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Big data, Evolution, Genetics, In the News, Research, Science, Stanford News

Flies, worms and humans – and the modENCODE Project

Flies, worms and humans - and the modENCODE Project

It’s a big day in comparative biology. Researchers around the country, including Stanford geneticist Michael Snyder, PhD, are publishing the results of a massive collaboration meant to suss out the genomic similarities (and differences) among model organisms like the fruit fly and the laboratory roundworm. A package of four papers, which describe how these organisms control how, when and where they express certain genes to generate the cell types necessary for complex life, appears today in Nature.

From our release:

The research is an extension of the ENCODE, or Encyclopedia of DNA Elements, project that was initiated in 2003. As part of the large collaborative project, which was sponsored by the National Human Genome Research Institute, researchers published more than 4 million regulatory elements found within the human genome in 2012. Known as binding sites, these regions of DNA serve as landing pads for proteins and other molecules known as regulatory factors that control when and how genes are used to make proteins.

The new effort, known as modENCODE, brings a similar analysis to key model organisms like the fly and the worm. Snyder is the senior author of two of the papers published today describing some aspects of the modENCODE project, which has led to the publication, or upcoming publication, of more than 20 papers in a variety of journals. The Nature papers, and the modENCODE project, are summarized in a News and Views article in the journal (subscription required to access all papers).

As Snyder said in our release, “We’re trying to understand the basic principles that govern how genes are turned on and off. The worm and the fly have been the premier model organisms in biology for decades, and have provided the foundation for much of what we’ve learned about human biology. If we can learn how the rules of gene expression evolved over time, we can apply that knowledge to better understand human biology and disease.”

The researchers found that, although the broad strokes of gene regulation are shared among species, there are also significant differences. These differences may help explain why humans walk, flies fly and worms slither, for example:

The wealth of data from the modENCODE project will fuel research projects for decades to come, according to Snyder.

“We now have one of the most complete pictures ever generated of the regulatory regions and factors in several genomes,” said Snyder. “This knowledge will be invaluable to researchers in the field.”

Previously: Scientists announce the completion of the ENCODE project, a massive genome encyclopedia

Cancer, Genetics, Research, Science, Stanford News

Unraveling the secrets of a common cancer-causing gene

Unraveling the secrets of a common cancer-causing gene

The Myc protein can cause a lot of trouble when it’s mutated or expressed incorrectly. Under those condition it’s called an oncogene, and it’s associated with the development of more than half of all human cancers. But because its cellular influence is vast (it controls the expression of thousands of genes and regulatory molecules), it’s been tough for scientists to learn which of its many effects are cancer-causing.

Now oncologist Dean Felsher, MD, PhD, and his colleagues have found that just a handful of genes are responsible for the Myc oncogene’s devastating outcomes. Their work was published today in Cancer Cell. As I wrote in our release:

The genes identified by the researchers produce proteins that govern whether a cell self-renews by dividing, enters a resting state called senescence or takes itself permanently out of commission through programmed cell suicide. Exquisite control of these processes is necessary to control or eliminate potentially dangerous tumor cells.

In particular, the researchers found that Myc works through a family of regulatory RNA molecules that govern how (and when) tightly packaged genes in the DNA/protein complex called chromatin are made available for transcription into proteins that do much of the work of the cell. Understanding this process might help researchers find ways to throw a molecular wrench into the Myc mechanism.

“One of the biggest unanswered questions in oncology is how oncogenes cause cancer, and whether you can replace an oncogene with another gene product,” Felsher told me. “These experiments begin to reveal how Myc affects the self-renewal decisions of cells. They may also help us target those aspects of Myc overexpression that contribute to the cancer phenotype.”

The reliance of many cancer cells on oncogenes like Myc is called oncogene addiction. In many cases, blocking the expression of an oncogene, or tinkering with its activity, causes cancer cells to stop growing and tumors in animals to regress. Recently Felsher and his colleagues published an article in the Proceedings of the National Academy of Sciences describing how inactivating two oncogenes at once can work better to fight cancer in animal models by making it more difficult for the cancer cells to develop resistance to therapy.

