The first people to arrive in America traveled as at least two separate groups to arrive in their new home at about the same time, according to new genetic evidence published online on January 8th in Current Biology, a Cell Press publication.

After the Last Glacial Maximum some 15,000 to 17,000 years ago, one group entered North America from Beringia following the ice-free Pacific coastline, while another traversed an open land corridor between two ice sheets to arrive directly into the region east of the Rocky Mountains.  (Beringia is the landmass that connected northeast Siberia to Alaska during the last ice age.)  Those first Americans later gave rise to almost all modern Native American groups of North, Central, and South America, with the important exceptions of the Na-Dene and the Eskimos-Aleuts of northern North America, the researchers said.

” Recent data based on archeological evidence and environmental records suggest that humans entered the Americas from Beringia as early as 15,000 years ago, and the dispersal occurred along the deglaciated Pacific coastline,” said Antonio Torroni of Università di Pavia, Italy.  “Our study now reveals a novel alternative scenario: Two almost concomitant paths of migration, both from Beringia about 15,000 to 17,000 years ago, led to the dispersal of Paleo-Indians—the first Americans.”

Such a dual origin for Paleo-Indians has major implications for all disciplines involved in Native American studies, he said.  For instance, it implies that there is no compelling reason to presume that a single language family was carried along with the first migrants.

When Columbus reached the Americas in 1492, Native American occupation stretched from the Bering Strait to Tierra del Fuego, Torroni explained.  Those native populations encompassed extraordinary linguistic and cultural diversity, which has fueled extensive debate among experts over their interrelationships and origins.

Recently, molecular genetics, together with archaeology and linguistics, has begun to provide some insights.  In the new study, Ugo Perego and Alessandro Achilli of Torroni’s team analyzed mitochondrial DNA from two rare haplogroups, meaning mitochondrial types that share a common maternal ancestor.  Mitochondria are cellular components with their own DNA that allow scientists to trace ancestry and migration because they are passed on directly from mother to child over generations.

Their results show that the haplogroup called D4h3 spread from Beringia into the Americas along the Pacific coastal route, rapidly reaching Tierra del Fuego.  The other haplogroup, X2a, spread at about the same time through the ice-free corridor between the Laurentide and Cordilleran Ice Sheets and remained restricted to North America.

” A dual origin for the first Americans is a striking novelty from the genetic point of view and makes plausible a scenario positing that within a rather short period of time, there may have been several entries into the Americas from a dynamically changing Beringian source,” the researchers concluded.

A new study reveals that the metadherin gene (MTDH) plays a role in both cancer metastasis and resistance to chemotherapy.  The research, published by Cell Press in the January 6th issue of the journal Cancer Cell, identifies MTDH as a promising therapeutic target for high risk breast cancers.

“Most breast cancer patients resist currently available therapeutic regimens and succumb to recurrent tumors that spread to distant vital organs, such as lung, bone, liver and brain,” explains senior study author, Dr. Yibin Kang from the Department of Molecular Biology at Princeton University.  “Resistance to chemotherapy and metastasis remain major challenges to curative therapy.”

Previous research identified several clinically applicable genetic signatures associated with poor clinical outcomes of breast cancer.  However, the signatures differed between independent studies, making it difficult to identify overlapping, functionally relevant genes that might be useful for understanding, and eventually preventing, breast cancer metastasis and chemoresistance.

To further unravel the complex genetic events involved in breast cancer, Dr. Kang and colleagues developed a sophisticated computational algorithm designed to identify genomic changes in an extensive collection of breast tumor samples.  The researchers discovered abnormally high copy numbers of chromosomal region 8q22 in more than 30% of breast cancers examined.  Patients having this type of breast cancer often had a shorter survival time due to recurrent and metastatic cancers.

The researchers went on to find that among a handful of genes in the 8q22 region, MTDH was responsible for both increased metastasis and increased resistance to chemotherapeutics.  MTDH protein increased metastasis of breast cancers to distant organs by enhancing the binding of cancer cells to blood vessels in these organs.  In addition, MTDH protein promoted cell survival, allowing cancer cells to become more resistant to a wide variety of chemotherapeutic agents that are currently used to treat breast cancer.  Further, when the researchers genetically altered the cancer cells to reduce expression of MTDH, the tumor cells became less capable of metastasis and more likely to be eliminated by chemotherapeutic agents.

“These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk,” concludes Dr. Kang.  “Molecular targeting of MTDH may not only prevent the seeding of breast cancer cells to the lung and other vital organs but also sensitize tumor cells to chemotherapy, thereby stopping the deadly spread of breast cancer.”

An international team led by University of Pittsburgh School of Medicine researchers has identified genetic markers associated with risk for ulcerative colitis.  The findings, which appear today as an advance online publication of the journal Nature Genetics, bring researchers closer to understanding the biological pathways involved in the disease and may lead to the development of new treatments that specifically target them.

