News Article | September 1, 2016
In the August 31 issue of Science Translational Medicine, new research from the University of Chicago shows how deficits in a specific pathway of genes can lead to the development of atrial fibrillation, a common irregular heartbeat, which poses a significant health risk. Researchers describe a complex system of checks and balances, including the intersection of two opposing regulatory methods that work to maintain normal cardiac rhythm, and offer insights that could lead to individualized treatment in humans. "We hope that this and similar studies contribute to a mechanistic understanding underlying the genetic basis of heart arrhythmias" said study author Ivan Moskowitz, MD, PhD, associate professor in the Department of Pediatrics, Pathology, and Human Genetics at the University of Chicago. "Such studies will allow clinicians to stratify patients based on their likely natural history of disease and potentially their response to specific therapeutics." Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. It affects more than 2.7 million Americans, according to the American Heart Association. AF occurs when the normal rhythm of the heart goes awry, causing a rapid, irregular heartbeat. When blood is not properly ejected from the heart, blood clots can form, leading to high risk of stroke. Patients with other forms of heart disease, such as congestive heart failure or hypertension, have an increased risk of AF. For decades this observation caused doctors to believe that AF was just a side effect of other heart-related issues. However, some patients with AF have no other cardiac issues and not all patients with congestive heart failure have AF. Having a family member with AF is associated with a greatly increased risk for the arrhythmia, suggesting a genetic component. One of the regions in the genome implicated in AF is near a gene named Tbx5. Although its role in AF was not understood, Tbx5 is known to control other genes and to be important in both the structure and the rhythm of the heart. It was long thought that a mouse heart could not develop primary AF, but when first author Rangarajan Nadadur and others in Moskowitz's team knocked out the Tbx5 gene from adult mice, they found that the mice developed spontaneous AF. Using this model system the researchers investigated what role Tbx5 played by looking for the genes it controlled. About 30 genes have been linked to AF in humans. The researchers found that half of those genes were decreased in the absence of Tbx5 and that Tbx5 directly targeted some of those genes. Pitx2, a gene controlled by Tbx5, is the most commonly identified gene in genome wide association studies for AF. This finding prompted the researchers to reach out to James Martin's research group at Baylor College of Medicine, collaborators on a Leducq Foundation grant to study AF, who were studying Pitx2. "Both Tbx5 or Pitx2 directly control important rhythm genes in the heart, but in opposite directions" said Moskowitz. "Removing either causes a susceptibility to AF." "The clinical application of this model is that we may be able to provide more precisely targeted treatments to AF patients depending on whether their cardiac rhythm network is up- or down-regulated," said Moskowitz. For example, if an important calcium channel is too active and causing AF, blocking it with medication would be helpful. However, if that calcium channel is not active enough and contributing to AF, prescribing a calcium channel blocker may be ineffective or even harmful. "We believe that a better understanding of the mechanisms underlying the genetic risk of the disease will ultimately have a significant impact on treatment."
News Article | January 8, 2016
Next time you are afflicted with a bout of hay fever and are casting around for someone to blame, look back — way back, to our extinct Neanderthal cousins, researchers suggest. Tens of thousands of years ago, interbreeding between modern humans and both Neanderthals and Denisovans — another early cousin species — introduced gene variations that improved our immune systems but may also have left some of us more prone to allergies, new studies suggest. Spreading out of Africa, early modern humans encountered and interbred with other ancient humans in Europe and Western Asia. As a result of the interbreeding, about one to six percent of the modern Eurasian genome comes from Neanderthals and Denisovans, researchers report in two studies appearing in The American Journal of Human Genetics. Some of the Neanderthal DNA in humans alive today may have helped us evolve the immune system that defends us against pathogens, they say. "The evidence suggests that this genetic region contributes to the immune system of modern day humans," says Michael Dannemann of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and an author of one of the studies. The genes involved help detect and respond to components of bacteria, fungi, parasites and other pathogens. The Neanderthal inheritance and its effect on the modern immune system may have left some people more prone to allergies, he suggests, although more research will be needed to investigate a possible link. Researchers in a second study said their findings about the amount of Neanderthal DNA still present today were unexpected. Many innate immunity genes in modern humans possess higher levels of Neanderthal ancestry than the remainder of the human genome, they say. "Our big surprise was to find that this gene region has such a high Neanderthal ancestry because this region has been shown to have a major biological relevance in host survival against pathogens," says Lluis Quintana-Murci of the Institut Pasteur in Paris, an author of the second study. The findings emphasize the importance of introgression events — the movement of genes across species — in the evolution of the immune system in modern humans, he says. "Maybe we should thank Neanderthals for having given us diversity in innate immunity to survive better against pathogens," he says. The retaining of ancient DNA in the modern genome makes sense, says researcher Janet Kelso from the Max Planck Institute. "Neanderthals, for example, had lived in Europe and Western Asia for around 200,000 years before the arrival of modern humans," she notes. "They were likely well adapted to the local climate, foods, and pathogens. By interbreeding with these archaic humans, we modern humans gained these advantageous adaptations."
