Category Archives: Human Genetics

Modern humanity's ancient cousins, the Neanderthals, lived in small groups that were isolated from one another, suggests an investigation into their DNA. The analysis also finds that Neanderthals lacked some human genes that are linked to our behavior. (Related: "Why Am I Neanderthal?")

In recent years, experts in ancient DNA have mapped out the genes of Neanderthals, a species of human that vanished some 30,000 years ago. These gene maps have revealed that many modern people share a small part of their ancestry, and a small percentage of their genes, with those early humans.

Now moving beyond ancestry, researchers are comparing these ancient gene maps to those of modern humans. The comparisons may point to genes that make us uniquely human and uncover links to the origins of genetic ailments.

Compared to Neanderthals, humanity appears to have evolved more when it comes to genes related to behavior, suggests a team headed by Svante Pbo, a pioneer in ancient genetics at Germany's Max Planck Institute for Evolutionary Anthropology. Their study was published today in the Proceedings of the National Academy of Sciences.

They note in particular that genes linked to hyperactivity and aggressive behavior in modern humans appear to be absent in Neanderthals. Also missing is DNA associated with syndromes such as autism.

"The paper describes some very interesting evolutionary dynamics," said paleoanthropologist John Hawks of the University of Wisconsin at Madison.

The Neanderthal genes suggest that sometime after one million to 500,000 years ago, Neanderthal numbers decreased and the population stayed small, Pbo's group determined. A small population size would have been bad news for Neanderthals, Hawks said, because it would have meant that "natural selection had less power to weed out bad mutations."

Ancient Answers

Pbo and colleagues looked at the genes of two ancient Neanderthals, one from Spain and one from Croatia. They compared the DNA of those individuals to that of a third Neanderthal who had lived in Siberia and whose DNA had been analyzed in an earlier study, and to the DNA of several modern humans.

"We find that [Neanderthals] had even less [genetic] variation than present-day humans," Pbo said by email. Genetic diversity among Neanderthals was about one-fourth as much as is seen among modern Africans, he said, and one-third that of modern Europeans or Asians.

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Neanderthals Lived in Small, Isolated Populations, Gene Analysis Shows

Human Genetics and Personalized Medicine, Dr. David Cox
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Research assistant Natalie Thomas pulls a slice of a cancerous tumor for analysis at the Anschutz Medical Campus. (Andy Cross, The Denver Post)

Ellen Smith received a death sentence for her advanced lung cancer five years ago, but it was commuted by a revolution in human genetics, drug therapies and clinical approaches unfolding at the University of Colorado Hospital.

The advances have saved her life, by her reckoning, four times.

The accelerating speed of DNA sequencing, drug development and data analysis has led UCHealth, the University of Colorado Medical School and Children's Hospital Colorado to join in an effort to fundamentally change the way they care for patients.

The partnership will invest more than $63 million over the next five years to create a new division, adding clinicians, genetic counselors, researchers and advanced practice nurses and also expanding a DNA bank and advanced data warehouse. It's called the Center for Personalized Medicine and Biomedical Informatics.

The pioneering field of personalized medicine uses molecular analysis to determine a patient's predisposition to developing certain diseases and to deliver tailored medical treatment.

"There is no doubt in my mind that this will change how we treat disease, how we teach our students, how physicians work, how we raise our kids and how we conduct public health policy," Dr. David Schwartz, chair of the CU Department of Medicine, said of the center.

The DNA bank, Schwartz said, probably will require a year of discussion with physicians, academicians, lawyers, ethicists and patient advocates about what it really means to secure patients' genetic blueprints and how they should be used.

While the center will be based on the Anschutz Medical Campus in Aurora, it will serve UCHealth's five hospitals and Children's Hospital. The DNA bank would sequence and analyze samples from around the region.

The benefits of personalized medicine have been evident for several years in cancer treatment, said Dr. Dan Theodorescu, director of the CU Cancer Center. It's why the center's survival rates are significantly better for certain types of cancers than the average national outcomes, he said. The new center will bring these kinds of lifesaving therapies to all disease fronts while providing more laboratory and analytical power to evaluate cancer DNA, he said.

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CU system resets health care with $63M personalized medicine division

Genomic Revolution: Catalina Lopez-Correa at TEDxHECMontreal
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When scientists first sequenced the genome of a Neanderthal, our extinct, heavy-browed human cousin, we learned a surprising amount about our own species too: many modern humans carry Neanderthal genes, proving we interbred with them long ago.

Now, researchers have offered the first glimpse of the Neanderthal epigenome, and once again their results offer tantalizing new theories about the modern human brain and skeleton.

While the findings are surprising, the fact that the Neanderthal epigenome holds important secrets should not be. In the past decade, scientists have discovered that epigenetics, the chemical signals that regulate how genes are expressed, are almost as important as genetics in understanding how organisms look and act.

By exploiting a trick of how ancient DNA degrades, an Israeli-led team of researchers has created a map of the Neanderthal epigenetic landscape and that of another extinct human species, the Denisovans. Their work, hailed as a fantastically exciting technical achievement, was published Thursday in the journal Science.

