Genetic Study Confirms that the First Dogs Came from East Asia

Researchers at Sweden's KTH Royal Institute of Technology say they have found further proof that the wolf ancestors of today's domesticated dogs can be traced to southern East Asia 
Wednesday, 23 November 2011

Researchers at Sweden's KTH Royal Institute of Technology say they have found further proof that the wolf ancestors of today's domesticated dogs can be traced to southern East Asia – findings that run counter to theories placing the cradle of the canine line in the Middle East.

Dr Peter Savolainen, KTH researcher in evolutionary genetics, says a new study released Nov. 23 confirms that an Asian region south of the Yangtze River was the principal and probably sole region where wolves were domesticated by humans.

Data on genetics, morphology and behaviour show clearly that dogs are descended from wolves, but there's never been scientific consensus on where in the world the domestication process began.

"Our analysis of Y-chromosomal DNA now confirms that wolves were first domesticated in Asia south of Yangtze River – we call it the ASY region – in southern China or Southeast Asia", Savolainen says.

The Y data supports previous evidence from mitochondrial DNA.

"Taken together, the two studies provide very strong evidence that dogs originated in the ASY region", Savolainen says.

Archaeological data and a genetic study recently published in Nature suggest that dogs originate from the Middle East. But Savolainen rejects that view.

"Because none of these studies included samples from the ASY region, evidence from ASY has been overlooked," he says.

Peter Savolainen and PhD student Mattias Oskarsson worked with Chinese colleagues to analyse DNA from male dogs around the world. Their study was published in the scientific journal Heredity.

Approximately half of the gene pool was universally shared everywhere in the world, while only the ASY region had the entire range of genetic diversity.

"This shows that gene pools in all other regions of the world most probably originate from the ASY region", Savolainen says.

"Our results confirm that Asia south of the Yangtze River was the most important – and probably the only – region for wolf domestication, and that a large number of wolves were domesticated", says Savolainen.

In separate research published recently in Ecology and Evolution, Savolainen, PhD student Arman Ardalan and Iranian and Turkish scientists conducted a comprehensive study of mitochondrial DNA , with a particular focus on the Middle East. Because mitochondrial DNA is inherited only from the mother in most species, it is especially useful in studying evolutionary relationships.

"Since other studies have indicated that wolves were domesticated in the Middle East, we wanted to be sure nothing had been missed. We find no signs whatsoever that dogs originated there", says Savolainen.

In their studies, the researchers also found minor genetic contributions from crossbreeding between dogs and wolves in other geographic regions, including the Middle East.

"This subsequent dog/wolf hybridisation contributed only modestly to the dog gene pool", Savolainen explains.

Source: Swedish Research Council

Contact: Katarina Ahlfort
.........

ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/

---

Dogs Likely Originated in the Middle East

Findings based on analysis of largest set of genetic markers ever studied
Thursday, 18 March 2010

Dogs likely originated in the Middle East, not Asia or Europe, according to a new genetic analysis by an international team of scientists led by UCLA biologists. The research, funded by the National Science Foundation and the Searle Scholars Program, appears March 17 in the advance online edition of the journal Nature.

"Dogs seem to share more genetic similarity with Middle Eastern gray wolves than with any other wolf population worldwide," said Robert Wayne, UCLA professor of ecology and evolutionary biology and senior author of the Nature paper.

"Genome-wide analysis now directly suggests a Middle East origin for modern dogs. We have found that a dominant proportion of modern dogs' ancestry derives from Middle Eastern wolves, and this finding is consistent with the hypothesis that dogs originated in the Middle East.”

---

This evolutionary tree shows dog breeds and gray wolves. Credit: UCLA.

---

"This is the same area where domestic cats and many of our livestock originated and where agriculture first developed," Wayne noted.

Previous genetic research suggested an East Asian origin for dogs, "which was unexpected," Wayne said, "because there was never a hint in the archaeological record that dogs evolved there."

"We were able to study a broader sampling of wolves globally than has ever been done before, including Middle Eastern wolves," said the paper's lead author, Bridgett vonHoldt, a UCLA graduate student of ecology and evolutionary biology in Wayne's laboratory who studies the genetics of dog domestication.

"In our analysis of the entire genome, we found that dogs share more unique markers with Middle Eastern wolves than with East Asian wolves. We used a genome-wide approach, which avoids the bias of single genome region."

The biologists report genetic data from more than 900 dogs from 85 breeds (including all the major ones) and more than 200 wild gray wolves (the ancestor of domestic dogs) worldwide, including populations from North America, Europe, the Middle East and East Asia. They used molecular genetic techniques to analyze more than 48,000 genetic markers. No previous study has ever analyzed anywhere near that many markers.