Previously: Tool to identify the origin of certain types of cancer could be a “boon to doctors prescribing therapies” and  Smoking gun or hit-and-run? How oncogenes make good cells go bad

From August 11-25, Scope will be on a limited publishing schedule. During that time, you may also notice a delay in comment moderation. We’ll return to our regular schedule on August 25.

Evolution, Genetics, Obesity, Research, Science, Stanford News

Tiny fruit flies as powerful diabetes model

Tiny fruit flies as powerful diabetes model

Seung Kim

Fruit flies in your kitchen are unquestionably annoying. But the next time you’re trying to bat one out of the air around your too-ripe apples and bananas (or maybe that’s just me?), spare a few seconds to realize how important the tiny insects have been to science. They’ve been a darling of developmental biology for decades, as researchers identified genes (subsequently shown to be shared in mammals and humans) critically important in the metamorphosis from egg to animal. Frankly, it’s hard to over-estimate their contribution to science.

Now they’re set to take up a starring role in diabetes research. Stanford developmental biologist and Howard Hughes Medical Institute investigator Seung Kim, MD, PhD, and research associate Sangbin Park, PhD, have devised a way to measure insulin levels in fruit flies at the picomolar level – the level at which insulin concentrations are measured in humans. They’ve done so by successfully tagging the fruit fly insulin-like-peptide 2, or Ilp2, with a chemical tag. Their research was published today in PLOS Genetics.

From our release:

The experimental model is likely to transform the field of diabetes research by bringing the staggering power of fruit fly genetics, honed over 100 years of research, to bear on the devastating condition that affects millions of Americans. Until now, scientists wishing to study the effect of specific mutations on insulin had to rely on the laborious, lengthy and expensive genetic engineering of laboratory mice or other mammals.

In contrast, tiny, short-lived fruit flies can be bred in dizzying combinations by the tens of thousands in just days or weeks in small flasks on a laboratory bench.

In 2002, Kim and developmental biologist Roel Nusse, PhD, surprised many researchers when they showed that fruit flies develop a diabetes-like condition when their insulin-producing cells are destroyed. Further research has been stymied, however, by the difficulty of accurately measuring circulating insulin levels in the tiny animals. When speaking to me about the research, Kim called the new technique a “breakthrough” in the field.

Unlike many previous attempts by many groups, Park found two places in Ilp2 where the tag can be placed without affecting its biological activity. This allowed Kim and Park to track Ilp2 through its life cycle, as it’s produced by neurons in the brain (this is different from humans, who make insulin in beta cells in the pancreas), secreted into the blood stream and binds to insulin receptors in cells throughout the body. Parsing the effect of each mutation on the way the body produces, secretes and responds (or not) to insulin is critical to further understand the disease and to devise new therapeutic approaches. More from our release:

Park and his colleagues then turned their attention to mutations associated with type-2 diabetes in genome-wide studies in humans. These studies don’t reveal how a specific mutation might work to affect development of a disease; they show only that people with the condition are more likely than those without it to have certain mutations in their genome. Hundreds of candidate-susceptibility genes have been identified in this way.

Continue Reading »

Research, Science, Stanford News, Stem Cells

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cells, also called iPS cells, made from easily accessible skin or other adult cells, are ideal for disease modeling, drug discovery and, possibly, cell therapy. That’s because they can be generated in large numbers and grown indefinitely in the laboratory. They also reflect the genetic background of the person from whom they were generated. However, some fundamental questions still remain before they’re ready for the full glare of the clinical limelight. Does it matter what type of starting cells scientists use to create the pluripotent stem cells? And what’s the best control to use when studying the effect of a particular, patient-specific mutation?