Ulcerative colitis is a chronic, relapsing disorder that causes inflammation and ulceration in the inner lining of the rectum and large intestine.  The most common symptoms are diarrhea (oftentimes bloody) and abdominal pain.  Ulcerative colitis and Crohn’s disease, another chronic gastrointestinal inflammatory disorder, are the two major forms of inflammatory bowel disease (IBD).

“Ulcerative colitis and Crohn’s disease are chronic conditions that impact the day-to-day lives of patients,” said senior author of the study Richard H. Duerr, M.D., associate professor of medicine and human genetics at the University of Pittsburgh School of Medicine and Graduate School of Public Health.  “IBD is most often diagnosed in the teenage years or early adulthood.  While patients usually don’t die from IBD, affected individuals live with its debilitating symptoms during the most productive years of their lives.”

Because IBD tends to run in families, researchers have long thought that genetic factors play a role.  Technology developed in recent years has enabled systematic, genome-wide searches for gene markers associated with common human diseases, and the discovery of more than 30 genetic risk factors for Crohn’s disease has been one of the major success stories in this new era of research.  While some genetic factors associated with Crohn’s disease also predispose individuals to ulcerative colitis, markers specific for ulcerative colitis had yet to be found.  To do so, researchers performed a genome-wide association study of hundreds of thousands of genetic markers using DNA samples from 1,052 individuals with ulcerative colitis and pre-exisiting data from 2,571 controls, all of European ancestry and residing in North America.  Several genetic markers on chromosomes 1p36 and 12q15 showed highly significant associations with ulcerative colitis, and the association evidence was replicated in independent European ancestry samples from North America and southern Italy.  Nearby genes implicated as possibly playing a role in ulcerative colitis include the ring finger protein 186 (RNF186), OTU domain containing 3 (OTUD3), and phospholipase A2, group IIE (PLA2G2E) – genes on chromosome 1p36, and the interferon, gamma (IFNG), interleukin 26 (IL26), and interleukin 22 (IL22) genes on chromosome 12q15.  RNF186 and OTUD3 are members of gene families involved in protein turnover and diverse cellular processes.  PLA2G2E, IFNG, IL26 and IL22 are known to play a role in inflammation and the immune response.  The study also found highly suggestive associations between ulcerative colitis and genetic markers on chromosome 7q31 within or near the laminin, beta 1 (LAMB1) gene, which is a member of a gene family known to play a role in intestinal health and disease, and confirmed previously identified associations between ulcerative colitis and genetic variants in the interleukin 23 receptor (IL23R) gene on chromosome 1p31 and the major histocompatibility complex on chromosome 6p21.

“My laboratory is focused on studying the genetic basis for IBD,” said Dr. Duerr.  “Through genetic mapping, we and our collaborators are successfully identifying regions of the genome that contain IBD genes.  The next steps are to understand the functional significance of IBD-associated genetic variants, and then to develop new treatments that specifically target biological pathways implicated by the genetic discoveries.  The overall goal of this work is to improve the lives of the millions of patients worldwide that suffer from IBD.”

RE1-silencing transcription factor (REST) inhibits expression of neuronal genes in non-neural cells.  Huntingtin sequesters REST in the cytoplasm of neurons, precluding transcriptional repression and allowing neuronal specification.  Mutations in huntingtin disrupt its interactions with REST, enabling repression of neuronal genes and contributing to Huntington’s disease (HD).  Among the genes inhibited by REST are several miRNAs — small, noncoding RNAs that inhibit translation by binding to complementary sequences in regulatory regions of mRNA.  Packer et al.  Found that the levels of several miRNAs decreased as HD progressed.  Of these, miR-9 and miR-9* had upstream regulatory regions that enabled repression by REST.  Interestingly, regulatory regions of REST and its cofactor CoREST have complementary sequences targeted by miR-9 and miR-9*, and miR-9 reduced expression of REST, while miR-9* targeted CoREST.  These molecules apparently form a double negative feedback loop, which is likely important for precise regulation of cell fate commitment.

Researchers at the University of Maryland School of Medicine have identified a common gene variant that appears to influence people’s risk of developing high blood pressure, according to the results of a study being published online Dec. 29, 2008 in the Proceedings of the National Academy of Sciences (PNAS).

The STK39 gene is the first hypertension susceptibility gene to be uncovered through a new technique called a genome-wide association study and confirmed by data from several independent studies.  Located on chromosome 2, the gene produces a protein that helps to regulate how the kidneys process salt, which plays a key role in determining blood pressure.

“This discovery has great potential for enhancing our ability to tailor treatments to the individual – what we call personalized medicine – and to more effectively manage patients with hypertension.  We hope that it will lead to new therapies to combat this serious public health problem worldwide,” says the senior author, Yen-Pei Christy Chang, Ph.D., an assistant professor of medicine and of epidemiology and preventive medicine at the University of Maryland School of Medicine.

