers from the University of Bristol’s Population Health Sciences (PHS) and MRC Integrated Epidemiology Unit (IEU) set out to determine whether this is because testosterone has an influence on socioeconomic position, as opposed to socioeconomic circumstances affecting testosterone levels, or if it was a case of health affecting both. The findings are published in Science Advances.
To isolate effects of testosterone itself, the investigators used Mendelian randomisation in a sample of 306,248 UK adults from UK Biobank. They explored testosterone’s influence on socioeconomic position, including income, employment status, neighborhood-level deprivation, and educational qualifications; on health, including self-rated health and BMI, and on risk-taking behaviour.
Dr Amanda Hughes, Senior Research Associate in Epidemiology in Bristol Medical School: Population Health Sciences (PHS), said: “There’s a widespread belief that a person’s testosterone can affect where they end up in life. Our results suggest that, despite a lot of mythology surrounding testosterone, its social implications may have been over-stated.”
First, the team identified genetic variants linked to higher testosterone levels, and explored their links to outcomes. Since genetic variations are essentially fixed throughout a lifetime, it is highly unlikely that they are affected by socioeconomic circumstances, health, or other environmental factors.
In common with prior studies, multivariate analysis showed men with higher testosterone had higher household income, lived in less deprived areas, and were more likely to have a university degree and a skilled job. Higher testosterone in women was linked to lower socioeconomic position, including lower household income, living in a more deprived area, and lower chance of having a university degree. Consistent with previous evidence, higher testosterone was associated with better health for men and poorer health for women, and greater risk-taking behaviour for men.
In contrast, the Mendelian randomisation method showed there was little evidence that the testosterone-linked genetic variants were associated with any outcome for men or women. The research team concluded that there is little evidence that testosterone meaningfully affected socioeconomic position, health, or risk-taking in men or women. The study suggests that – despite the mythology surrounding testosterone – its importance is much less than previously held.
Since the results for women were less precise than the men’s, the influence of testosterone in women could be further explored with larger sample sizes.
Dr Hughes added: “Higher testosterone in men has previously been linked to various kinds of social success. A study of male executives found that testosterone was higher for those who had more subordinates. A study of male financial traders found that higher testosterone correlated with greater daily profits. Other studies have reported that testosterone is higher for more highly educated men, and among self-employed men, suggesting a link with entrepreneurship.
“Such research has supported the widespread idea that testosterone can influence success by affecting behaviour. There is evidence from experiments that testosterone can make a person more assertive or more likely to take risks – traits which can be rewarded in the labor market, for instance during wage negotiations. But there are other explanations. For example, a link between higher testosterone and success might simply reflect an influence of good health on both. Alternatively, socioeconomic circumstances could affect testosterone levels. A person’s perception of their own success could influence testosterone: in studies of sports matches, testosterone has been found to rise in the winner compared to the loser.”
Journal information: Testosterone and socioeconomic position: Mendelian Randomization in 306,248 men and women in UK Biobank’, Science Advances (2021).
For the first time, mice have been born from gametes that have been created entirely from stem cells, marking the beginning of a revolutionary new reproductive option.
The experiment is the brainchild of Dr Katsuhiko Hayashi of Kyushu University, who has led the pursuit of making gametes outside of a living body. If adapted for humans, these wild reproductive pursuits are bound to shake up our entire conception of the beginning of life, similar to the way “test-tube” babies did when in vitro fertilisation (IVF) was first introduced.
Dr Hayashi dreams of even bigger possibilities; since stem cells can be rapidly created from skin or other cells, they are an endless source of raw material to make sperm and egg cells. These gametes, if fully functional, can merge into a zygote inside a test tube, be transplanted into a surrogate, and birth a new generation without ever seeing testes or ovaries.
Though still far off for humans, in vitro gametogenesis, or IVG, has great potential. Researchers can use these lab-grown models to better understand how reproductive cells form and mature. For couples struggling to conceive, or people who’ve lost reproductive function due to diseases like cancer, IVG would offer a new route towards pregnancy. Same-sex couples could also potentially conceive children with their own genetic makeup. There are many possibilities, and a wide range of ethical problems.
The basis of the technology uses induced pluripotent stem cells (iPSCs), which can be nudged in any direction, including sperm and egg. Back in 2011, Dr Hayashi showed that by bathing stem cells in a particular chemical soup, his team was able to produce sperm cell precursors, with the capacity to turn into functional sperm.
In 2016, the team achieved the same with eggs in mice, mimicking the entire process of how ovaries make eggs – which were used to produce healthy pups. However, eggs made in a test tube couldn’t develop naturally outside the ovary. Fresh ovarian tissue from mice was needed, creating an obvious challenge for fertility treatments in humans.
In the current study, the team focused on the support cells that normally encapsulate a developing egg. These support cells thrive inside the ovary, secreting hormones and nutrients that help support the metabolic needs of an egg – a crucial step, which includes forming ovarian follicles for the eggs to mature in.
These ovary-supporting cells can also be made from stem cells if the right chemical keys are used, and so after five years Dr Hayashi figured out those keys. Many of them sport fanciful names like ‘sonic hedgehog‘ (SHH), but most of these proteins belong to the morphogen family, in that they can morph the physical structure and identity of a tissue.
