- Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk Nature.com
- Scientists discover evidence of 4 more breast cancer genes—and potentially many others: ‘The risks can be significant for women who carry them Fortune
- Unraveling the Genetic Code: New Suspects in Breast Cancer Identified SciTechDaily
- Thousands more women could discover they’re at increased risk of breast cancer as scientists identify 4 n… The US Sun
- Blood test may spot women at risk of breast cancer as scientists discover another four genes linked to disease Daily Mail
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Tag Archives: genes
Dad’s genes make baby ‘greedy’ and ‘manipulate’ mom in the womb – New York Post
- Dad’s genes make baby ‘greedy’ and ‘manipulate’ mom in the womb New York Post
- Study finds, ‘greedy’ genes from father encourage unborn babies to steal their mother’s food Interesting Engineering
- Unborn babies inherit ‘greedy gene’ from father, scientists discover BBC Science Focus Magazine
- Unborn babies use ‘greedy’ gene from dads to ‘remote-control’ mums into feeding them extra food University of Cambridge news
- Unborn babies use ‘greedy’ gene from fathers to ‘remote-control’ mothers into feeding them extra food – study finds The Irish Times
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Autism-related genes in non-autistic individuals show a long-term socioeconomic influence – Medical Xpress
- Autism-related genes in non-autistic individuals show a long-term socioeconomic influence Medical Xpress
- Research sheds light on genetic variants’ impact beyond autism diagnosis News-Medical.Net
- Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics | Scientific Reports Nature.com
- The Connection Between Autism And The Gut Microbiome Is Clearer Than Ever ScienceAlert
- Elucidating the role of the gut-brain-axis in autism News-Medical.Net
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“Superager” Genes Can Shave a Decade Off Heart Age, Scientists Say
The genes of people who live to be over the age of 100 could one day help others stay heart-healthy for longer, according to some exciting new research.
A team of British and Italian researchers has found that a specific mutated gene in so-called “superagers” who make it into their centenarian years could be used to help those with heart failure turn back the clock by ten years, as detailed in a groundbreaking study published in the journal Cardiovascular Research.
Building on the discovery of the longevity-associated gene variant known as BPIFB4 in 2018, the researchers conducted experiments on human cells in test tubes and later on mice to see if the genes were still able to turn back the biological clock when introduced in a lab instead of being inherited.
Incredibly, they found that its introduction to damaged cells can both halt and even reverse heart aging.
“The cells of the elderly patients, in particular those that support the construction of new blood vessels, called ‘pericytes’, were found to be less performing and more aged,” said Monica Cattaneo, a researcher at the MultiMedica Group in Italy and co-author, in a press release.
“By adding the longevity gene/protein to the test tube, we observed a process of cardiac rejuvenation: the cardiac cells of elderly heart failure patients have resumed functioning properly, proving to be more efficient in building new blood vessels,” Cattaneo added.
The researchers also found that those same cells seemed to have reduced expression of BPIFB4 as well. In other words, people who tend to develop heart problems may actually be missing this key longevity protein.
As University of Bristol professor and co-author Paolo Madedu notes, these findings suggest that introducing a protein to the cells of patients with heart problems may be an alternative to gene therapy, which, in spite of being a promising branch of medical treatment, still carries a number of associated risks, including the potential of developing cancer.
“Our findings confirm the healthy mutant gene can reverse the decline of heart performance in older people,” Madedu said in the press release. “We are now interested in determining if giving the protein instead of the gene can also work.”
Obviously, this kind of potential treatment will take many years to perfect — but regardless, this could be a huge win in the war against heart disease.
More on genetics: Scientists Think Gregor Mendel Would Be “Happy” That They Dug Up His Body to Study His Genetics
Tiny New Genes Appearing in Human DNA Show How We’re Still Evolving : ScienceAlert
We may have parted ways with our primate cousins millions of years ago, but a new study shows just how human beings continue to evolve in ways we never imagined.
Researchers from Biomedical Sciences Research Center “Alexander Fleming” (BSRC Flemming) in Greece and Trinity College Dublin, Ireland, have identified 155 genes in our genome that emerged from small, non-coding sections of DNA. Many appear to play a critical role in our biology, revealing how completely novel genes can rapidly evolve to become essential.