Human genetic material is stored at a laboratory in Munich May 23, 2011. REUTERS/Michael Dalder More LONDON, Feb 1 (Reuters) - Scientists in Britain have been give the go-ahead to edit the genes of human embryos for research purposes, using a technique that some say could eventually be used to create "designer babies". Less than a year after Chinese scientists caused an international furore by saying they had genetically modified human embryos, Kathy Niakan, a stem cell scientist from London's Francis Crick Institute, was granted a licence to carry out similar experiments. "The Human Fertilisation and Embryology Authority (HFEA) has approved a research application from the Francis Crick Institute to use new 'gene editing' techniques on human embryos," Niakan's lab said on Monday. It said the work carried out "will be for research purposes and will look at the first seven days of a fertilised egg's development, from a single cell to around 250 cells". The scientists will not be allowed to develop the modified embryos for clinical purposes or implant them into any women. Niakan plans to carry out her experiments using what is known as CRISPR-Cas9, a technology that is already the subject of fierce international debate because of fears that it could be used to create babies to order. CRISPR can enable scientists to find and modify or replace genetic defects. Many experts have called it "game-changing". David King, director of the UK campaign group Human Genetics Alert, said Niakan's plans would eventually lead to "a future of consumer eugenics". "This research will allow the scientists to refine the techniques for creating GM babies," he said in a statement. But Sarah Norcross, director of Progress Educational Trust, which campaigns for ethically sound research in genetics, said the HFEA's decision was "a victory for level-headed regulation over moral panic". Niakan says she has no intention of genetically altering embryos for use in human reproduction, but wants to deepen scientific understanding of how a healthy human embryo develops, something that could, in the long term, help to improve infertility treatments such as in vitro fertilsation (IVF). The work will be carried out on embryos that have become surplus to donor patients IVF treatment. At a briefing for reporters in London last month, she said the first gene she planned to target was one called Oct4, which she believes may have a crucial role in the earliest stages of human foetal development. Bruce Whitelaw, a professor of animal biotechnology at Edinburgh University's Roslin Institute on Scotland, said the HFEA's decision had been reached "after robust assessment". "This project, by increasing our understanding of how the early human embryo develops and grows, will add to the basic scientific knowledge needed for devising strategies to assist infertile couples and reduce the anguish of miscarriage," he said in an emailed comment.
The relationship between surnames and Y chromosomes -both paternally inherited- has previously been a subject of research in Great Britain and Ireland. For the first time, a study has now explored the correlation between surnames and chromosomes in Spain using samples from over 2,000 volunteers, resulting in an inverse correlation between the frequency of the family name and the prevalence of the Y chromosome. "There is a strong relationship between the surname and the Y chromosome in Spain. The majority of men who share relatively unusual family names -those carried by less than 6,000 people in all of Spanish national territory- also tend to share an identical or very similar Y chromosome, thus demonstrating that these surname carriers descended from the same original bearers of those paternal surnames," explains Conrado Martínez-Cadenas, a researcher from the Department of Medicine at Jaume I University in Castellón and from the Human Evolutionary Genetics Group at the University of Oxford, as well as the main author of the article published in the journal European Journal of Human Genetics. Nonetheless, the analysis shows that as a surname becomes more common, the correlation with the Y chromosome gradually disappears. The data indicate that common family names do not represent men from the same family line given that all of them have different Y chromosomes. For the study, in which the Forensic Science Institute at the University of Santiago de Compostela also participated, 37 Spanish surnames were selected with the aim of providing wide geographic coverage in addition to representing a broad spectrum of frequency. Next, the surnames were classified into five groups: very common, surnames with over 150,000 bearers nationwide -Fernández, Martínez-; common, surnames with between 15,000 and 150,000 bearers nationwide -Aguirre, Díez-; uncommon, surnames with between 5,000 and 15,000 individuals -Tirado, Ibarra-; rare, surnames with between 3,000 and 5,000 bearers -Bengoechea, Cadenas-; and very rare, with between 100 and 3,000 individuals nationwide -Nortes, Albiol-. A total of 1,766 samples of DNA were collected from unrelated male volunteers representing each of the 37 surnames, and another 355 control samples were obtained. "The data show that the correlation or coancestry between the surname and the Y chromosome does not at all depend on the geographical origin (Castilian, Catalan or Basque) nor the type of surname (derived from the father's name, a place name, a profession, a nickname, a physical trait) -explains Martínez-Cadenas-. It only depends on the frequency of the surname". According to the study, the origins of the Spanish surnames date back to an estimated 536 years ago on average. However, some surnames are older than others: their ages vary between 200 and 800 years old. "This age is calculated by determining the most recent common ancestor of study participants with a particular surname. This is not the true age of the surname, however, but rather the point in time when study participants of the same