But, Dr. Chang says, more research is needed.  “Hypertension is a very complex condition, with numerous other genetic, environmental and lifestyle factors involved.  The STK39 gene is only one important piece of the puzzle,” she says.  “We want to determine how people with different variations of this gene respond to diuretics and other medications, or to lifestyle changes, such as reducing the amount of salt in their diet.  This information might help us discover the most effective way to control an individual patient’s blood pressure.”

One in four Americans has elevated blood pressure, or hypertension, which can lead to death or result in complications, such as cardiovascular disease, stroke and end-stage kidney disease.  Doctors consider the ideal systolic and diastolic blood pressure to be less than 120/80.  (The numbers reflect the pressure of the blood against the arteries when the heart beats and is at rest.)  When blood pressure is elevated, doctors recommend lifestyle changes or prescribe medications, such as diuretics, which force the kidneys to remove water from the body, in order to treat the condition.

However, patients respond differently to treatments and finding the best treatment among all the possible ones for specific patients is still a “try and see” process, according to Dr. Chang.

Scientists believe multiple genes are involved in the most common form of high blood pressure called essential hypertension.  But, because so many factors affect blood pressure, including diet, exercise and stress levels, it has been difficult to pinpoint a specific gene or group of genes, says the lead author, Ying Wang, Ph.D., a researcher at the University of Maryland School of Medicine.

The University of Maryland researchers identified the link between the STK39 gene and blood pressure by analyzing the DNA of 542 members of the Old Order Amish community in Lancaster County, Pa., scanning approximately 100,000 genetic markers across the entire genome for variants known as single nucleotide polymorphisms, or SNPs, associated with systolic and diastolic blood pressure.  The researchers found strong association “signals” with common variants of the serine/threonine kinase gene, or STK39, and confirmed their findings in another group of Amish people and in four other groups of Caucasians in the United States and Europe.

People with one particular variant showed slight increases in blood pressure compared to those with a more common form of the gene and were more likely to develop hypertension, researchers found.  The researchers estimate that about 20 percent of Caucasians in the general population have this variant of the STK39 gene.

“With this new ’scanning’ approach – the genome-wide association study – we are able to uncover genes that have previously eluded us.  The field of complex disease genetics has undergone a revolution in terms of discovering new genes and understanding the genetic basis of common adult-onset diseases,” says co-author Alan R. Shuldiner, M.D., professor of medicine; head of the Division of Endocrinology, Diabetes and Nutrition; and director of the Program in Genetics and Genomic Medicine at the University of Maryland School of Medicine.

The study being published online in PNAS is titled, “Whole-genome association study identifies STK39 as a novel hypertension susceptibility gene.”  It will appear in the print edition of PNAS early next month.

The Amish are ideal for such studies because they are a genetically homogeneous people whose forefathers came to Pennsylvania from Europe in the mid-1700s and share a similar diet and rural lifestyle.  Because many in the Amish community don’t have regular medical check-ups, they often don’t know they have high blood pressure or take medications for it, according to Dr. Chang.  The Amish appear to have as much hypertension as other Caucasians.  As a result of the study, some of the participants learned that they had hypertension and were able to start treatment.

The research, which was funded by the National Institutes of Health, is a spin-off project of another University of Maryland study – the Amish Family Diabetes study – looking for genes that may cause type 2 diabetes.  Researchers at the School of Medicine already have identified a number of genes that may play a role in the development of this type of diabetes.

A new study uses a sophisticated genetic strategy to reveal new roads past an apparent dead end in the historical record of a distinctive civilization that dominated the Mediterranean Sea during the first millennium BC.  The research from National Geographic and IBM’s Genographic Project, published by Cell Press in the November 14th issue of the American Journal of Human Genetics, describes a methodology that may prove to be useful for discovering previously undetected signals left by migrations for any historically documented expansion.

Although extensive documentation by writers and archeologists has provided detailed insight into the origins and early expansion of the Phoenician people, their genetic contributions to the current population are unknown.  “The Phoenicians were the dominant traders in the Mediterranean Sea two to three thousand years ago, and expanded from their homeland in the Levant to establish colonies and trading posts throughout the Mediterranean, but then disappeared from history.  We wished to identify their male genetic traces in modern populations,” explains senior study author Dr. Chris Tyler-Smith from The Wellcome Trust Sanger Institute.