The biologists have samples from Israel, Saudi Arabia and Iran — but they have not pinpointed a specific location in the Middle East where dogs originated.

"This study is unique in using a particular technology called a single nucleotide polymorphism, or SNP, genotyping chip; these chips interrogate the nucleotides at 48,000 locations in the genome," said John Novembre, UCLA assistant professor of ecology and evolutionary biology and a member of UCLA's Interdepartmental Program in Bioinformatics.

"We are able to compare dogs looking at not just one small part of the genome, but at 48,000 different locations. That gives us the fine-scale resolution to analyze how these breeds are related to one another and how they are related to wolves."

Previous genetic research had suggested an East Asian origin based on the higher diversity of mitochondrial sequences in East Asia and China than anywhere else in the world. (Mitochondria are tiny cellular structures outside the nucleus that produce energy and have their own small genome.) However, that research was based on only one sequence, a small part of the mitochondrial genome, Wayne noted.

"That research made extrapolations about how the domestic dog has evolved from examination of one region in the mitochondrial genome," Wayne said.

"This new Nature paper is a much more comprehensive analysis because we have analyzed 48,000 markers distributed throughout the nuclear genome to try to conclude where the most likely ancestral population is.”

"What we found is much more consistent with the archaeological record," he said.

"We found strong kinship to Middle Eastern gray wolves and, to some extent, European gray wolves — but much less so to any wolves from East Asia. Our findings strongly contradict the conclusions based on earlier mitochondrial DNA sequence data."

Eighty percent of dog breeds are modern breeds that evolved in the last few hundred years, Wayne said. But some dog breeds have ancient histories that go back thousands of years.

"We sampled both groups, the modern explosion of dog breeds and some of the ancient lineages," he said.

"Our data were aimed at resolving questions about the origin of domestic dogs, the evolution of dog breeds, and the history of dog breeds and relationships to their closest wild progenitor, the gray wolf."

The first dogs that appeared in the Middle Eastern archaeological record date back some 12,000 to 13,000 years, Wayne said. Wolves have been in the Old World for hundreds of thousands of years. The oldest dogs from the archaeological record come from Europe and Western Russia. A dog from Belgium dates back 31,000 years, and a group of dogs from Western Russia is approximately 15,000 years old, Wayne said.

"We know that dogs from the Middle East were closely associated with humans because they were found in ancient human burial sites," Wayne said.

"In one case, a puppy is curled up in the arms of a buried human."

Some very old strains of dogs, with a history dating back more than several thousand years, may be mixed with modern breeds, enhancing their diversity in certain areas such as East Asia, Wayne said, interpreting the higher mitochondrial DNA diversity in that area of the globe.

There is one small set of East Asian breeds that does not indicate a strong Middle East origin, showing instead a high level of genetic sharing with Chinese wolves. This finding suggests there was some intermixing between East Asian dog breeds and East Asian wolves; the data do not make clear how long ago this occurred.

"However, the vast majority of dogs that we studied show significant levels of sharing with Middle Eastern wolves," said Novembre, a population geneticist who studies genetic diversity and the lessons that can be learned from it.

Co-authors on the Nature paper include a group of researchers from the National Institutes of Health/National Human Genome Research Institute led by Elaine Ostrander; a group led by Carlos Bustamante, formerly of the Cornell University Department of Biological Statistics and Computational Biology and now a professor of genetics at the Stanford University School of Medicine; and scientists from China, Israel, Australia, Europe and Canada.

UCLA co-authors include Eunjung Han, a UCLA graduate student of Novembre's in biostatistics; John Pollinger, director of UCLA's Conservation Genetics Resource Center and associate director of the Center for Tropical Research at UCLA's Institute of the Environment; and James Knowles, a graduate student from Canada's University of Alberta working in Wayne's laboratory. Wayne and Novembre's research is federally funded by the National Science Foundation. Novembre's research is also funded by the Searle Scholars Program.

"By analyzing a sea of scientific data, Bob Wayne and John Novembre are at the forefront of the 'new life sciences' — which represents new ways to make discovery," said Victoria Sork, dean of the UCLA Division of Life Sciences.

"Their integration of genomic data with bioinformatics approaches illustrates how integration has enhanced our ability to analyze biological systems. Integration of knowledge is changing how we think about how life works. We are no longer limited to studying just one piece of a puzzle."

Toy dogs and an evolutionary framework for dog domestication
The biologists have also found that when one looks at a relationship tree of modern and ancient dog breeds, there is surprising structure to it, and the structure mimics the classifications of dogs by breeders into herding dogs, retrievers, sight hounds, small terriers and others.

"We found there is a surprising genetic structure that accords with functional classifications — suggesting that new breeds are developed from crosses within specific breed groups that share particular traits," Wayne said.