New genes typically arise through well known mechanisms like duplication events, where our genetic machinery accidently produces copies of pre-existing genes that can end up suiting new functions over time.
But the 155 microgenes pinpointed in this study seem to have appeared from scratch, in stretches of DNA that didn’t previously contain the instructions that our bodies use to build molecules.
Since the proteins these new genes are thought to encode would be incredibly tiny, these DNA sequences are hard to find and difficult to study, and therefore are often overlooked in research.
“This project started back in 2017 because I was interested in novel gene evolution and figuring out how these genes originate,” says evolutionary geneticist Nikolaos Vakirlis, from BSRC Flemming in Greece.
“It was put on ice for a few years, until another study got published that had some very interesting data, allowing us to get started on this work.”
That other study, published in 2020 by a team of researchers at the University of California San Francisco, catalogued a stack of microproteins that are produced by non-coding regions once described as ‘junk DNA’.
The team behind this new study subsequently created a genetic ancestral tree to compare those tiny sequences found in our genomes against those in 99 other vertebrate species, tracking the evolution of the genes over time.
Some of the new ‘microgenes’ identified in this new study can be tracked all the way back to the earliest days of mammals, while others are more recent additions. Two of the genes identified by the study seem to have emerged since the human-chimpanzee split, the researchers found.
“We sought to identify and examine cases in the human lineage of small proteins that evolved out of previously noncoding sequences and acquired function either immediately or shortly thereafter,” the team writes in their published paper.
“This is doubly important: for our understanding of the intriguing, and still largely mysterious phenomenon of de novo gene birth, but also for our appreciation of the full functional potential of the human genome.”
Microproteins are already known to have a diverse range of functions from helping to regulate the expressions of other genes to joining forces with larger proteins including our cell membranes. However, while some microproteins perform vital biological tasks, others are plain useless.
“When you start getting into these small sizes of DNA, they’re really on the edge of what is interpretable from a genome sequence, and they’re in that zone where it’s hard to know if it is biologically meaningful,” explains Trinity College Dublin geneticist Aoife McLysaght.
One gene with a role in constructing our heart tissue emerged when an ancestor common to humans and chimps branched off from the gorilla’s ancestry. If indeed this microgene emerged in the last few million years, it’s striking evidence that these evolving parts of our DNA can quickly become essential to the body.
The researchers then probed the sequences’ functions by deleting genes, one by one, in lab-grown cells. Forty-four of the cell cultures went on to show growth defects, confirming those now missing sections of DNA play critical roles in keeping us functioning.
In other comparative analyses, the researchers also identified in three of the new genes known variants associated with disease. The presence of these happenstance mutations at a single base position in the DNA may suggest some connection to muscular dystrophy, retinitis pigmentosa, and Alazami syndrome, but further research is going to be required to clarify these relationships.
In light of modern technology and medicine, appreciating the scale of biological change humans have experienced as a species at the hand of natural selection can be challenging. But our fitness has been shaped considerably by pressures of diet and disease over the millennia, and will undoubtedly continue to adapt even within a technologically advanced world.
Exactly how the spontaneous creation of new genes within the non-coding region happens is not yet clear, but with our newfound ability to track these genes, we may be closer to finding out.
“If we’re right in what we think we have here, there’s a lot more functionally relevant stuff hidden in the human genome,” says McLysaght.
The research has been published in Cell Reports.
How Genes Drive Your Dog’s Lovable and Wacky Behavior
A new study may help us understand our canine companions a bit better. Scientists at the National Institutes of Health say they’ve uncovered some of the ways that genes can influence the behaviors of certain breeds, such as dogs meant to herd livestock.
For about two decades, a team led by Elaine Ostrander at the National Human Genome Research Institute has been working on the Dog Genome Project. The ultimate goal of the project is to get a grasp on how genetics affect everything from a dog’s vulnerability to illness to the shape of their bodies. In their new study, published Thursday in Cell, her team did a deep dive into the genetic underpinnings of doggy behavior.
“Our study analyzed the genomes of thousands of dogs from hundreds of breeds and populations across the world in order to uncover the genetic basis of behavioral diversity across modern dogs,” Ostrander said in an email to Gizmodo. “We wanted to understand what in their genes makes sheepdogs move livestock, terriers kill vermin, hounds help us hunt, etc.”