surname had the most recent common ancestor in the direct male line," specifies the researcher. Prior to this study on Spanish surnames, the only detailed research conducted had analysed the relationship between surnames and the Y chromosome in Great Britain and Ireland. The researchers decided to compare these analyses in order to find similarities and differences among these three populations. They discovered that the correlation patterns between surnames and the Y chromosome in Spain were similar to those of the British study, but different from those of the Irish study. "The analyses indicate that the Irish surnames are much older than those from Spain and the United Kingdom, in addition to presenting a correlation that does not depend on surname frequency" affirms Martínez-Cadenas. "In Ireland, some very common surnames present a strong correlation between surname and the Y chromosome -something that is not observed in Spain or the United Kingdom-, while others do not," sums up the researcher. According to the study, despite the fact that Spain is a population with a historical, demographic and genetic background different from that of the British Isles, similarities with the development of British surnames suggest that the inverse correlation between the frequency of family names and the prevalence of the Y chromosome could be a general process. The development of Irish surnames, appearing in clans in which even unrelated individuals share the same surname, would be the result of more unusual, specific circumstances. More information: Conrado Martinez-Cadenas et al. The relationship between surname frequency and Y chromosome variation in Spain, European Journal of Human Genetics (2015). DOI: 10.1038/ejhg.2015.75
News Article | April 12, 2016
Although it’s widely known that modern humans carry traces of Neanderthal DNA, a new international study led by researchers at the Stanford University School of Medicine suggests that Neanderthal Y-chromosome genes disappeared from the human genome long ago. The study was published April 7 in The American Journal of Human Genetics, in English and in Spanish, and will be available to view for free. The senior author is Carlos Bustamante, Ph.D., professor of biomedical data science and of genetics at the School of Medicine, and the lead author is Fernando Mendez, Ph.D., a postdoctoral scholar at Stanford. The Y chromosome is one of two human sex chromosomes. Unlike the X chromosome, the Y chromosome is passed exclusively from father to son. This is the first study to examine a Neanderthal Y chromosome, Mendez said. Previous studies sequenced DNA from the fossils of Neanderthal women or from mitochondrial DNA, which is passed to children of either sex from their mother. Other research has shown that the DNA of modern humans is from 2.5 to 4 percent Neanderthal DNA, a legacy of breeding between modern humans and Neanderthals 50,000 years ago. As a result, the team was excited to find that, unlike other kinds of DNA, the Neanderthal Y chromosome DNA was apparently not passed to modern humans during this time. “We’ve never observed the Neanderthal Y chromosome DNA in any human sample ever tested,” Bustamante said. “That doesn’t prove it’s totally extinct, but it likely is.” Why is not yet clear. The Neanderthal Y chromosome genes could have simply drifted out of the human gene pool by chance over the millennia. Another possibility, said Mendez, is that Neanderthal Y chromosomes include genes that are incompatible with other human genes, and he and his colleagues have found evidence supporting this idea. Indeed, one of the Y chromosome genes that differ in Neanderthals has previously been implicated in transplant rejection when males donate organs to women. “The functional nature of the mutations we found,” said Bustamante, “suggests to us that Neanderthal Y chromosome sequences may have played a role in barriers to gene flow, but we need to do experiments to demonstrate this and are working to plan these now.” Several Neanderthal Y chromosome genes that differ from those in humans function as part of the immune system. Three are "minor histocompatibility antigens," or H-Y genes, which resemble the HLA antigens that transplant surgeons check to make sure that organ donors and organ recipients have similar immune profiles. Because these Neanderthal antigen genes are on the Y chromosome, they are specific to males. Theoretically, said Mendez, a woman’s immune system might attack a male fetus carrying Neanderthal H-Y genes. If women consistently miscarried male babies carrying Neanderthal Y chromosomes, that would explain its absence in modern humans. So far this is just a hypothesis, but the immune systems of modern women are known to sometimes react to male offspring when there’s genetic incompatibility. When did we part ways? The Y chromosome data also shed new light on the timeline for the divergence of humans and Neanderthals. The human lineage diverged from other apes over several million years, ending as late as 4 million years ago. After the final split from other apes, the human lineage branched into a series of different types of humans, including separate lineages for Neanderthals and what are now modern Previous estimates based on mitochondrial DNA put the divergence of the human and Neanderthal lineages at between 400,000 and 800,000 years ago. The last common ancestor of Neanderthals and humans — based on the Y chromosome DNA sequenced in the study — is about 550,000 years ago. Scientists believe Neanderthals died out about 40,000 years ago. Sequencing the Neanderthal Y chromosome may shed further light on the relationship between humans and Neanderthals. One challenge for the research team is to find out whether the Y chromosome Neanderthal gene variants identified were indeed incompatible with human genes. The data for the study came from public gene sequencing databases. "We did not collect any data for this work," said Mendez. "It was all public data."