Genomic expression carried over from Neanderthal DNA
Larry H. Bernstein, MD, FCAP, Curator
LPBI
Neanderthal DNA Shapes Clinical Traits for Modern Humans
GEN http://www.genengnews.com/gen-news-highlights/neanderthal-dna-shapes-clinical-traits-for-modern-humans/81252363/
https://youtu.be/D8vYSiKE3E4
Modern humans have inherited many physical traits from the Neanderthals. John Capra, Ph.D., from Vanderbilt University, explains how many of these variants affect a variety of clinical disorders
This graphic shows some of the numerous Neanderthal-influenced traits. [Deborah Brewington, Vanderbilt University]
Today being the 207th birthday celebration of renowned naturalist and evolutionary biologist Charles Darwin, it seemed only appropriate to discuss the recent findings of how Neanderthal DNA has shaped and continues to shape human evolution.
Recent studies have identified that individuals of Eurasian origins inherited somewhere between one and four percent of their DNA from Neanderthals. These findings have led to numerous postulations about how these genetic variants may have affected physical characteristics or the behavior of modern humans, ranging from skin color to heightened allergies to fat metabolism.
Now, a new study from a team of scientists led by researchers at Vanderbilt University has directly compared Neanderthal DNA in the genomes of a large population of adults from European ancestry with their clinical records—confirming that this archaic genetic legacy has a subtle but significant effect on modern human biology.
“Our main finding is that Neanderthal DNA does influence clinical traits in modern humans: We discovered associations between Neanderthal DNA and a wide range of traits, including immunological, dermatological, neurological, psychiatric, and reproductive diseases,” explained senior study author John Capra, Ph.D., assistant professor in the department of biomedical informatics and an investigator in the Center for Human Genetics Research at Vanderbilt University Medical School.
The results of this study were published February 12 in Science through an article entitled “The phenotypic legacy of admixture between modern humans and Neanderthals.
Interestingly, Dr. Capra and his colleagues were able to confirm a few of the previous hypotheses about the influence of Neanderthal DNA on modern Homo sapiens. For instance, investigators found that Neanderthal DNA affects keratinocytes, which help protect the skin from environmental damage such as ultraviolet radiation and pathogens. The new analysis found Neanderthal DNA variants influence skin biology in modern humans, in particular, the risk of developing sun-induced skin lesions called keratosis, which are caused by abnormal keratinocytes.
Surprisingly, the research team found that some regions of Neanderthal DNA were associated with psychiatric and neurological effects. In one example, they found that a specific bit of Neanderthal DNA significantly increased the risk for nicotine addiction, while a separate set of variants influenced the risk for depression (positively and negatively).
“The brain is incredibly complex, so it’s reasonable to expect that introducing changes from a different evolutionary path might have negative consequences,” noted lead author and Vanderbilt doctoral student Corinne Simonti.
In the current study, the authors discussed that the pattern of associations they discovered suggests today’s population retains Neanderthal DNA that may have provided modern humans with some adaptive advantages 40,000 years ago as they migrated into regions outside of Africa with different pathogens and levels of sun exposure.
To study these associations, the scientists used a database containing 28,000 patients whose biological samples have been linked to anonymized versions of their electronic health records. The data came from eMERGE—the Electronic Medical Records and Genomics Network—which links digitized records from Vanderbilt University Medical Center’s BioVU databank and eight other hospitals around the country.
This massive amount of genomic data allowed the researchers to determine if each individual had ever been treated for a particular set of medical conditions, such as heart disease, arthritis, or depression. Subsequently, they analyzed the genomes of each individual to identify the unique set of Neanderthal DNA that each person carried. The comparison of each data set allowed the researchers to test whether each bit of Neanderthal DNA individually and in aggregate influences risk for the traits derived from the medical records.
“Vanderbilt’s BioVU and the network of similar databanks from hospitals across the country were built to enable discoveries about the genetic basis of disease,” Dr. Capra remarked. “We realized that we could use them to answer important questions about human evolution.”
While Dr. Capra and his colleagues were thrilled by their findings—this work establishes a new way to investigate questions about the effects of events in recent human evolution—the researcher team also realized that there is a lot of additional information contained in the medical records, such as lab tests, doctors’ notes, and medical images, that could be used in future analyses to refine their data.
Neanderthals’ Genetic Legacy
Ancient DNA in the genomes of modern humans influences a range of physiological traits.
People of Eurasian origin are, genetically speaking, between 1 percent and 4 percent Neanderthal, and new research shows how this archaic DNA in their genomes may be impacting their health. The study, published today (February 11) in Science, utilized the electronic medical records and associated DNA data of more than 28,000 individuals to show that Neanderthal DNA had small but significant effects on the risks of developing—among other things—depression, skin lesions, and excessive blood clotting.
“They’ve looked at huge databases of medical records to see if there are traits that correlate with the presence of particular genes from Neanderthals and have found a number of them,” said anthropologist John Hawks of the University of Wisconsin who was not involved in the study. “The take-away is that these genes that we have from these ancient people have effects on our phenotypes, and that’s pretty cool. They are not just shadows that are not doing anything, they are actually participating in our biology.”