Now Stanford cardiologist Joseph Wu, MD, PhD, and his colleagues have addressed and answered these questions. Their work was published yesterday in two back-to-back papers in the Journal of the American College of Cardiology. (Each paper is also accompanied by an editorial.) As Wu explained in an e-mail to me:

If your goal is to generate healthy iPS cell derivatives for regenerative therapy, it’s important to know whether the starting material makes a difference. For example, if I’m treating Alzheimer’s disease, is there a benefit to using iPS cell-derived brain cells made from brain cells? Likewise, if I’m treating a skin disorder, is there a benefit to using iPS cell-derived skin cells made from skin cells? As cardiologists, we are asked this quite often and each time, I had to say “I don’t know.” So we decided to do a study comparing the differentiation and functional ability of iPS cell-derived cardiomyocytes generated from two different sources: skin and heart. We also wanted to devise more efficient ways for researchers to quickly and easily create their own “designer” iPS cell lines to study particular mutations.

To answer the first question, the researchers created iPS cells from two types of starter cells: human fetal skin cells and cardiac progenitor cells. Not surprisingly, only the cardiac progenitor cells expressed genes known to be expressed in heart tissue. Wu and his colleagues then exposed the newly created pluripotent stem cells to growing conditions that favor the development of heart muscle cells called cardiomyocytes. They found that, although iPS cells derived from cardiac progenitor cells were more efficient at becoming cardiomyocytes, both types of starting material produced heart muscle cells that functioned similarly after a period of growth in the laboratory. As Wu explained:

These two populations of cells are essentially no different from one another over time. It appears that they lost the memory of their starting material (this memory is stored in the form of chemical tags on the cells’ DNA in a phenomena known as epigenetic marking). This suggests that I could take my own skin cells, make iPS cells and then create specialized brain, heart, liver or kidney cells for cell therapy. This is much easier than biopsying each tissue, and could be a good way to create universal iPS cell lines for research or cell therapy.

In the second paper, Wu and his colleagues devised a way to introduce specific mutations into iPS cells before transforming them into particular tissues. The approach relies on the use of what’s known as “dominant negative” mutations that exert their disruptive effect even when the unmutated gene is still present. This is important because it’s much easier and quicker than previous similar efforts, which required a complicated, time-consuming procedure to snip out and then replace individual genes. The technique also allows researchers to generate two cell lines that are identical except for the mutation under study. That way researchers can be confident that differences between the cell lines are due only to that mutation, which is particularly important when the lines are used to test the effect of therapeutic drugs. Again, from Wu:

Investigators can make their own designer iPS cell lines to study particular mutations with genetically identical controls to use in their experiments. We won’t have to make new iPS cells from each patient, which is laborious and time consuming. Instead we can create standardized lines to study many different mutations alone and in combination. This has the potential to revolutionize the field of disease modeling and drug discovery.

The two papers describe ongoing research in the Wu lab designed to optimize iPS cells for a variety of applications. The group, including graduate student Arun Sharma, recently published research using human iPS cell-derived cardiomyocytes to investigate the effect of various antiviral drugs againse coxsackievirus, a leading cause of an infection of the middle layer of the heart wall in children and the elderly. The research is the first time that iPS cell-derived heart muscle has been used to investigate the mechanisms behind an acquired viral disease.

Previously: A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells, “Clinical trail in a dish” may make common medicines safer, say Stanford scientists and Lab-made heart cells mimic common cardiac disease in Stanford study

Cancer, Research, Science, Stanford News, Stem Cells

Radiation therapy may attract circulating cancer cells, according to new Stanford study

Radiation therapy may attract circulating cancer cells, according to new Stanford study

Localized radiation therapy for breast cancer kills cancer cells at the tumor site. But, in a cruel irony, Stanford radiation oncologist Edward Graves, PhD, and research associate Marta Vilalta, PhD, have found that the dying cells in the breast may send out a signal that recruits other cancer cells back to the site of the initial tumor. Their work was published today in Cell Reports. As Graves explained in an e-mail to me:

Cancer spreads by shedding tumor cells into the circulation, where they can travel to distant organs and form secondary lesions.  We’ve demonstrated with this study that cancer radiation therapy may actually attract these circulating tumor cells, or CTCs, back to the primary tumor, which may lead to the regrowth of the tumor after radiation therapy.