Overall, they studied the genes of over 4,000 purebred dogs, mixed-breed mutts, semi-feral dogs, and even wild cousins of the domestic dog. Based on this analysis, they identified 10 genetically distinct lineages. The team noticed that breeds with similar behavioral traits often grouped together within these lineages, such as dogs that hunt primarily using their sight compared to hunting dogs that rely on scent. They then cross-referenced what they found with survey data from more than 46,000 purebred dog owners.
From there, Ostrander said, the team “determined that each lineage has their own unique mix of behavioral tendencies that make them good at the jobs they were originally kept for.” Terrier breeds, for example, tend to be more enthusiastic in chasing down potential prey, which makes sense, since these dogs were originally bred to chase down pests. Finally, the team tried to find specific genetic variations that might drive the behaviors of certain breeds, including those that affect early brain development.
“For example, among sheepdogs, a behaviorally unique collection of breeds historically used to herd livestock, we identified variants associated with genes controlling axon guidance, a process that lays the foundation of connectivity in the brain that modulates complex behavioral traits,” Ostrander said. These variants, some of which have been linked to attention-deficit hyperactivity disorder in humans, might help explain why sheepdogs tend to become incredibly focused while herding.
While humans have domesticated many animals, dogs were likely the first. And they’ve since become perhaps the most diverse creature around, especially in the last couple hundred years, when intentional dog breeding became widely practiced (a pug looks very little like a husky, for instance). But importantly, Ostrander and her team’s research also indicates that many of the genetically driven behavioral differences we see in dogs now weren’t created by modern-day breeding.
“Instead, early dog ‘types’ likely rose to prominence in different parts of the world over thousands of years as humans kept them for different purposes,” Ostrander said. “Our work shows that as humans began to categorize dogs into ‘breeds’ a few hundred years ago, they were preserving single snapshots of dog genetic diversity that existed in a certain place at a certain time, and that this genetic diversity was relevant to behavior.”
This work is only the beginning for Ostrander’s team. They plan to continue looking for specific gene variants that drive breed behaviors. The same unique approach developed for this study should also allow them to study how a dog’s genetics can influence other complex traits, including their risk of certain diseases. And just as dogs have done for us so many times in the past, what we learn from this research could someday help humans, too.
“Dogs and humans get the same diseases, those diseases present in much the same way, and anything we learn about canine genetic health impacts our understanding of our own susceptibility to disease,” Ostrander said.
World’s Largest Autism Whole Genome Sequencing Study Reveals 134 Autism-Linked Genes
Summary: Researchers have identified 134 genes associated with autism and a range of genetic alterations associated with ASD. Notably, the study identified changes in copy number variations with likely associations with ASD, including autism-associated variants in 14% of people on the autism spectrum.
Source: Hospital for Sick Children
Researchers from The Hospital for Sick Children (SickKids) have uncovered new genes and genetic changes associated with autism spectrum disorder (ASD) in the largest autism whole genome sequencing analysis to date, providing better understanding into the ‘genomic architecture’ that underlies this disorder.
The study, published today in Cell, used whole genome sequencing (WGS) to examine the entire genomes of over 7,000 individuals with autism as well as an additional 13,000 siblings and family members.
The team found 134 genes linked with ASD and discovered a range of genetic changes, most notably gene copy number variations (CNVs), likely to be associated with autism, including ASD-associated rare variants in about 14 per cent of participants with autism.
The majority of data was drawn from the Autism Speaks MSSNG database, the world’s largest autism whole genome dataset, which provides autism researchers with free, open access to thousands of sequenced genomes.
“By sequencing the entire genome of all participants, and with deep involvement from the participating families in MSSNG on forming our research priorities, we maximize the potential for discovery and allow analysis that encompasses all types of variants, from the smallest DNA changes to those that affect entire chromosomes,” says Dr. Stephen Scherer, Senior Scientist, Genetics & Genome Biology and Chief of Research at SickKids and Director of the McLaughlin Centre at the University of Toronto.
Dr. Brett Trost, lead author of the paper and a Research Associate in the Genetics & Genome Biology program at SickKids, notes the use of WGS allowed researchers to uncover variant types that would not have otherwise been detectable.
These variant types include complex rearrangements of DNA, as well as tandem repeat expansions, a finding supported by recent SickKids research on the link between autism and DNA segments that are repeated many times.