The most intriguing findings of the study are the clues that emerged when the researchers compared those archaic epigenetic maps to those of present-day humans.

More than 99 per cent of the ancient and modern maps were the same, which is what one would expect to find in closely-related human species that shared a common ancestor approximately 600,000 years ago.

But the maps were almost twice as likely to differ in regions associated with disease and, in a third of those cases, in regions associated with psychological and neurological diseases.

Scientists are a long way from being able to understand what this means, stressed Liran Carmel, who led the study along with Eran Meshorer and David Gokhman, all of the Hebrew University of Jerusalem.

But this raises the hypothesis that perhaps many genes in our brain have changed recently, specifically in our lineage, the lineage leading to Homo sapiens. And perhaps things like autism, schizophrenia and Alzheimers are side-effects of these very recent changes, said Carmel.

This is an interesting suggestion, that (brain disease) is a side-effect of us being Homo sapiens and having our unique cognitive capabilities.

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Neanderthal genetic landscape reveals key differences with humans

PUBLIC RELEASE DATE:

17-Apr-2014

Contact: Marjorie Montemayor-Quellenberg mmontemayor-quellenberg@partners.org 617-525-6383 Brigham and Women's Hospital

Boston, MA When talking about genetic abnormalities at the DNA level that occur when chromosomes swap, delete or add parts, there is an evolving communication gap both in the science and medical worlds, leading to inconsistencies in clinical and research reports.

Now a study by researchers at Brigham and Women's Hospital (BWH) proposes a new classification system that may standardize how structural chromosomal rearrangements are described. Known as Next-Gen Cytogenetic Nomenclature, it is a major contribution to the classification system to potentially revolutionize how cytogeneticists worldwide translate and communicate chromosomal abnormalities. The study will be published online April 17, 2014 in The American Journal of Human Genetics.

"As scientists we are moving the field of cytogenetics forward in the clinical space," said Cynthia Morton, PhD, BWH director of Cytogenetics, senior study author. "We will be able to define chromosomal abnormalities and report them in a way that is integral to molecular methods entering clinical practice."

According to the researchers, advances in next-generation sequencing methods and results from BWH's Developmental Genome Anatomy Project (DGAP) revealed an assortment of genes disrupted and dysregulated in human development in over 100 cases. Given the wide variety of chromosomal abnormalities, the researchers recognized that more accurate and full descriptions of structural chromosomal rearrangements were needed.

The nomenclature proposed by Morton and her team goes beyond uncovering chromosomal abnormalities under a microscope to focusing on the unique molecules that are the building blocks of DNAnucleotides.

"Cytogeneticists compare karyograms, or pictures of chromosomes, to identify chromosomal abnormalities," said Morton. "In the current system available, we are able to describe certain characteristics of chromosomes, such as chromosome band levels. What we have developed is a new system for describing chromosomal abnormalities at a much more precise level."

"Currently, most DNA sequencing reports only provide nucleotide numbers of the breakpoints in various formats based on the reference genome sequence alignment," said Zehra Ordulu, MD, BWH Department of Obstetrics, Gynecology and Reproductive Medicine, lead study author. "But there are other important characteristics of the rearrangementincluding reference genome identification, chromosome band level, direction of the sequence, homology, repeats, and nontemplated sequencethat are not described."

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Refining the language for chromosomes

It's long been known that certain strains of human papillomavirus (HPV) cause cancer. Now, researchers at The Ohio State University have determined a new way that HPV might spark cancer development -- by disrupting the human DNA sequence with repeating loops when the virus is inserted into host-cell DNA as it replicates.

Worldwide, HPV causes about 610,000 cases of cancer annually, accounting for about five percent of all cancer cases and virtually all cases of cervical cancer. Yet, the mechanisms behind the process aren't yet completely understood.

This study, recently published in the journal Genome Research and reviewed in The Scientist, leveraged the massive computational power of the Ohio Supercomputer Center (OSC) systems. The researchers employed whole-genome sequencing, genomic alignment and other molecular analysis methods to examine ten cancer-cell lines and two head and neck tumor samples from patients -- each sequence comprising the three billion chemical units within the human genetic instruction set.

"Our sequencing data showed in vivid detail that HPV can damage host-cell genes and chromosomes at sites of viral insertion," said co-senior author David Symer, M.D., Ph.D., assistant professor of molecular virology, immunology and medical genetics at Ohio State's Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James).

"HPV can act like a tornado hitting the genome, disrupting and rearranging nearby host-cell genes," he said. "This can lead to overexpression of cancer-causing genes in some cases, or it can disrupt protective tumor-suppressor genes in others. Both kinds of damage likely promote the development of cancer."

The study's first author Keiko Akagi, Ph.D., a bioinformatics expert and research assistant professor of molecular virology, immunology and medical genetics at OSUCCC -- James, utilized the computational capabilities of OSC's HP-built Intel Xeon cluster. The 8,300+ cores of the Oakley Cluster offer Ohio researchers a total peak performance of 154 teraflops -- tech speak for making 154 trillion calculations per second -- and OSC's Mass Storage System provides them with more than 2 petabytes of storage.