The researchers studied mouse and human breast cancer cells growing in a laboratory dish, as well as human breast cancer cells implanted into mice. They found that irradiated cells secreted a molecule called granulocyte macrophage colony stimulating factor, or GM-CSF. Blocking the expression of GM-CSF by the cells inhibited (but didn’t completely block) their ability to recruit other cells to the cancer site. The finding is particularly interesting, since physicians sometimes give cancer patients injections of GM-CSF to enhance the growth of infection-fighting white blood cells that can be damaged during chemotherapy. As Graves explained, “This work has important implications for clinical radiotherapy, and for the use of GM-CSF in treating neutropenia in cancer patients during therapy.”

The researchers say, however, that cancer patients shouldn’t eschew radiation therapy. Rather, the finding may help clinicians devise better ways to fight the disease – perhaps by blocking GM-CSF signaling. Graves concluded:

It should be emphasized that radiation therapy remains one of the most effective treatments for cancer. Our findings will help us to further optimize patient outcomes following this already potent therapy.

Previously: Using 3-D technology to screen for breast cancer, Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers and Common drug class targets breast cancer stem cells, may benefit more patients, says study

Cancer, FDA, Genetics, Research, Science, Stanford News

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

6825694281_dfb79615d6_zIf you’re a regular reader of this blog, or follow cancer literature, you’ll have heard of a signaling pathway called Hedgehog that is activated in many cancers, including brain, skin and even bladder. It’s a cute name for cellular cascade that can kill when inappropriately activated.

Neurologist Yoon-Jae Cho, MD, treats children with brain tumors called medulloblastomas. He and postdoctoral fellow in his lab, Yujie Tang, PhD, published a study yesterday in Nature Medicine that could one day help some patients whose Hedgehog-driven tumors have become resistant to available therapies.

As Cho explained in an e-mail to me:

Medulloblastomas are the most common malignant brain tumors in children. They are comprised of various subgroups, including one with activation of a strong oncogenic signal called the Hedgehog pathway. Notably, the Hedgehog pathway is also activated in several other cancers including basal cell carcinoma, the most common cancer worldwide. Therefore, pharmaceutical companies and several research groups have developed drugs to target this pathway.

The most common of these drugs targets a downstream protein component of the pathway called Smoothened, including one currently marketed by Genentechcalled vismodegib (trade name Erivedge) and an investigational drug produced by Novartis called LDE225. Blocking the activity of Smoothened stops the chain reaction leading to division of the cancer cells. You can think of it (in simplified terms) as a line of dominoes standing on end, waiting for an eager finger to begin the chain reaction. Removing one domino (nixing Smoothened activity) can sometimes stop the rest of the row from falling and block the cancerous cell from dividing. But, as Cho explained:

Unfortunately, many cancers activate the Hedgehog pathway downstream of Smoothened and are inherently resistant to these therapies. Other cancers that are initially responsive to these drugs develop resistance through activation of downstream Hedgehog pathway components.

Cho and his colleagues have now described a new, novel way to interfere with the Hedgehog pathway. They’ve found that compounds that inhibit a protein called BRD4 can stop the growth of human Hedgehog-driven cancers – even when they’re resistant to drugs blocking Smoothened activity. This is particularly interesting because the BRD family of proteins recognizes and binds to particular chemical tags on chromatin that control whether (and when) a gene is made into a protein. It’s the first time such an epigenetic regulator has been implicated as a target in the Hedgehog pathway. Additionally, it’s a new avenue to explore for patients with Hedgehog-driven medulloblastomas – as many as half of whom will be resistant to Smoothened inhibition, according to a previous study co-authored by Cho and members of the International Cancer Genome Consortium’s Pediatric Brain Tumor Project. Cho concludes, “Our study offers a promising new treatment strategy for patients with Hedgehog-driven cancers that are resistant to the currently used Smoothened antagonists.”

Previously: New skin cancer target identified by Stanford researchers, Humble anti-fungal pill appears to have noble side-effect: treating skin cancer and Studies show new drug may treat and prevent basal cell carcinoma
Photo by Phillip Taylor

Cardiovascular Medicine, Genetics, Patient Care, Pediatrics, Research, Stanford News

When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn

When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn

8963661410_d59cc4c08f_z

It’s an ‘edge-of-your-seat’ story: The newborn’s heart had stopped multiple times in the hours since her birth. Her doctors at Lucile Packard Children’s Hospital Stanford had tried everything to help her, but her situation was dire.