The role of the maternally inherited mitochondrial DNA was also examined in the study and found to account for two percent of autism.
The paper also points to important nuances in autism genetics in families with only one individual with autism compared with families that have multiple individuals with autism, known as multiplex families.
Surprising to the team was that the “polygenic score” – an estimation of the likelihood of an individual having autism, calculated by aggregating the effects of thousands of common variants throughout the genome – was not higher among multiplex families.
“This suggests that autism in multiplex families may be more likely to be linked to rare, highly impactful variants inherited from a parent. Because both the genetics and clinical traits associated with autism are so complex and varied, large data sets like the ones we used are critical to providing researchers with a clearer understanding of the genetic architecture of autism,” says Trost.
The research team says the study data can help expand inquiries into the range of variants that might be linked to ASD, as well as efforts to better understand contributors to the 85 percent of autistic individuals for which the genetic cause remains unresolved.
In a linked study of 325 families with ASD from Newfoundland published this same month in Nature Communications, Dr. Scherer’s team found that combinations of spontaneous, rare-inherited, and polygenic genetic factors coming together in the same individual can potentially lead to different sub-types of autism.
Dr. Suzanne Lewis, a geneticist and investigator at the BC Children’s Hospital Research Institute who diagnosed many of the families enrolled in the study said, “Collectively, these latest findings represent a massive step forward in better understanding the complex genetic and biological circuitry linked with ASD.
“This rich data set also offers an opportunity to dive deeper into examining other factors that may determine an individual’s chance of developing this complex condition to help individualize future treatment approaches.”
Funding: Funding for this study was provided by the University of Toronto McLaughlin Centre, Genome Canada/Ontario Genomics, Genome BC, Government of Ontario, Canadian Institutes of Health Research, Canada Foundation for Innovation, Autism Speaks, Autism Speaks Canada, Brain Child, Kids Brain Health Network, Qatar National Research Fund, Ontario Brain Institute, SFARI and SickKids Foundation.
See also
About this genetics and autism research news
Author: Jelena Djurkic
Source: Hospital for Sick Children
Contact: Jelena Djurkic – Hosptial for Sick Children
Image: The image is in the public domain
Original Research: Closed access.
“Genomic architecture of autism from comprehensive whole-genome sequence annotation” by Stephen Scherer, et al. Cell
Abstract
Genomic architecture of autism from comprehensive whole-genome sequence annotation
Highlights
- New MSSNG release contains WGS from 11,312 individuals from families with ASD
- Extensive variant data available, including SNVs/indels, SVs, tandem repeats, and PRS
- Annotation reveals 134 ASD-associated genes, plus SVs not detectable without WGS
- Rare, dominant variation has a prominent role in multiplex ASD
Summary
Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312).
Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%).
Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants.
Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.
A Woman Had Cancer 12 Times by Age 36. Her Genes Showed Something Never Seen Before : ScienceAlert
When Spanish scientists came across a strange case of a woman who had experienced 12 different types of tumor before the age of 36, they decided to dig a little deeper to find out why she was so susceptible to cancer.
The 36-year-old woman was first treated for cancer at the age of two. At the age of 15, she was diagnosed with cervical cancer.
At 20, a salivary gland tumor was surgically removed. A year later, she had further surgery to remove a low-grade sarcoma.
And, as she went through her 20s and 30s, several different tumors were diagnosed.
In total, she has experienced 12 tumors, including five that were malignant.
With the permission of the woman and her family, an international team of researchers, led by the Spanish National Cancer Research Center, took samples of blood and used single-cell DNA sequencing to look at the genetic mutations inside thousands of individual cells.
The researchers discovered something strange; this woman had a one-of-a-kind mutation that made her more prone to cancers.
She had a mutation in both copies of the MAD1L1 gene, which is unheard of in humans.
The MAD1L1 gene is responsible for a key piece of machinery that helps align chromosomes before a cell divides. MAD1L1 has previously been suspected of playing a role in suppressing tumors.
Mutations in the gene aren’t unknown – in fact, members of the woman’s family carried one. But this is the first time both copies of the gene have been found to carry this particular change.
A double (or homozygous) MAD1L1 gene mutation is lethal to mouse embryos, so it’s a very surprising find in humans.