"We observed fragments of the host-cell genome to be removed, rearranged or increased in number at sites of HPV insertion into the genome," said co-senior author Maura Gillison, M.D., Ph.D., professor of medicine, epidemiology and otolaryngology and the Jeg Coughlin Chair of Cancer Research at OSUCCC -- James. "These remarkable changes in host genes were accompanied by increases in the number of HPV copies in the host cell, thereby also increasing the expression of viral E6 and E7, the cancer-promoting genes."

Cancer-causing types of HPV produce two viral proteins, called E6 and E7, which are essential for the development of cancer, but are not alone sufficient to cause cancer. Additional alterations in host-cell genes are necessary for cancer to develop, which is where the destabilizing loops might play a significant role; genomic instability is a hallmark of human cancers, including the HPV virus.

"Our study reveals new and interesting information about what happens to HPV in the 'end game' in cancers," Symer says. "Overall, our results shed new light on the potentially critical, catastrophic steps in the progression from initial viral infection to development of an HPV-associated cancer."

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DNA looping damage tied to HPV cancer, researcher discovers

PHILADELPHIA Daniel J. Rader, MD, a widely recognized international leader in the human genetics of lipoprotein biology and cardiovascular disease, has been named the new chair of the Department of Genetics in the Perelman School of Medicine at the University of Pennsylvania. He has been a faculty member at Penn for 20 years and is currently the chief of the Division of Translational Medicine and Human Genetics and the Edward S. Cooper, MD/Norman Roosevelt and Elizabeth Meriwether McLure Professor of Medicine.

As a prominent physician-scientist, Dr. Rader will bring his robust knowledge of genetic approaches to improving health to guide the department of Genetics into an era where genes play a role in our strategies to prevent and treat a broad array of diseases, said J. Larry Jameson, MD, PhD, Executive Vice President for the Health System and Dean of the Perelman School of Medicine. His long record of leadership in the classroom, the exam room, and the lab will be invaluable to the department and overall genetics research at Penn.

Dr. Rader holds multiple leadership roles at Penn Medicine. In addition to heading the Division of Translational Medicine and Human Genetics within the Department of Medicine, he also serves as Associate Director of the Institute for Translational Medicine and Therapeutics (ITMAT).

He co-directs the new Penn Medicine BioBank, an integrated, centralized resource for consenting, collecting, processing, and storing DNA, plasma/serum, and tissue for human genetics and translational research. This venture is a cornerstone of Penn Medicines efforts in human genetics and translational and personalized medicine. Dr. Rader also has key relationships with Penns Cardiovascular Institute (CVI) and Institute for Diabetes, Obesity, and Metabolism (IDOM).

In his research program, Dr. Rader has used human genetics and model systems to elucidate novel biological pathways in lipoprotein metabolism and atherosclerosis. His lab discovered and characterized the enzyme endothelial lipase, demonstrated its effects on high density lipoproteins (HDL) in mice, and then found that loss-of-function mutations in the gene cause high levels of HDL in humans. He is among the worlds leaders in using both humans and model systems to dissect the functional genomics of human genetic variants associated with plasma lipid traits as well as coronary heart disease.

He has had a long interest in Mendelian disorders of lipoprotein metabolism and has a strong translational interest in development of novel therapies for these disorders. He was involved in the identification of the molecular defect in a rare genetic disorder causing very low levels of low density lipoproteins (LDL), which spurred the development of inhibitors of this protein to reduce levels of LDL. Indeed, when one such drug was abandoned by a pharmaceutical firm, he went on to oversee its development for the orphan disease homozygous familial hypercholesterolemia (HoFH), characterized by extremely high levels of LDL and heart disease in childhood. This decade-long endeavor led to FDA and European approval of lomitapide, the first effective medication for the treatment of HoFH.

Dr. Rader has received numerous awards as a physician-scientist, including the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, the Bristol Myers Squibb Cardiovascular Research Award, the Doris Duke Charitable Foundation Distinguished Clinical Investigator Award, the Jeffrey M. Hoeg Award for Basic Science and Clinical Research from the American Heart Association, the American Heart Associations Clinical Research Prize, and the Clinical Research Forums Distinguished Clinical Research Award. He has been elected to the American Society of Clinical Investigation and to the Association of American Physicians. In 2011, he received one of the nations highest honors in biomedicine when he was elected to the Institute of Medicine.

Dr. Rader has also received many awards for his outstanding teaching activities. At the Perelman School of Medicine, he has received the William Osler Patient Oriented Research Award, as well as the Donald B. Martin Outstanding Teacher Award and the Outstanding Faculty Award from the Department of Medicine. Along with these accolades, Dr. Rader has been honored by Philadelphia magazine, which has named him to its Top Docs honor roll every year since 2002.

Dr. Rader earned his medical degree at the Medical College of Pennsylvania, followed by an internship and a residency at Yale-New Haven Hospital. Next, he served as a post-doctoral fellow at the National Institutes of Health, where he developed skills in basic science as well as translational research involving patients with genetic lipid disorders.

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