The baby had an unusually severe form of an inherited cardiac condition called long QT syndrome. The syndrome, which is most often diagnosed in older children or adults, can be caused by a mutation in any of several genes; until the doctors knew exactly which genetic mutation was causing the condition they wouldn’t know what drug would be most likely to help. The stakes were high: by her second day of life she’d received an implantable defibrillator and several intravenous drug infusions.

As cardiologist Euan Ashley, MD, PhD, explained to me:

The team literally tried everything we could think of to help this child, including trying every drug that could possibly make a difference. It was a heroic effort by a very diverse group of professionals.

The clinicians and researchers, including pediatric cardiologist Scott Ceresnak, MD, who managed the baby’s clinical care, realized it was critically important to identify the baby’s disease-causing mutation to learn which drug would be best for her. To do so, they dropped everything else they were doing and sequenced her entire genome to pinpoint the culprit within just ten days – an unprecedented feat. Ashley, who directs Stanford’s new Clinical Genomics Service as well as its  Center for Inherited Cardiovascular Disease, and pediatric cardiology fellow James Priest, MD, recently published the case study in the journal Heart Rhythm.

This is the future of genetic testing and we hope, the future of medicine.

Using customized commercial software and tools developed at Stanford, the researchers were able to zero in on a mutation in a gene called KCNH2 known to be associated with long QT. They also found another, novel mutation in a gene involved in determining the structure of the heart during development.

As Priest explained in an e-mail to me:

Whether it is a CT scan, x-ray, or genetic test, we work hard to make a diagnosis as quickly as possible when there is a critically-ill baby under our care. Whole genome sequencing returned this diagnosis in days instead of weeks. We were able to turn the raw sequence data into a diagnosis in about 12 hours.

Continue Reading »

Cardiovascular Medicine, Genetics, In the News, Research, Science, Stanford News

A simple blood test may unearth the earliest signs of heart transplant rejection

A simple blood test may unearth the earliest signs of heart transplant rejection

2123984831_b7d09079a4_oIs there an organ more precious than a donated heart? Heart transplant recipients would likely say no. But, in order to keep their new heart healthy, they have to identify any signs of rejection as early as possible. Unfortunately (and ironically), the gold standard procedure to detect rejection – repeated heart biopsies – involves snipping away and analyzing tiny bits of tissue from the very organ they waited so long to receive. The procedure is also uncomfortable, and can cause complications.

Now, Stanford bioengineer Stephen Quake, PhD, and his colleagues have found that a simple blood test that detects donor DNA in the bloodstream of the recipient can detect signs of rejection far earlier than biopsy. Their results were published today in Science Translational Medicine.

From our release:

The study of 65 patients (21 children and 44 adults) extends and confirms the results of a small pilot study completed in 2011 by the Stanford researchers. Whereas the earlier study used stored blood samples and medical histories from seven people, the new study followed patients in real time before and after transplant. The researchers directly compared the results of simultaneously collected biopsies and blood samples, and tracked how the values changed during the rejection process.

The blood test takes advantage of the fact that dying heart cells release genetic material into the recipient’s blood. Any increase beyond a normal baseline level indicates a possible attack by the immune system on the donated organ. As described in our release:

In the pilot study of 2011, the researchers first used the presence of the Y chromosome to track the donor DNA when a woman received a heart from a male donor. Then they hit upon using differences in SNPs instead; this method doesn’t require a gender mismatch between donor and recipient. They found that, in transplant recipients not experiencing rejection, the donor DNA accounted for less than 1 percent of all cell-free DNA in the recipient’s blood. During rejection episodes, however, the percentage of donor DNA increased to about 3 or 4 percent.

In the new study, the researchers monitored 565 samples from the 65 patients to assess the assay under real-time clinical conditions. They found they were able to accurately detect the two main types of rejection (antibody-mediated rejection and acute cellular rejection) in 24 patients who suffered moderate to severe rejection episodes, one of whom required a second transplant. They were also able to detect signs of rejection up to five months before the biopsies indicated anything troubling.