In this woman, the mutation was causing cell replication dysfunction and creating cells with different numbers of chromosomes. Around 30-40 percent of her blood cells had an abnormal number of chromosomes.
Humans normally have 23 pairs of chromosomes inside the nucleus of every cell in our bodies.
Chromosomes are condensed packages of DNA that come in an ‘X’ shape and form when a cell is about to undergo mitosis or cell replication.
In each pair of chromosomes, one comes from the person’s mother and the other comes from the person’s father.
People with a rare condition called ‘mosaic variegated aneuploidy’ (MVA) have various numbers of chromosomes in different cells, like a mosaic of different colored tiles. This condition can be caused by several different genetic mutations, including the one seen in the woman with 12 cancers.
People born with MVA often experience developmental delay, microcephaly (where a child’s head is smaller than normal), intellectual disability, and other congenital defects. They are often predisposed to cancer.
In this case, the woman had no intellectual disabilities and was living a relatively normal life (considering the number of rounds of cancer treatment she had undergone).
“We still don’t understand how this individual could have developed during the embryonic stage, nor could have overcome all these pathologies,” says Marcos Malumbres, a molecular biologist, co-author and the head of the Cell Division and Cancer Group at the Spanish National Cancer Research Center, where this study was done.
While the role of aneuploidy is not well understood in cancer, we do know that around 90 percent of tumors have cancer cells with extra or missing chromosomes.
And we know that a high degree of aneuploidy is associated with worse outcomes in cancer.
The study revealed that people with aneuploidy, such as this woman in the case study, have an “enhanced immune response” that “could provide new opportunities for the clinical management of these patients”, the researchers say.
This paper was published in Science Advances.
Woman, 36, with ‘one-in-8billion’ genes has survived TWELVE tumors could hold key to cancer
A woman who has survived a dozen different tumors could hold the secret to curing cancer, scientists claim.
The unnamed patient, 36, was diagnosed with her first mass when she was a toddler and a new growth has formed every couple of years in different parts of her body since.
Of her 12 tumors that doctors know about, at least five were cancerous — forming in her brain, cervix and colon.
Researchers in Spain who are monitoring her condition say her immune system is ‘exceptional’ at shutting down cancer.
She is believed to be the only person in the world with a genetic quirk that serves as a double-edged sword.
On one hand, she has an unnatural ability able to defeat cancerous growths. but on the other, it makes them extremely susceptible to tumors forming in the first place.
She possess two mutation on the MAD1L1 gene, which in normal circumstances should kill an embryo before it gets a chance to develop in utero.
The gene is crucial in the process of a cell splitting and proliferating and the mutations cause it to go haywire and start over-replicating itself.
When the cell begins to split at a rate that is not necessary it can lead to tumorous growth which can often form into cancer.
Dr Marcus Malumbres, head of the cancer group at the Spanish National Cancer Research Centre (CNIO), said: ‘We still don’t understand how this individual could have developed during the embryonic stage, nor could have overcome all these pathologies.’
A woman, 36, has a rare mutation that leads to her cells rapidly replicating. As a result, she has suffered a dozen tumors throughout her life. The same mutation that causes the growth also protects her from it, as it leads to the rapid production of defense cells. (file photo)
The woman was examined at the CNIO cancer researcher center in Madrid, Spain (pictured)
A team from the CNIO in Madrid published their case report on the person on Wednesday.
Scientists found the woman was more likely to develop tumors and cancers because of mutations to the MAD1L1 gene. Her condition is so rare it does not have a name.
The person also has skin spots, microcephaly – a condition where a baby’s head is much smaller than expected – and other physical conditions.
When the patient first visited the CNIO’s Familial Cancer Clinical Unit, a blood sample was taken to sequence the genes most frequently involved in hereditary cancer, but no alteration was detected in them.
Researchers then analysed the female’s entire genome and found mutations in a gene called MAD1L1.
This gene is essential in the process of cell division and proliferation.
Researchers analysed the effect of the mutations, and concluded they cause alterations in the number of chromosomes in the cells – all cells in the human body – have 23 pairs of chromosomes.
Animal models have suggested that when there are mutations in both copies of this gene – each coming from one parent – the embryo dies.
To the astonishment of the researchers, the person in this case has mutations in both copies but has survived, living as normal a life as can be expected of someone suffering from ill health.