Drs.  Zalloua, Platt, Tyler-Smith and colleagues developed a strategy to identify a genetic pattern associated not with an overall geographical gradient, but with the specific historical expansion of the Phoenician people.  They chose Phoenician-influenced sites based on well-documented historical records and collected new Y chromosomal data from 1330 men in these sites as well as comparative data from the literature.  “We chose the Y chromosome because its male-specificity means that it would have been carried by the predominantly male Phoenician traders, and is high level of geographical differentiation provides the best chance of recognizing colonization events,” offers Dr. Tyler-Smith.  The researchers developed an analytical strategy to distinguish between lineages linked with Phoenicians and those associated with geographically similar but historically distinct events.

This technique allowed them to identify weak but systematic genetic signatures shared by the Phoenician sites that could not be explained by chance or by other expansions.  Specifically, the Phoenician signature contributed at least 6% to the modern Phoenician-influenced populations that were examined.  “Our work underscores the effectiveness of Y-chromosomal variability when combined with appropriate computational analysis for studying complex patterns of human migration, and the utility of wide geographical sampling using a uniform marker set.  This method is applicable to any type of genetic information from which descent could be inferred,” concludes Dr. Tyler-Smith.

Researchers have revealed the complete mitochondrial genome of one of the world’s most celebrated mummies, known as the Tyrolean Iceman or Ötzi.  The sequence represents the oldest complete DNA sequence of modern humans’ mitochondria, according to the report published online on October 30th in Current Biology, a Cell Press publication.

Mitochondria are subcellular organelles that generate all of the body’s energy and house their own DNA, which is passed down from mother to child each generation.  Mitochondrial DNA thus offers a window into our evolutionary past.

“Through the analysis of a complete mitochondrial genome in a particularly well-preserved human, we have obtained evidence of a significant genetic difference between present-day Europeans and a representative prehistoric human—despite the fact that the Iceman is not so old—just about 5,000 years,” said Franco Rollo of the University of Camerino in Italy.

The Tyrolean Iceman witnessed the Neolithic-Copper Age transition in Central Europe more than 5,000 years ago.  His mummified corpse was recovered from an Alpine glacier on the Austro-Italian border in 1991.  In 2000, scientists defrosted the Iceman’s body for the first time and sampled DNA from his intestines.

Earlier study of the DNA showed that he belonged to the lineage, or “subhaplogroup,” known as K1.  About 8% of modern Europeans belong to the K haplogroup, meaning that they share a common ancestor, and that group is divided into two “subhaplogroups,” K1 and K2.  The K1 haplogroup, in turn, can be divided into three clusters.

In the new study, the researchers took advantage of advanced genome-sequencing technologies to shed more light on the Iceman’s genetics.  They sequenced his entire mitochondrial genome and compared that sequence to other published human mitochondrial DNA sequences to construct his evolutionary (or phylogenetic) family tree.

“The surprise came when we found that the lineage of the Iceman did not fit any of the three known K1 clusters,” Rollo said.  His team has informally named the newly discovered branch on the human family tree “Ötzi’s branch.”

“This doesn’t simply mean that Ötzi had some ‘personal’ mutations making him different from the others but that, in the past, there was a group—a branch of the phylogenetic tree—of men and women sharing the same mitochondrial DNA,” Rollo said.  “Apparently, this genetic group is no longer present.  We don’t know whether it is extinct or it has become extremely rare.”

At least for the moment, he said, that means no one can claim to be “the issue of Ötzi.”

Researchers at Georgetown University Medical Center (GUMC) have successfully tested a genetic strategy designed to improve treatment of human infections caused by the yeast Candida albicans, ranging from diaper rash, vaginitis, oral infections (or thrush which is common in HIV/AIDS patients), as well as invasive, blood-borne and life-threatening diseases.Their findings confirm that inhibiting a key protein could provide a new drug target against the yeast, which inhabits the mucous membranes of most humans. The research was presented today at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America (ICAAC/IDSA) in Washington, DC.

“This is a genetically intelligent approach to target identification and drug design,” says the study’s lead author, Richard Calderone, PhD, professor and chair of the department of microbiology and immunology and co-director of the PhD program in the global infectious disease program at GUMC.

“Candida infections are often treatable, however, in patients that are immunocompromised following cancer chemotherapy, bone marrow transplantation, or surgery, diagnosis is often delayed, postponing therapy,” he says. “Also when drug-resistant yeast pathogens cause the infection, clinical management of the patient becomes a problem.”

Candida invasive, blood-borne infections are the fourth most common hospital-acquired infection in the United States, costing the healthcare system about $1.8 billion each year, Calderone says.

“More drug resistance is being seen clinically, so there is significant room for improvement in the therapies used today,” he says

This study continues research in which Calderone and his colleagues identified a protein, the product of the Ssk1 gene that Candida needs to infect its host. To date, this protein has not been found in humans or in animals, which means it could be “targeted” with a novel drug without producing toxicity because such an agent should only attack the fungus.

The researchers found that if the Ssk1 gene is deleted from Candida albicans, the “triazole” drugs that are now used to treat these diseases are much more effective in the laboratory. “This allows the triazole drugs to do their job,” Calderone says. “We propose that this finding might lead to other, possibly more effective, treatment options.”