The test will still need to be optimized for regular clinical use. However, cardiologist Kiran Khush, MD, a co-senior author of the study, explained what the advance could mean to heart transplant recipients:

This test has the potential to revolutionize the care of our patients… It may also allow us to conduct several diagnostic tests simultaneously. For example, we could also look for microbial sequences in the blood sample to rule out infection or other complications sometimes experienced by transplant recipients. It could allow us to determine whether shortness of breath experienced by a patient is due to an infection or the start of a rejection episode. It could be a one-stop shop for multiple potential problems.

Full disclosure: Stanford has applied for a patent relating to the test described in this study. Quake is a consultant for and holds equity in CareDX Inc., a molecular diagnostics company that has licensed a patent from Stanford related to a method used in the study and is developing it for clinical use.

Previously: ‘Genome transplant’ concept helps Stanford scientists predict organ rejection, Stanford study in transplant patients could lead to better treatment and New techniques to diagnose disease in a fetus
Photo by Desi

Research, Science, Stanford News, Stem Cells

A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells

A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells

Ford assembly lineIn the early 1900s, Henry Ford was lauded for his use of the assembly line, which allowed the rapid, reliable and uniform production of over 15 million Model T automobiles. By codifying each step of production and using identical, interchangeable parts, he brought car ownership within reach of the average American and changed the face of our country.

Now Stanford cardiologist Joseph Wu, MD, PhD, and instructor Paul Burridge, PhD, have done something similar with stem cells. They’ve devised a way to create large numbers of heart muscle cells called cardiomyocytes from stem cells without using human or animal-derived products, which can vary in composition and concentration among batches. Their technique was published Sunday in Nature Methods. Wu, who is the director of the Stanford Cardiovascular Institute explained to me in an e-mail:

This technique solves an important hurdle for the use of iPS-derived heart cells. In order to fully realize the potential of these cells in drug screening and cell therapy, it’s necessary to be able to reliably generate large numbers at low cost. Due to their chemically defined nature, this system is highly reproducible, massively scalable and substantially reduces costs to allow the production of billions of cardiomyocytes matching a specific patient’s heart phenotype.

Chemically defined cell culture means that scientists know exactly what (and how much) is in the liquid in which the cells are grown. In contrast, many common cell culture methods involve the use of nutrient-rich broth derived from animal or human sources. These liquids are teaming with proteins, some known and some unknown, that can promote stem cell growth. They get the job done, but their components can vary among batches and the outcome isn’t always reproducible.

In the new method, Wu and his colleagues collected cells from the skin or blood of an individual. They used a virus called the Sendai virus encoding four reprogramming genes to create induced pluripotent stem cells. These cells were then grown in a liquid in which everything needed for growth was precisely defined. As Wu explained, “This approach gives us an opportunity to fully understand the molecular and macromolecular requirements for cardiac differentiation and eliminates any animal-derived components that were previously used.”

The researchers found they were able to produce about 100 cardiomyocytes for every one stem cell by following a systematic series of steps and using a growing medium that contained just three well-defined components. They showed the technique worked on 11 different batches of induced pluripotent stem cells. The cardiomyocytes were more than 95 percent pure, making it easier to get large numbers of cells to study disease processes or to test the effects of compounds during drug development. According to Wu:

We can use this approach to assess the effect of a particular medication on a specific patient’s heart cells, to discover new drugs, to better understand the process of heart development and to generate cardiomyocytes for use in regenerative medicine approaches, such as for injection into the heart to aid recovery after a heart attack. The system also serves as a platform to study cardiomyocyte subtype specification and maturation.

Of course, stem cells are nothing like automobiles, and regular people aren’t lining up clamoring for a fresh vial of heart muscle cells. But it’s possible that the ability to reliably generate large numbers of cardiomyocytes for study and therapy could be as transformative to cardiac medicine as the Model T was to our grandparents and great grandparents.