Sequencing of Neanderthal genomes isolated from fragments of bones has revealed that modern humans contain remnants of Neanderthal DNA—a result of interbreeding between the two subspecies. But while certain loci in human genomes have been found to contain an abundance of Neanderthal alleles, it has been unclear whether these alleles have actual functional effects on human traits and, if so, what those are.
Evolutionary and computational geneticist John Capra of Vanderbilt University in Nashville, Tennessee, and colleagues devised an ingenious way to investigate such functional effects on a genome-wide scale. “We realized that we had a great opportunity to answer these questions using large databases of anonymized versions of patient electronic health records linked to their genetic information,” Capra said in a statement.
“A number of previous studies have focused on individual genes,” said evolutionary geneticist Rasmus Neilsen of the University of California, Berkeley, who did not participate in the research. “But this is the first study that really systematically goes through and uses the knowledge we have about genetic variations in humans to answer the question: How much has integration of DNA from Neanderthals affected observable traits in humans?”
Within Neanderthal DNA found in humans, the researchers focused on the most common variants—single nucleotide polymorphisms (SNPs)—and asked, individually and en masse, whether these variants were associated with any of the medical traits listed for the 28,000 patients.
Investigating the SNPs en masse through a genome-wide complex trait analysis (GCTA), the researchers discovered associations with depression, mood disorders, and a particular type of skin lesion caused by sun exposure. Investigating individual SNPs, on the other hand, the researchers picked out associations tied to tobacco use, urinary problems, and blood hypercoagulation.
Why have such apparently detrimental gene variants been maintained in the human genome? It is important to realize, said Hawks, that “when you look at people’s medical records, you don’t see the good stuff.”
Hawks also noted that “the [observed] associations are really, really small,” meaning that while the links between Neanderthal alleles and certain medical traits were statistically significant, they only represented a tiny percentage of the risk—1 percent to 2 percent in the case of depression, for example.
Further, “many genetic variants, regardless of evolutionary origin and temporal context, are beneficial in some respects but detrimental in others,” Capra added in the statement. For example, while hypercoagulation may increase a person’s thrombosis risk , coagulation is an early innate immune response that protects against injury and infection. As Neanderthals colonized new territories and were exposed to new pathogens, having a souped-up version of this response may therefore have been a favorable defense mechanism.
Capra’s team carried out further experiments to look at whether Neanderthal alleles were associated with classes of traits rather than individual ones, finding neurological and psychiatric traits were both over-represented.
Together with the findings that depression, mood disorders and tobacco use were individually associated with Neanderthal SNPs, this suggested to the researchers that the brains of modern humans have been particularly influenced by Neanderthal DNA. And this might overturn notions of Neanderthals as not-so-bright, said Hawks. “If you had the hypothesis that Neanderthals [died out] because they were stupid,” he said, “you have to explain why their genes are here doing stuff in our brains.”
C.N. Simonti et al., “The phenotypic legacy of admixture between modern humans and Neandertals,” Science, 351:737-41, 2016.
Capra Lab Evolutionary and Computational Genomics at Vanderbilt University
We use the tools of computer science and statistics to address problems in genetics, evolution, and biomedicine.
Our group is located in the Department of Biological Sciences and affiliated with theVanderbilt Genetics Institute, the Center for Structural Biology, and the Department of Biomedical Informatics at Vanderbilt University.
Humans differ from one another and our closest living relatives, the chimpanzees, in a wide range of traits, including our susceptibility to many diseases. We model the evolutionary processes that have produced these novel traits and develop algorithms that compare genomes to predict the functional relevance of specific genetic differences between individuals and species.
Our research is motivated by several questions:
- How have evolutionary processes produced the astonishing diversity of form and function present in the natural world?
- How can better algorithms lead to a deeper understanding of biological systems and networks?
- How do genomes encode and maintain the information necessary to produce life?
- How can our increasing knowledge of genomic variation be translated into the treatment and prevention of disease?
We investigate these questions in a number of model systems, but our main focus is on the origins and recent evolution of human populations and their primate relatives.
Borrowing Immunity Through Interbreeding
Neanderthals and Denisovans contributed innate immune genes to modern humans, scientists show.
Modern humans adopted innate immune genes responsible for recognizing invading microbes from Neanderthals and Denisovans, according to two studies published today (January 7) in The American Journal of Human Genetics. The two teams, based in France and Germany, independently concluded that humans picked up some versions of a cluster of toll-like receptors by interbreeding with archaic hominin relatives.
“Once humans came out of Africa and then encountered archaic species, they might also have encountered their pathogens,” said Rasmus Nielsen, an evolutionary biologist at the University of California, Berkeley, who was not involved in the studies. “There might have been pathogens that could affect Neanderthals and Denisovans that also could jump into modern humans.”
“At least partially, Neanderthals may have harbored already adaptive mutations, mutations that rendered them more resistant to infections,” said Lluis Quintana-Murci, an evolutionary geneticist at the Pasteur Institute in Paris and a coauthor of one of the new papers.