In this study, the researchers used a gene microarray analysis to further understand what knocking out the Ssk1 gene does to the organism, and they discovered that the gene is critical to the pathogenic nature of the fungi.

What this means is that an Ssk1 inhibitor might work in synergy with a triazole or perhaps as an effective stand-alone drug to treat Candida infections, the researchers say. If it works in Candida, it may have broader activity in other pathogens because Ssk1p is found in other fungi.

“Using the genome of the organism to find genes to target is a logical approach to drug design,” he says. The researchers are now working with other groups to find the right agent to target the Ssk1protein.

Researchers from Uppsala University have discovered a mechanism that silences several genes in a chromosome domain.  The findings, published in today’s on-line issue of Molecular Cell, have implications in understanding the human disorder Beckwith-Wiedemann syndrome.

In mammals the cells contain two copies of each chromosome, one inherited from the mother and one from the father.  The genes on the chromosomes can either be active or inactive.  If a gene is active on the maternal chromosome, the corresponding gene is usually active also on paternal chromosome.  However, in some domains of the chromosome the activity is shut down on one of the chromosomes but not on the other.  The genes in these domains cannot be activated the normal way but are completely silenced.  The present study shows for the first time how this silencing of several genes on a chromosome is accomplished.

The research group, led by Chandrasekhar Kanduri, has studied a domain with several silenced genes on chromosome 7 in the mouse.  The corresponding domain with silenced genes is located on the human chromosome 11.  When part of this domain is transcribed a long RNA molecule, Kcnq1ot1-RNA, is formed.  This RNA does not give rise to any protein, instead it mediates the silencing of eight to ten genes in a much larger area on the chromosome.  Based on their findings the researchers have suggested a model for how this is accomplished.  The Kcnq1ot1-RNA binds to the DNA in the domain and recruits specific enzymes that chemically modify DNA-binding proteins.  This modification makes the DNA inaccessible for transcription and thereby the genes cannot be activated.  In addition, the Kcnq1ot1-RNA targets the silenced domain to a specific area in the cell nucleus.  There it is protected during cell division and the genes will stay silenced also in the daughter cells.

– We show for the first time how a long RNA molecule can establish and maintain silencing of multiple genes in a large domain on the chromosome, says Chandrasekhar Kanduri.  The popular belief is that it is only a gene located in the same area as where the long RNA molecule is transcribed from that can be silenced.

This mechanism is important for understanding the genetic disorder Beckwith-Wiedemann Syndrome.  In this condition silencing of the chromosome 11 domain does not function properly and both copies of the genes in the domain become inactive, instead of just one.  Less protein is produced from the genes, leading to the excess growth characteristics associated with the syndrome: enlargement of organs in the foetus and an increased risk for tumours in the affected organs.

The study, led by researcher Päivi Lahermo from Institute for Molecular Medicine Finland (FIMM) and University of Helsinki, Finland, and professor Juha Kere from Karolinska Institutet, Sweden, will be published in PloS ONE journal October 24th, 2008.

— The understanding of genetic variation in human populations is important not only for obtaining information on population history, but also for successful studies of genetic factors behind human diseases, says Juha Kere.

Human population genetic studies have recently gained a new powerful tool from the analysis of densely spaced single nucleotide polymorphisms (SNPs) across the whole genome.  In this study, almost 250 000 such polymorphisms were used to analyze genetic differences between the Germans, British, Eastern and Western Finns, and Swedes, based on ca.  1000 samples.

The Germans and British are genetically close to each other, which has been observed also in other recently published studies.  In contrast, the genetic distances between the Swedes and Eastern and Western Finns are larger, and the diversity in these populations is lower.

The genetic difference between Eastern and Western Finland is substantial in a European scale, and there are also clear differences between Finnish counties.

— The larger genetic distances in the north are caused by differences in population history: the northernmost parts of Europe were inhabited later than Central Europe and by fewer people, and have had smaller populations since then, says Päivi Lahermo.

Clubfoot, one of the most common birth defects, has long been thought to have a genetic component.  Now, researchers at Washington University School of Medicine in St. Louis report they have found the first gene linked to clubfoot in humans.

Their research will be published in the Nov. 7 issue of the American Journal of Human Genetics.

By studying a multi-generation family with clubfoot, the scientists traced the condition to a mutation in a gene critical for early development of lower limbs called PITX1.  While other genes are also likely to be linked to clubfoot, the new finding is a first step toward improved genetic counseling and the development of novel therapies.

“To our knowledge this report is the first evidence for PITX1 mutation in human disease,” said Christina Gurnett, M.D., Ph.D., assistant professor of neurology, of pediatrics and of orthopedic surgery at the School of Medicine.  “Once we identified the mutation, we proved that all of the individuals in this family with lower extremity malformations also have the mutation.  Having large families to work with is very helpful in genetic research.”