"If they want a new sight hound, they tend to cross sight hounds with each other, and the same with herding dogs and retrieving dogs. That may not seem so surprising, but we had no reason to think beforehand that these groups would be strongly genealogical.”

"There are some notable exceptions, such as 'toy dogs.' In this grouping, there are many different kinds of lineages represented, including traces of herding dogs and retrievers. When it comes to miniaturizing a dog, breeders start with a larger breed and cross that with a miniature dog to make a dwarfed breed on a new genetic background, causing the mixing of various lineages. It is a mix-and-match approach for some of these breed groupings. But in other cases, new breeds have been based on combinations of breeds that have specific traits."

New insights into the evolution of dogs have emerged from this Nature paper and several other recent studies by biologists, including Wayne and his colleagues.

"A framework about dog evolution is emerging," Wayne said.

"Even though dogs have an almost infinite variety of forms, geneticists have been discovering that much of this diversity has a simple genetic basis. Short-legged dogs — there are at least 19 such breeds, including dachshunds, corgis and basset hounds — have short legs due to the appearance of just one unique gene, a mutant growth-factor gene."

Recent research by Wayne and his colleagues has identified genes responsible for short legs, small size, different fur types and different coat patterns and colours.

"It seems that in dogs, unlike other domesticated species, many of these different phenotypes distil to just a handful of genes," Wayne said.

"These genes have been mixed with retrievers, herding dogs and sight hounds to create new breeds."

In humans, by contrast, most differences in height and weight involve many genes, each of which has only a small effect; most of the genes account for only about 1 or 2 percent of variability. Even in agricultural plants, most genes have only a small influence on a single trait.

In dogs, however, one gene that is responsible for differences in size accounts for more than 50 percent of the variation in body size, Wayne said. A small number of genes, he said, have been moved around in dogs to create the appearance of amazing diversity.

"Because we analyzed 48,000 locations in the genome, we can ask which regions are the most different between dogs and wolves," said Novembre, whose research group investigated whether specific regions of the genome have changed under domestication.

"We identified a few regions that are exceptionally different between dogs and wolves; these might be places in the genome where some of the changes occurred that make dogs and wolves different from each other today. These are good candidate regions for follow-up research."

In a separate paper, Melissa Gray, who earned her Ph.D. from UCLA in Wayne's laboratory, reported in February, along with Wayne and colleagues, on an important gene known as IGF1, which is responsible for small size in dogs, and analyzed which wolf populations are closest evolutionarily to this gene. The findings, published in the journal BMC Biology show that the gene appears to have arisen in Middle Eastern wolves, giving further support to the major claim in the new Nature paper.

Reference:
Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication
Bridgett M. vonHoldt, John P. Pollinger, Kirk E. Lohmueller, Eunjung Han, Heidi G. Parker, Pascale Quignon, Jeremiah D. Degenhardt, Adam R. Boyko, Dent A. Earl, Adam Auton, Andy Reynolds, Kasia Bryc, Abra Brisbin, James C. Knowles, Dana S. Mosher, Tyrone C. Spady, Abdel Elkahloun, Eli Geffen, Malgorzata Pilot, Wlodzimierz Jedrzejewski, Claudia Greco, Ettore Randi, Danika Bannasch, Alan Wilton, Jeremy Shearman, Marco Musiani, Michelle Cargill, Paul G. Jones, Zuwei Qian, Wei Huang, Zhao-Li Ding, Ya-ping Zhang, Carlos D. Bustamante, Elaine A. Ostrander, John Novembre & Robert K. Wayne
Nature advance online publication 17 March 2010, doi:10.1038/nature08837
.........


ZenMaster

---

For more on stem cells and cloning,
go to CellNEWS at http://cellnews-blog.blogspot.com/