Previous studies have shown that modern humans interbred with Neanderthals and Denisovans. For instance, Nielsen and his colleagues showed that humans who migrated to Tibet likely picked up an allelecontrolling blood hemoglobin concentration from local Denisovans, allowing them to adapt to living at high altitudes. Another paper indicated that humans had picked up major histocompatibility genes from Denisovans and Neanderthals.
The authors of the two new studies approached the topic of ancient human evolution from different directions. Quintana-Murci and his colleagues decided to do a broad survey of innate immune genes and their variability among present-day humans around the world, using sequence data gathered through the1,000 Genomes Project. The team demonstrated that innate immune genes have been under stronger-than-average selective pressures. Some innate genes are highly conserved, with little tolerance for variability. Other protein-coding genes have picked up adaptive mutations, mostly occurring within the last 6,000 to 13,000 years after humans transitioned from a hunter-gatherer to agricultural society. The resulting increase in density of human settlements, cohabitation with animals, and increased exposure to sewage may have made humans easier targets for microbial disease, the researchers speculated.
Quintana-Murci and his colleagues also took advantage of a previously published map of areas of the human genome where Neanderthal genes are present, showing that innate immune genes are generally more likely to have been borrowed from Neanderthals than genes coding other types of proteins. Specifically, they noted that 126 innate immune genes in present-day Europeans, Asians, or both groups were among the top 5 percent of genes in the genome of each population most likely to have originated in Neanderthals. The cluster of toll-like receptor genes, encoding TLR 1, TLR 6, and TLR 10, both showed signs of having been borrowed from Neanderthals and having picked up adaptive mutations at various points in history.
Meanwhile, a group led by Janet Kelso of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, used both the same previously published Neanderthal introgression map that Quintana-Murci used and a second introgression map. The researchers searched for borrowed regions of the genome that were especially long and common in present-day humans, eventually zeroing in TLR6, TLR10, and TLR1. These receptors, which detect conserved microbial proteins such as flagellin, are all encoded along the same segment of DNA on chromosome four.
By looking at 1,000 Genomes Project data, Kelso and her colleagues were able to identify seven distinct versions of the TLR cluster. The researchers were able to match two of these versions to DNA from Neanderthals, and one version to DNA from Denisovans.
“There have been three potentially independent admixtures,” said Kelso. “We suspect it was two different Neanderthals and a Denisovan.”
Kelso and her colleagues then attempted to figure out the functional differences between the Neanderthal and Denisovan versions of the TLR cluster and the versions that likely originated with the modern humans who migrated from Africa to Europe and Asia later than these archaic hominids.
The changes in the Neanderthal and Denisovan TLR clusters do not lead to altered proteins. However, the researchers found that in white blood cells, the Neanderthal and Denisovan TLRs are more highly expressed than the non-borrowed human TLR clusters.
Kelso and her colleagues also did a survey of already-completed genome wide association studies, finding that present-day people who have the borrowed TLR clusters show lower levels of the bacteriumHelicobacter pylori in their bloodstreams than people descended from humans that did not pick up TLR clusters from Neanderthals or Denisovans. People with the borrowed TLR clusters also tend to have elevated allergies to dust and pollen.
Kelso hypothesized that the Denisovan and Neanderthal TLR clusters may have strengthened the human immune systems against novel pathogens they encountered in their new homes in Europe and Asia. This may have yielded an immune system both skilled at fighting off pathogens and slightly oversensitive, leading to the allergies people carrying the archaic TLRs sometimes have today.
But it is less clear exactly how the immune system was strengthened, or what pathogens ancient humans were trying to fight. “What the gene expression results tell us is that there is some kind of a functional effect for introgression,” said Sri Sankararaman, a statistical geneticist at University of California, Los Angeles, who was not involved in the studies but did help make one of the preexisting introgression maps used in the papers. “That’s basically what it has established. Going from there to making a claim about its fitness effect is less obvious.”
And the reduced H. pylori prevalence associated with the borrowed TLR alleles is simply a sign that the variants are associated with altered immunity, not necessarily an indication that breeding with Neanderthals helped humans avoid this particular pathogen. “We may not have the pathogens around today that selection was acting in response to,” said Nielsen.
The studies help confirm that interbreeding between humans, Neanderthals, and Denisovans shaped human evolution, sometimes offering key advantages people of combined lineage. “The things that modern humans took away from the interbreeding with the Neanderthals were regions of the genome involved in adaptation to the environment,” said Kelso.
M. Deschamps et al., “Genomic signatures of selective pressures and introgression from archaic hominins at human innate immunity genes,” The American Journal of Human Genetics, doi:10.1016/j.ajhg.2015.11.014, 2016.
M. Dannemann et al., “Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human toll-like receptors,” The American Journal of Human Genetics,doi:10.1016/j.ajhg.2015.11.015
Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes
Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000–13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change—containing variation acquired from archaic hominins or adaptive variants in specific populations—improving our understanding of the relative biological importance of innate immunity pathways in natural conditions.
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