After dousing stem cells with this soup, the cells differentiated into foetal ovary supporting cells, with a gene expression profile closely mimicking that of their natural counterparts.
Next, the researchers added precursor immature egg cells, also made from stem cells. Together, the cells coalesced into tiny ovarian follicles, with support cells forming a bubble wrapping the developing egg. The eggs were then fertilised with sperm, transplanted into surrogate mouse mothers, and after normal pregnancies, resulted in about a dozen healthy pups. Those mice eventually gave birth to babies of their own.
The artificial ovary produces mature eggs less effectively than its natural counterpart, suggesting there’s still much to be learned about this stage of reproduction.
Application of this technology to assisted reproduction in humans is still decades away: human reproductive cells take far longer to mature than those in mice, and likely require different supporting nutrients for the sperm, egg, and surrounding tissue.
The team is now testing their chemical soup in marmosets, to be followed by primates.
Currently no laws or ethical frameworks deal with IVG, since the technology is so new.
Dr Hayashi is taking it step by step, and welcoming public discourse before even considering any clinical use. The first step, he said, is verifying the quality of the stem-cell derived eggs, adding, “That could take a long, long time.”
Researchers from St Jude Children’s Research Hospital have demonstrated the feasibility of comprehensive genomic sequencing for all paediatric cancer patients, which maximises the lifesaving potential of precision medicine.
All 309 patients who enrolled in the study were offered whole genome and whole exome sequencing of germline DNA. For the 253 patients for whom adequate tumour samples were available, whole genome, whole exome and RNA sequencing of tumour DNA was carried out.
Overall, 86% of patients had at least one clinically significant variation in tumour or germline DNA. Those included variants related to diagnosis, prognosis, therapy or cancer predisposition. An estimated 1 in 5 patients had clinically relevant mutations that would not have been picked up with standard sequencing methods.
“Some of the most clinically relevant findings were only possible because the study combined whole genome sequencing with whole exome and RNA sequencing,” said Jinghui Zhang, PhD, St Jude Department of Computational Biology chair and co-corresponding author of the study.
While such comprehensive clinical sequencing is not widely available, as the technology becomes less expensive and accessible to more patients, comprehensive sequencing will become an important addition to paediatric cancer care.
“We want to change the thinking in the field,” said David Wheeler, PhD, St Jude Precision Genomics team director and a co-author of the study. “We showed the potential to use genomic data at the patient level. Even in common pediatric cancers, every tumor is unique, every patient is unique.
“This study showed the feasibility of identifying tumour vulnerabilities and learning to exploit them to improve patient care,” he said.
Tumour sequencing resulted in a change in treatment for 12 of the 78 study patients for whom standard of care was unsuccessful. In four of the 12 patients, the treatment changes stabilised disease and extended patient lives. Another patient, one with acute myeloid leukaemia, went into remission and was cured by blood stem cell transplantation.
“Through the comprehensive genomic testing in this study, we were able to clearly identify tumor variations that could be treated with targeted agents, opening doors for how oncologists manage their patients,” said co-corresponding author Kim Nichols, MD, St Jude Cancer Predisposition Division director.
The results of the study were published online in the journal Cancer Discovery.
Journal information: Newman, S., et al (2021) Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discovery. doi.org/10.1158/2159-8290.CD-20-1631.
Findings from a new study into ‘junk DNA’ have brought scientists one step closer to solving the mysteries of ageing and cancer.
Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, led a team which recently identified a DNA region known as VNTR2-1 which seems to drive activity of the telomerase gene, which has been shown to prevent ageing in certain types of cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).
The telomerase gene controls the activity of the telomerase enzyme, which helps produce telomeres, the caps at the end of each strand of DNA that protect the chromosomes within our cells and which shorten over time until cells are no longer able to divide.
However, in certain cell types, such as reproductive cells and cancer cells, the telomerase gene’s activity ensures that telomeres are reset to the same length when DNA is copied. This is essentially what restarts the aging clock in new offspring but is also the reason why cancer cells can continue to multiply and form tumors.
Understanding how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Prof Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.
Zhu said that VNTR2-1’s discovery is especially noteworthy due to the type of DNA sequence it represents.
“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” noted Prof Zhu. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matter in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”
In previous work, deleting the DNA sequence from human and mouse cancer cells caused telomeres to shorten, cells to age, and tumours to stop growing. They conducted a subsequent study measuring the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats of the DNA to as long as 160 repeats.
“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Prof Zhu said.
Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Prof Zhu said that a shorter sequence does not necessarily translate to a shorter lifespan, since the telomerase gene is less active with possibly a shorter telomere length which could reduce cancer risk.
“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Prof Zhu said. “We know that oncogenes–or cancer genes–and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”
Prof Zhu observed that many African Americans in the United States for generations have Caucasian ancestry, which could have added this sequence. So he and his team hope to next be able to study the sequence in an African population.
Journal information: Xu, T., et al. (2021) Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene. PNAS. doi.org/10.1073/pnas.2019043118.