---

Dogs May Provide an Excellent Model for Understanding Human Complex Diseases

Dogs May Provide an Excellent Model for Understanding Human Complex Diseases Monday, 01 February 2010 In a new Swedish-Finnish study, published in Nature Genetics, researchers at Uppsala University and the Swedish University of Agricultural Sciences (SLU), in collaboration with scientists at University of Helsinki, Finland and USA, identified five loci that predispose to an SLE-related disease in Nova Scotia duck tolling retrievers. The study indicates that the homogeneity of strong genetic risk factors within dog breeds make dogs an excellent model in which to identify pathways involved in human complex diseases. The results of the study also open the door for further studies of specific T-cell activation pathways in human populations. To find genes for human common diseases, thousands of blood samples are needed from both patients and healthy controls. The structure provided by dog breeding, and the refinement of various properties within the breeds, make it much easier to find pathogenic genes with a smaller number of samples. The unique canine breed structure makes dogs an excellent model for studying genetic diseases. Incidences of specific diseases are elevated in different breeds, indicating that a few genetic risk factors might have accumulated through drift or selective breeding. In the new Swedish-Finnish study with 81 affected dogs and 57 controls from the Nova Scotia duck tolling retriever breed the researchers identified five loci associated with a canine systemic lupus erythematosus (SLE) -related disease complex. Fine mapping with twice as many dogs validated these loci. "It's extremely interesting and feels fantastic that we can so readily find genes even for complex diseases in dogs. The study also provides entirely new avenues for studying SLE in humans," says Professor Kerstin Lindblad-Toh, who directed the study. "Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases," says Professor Hannes Lohi, University of Helsinki and Folkhälsan Research Center, Finland. Nova Scotia duck tolling retrievers (NSDTRs) are strongly predisposed to many immune-mediated diseases, including a systemic lupus erythematosus (SLE) -related disease complex comprising an immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arthritis (SRMA). The NSDTR breed was developed in the Yarmouth region of Nova Scotia in the early 1800s as a hunting and retrieving dog. The breed descended from a very small population of dogs that survived two devastating outbreaks of canine distemper virus in 1908 and 1912. One hypothesis for the abnormally high rates of autoimmune diseases in modern NSDTRs world-wide is that dogs with particularly strong or reactive immune systems were much more likely to survive these outbreaks. Pedigree analysis of the SLE disease complex in NSDTRs has indicated that it involves multi-genetic inheritance, like most autoimmune diseases in humans. The IMRD disease complex involves chronic musculoskeletal signs with a clinical picture indicative of immune-mediated non-erosive polyarthritis. Many of the clinical features of the canine IMRD complex are similar to those of human SLE. "It's worth pointing out that the canine risk factors are very strong," says Kerstin Lindblad-Toh. "The risk factors that have been found thus far in humans with SLE may double the risk, but in dogs, each disease gene increases the risk about five times." "In this study, we have identified five loci that predispose to an SLE-related disease in NSDTRs. The study highlights the strength of disease mapping in dogs, where a canine breed may carry a few disease loci, each with a strong effect, that together are sufficient to predispose to a complex disease," Professor Lohi states. Some types of genetic risk factor will be more easily traced in dogs than in humans, and the dog studies might be a valuable complement to human study for identifying new genes and pathways that are important in disease pathogenesis. "The genes that have thus far been found in humans with SLE do not primarily regulate T cells, but a major share of the genetic risk factors are still unknown in humans. It will therefore be interesting to move on and look at various subtypes of SLE and see whether genes that regulate T cells cause any of them," says Kerstin Lindblad-Toh. "Although we plan to identify and characterize the functions of the canine mutations, this study opens the door for further studies of specific T-cell activation pathways in human populations. In the more long term, the development of clinical treatment regimens based on a dog's particular risk genotype might be possible. For instance, the effect of calcineurin inhibitors could be studied in dogs as a complement or alternative to traditional corticosteroid therapy. Such studies might also lead to better treatment options for human rheumatic diseases and SLE," Lohi says. Reference: Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex Maria Wilbe, Päivi Jokinen, Katarina Truvé, Eija H Seppala, Elinor K Karlsson, Tara Biagi, Angela Hughes, Danika Bannasch, Göran Andersson, Helene Hansson-Hamlin, Hannes Lohi & Kerstin Lindblad-Toh Nature Genetics, Published online: 31 January 2010, doi:10.1038/ng.525 ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/