Previously: Oh grow up! “Specialized” stem cells tolerated by the immune system, say Stanford researchers, Stem cell medicine for hearts? Yes, please, says one amazing family and “Clinical trial in a dish” may make common medicines safer, say Stanford scientists
Photo by Kyle Harris

Evolution, Genetics, Global Health, Public Health, Research, Stanford News

Melting pot or mosaic? International collaboration studies genomic diversity in Mexico

Melting pot or mosaic? International collaboration studies genomic diversity in Mexico

6626429111_df791cbb8d_zMexico is a vast country with a storied past. Indigenous Native American groups across the country maintain their own languages and culture, while its cosmopolitan residents of large cities are as globally connected as anywhere on Earth. But Mexicans and Mexican Americans are usually lumped together as “Latinos” for the purposes of genetic or medical studies.

Now an international collaboration headed by Stanford geneticist Carlos Bustamante, PhD, and the University of California, San Francisco pulmonologist and public-health expert Esteban Burchard, MD, MPH, has assessed the breadth and depth of genomic diversity in Mexico for the first time. Their work was published today in Science. As I explain in our release:

The researchers compared variation in more than 1 million single nucleotide polymorphisms, or SNPs, among 511 people representing 20 indigenous populations from all over Mexico. They compared these findings with SNP variation among 500 people of mixed Mexican, European and African descent (a category called mestizos) from 10 Mexican states, a region of Guadalajara and Los Angeles, as well as with SNP variation among individuals from 16 European populations and the Yoruba people of West Africa.

The researchers found that Mexico’s indigenous populations diverge genetically along a diagonal northwest-to-southeast axis, with differences becoming more pronounced as the ethnic groups become more geographically distant from one another. In particular, the Seri people along the northern mainland coast of the Gulf of California and a Mayan people known as the Lacandon found near the country’s southern border with Guatemala are as genetically different from one another as Europeans are from Chinese.

Surprisingly, this pattern of diversity is mirrored in the genomes of Mexican individuals with mixed heritage (usually a combination of European, Native American and African):

Consistent with the history of the Spanish occupation and colonization of Mexico, the researchers found that the European portion of the mixed-individuals’ genomes broadly corresponded to that of modern-day inhabitants of the Iberian Peninsula. The Native American portion of their genomes, however, was more likely to correspond to that of local indigenous people. A person in the Mexican state of Sonora, for example, was likely to have ancestors from indigenous groups in the northern part of the country, whereas someone from Yucatan was more likely to have a southern native component in their genome, namely Mayan.

“We were really fascinated by these results because we had expected that 500 years of population movements, immigration and mixing would have swamped the signal of pre-Columbian population structure,” said Bustamante

Finally, the researchers found that the origin of the Native America portion of an individual’s genome affected a clinical measure of lung function abbreviated FEV1:

The researchers drew on data that calculated the predicted normal FEV1 for each subject based on age, gender, height and ethnicity (in this case, the reference was a standard used for all people of Mexican descent). To understand implications of these results within Mexico, they modeled the predicted lung function across Mexico, accounting for differences in local Native American ancestry for a large cohort of mestizos from eight states. The model predicts a marked difference across the country, with the average predicted FEV1 for a person from the northern state of Sonora and another from the state of Yucatan differing by about 7.3 percent. (That is, the population from Sonora has predicted values that were slightly higher than the average for the country, and those from the Yucatan were slightly lower.)

“There’s a definite predicted difference that’s due only to an individual’s Native American ancestry,” said Gignoux. “Variations in genetic composition clearly give a different physiological response.”

The researchers emphasize that a lower FEV1 does not necessarily mean a particular ethnic group has impaired lung function. Disease analysis takes place in the context of standardized values of matched populations, and the study points out how it is necessary to match people correctly to their ethnic backgrounds before making clinical decisions.

Stanford’s Andres Moreno Estrada, MD, PhD, and Christopher Gignoux, PhD, share first authorship of the study with Juan Carlos Fernandez Lopez, a researcher at Mexico’s National Institute of Genomic Medicine.

Previously: Roots of disease may vary with ancestry, according to Stanford geneticist, Recent shared ancestry between southern Europe and North Africa identified by Stanford researchers, and Caribbean genetic diversity explored by Stanford/University of Miami researchers
Photo by DL

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