According to Miguel Urioste, the co-author of the study who headed the CNIO’s Familial Cancer Clinical Unit until his retirement in January this year said no other case like this has ever been described.
He said: ‘Academically we cannot speak of a new syndrome because it is the description of a single case, but biologically it is.’
While other genes whose mutations alter the number of chromosomes in cells are known, researchers say this case is different because of the aggressiveness, the percentage of aberrations it produces and the extreme susceptibility to a large number of different tumours.
The search team was intrigued by the fact that the five aggressive cancers developed by the patient disappeared relatively easily.
Their hypothesis is that ‘the constant production of altered cells has generated a chronic defensive response in the patient against these cells, and that helps the tumours to disappear’.
‘We think that boosting the immune response of other patients would help them to halt the tumoural development,’ explained Dr Malumbres.
Researchers say one of the most important aspects of the study is the discovery that the immune system is capable of unleashing a defensive response against cells with the wrong number of chromosomes.
The findings may open up new therapeutic options in the future, they suggest.
The study is published in the Science Advances journal.
Black Death Drove Selection of Human Immune-Related Genes, Affecting Our Susceptibility to Disease Today
Research has uncovered new evidence that one of the darkest periods in recorded human history placed considerable selective pressure on the human population, changing the frequency of certain immune-related genetic variants and affecting our susceptibility to disease today.
The Black Death, which killed up to 50% of the European population in less than five years, was the single greatest mortality event in recorded history. New research has discovered evidence that one of the darkest periods in recorded human history placed a substantial selective pressure on the human population, changing the frequency of certain immune-related genetic variants and affecting our susceptibility to disease today.
The Black Death (also called the Pestilence, the Great Mortality or simply the Plague) was a bubonic plague pandemic that occurred in Western Eurasia and North Africa from 1346 to 1353. It is the most fatal pandemic in recorded human history, causing the deaths of 75–200 million people. The plague created significant religious, social, and economic upheavals, with profound effects on the course of European history.
The results of the study, which was conducted by the
Caused by the bacterium Yersinia pestis (Y. pestis), the global pandemic of the bubonic plague wiped out 30% to 60% of people in cities across North Africa, Europe, and Asia, with massive repercussions for the human race — and, apparently, our genome.
“This was a very direct way to evaluate the impact that a single pathogen had on human evolution,” said co-senior author on the study, Luis Barreiro, PhD, Professor of Genetic Medicine at UChicago. “People have speculated for a long time that the Black Death might be a strong cause of selection, but it’s hard to demonstrate that when looking at modern populations, because humans had to face many other selective pressures between then and now. The only way to address the question is to narrow the time window we’re looking at.”
New research from the University of Chicago, McMaster University, and the Institut Pasteur has found evidence that one of the darkest periods in recorded human history placed a significant selective pressure on the human population, changing the frequency of certain immune-related genetic variants and affecting our susceptibility to disease today. Credit: UChicago Medicine
In the study, the scientists took advantage of recent advances in sequencing technology to examine ancient 
A member of the Barreiro lab works in the tissue culture hood. Credit: UChicago Medicine
The research team zeroed in on one gene with a particularly strong association to susceptibility: ERAP2. Individuals who possessed two copies of one specific genetic variant, dubbed rs2549794, were able to produce full-length copies of the ERAP2 transcript, therefore producing more of the functional protein, compared to another variant that led to a truncated and non-functional version of the transcript. Functional ERAP2 plays a role in helping the immune system recognize the presence of an infection.
“When a macrophage encounters a bacterium, it chops it into pieces for them to be presented to other immune cells signaling that there’s an infection,” said Barreiro. “Having the functional version of the gene appears to create an advantage, likely by enhancing the ability of our immune system to sense the invading pathogen. By our estimate, possessing two copies of the rs2549794 variant would have made a person about 40% more likely to survive the Black Death than those who had two copies of the non-functional variant.”
Luis Barreiro, PhD, co-senior author on the study. Credit: UChicago Medicine
The team even went so far as to test how the rs2549794 variant affected the ability of living human cells to help fight the plague, determining that macrophages expressing two copies of the variant were more efficient at neutralizing Y. pestis compared to those without it.