---

Dog Genome Researchers Track Paw Prints of Selective Breeding

Genes are being tested for roles in most conspicuous variations among dogs Thursday, 14 January 2010 From the Dachshund's stubby legs to the Shar-Pei's wrinkly skin, breeding for certain characteristics has left its mark on the dog genome. Researchers have identified 155 regions on the canine genome that appear to have been influenced by selective breeding. With more than 400 distinct breeds, dogs come in a wide range of shapes, sizes, fur-styles, and temperaments. The curly-haired toy poodle, small enough to sit in a teacup, barely looks or acts like the smooth-coated Great Dane tall enough to peer like a periscope out of a car's sunroof. Not so apparent are breed differences in how the dogs' bodies function and their susceptibility to various diseases. Although domestication of dogs began over 14,000 years ago, according to Dr. Joshua Akey, University of Washington (UW) assistant professor of genome sciences, the spectacular diversity among breeds is thought to have originated during the past few centuries through intense artificial selection of and strict breeding for desired characteristics. Akey is the lead author of the effort to map canine genome regions that show signs of recent selection and that contain genes that are prime candidates for further investigation. Those genes are being examined for their possible roles in the most conspicuous variations among dog breeds: size, coat colour and texture, behaviour, physiology, and skeleton structure. The researchers performed the largest genome-wide scan to date for targets of selection in purebred dogs. The genomes came from 275 unrelated dogs representing 10 breeds that were very unlike each other. The breeds were: Beagle, Border Collie, Brittany, Dachshund, German Shepherd, Greyhound, Jack Russell Terrier, Labrador Retriever, Shar-Pei, and Standard Poodle. The study was conducted, the researchers said, because the canine genome, the product of centuries of strong selection, contains many important lessons about the genetic architecture of physical and behavioural variations and the mechanisms of rapid, short-term evolution. The findings, the researchers said, "provide a detailed glimpse into the genetic legacy of centuries of breeding practices." Their results were published Jan. 11 in the Proceedings of the National Academy of Science, in the article "Tracking footprints of artificial selection in the dog genome." The researchers catalogued more than 21,000 tiny variations in the genome. In investigating the relationships among the 10 breeds, they found that, genetically, the German Shepherd, Shar-Pei, Beagle, and Greyhound were especially distinct. Their list of most differentiated regions of the dog genome included five genes already linked to hallmark traits of certain breeds: one for small size, one for short limbs like those in Dachshunds and other stubby-legged dogs, and three for coats. In calculating the overlap of the signatures marking selection in the genome, the researchers found that approximately 66 percent occurred in only one or two breeds. They noted it was likely that these genome regions contain genes that confer qualities that distinguish a breed, such as skin wrinkling in the Shar-Pei. In contrast, signatures of selection found in five or more breeds tended to sort the dogs into classes, and include, for example, a gene that governs the miniature size of breeds in the toy group. A gene associated with dwarfism in mice, the study reports, appears to mediate variations in dog breed size and weight. Small-size breeds, like Dachshund, Beagle, Jack Russell Terrier, and Brittany have enormous differentiation in this gene, compared to larger-size breeds. Another region of peak differentiation in the dog genome, in an area thought to regulate muscle cell formation in embryos, seems to separate the German Shepherd, Jack Russell Terrier, Border Collie and Greyhound from the Dachshund, Beagle, Brittany, and Shar-Pei. The 155 regions of the genome that appear to have been influenced by selective breeding contain 1,630 known or predicted protein-coding genes. The researchers tried to obtain a broad overview of the molecular functions of these genes. The were surprised to discover that genes involved in immunity and defence were overrepresented in the 155 regions, a phenomenon also discovered in genome analysis of selection in natural populations. Natural and artificial selection were not expected to act on similar classes of genes, the researchers noted, but immune-related genes may be frequent targets of selection because of their critical role in defending against ever-changing infections. The researchers honed in on a particular genome region in the Shar-Pei. Many of these dogs have excessive wrinkles, but some are smooth. A gene in this region may govern the degree of skin folding correlates with levels of certain molecules whose production. Rare mutations in this same gene also cause severe skin wrinkling in people. Tiny genetic variations in this gene seemed linked to whether a Shar-Pei would be smooth or wrinkled, and a rare genetic mutation was found in the Shar-Pei but not in other dogs. The researchers explained that, despite the many insights emerging from their data, there were several limitations to their study and in interpreting the findings. They pointed out that a pattern of variation that is unusual to the dog genome at large does not prove that specific genome region is under selection. A major impetus behind studying dog genomics, the researchers pointed out, is its potential to advance knowledge about the genetic basis of human form variations and of differences in disease susceptibility among people. In many cases, the researchers said, it may be easier to locate the genetic targets of selection in dogs, and then map these to related regions in the human genome. Scientists are intrigued by the possibility that recent selection may have affected genome regions common to both human and dog lineages. "This research has shown that artificial selection in dogs has acted on many of the same genes as natural selection in humans, and that many of these genes are regulators of gene activity," said Dr. Irene Eckstrand, who oversees evolution grants at the National Institute of General Medical Sciences at the National Institutes of Health. "The statistical and computational approaches used in this study will be of great value in deciphering the organization of human genetic variation, and in identifying the genetic basis of human characteristics." The researchers also said that a better understanding of artificial selection in dogs may reveal the molecular mechanisms of rapid, short-term evolution. Future work, they hope, may uncover the gene activities responsible for shaping the incredible diversity among the world's dogs. ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/

---

Understanding Human Dwarfism from Dog Breeds

Researchers discover evolutionary event underlying the origin of dachshunds, dogs with short legs
Thursday, 16 July 2009


A single evolutionary event appears to explain the short, curved legs that characterize all of today's dachshunds, corgis, basset hounds and at least 16 other breeds of dogs, a team led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, reported today. 