Gurnett and her colleagues analyzed the DNA of 35 extended family members of an infant male patient of Matthew Dobbs, M.D., associate professor of orthopedic surgery at the School of Medicine and a clubfoot specialist at St. Louis Children’s Hospital and St. Louis Shriners Hospital.  The patient, the most severely affected in the family, had clubfoot in both feet, duplicated first toes and was missing the tibia in the right leg.

Gurnett and Dobbs visited the family members in their community to examine their lower limbs and to take DNA samples.  They found that 13 family members were affected: Five additional family members had clubfoot, which was more severe in the right foot in three of them.  Five others had lower limb abnormalities including flatfoot, an underdeveloped patella and hip dysplasia.

Through the genome-wide study, Gurnett and her colleagues found a region on chromosome 5 that was common to all family members affected.  From there, they identified a mutation in a gene critical for early development of lower limbs called PITX1.  The PITX1 mutation was found in all affected family members and in three carriers who showed no clinical symptoms.

Dobbs, senior author of the study, said the finding is an exciting step in developing a better understanding of the genetic basis of clubfoot, which affects about 1 in 1,000 new births.

“Clubfoot is a complex disorder meaning that more than one gene as well as environmental factors will be discovered to play a role in its etiology,” Dobbs said.  “Identifying the genes for clubfoot will allow for improved genetic counseling and may potentially lead to new and improved treatment and preventive strategies for this disorder.”

Dobbs treats children with clubfoot and other orthopedic abnormalities using the Ponseti method, a treatment that involves weekly casting and the manipulation of clubfoot soon after birth.  In 2007, Dobbs developed a new dynamic brace called the Dobbs brace for clubfoot that allows active movement, preservation of muscle strength in the foot and ankle and fewer restrictions on the child than the traditional brace.

About 80 percent of clubfoot cases are idiopathic, meaning the cause is unknown and the patient has no other birth defects.  A familial link plays a role in about 25 percent of cases.  The condition occurs in males twice as often as in females and occurs more often in the right foot.  About half of the cases affect both feet, including the bones, muscles, tendons and blood vessels.  If untreated, those affected walk on the outside of their feet, which can lead to long-term pain and disability.

Gurnett said some clinical characteristics of the family members with the PITX1 mutation suggest that the genetic defect may be linked to idiopathic clubfoot.  First, the majority of the affected family members had clubfoot, but no other abnormalities.  Second, there were five females who carried the gene but did not have clubfoot, which supports the lower incidence of clubfoot in females.  Third, clubfoot affects the right foot more frequently, a hallmark of mutations in PITX1.

Previous studies had shown a relation between PITX1 and the development of hindlimbs in other vertebrates.  In mice, a loss of PITX1 leads to shorter femur length and fewer digits on the right foot than on the left.  An alteration of the gene in a developing chick wing changes it so that it looks more like a leg.  In vertebrates such as the manatee and stickleback fish, an alteration has resulted in evolutionary changes in the development of the pelvis.

“It’s our job to prove that this is going to be important for many kids with clubfoot,” Gurnett said.  “Until now, we didn’t know whether clubfoot was a muscle, nerve, spinal cord or brain problem.  Now, we have an idea that clubfoot may result from mutations of genes that are involved in early limb development.”

Gurnett said she and her colleagues will take the finding back to the lab to look for other factors involved in the pathway or how environmental effects may influence the gene.  She and Dobbs, who have been studying the genetics of clubfoot for a decade, plan to investigate the frequency of PITX1 gene mutations in other families with clubfoot.

Researchers have put forward a simple model of development and gene regulation that is capable of explaining patterns observed in the distribution of morphologies and body plans (or, more generally, phenotypes). The study, by Elhanan Borenstein of the Santa Fe Institute and Stanford University and David Krakauer of the Santa Fe Institute was published in this month’s issue of PLoS Computational Biology.

Nature truly displays a bewildering variety of shapes and forms. Yet, with all its magnificence, this diversity still represents only a tiny fraction of the endless ’space’ of possibilities, and observed phenotypes actually occupy only small, dense patches in the abstract phenotypic space. Borenstein and Krakauer demonstrate that the sparseness of variety in nature can be attributed to the interactions between multiple genes and genetic controls involved in the development of organisms – a much simpler explanation than previously suggested.

Borenstein and Krakauer further integrated their model with phylogenetic dynamics, allowing developmental plans to evolve over time. They showed that this hybrid developmental-phylogenetic model reproduces patterns that are observed in the fossil record, including increasing variation between taxonomic groups, accompanied by decreasing variation within groups. This pattern is consistent with the Cambrian radiation associated with a rapid proliferation of highly disparate, multicellular animals, and suggests that much of the variation seen today is as a result of simpler genetic controls dating from much earlier in evolutionary time.