“Examining the effects of the ERAP2 variants in vitro allows us to functionally test how the different variants affect the behavior of immune cells from modern humans when challenged with living Yersinia pestis,” said Javier Pizarro-Cerda, PhD, head of the Yersinia Research Unit and director of the World Health Organization Collaborating Centre for Plague at Institut Pasteur. “The results support the ancient DNA evidence that rs2549794 is protective against the plague.”
Tauras Vilgalys, PhD, analyzing sequencing data obtained from ancient DNA. Credit: UChicago Medicine
The team further concluded that the selection for rs2549794 is part of the balancing act evolution places upon our genome; while ERAP2 is protective against the Black Death, in modern populations, the same variant is associated with an increased susceptibility to autoimmune diseases, including acting as a known risk factor for Crohn’s disease.
“Diseases and epidemics like the Black Death leave impacts on our genomes, like archeology projects to detect,” said Hendrik Poinar, PhD, Professor of Anthropology at McMaster University and co-senior author on the study. “This is a first look at how pandemics can modify our genomes but go undetected in modern populations. These genes are under balancing selection — what provided tremendous protection during hundreds of years of plague epidemics has turned out to be autoimmune-related now. A hyperactive immune system may have been great in the past but in the environment today it might not be as helpful.”
Members of the Barreiro Lab conduct cell culture experiments. Credit: UChicago Medicine
Future research will scale the project to examine the entire genome, not just a selected set of immune-related genes; and the team hopes to explore genetic variants that affect susceptibility to bacteria in modern humans and compare them to these ancient DNA samples to determine if those variants were also a result of natural selection.
“There is a lot of talk about how pathogens have shaped human evolution, so being able to formally demonstrate which pathways and genes have been targeted really helps us understand what allowed humans to adapt and exist today,” said Barreiro. “This tells us about the mechanisms that allowed us to survive throughout history and why we’re still here today.”
Reference: “Evolution of immune genes is associated with the Black Death” by Jennifer Klunk, Tauras P. Vilgalys, Christian E. Demeure, Xiaoheng Cheng, Mari Shiratori, Julien Madej, Rémi Beau, Derek Elli, Maria I. Patino, Rebecca Redfern, Sharon N. DeWitte, Julia A. Gamble, Jesper L. Boldsen, Ann Carmichael, Nükhet Varlik, Katherine Eaton, Jean-Christophe Grenier, G. Brian Golding, Alison Devault, Jean-Marie Rouillard, Vania Yotova, Renata Sindeaux, Chun Jimmie Ye, Matin Bikaran, Anne Dumaine, Jessica F. Brinkworth, Dominique Missiakas, Guy A. Rouleau, Matthias Steinrücken, Javier Pizarro-Cerdá, Hendrik N. Poinar and Luis B. Barreiro, 19 October 2022, Nature.
DOI: 10.1038/s41586-022-05349-x
The study was supported by the National Institutes of Health (R01-GM134376, F32GM140568, R01GM146051), the Wenner-Gren Foundation (8702), the UChicago DDRCC, Center for Interdisciplinary Study of Inflammatory Intestinal Disorders (C-IID) (NIDDK P30 DK042086) and an Insight Grant (20008499). Additional authors include Tauras P. Vilgalys, Xiaoheng Cheng, Mari Shiratori, Derek Elli, Maria I. Patino, Anne Dumaine, Dominique Missiakas and Matthias Steinrücken of the University of Chicago; Jennifer Klunk of McMaster University and Daicel Arbor Biosciences; Christian E. Demeure, Julien Madej and Rémi Beau of the Institut Pasteur; Rebecca Redfern of the Museum of London; Sharon N. DeWitte of the University of South Carolina; Julia A. Gamble of the University of Manitoba; Jesper L. Boldsen of the University of Southern Denmark; Ann Carmichiael of Indiana University; Nükhet Varlik of Rutgers University; Katherine Eaton and G. Brian Golding of McMaster University; Jean-Christophe Grenier of the Université de Montréal; Alison Devault of Daicel Arbor Biosciences; Jean-Marie Rouillard of Daicel Arbor Biosciences and the University of Michigan Ann Arbor; Vania Yotova and Renata Sindeaux of the Universitaire Saint-Justine; Chun Jimmie Ye and Matin Bikaran of the University of California San Francisco; Jessica F. Brinkworth of the University of Illinois Urbana-Champaign; and Guy A. Rouleau of McGill University.