In addition to what it reveals about short-legged dogs, the unexpected discovery provides new clues about how physical differences may arise within species and suggests new approaches to understanding a form of human dwarfism. In a study published in the advance online edition of the journal Science, the researchers led by NHGRI's Elaine Ostrander, Ph.D., examined DNA samples from 835 dogs, including 95 with short legs. 


Their survey of more than 40,000 markers of DNA variation uncovered a genetic signature exclusive to short-legged breeds. Through follow-up DNA sequencing and computational analyses, the researchers determined the dogs' disproportionately short limbs can be traced to one mutational event in the canine genome — a DNA insertion — that occurred early in the evolution of domestic dogs. 


"Every species, including canine and human, carries an amazing record of evolution scripted in its genome that can teach us about the mechanisms at work in biology, as well as about human health and disease," said NHGRI Scientific Director Eric Green, M.D., Ph.D.. 


"This work provides surprising evidence of a new way in which genome evolution may serve to generate diversity within a species."


Specifically, the researchers found that in contrast to other dog breeds, all short-legged dog breeds have an extra copy of the gene that codes for a growth-promoting protein called fibroblast growth factor 4 (FGF4). Although functional, the extra gene lacks certain parts of the DNA code, called introns, found in normal genes. These characteristics led researchers to conclude that the extra gene is a so-called retrogene that was inserted into the dog genome some time after the ancestor of modern dog breeds diverged from wolves. 


To understand retrogenes, one first needs to understand how the cell normally makes proteins. To produce a protein, a gene's DNA code is transcribed into a molecule called messenger RNA (mRNA). The mRNA then leaves the cell's nucleus and enters the outer region of the cell, called the cytoplasm. There the mRNA is read by tiny molecular machines, called ribosomes, which use the information to assemble proteins. 


Retrogenes are formed when the mRNA encounters something — often a type of virus called a retrovirus — that turns it back into DNA through a process referred to as reverse transcription. This new piece of DNA, which contains the same protein-coding information as the gene that produced the mRNA, may then be inserted back into the genome, usually at a much different place than the original gene. Depending on where it is inserted, this piece of DNA may or may not be capable of producing proteins. If it is functional, it is called a retrogene. 


 In the case of short-legged dogs, the inserted retrogene results in the overproduction of the FGF4 protein, which researchers hypothesize may turn on key growth receptors at the wrong times during foetal development. Veterinary researchers already know that in certain dog breeds the development of long bones is curtailed due to calcification of growth plates, resulting in short legs with a curved appearance. The trait, called disproportional dwarfism, or chondrodysplasia, is an American Kennel Club standard for more than a dozen domestic dog breeds, including the dachshund, corgi, Pekingese and basset hound. This trait is distinct from the uniformly miniature size of toy breeds, such as the toy poodle. 


"Our findings suggest that retrogenes may play a larger role in evolution than has been previously thought, especially as a source of diversity within species," said the study's first author, Heidi G. Parker, Ph.D. of NHGRI. 


"We were surprised to find that just one retrogene inserted at one point during the evolution of a species could yield such a dramatic physical trait that has been conserved over time." 


 In the past, retrogenes have been recognized as an important source of changes that have fuelled the divergence of species. However, the dog findings are the first example of a retrogene that has spurred significant and long-lasting variation within a single species. 


The findings also may have implications for understanding human biology and disease. Researchers note that some people are affected by a similar appearing growth disorder, called hypochondroplasia, which belongs to a group of conditions commonly referred to as dwarfism. While about two-thirds of cases of human hypochondroplasia have been linked to a different gene, the cause of the other one-third remains a mystery.


"This study points to a new gene that should be investigated for its possible role in human hypochondroplasia," said Dr. Ostrander, the study's senior author and a senior investigator in NHGRI's Division of Intramural Research. 


"Our findings may prove valuable to scientists studying other aspects of human growth and development. The work also underscores the value of canine studies for uncovering new biological mechanisms that are likely relevant to human disease." 


Reference: 
An Expressed Fgf4 Retrogene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs 
Heidi G. Parker, Bridgett M. VonHoldt, Pascale Quignon, Elliott H. Margulies, Stephanie Shao, Dana S. Mosher, Tyrone C. Spady, Abdel Elkahloun, Michele Cargill, Paul G. Jones, Cheryl L. Maslen, Gregory M. Acland, Nathan B. Sutter, Keiichi Kuroki, Carlos D. Bustamante, Robert K. Wayne, and Elaine A. Ostrander 
Science, July 16 2009; 10.1126/science.1173275 
......... 


ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at 
http://cellnews-blog.blogspot.com/ 

---

Man's Best Friend Recruited in the Hunt for Disease Genes

Man's Best Friend Recruited in the Hunt for Disease Genes Thursday, 16 October 2008 For centuries man has had a uniquely close relationship with dogs – as a working animal, for security and, perhaps most importantly, for companionship. Now, dogs are taking on a new role – they are helping in the hunt for genetic mutations that lead to diseases in humans. "Dogs get very similar diseases to humans," said Kerstin Lindblad-Toh of Institute of Medical Biochemistry and Microbiology, Uppsala University in Sweden and the Broad Institute of MIT and Harvard, Cambridge, Massachusetts. "If you ask a dog owner what sort of conditions their pets get, they will say cancer, allergies, eye diseases." Lindblad-Toh was speaking at the European Science Foundation's 3rd Functional Genomics Conference, held in Innsbruck, Austria, on 1-4 October. Functional genomics describes the way in which genes and their products, proteins, interact together in complex networks in living cells. If these interactions are abnormal, diseases can result. The Innsbruck meeting brought together more than 450 scientists from across Europe to discuss recent advances in the role of functional genomics in disease. Many canine diseases could share the same genetic basis in humans and dogs, Lindblad-Toh told the conference, and because dogs have been bred into clear isolated populations – the different breeds – it is often easier to detect a genetic flaw that leads to a disease than it is in humans. Once the rogue gene has been found in the dog, it could make it easier look for mutations in the same gene in man. "For example we have found genetic mutation that results in a condition called day blindness that can affect dachshunds," Lindblad-Toh said. A similar condition can arise in humans, and analysis of the mutated protein in the dog is providing new information about the disease in man. The team is also looking at genes associated with cancer of the blood vessels to which golden retrievers are prone. A new European consortium has been set up called LUPA, where twenty veterinary schools from 12 countries spread across Europe will work together to collect 10,000 DNA samples from purebred dogs, comparing healthy animals with those affected by similar diseases as human. The analysis of the genome of affected dogs compared to healthy ones of the same breed will lead to the identification of genes implied in the mechanisms of these diseases. The four-year project aims initially to pinpoint genetic markers for dog diseases and help to reduce the high level of inherited disease in purebred dogs. The identification of these genes implied in disease development will help to understand the mechanisms and pathways of the pathology. For example in Sweden, more than one-third of English Springer Spaniels are diagnosed with mammary tumours, analogous to breast cancers in humans. An increased risk for malignant mammary tumours has been reported also in other breeds, including Cocker Spaniels, German Shepherds and Boxers, suggesting that these breeds may carry genetic risk factors for this type of cancer. If the genes implicated in the disease can be singled out this could provide a new opportunity to improve prevention, diagnosis and treatment of human breast cancer. "We want to find a lot of risk factors and bring them back to human patients over the next few years," Lindblad-Toh said. Lupa was the female wolf (Canis lupus) that according to Roman mythology was nurturing the twins Romulus and Remus, founders of Rome. ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