The findings presented in this study also bear directly on issues of convergence (when very different organisms independently evolve similar features). By including a model of development, rather different genotypes can produce very similar phenotypes. Consequently, convergent evolution, which the vast space of genotypes would suggest to be rare, is allowed to become much more common.

One of the paradoxical implications of this study has been to show how innovations in development that lead to an overall increase in the number of accessible phenotypes, can lead to a reduction in selective variance. In other words, while the potential for novel phenotypes increases, the fraction of space these phenotypes occupies tends to contract. They concluded that “The theory presented in our paper complements the view of development as a key component in the production of endless forms and highlights the crucial role of development in constraining (as well as generating) biotic diversity.”

Scientific research shows that certain genes can influence a person’s likelihood to contract particular diseases, cancer for example. New research at the Masonic Cancer Center, University of Minnesota demonstrates that genetic markers may also show a person’s likelihood to survive the disease.

A research study led by Brian Van Ness, Ph.D., has successfully identified combinations of genes associated with early clinical relapse of multiple myeloma, a cancer of the white blood cells that produce antibodies. These results raise the possibility that a patient’s genetic background exerts an important influence on the patient’s prognosis and response to treatment.

“Ultimately, the goal of this research is to predict drug efficacy and toxicity based on a patient’s genetic profile, and develop individualized assessments and predictions for the right drug, at the right dose, for the right patient,” Van Ness said. This approach offers the dual benefits of avoiding unnecessary treatment for patients less likely to respond to a particular drug, and targeting treatments to those who will benefit most.

The findings are reported in the current issue of the research journal BMC Medicine. Van Ness heads the University’s Department of Genetics, Cell Biology, and Development, and conducts research through the Masonic Cancer Center.

In this study, Van Ness and his colleagues used genetic information that the International Myeloma Foundation has gathered from myeloma patients worldwide through its program, Bank On A Cure®. This first-of-its-kind program involves several of the major treatment and research centers for myeloma worldwide and thousands of myeloma patients who donate DNA samples to the bank. The University of Minnesota houses one of the program’s two DNA banks (the other is in London), and Van Ness is co-director of the program.

“Although myeloma is considered a fatal disease, individual patients have widely varied rates of disease progression and response to treatment because of attributes encoded in their DNA,” Van Ness said.

According to Van Ness, the research study findings demonstrate that cancer outcomes differ because patients vary in the ways they absorb, distribute, metabolize, and transport drugs across cell membranes. Individual variations in genes that regulate these biologic processes may not only affect the effectiveness of the drug, but also can result in adverse side effects.

The findings from this study pave the way for similar investigations into other cancers, neurological and cardiovascular conditions, organ transplants, and other diseases.

In research aimed at addressing a global epidemic, a team of scientists from around the world has cracked the genetic code for the parasite that is responsible for up to 40 percent of the 515 million annual malaria infections worldwide, Nature reveals in its October 9 cover story.

Led by a parasitologist from NYU Langone Medical Center, Jane Carlton, PhD, some 40 researchers sequenced the genome of Plasmodium vivax (P.  Vivax), one of four malaria parasites that routinely affect humans.  P. vivax, which is increasingly resistant to some antimalarial drugs, is the species most common outside Africa, particularly in Asia and the Americas, including the United States, the site of periodic outbreaks.

Vivax malaria, as it is known, is believed more robust and resilient than its cousin, the more deadly malaria species, P. falciparum – and is thus more difficult to eradicate.  Distinctively, vivax malaria can be transmitted by mosquitoes in cooler temperatures.  It also has a dormant stage that enables it to re-emerge as climates warm, causing “relapses” of the disease months and even years after a first attack.

Symptoms for the two strains of malaria are similar – flu-like, featuring fever and abdominal pain, often leading to severe anemia – and, in children, lifelong learning disabilities.  Malaria is a disease of poorer populations, and overall is estimated annually to kill more than a million people worldwide.

Researchers also identified several pathways in the P. vivax parasite that could eventually be targets for drug treatment.  Both P. vivax and P. falciparum vivax are also being studied to identify potential vaccine targets.

The research is regarded as all the more significant in that P. vivax has long remained little-researched, little-known and little-understood.  Such neglect is mainly due to the focus on the more deadly malaria species, P. falciparum -P.  Vivax is seldom lethal -and also because the parasite cannot be grown in a lab setting.  Further, the growing burden of vivax malaria will complicate efforts to control P. falciparum in areas where the two coincide.

Indeed, the project that led to the landmark genetic decoding was in the works for a total of six years, involving researchers from England, Spain, Australia and Brazil as well as the United States.  After two years, remaining funds from the P. falciparum genome project were exhausted, and funding from the Burroughs Wellcome Fund and the National Institutes of Health allowed its completion.