---

Unpicking the Complexity of Human Disease

Impressive advances in our understanding of the genetic basis of disease were outlined at the 3rd ESF Functional Genomics Conference in Innsbruck, Austria Wednesday, 15 October 2008 The mysteries of the human genome are slowly being revealed – but the more we uncover the more complicated the picture becomes. This was one key message to emerge from the European Science Foundation's 3rd Functional Genomics Conference held in Innsbruck, Austria, on 1-4 October. Functional genomics describes the way in which genes and their products, proteins, interact together in complex networks in living cells. If these interactions are abnormal, diseases can result. "The human genome is just a string of letters which has to be interpreted so that we can understand the function of the genes," said Mike Taussig of Babraham Bioscience Technologies in Cambridge, UK, who organised the conference, which focused on the role of functional genomics in disease. More than 450 scientists from across Europe were told of new developments in research ranging from pinpointing genes involved in diabetes and cancer to using the genetic sequences of different breeds of dog to throw light on human diseases. "What we have tried to do is bring together genome knowledge as it is now, the work which has been done, what it means in functional terms and where it affects our susceptibility to disease," Taussig said. "Conferences like these are important because we try to cover a broad field – there are so many aspects of genomics that it would be impossible to encompass everything in a single lecture. It is very useful for researchers who want to improve their general view of the field, because when you are immersed in one specialty you often do not appreciate how well connected everything is." Dr Patrik Kolar, head of the unit for genomics and systems biology in the European Commission's research directorate, said: "Functional genomics and systems biology is an important and integral part of our health research programme because an understanding of these basic biological processes has huge potential and real applications for understanding disease, and when you understand disease you can design new drugs." "This kind of conference is one of the things that brings together the European community in functional genomics and I am really happy to see that most of the participants are from collaborative projects funded though our Framework programme," Dr Kolar added. Professor Mark McCarthy of the University of Oxford in the UK, who is searching for genes involved in type 2 diabetes, illustrated the unexpected complexity of the role of genes in disease. Here, so-called genome-wide scans, which compare the genetic profiles of healthy people with those who have the disease, have so far revealed around 20 individual gene mutations that can be present in people with type 2 diabetes. However, these variants explain only a small proportion of people's overall susceptibility to the condition. "If you look at the variants we are finding from really large sample sizes, the effects are pretty small," McCarthy told the conference. "For diabetes, weight and age are still better predictors of risk than the gene profile. So, on the one hand we are happy that we have found more signals that we might have imagined, but on the other hand, we are disappointed because we are explaining so little of the variance. There is much work to be done to turn these association signals into function and mechanism." Mutations in cancer genes have also turned out to be far more complicated than people might have first suspected. Professor Mike Stratton, head of the Cancer Genome Project at the Wellcome Trust Sanger Institute in Cambridge, UK, led the team that mapped and identified the high-risk breast cancer susceptibility gene BRCA2. His group is searching for particular types of gene mutations in cancer cells, and is revealing new insights into a class of mutation called rearrangement, where one gene breaks and is fused to another. This rearrangement process could result in the creation of a rogue protein that promotes cancer. Until recently, it has been difficult to study rearrangement mutations because technologies have been lacking. "For many years we have wanted a screen which would allow us to extract rearranged parts of the cancer genome and make a catalogue," Stratton told conference delegates. Techniques have now been developed that are allowing researchers to pinpoint rearrangements and look at them in detail. "New sequencing technologies are enabling us to look at a much larger number of rearrangements, allowing us to do genome-wide screens to identify fusion genes that could be cancer genes," Stratton said. "It turns out there is a lot of complexity in these rearrangements that we would not anticipated before we started." For example it is becoming clear that while there are many more rearrangement mutations than people first thought, the majority of these seem to be effectively harmless, or 'passenger' mutations. The significant mutations are the 'drivers', and these are much more elusive to track down. Meanwhile Dr Kerstin Lindblad-Toh of Uppsala University in Sweden and the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, is analysing gene mutations in different breeds of dog to throw light on human diseases. Because dogs have been reared as distinct breeds with clear isolated populations, it is often easier to detect a genetic flaw than it is in humans, and dogs are susceptible to many similar diseases that occur in man. Professor Olli Kallioniemi's team at the Institute for Molecular Medicine in Finland is working on innovative ways to discover the effects of small strands of RNA, called small interfering RNAs (siRNAs), which can 'silence' genes and are showing promise in the fight against diseases such as cancer. The Finnish researchers have developed new high-throughput techniques for testing thousands of different siRNAs on living cells in one go. "This is a new cell array screening platform which we think has great potential for showing real utility in biological experiments," Kallioniemi told the meeting. Professor Patrik Brundin of Lund University in Sweden leads a team that is learning how best to repair the brain of people with neurodegenerative disorders such as Parkinson's disease, where a part of the brain called the substantia nigra degenerates, leading to slow movement and tremors. Brundin told the meeting that his university has over the past 20 years transplanted brain tissue into 18 patients with Parkinson's, whose condition improved markedly and remained stable for many years. However, certain unexplained side effects have arisen, including uncontrollable movements. "Nigral transplants have clearly worked well in select cases, but the technique needs refinement and is difficult to perform in large series of patients," Brundin said. One key issue is a safe and sustainable supply of tissue, and embryonic stem cells could hold promise. However, Brundin warned that many hurdles remain to be overcome. "Today some people are saying that you can do this with stems cells, but stem cell transplantation to the brain is currently science fiction and should remain so for the moment – there are many challenges before we can do clinical trials." In all, leading scientists, from Europe and the US, gave twelve key lectures at the meeting. In addition, there were more than 40 symposia, with topics ranging from the role of proteins in ageing to new ways to disable viruses that cause influenza. ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

---

Cloned Dog Snuppy Get Puppies!

Cloned Dog Snuppy Get Puppies 
Saturday, 06 September 2008

Snuppy, the Afghan hound that was produced by cloning in 2005 have recently produced a litter of puppies by the laboratory, once headed by Hwang Woo-suk, who fell from grace in South Korea after two of his papers on cloning human embryonic stem cells were discovered to be fake. The Afghan hound impregnated two cloned bitches of the same breed through artificial insemination, a Seoul National University (SNU) research team said in a statement last week.  

"This is the first time in the world that puppies have been born from cloned parents," team leader Lee Byung-Chun told AFP. One of the 10 puppies, which were born between May 14 and 18, died but nine others are healthy, he said.

"This shows the reproductive ability of a cloned dog," Lee said. Lee's team, which says it also produced the world's first cloned wolves, plans to carry out a similar breeding experiment with them. 
......... 

ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at 
http://cellnews-blog.blogspot.com/ 

---