P. vivax is the second species of human malaria parasite to be sequenced.  Researchers found the genome for P. vivax dramatically different from the genomes of three other sequenced malaria parasites – different in content, structure and complexity.  They used whole genome shotgun methods to produce high-quality sequences that will enable malaria researchers worldwide to undertake further research on the parasite.  The next step is to sequence six other P. vivax genomes – from Brazil, Mauritania, India, North Korea and Indonesia -to identify novel vaccine candidates and generate an evolutionary map of the species.

“This project is a tribute to the collegiality and tenacity of the vivax malaria community,” says Jane M. Carlton, associate professor at NYU School of Medicine’s Department of Medical Parasitology, who led a team of investigators from around the world.  “They have persevered despite financial tribulations and lack of interest to generate an invaluable resource.  These findings will be used by all malariologists for years to come to advance scientific investigation into this neglected species.”

“The availability of genome sequence data has great potential to accelerate the identification and development of novel vaccines and therapeutics against this major human pathogen,” says Claire Fraser-Liggett, PhD, director of the Institute of Genomic Sciences at University of Maryland School of Medicine and formerly president of The Institute for Genomic Research, Rockville Maryland where the project began.  “Dr.  Carlton is to be congratulated for her leadership role in bringing this project to completion.”

“Unveiling the full genome sequence of Plasmodium vivax is a tremendous advance – a huge step forward in parasite biology and the fight against malaria,” says Nick White, MD, professor of tropical medicine, Oxford University, England and Mahidol University, Thailand.

What became a scientific quest for Dr. Hugo Bellen and his colleagues at Baylor College of Medicine in Houston began with trying to define the function of a protein that plays a role in the nervous system.

That led to work with similar proteins in the nerve cells of worms, fruit flies, and people and culminated in important clues about what goes wrong in the nerves and muscles of people with amyotrophic lateral sclerosis (better known as ALS or Lou Gehrig’s disease), said Bellen, a professor molecular and human genetics at BCM.

In a report in the current issue of the journal Cell, his team and that of Dr. Michael Miller from the University of Alabama at Birmingham show how a single mutation in the human form of the VAMP-Associated Protein B (VAPB) contributes to the nerve and muscle breakdown in flies and worms, similar to ALS in humans.

The story actually begins around 500 years ago, when a Portuguese immigrant to Brazil brought along an uninvited guest – a mutation in the gene for VAPB. That mutation leads to a rare form of inherited ALS that has so far been identified in about 200 people. ALS is a devastating disease that begins in middle age and affects nerves and muscles, destroying the individual’s ability to move, talk, swallow and breathe, eventually killing the person who has it. There are an estimated 30,000 people with ALS in the United States alone. It affects people of all ethnicities worldwide.

Working in Drosophila or fruit flies, Bellen and his colleagues found that when the fly VAPB gene equivalent called VAP33 is lacking, the nerve endings are abnormal, suggesting that in its normal form, the protein associated with VAP33 is important at the junction between nerve and muscle.

Then Dr. Mayana Zatz, a professor at the University of Sao Paolo, found several large Brazilian families with a gene mutation or defect in VAPB that led to ALS. (There are mutations in other genes that cause ALS as well). At that point, a postdoctoral fellow in the Bellen lab, Dr. Hiroshi Tsuda, took over.

One of the domains of VAPB is similar to a protein in C. elegans called the major sperm protein (MSP). MSP plays a major role in readying the hermaphroditic worm to reproduce. In effect, it acts as a hormone. Tsuda dubbed the part of the VAP33 protein that resembled major sperm protein the MSP domain in its honor.

They then found that somehow the MSP domain of VAPB was being secreted and circulated in the blood throughout the human body.

“The protein is cleaved, secreted and functions as a hormone,” said Bellen.

In collaboration with Miller’s team at UAB, they found that MSP actually binds to ephrin receptors, regulating their role in nerve cells and muscles. (Ephrin receptors affect cell interactions, mediating when cells adhere to or repel one another as well as in clustering specific receptors present on neurons and muscle cells).

The scientists’ work indicates that the mutated form of the human VAPB protein accumulates in the cell’s cytoplasm. As more and more abnormal protein accumulates, both normal and abnormal protein (mutant VAPB) becomes trapped in the cell’s cytoplasm. This prevents it from secreting the MSP domain, which means that the body no longer has its hormonal action. The accumulation also prevents proper protein folding, which can be toxic to neurons.

Bellen and his colleagues found that the mutant form of the protein has two effects. One, it causes the unfolded protein response that ultimately is harmful to the neurons and may affect motor function. Second, it leads to reduced secretion of MSP and a loss of the signaling mediated by ephrin receptors. They believe that these two problems work together to produce some of the key features of ALS.