NEWS: Hares, tortoises, and the race to unravel the genetic diversity

Hares, tortoises, and the race to unravel the genetic diversity : Sun, Apr 28th, 2013 |

If you thought the only way to solve a puzzle was by looking at a picture of its end result as you go, guess again. Using an innovative approach to the study of genetic diversity, an international research team, comprising three researchers from the Research Center in Biodiversity and Genetic Resources – CIBIO/InBIO Laboratório Associado, in Portugal, demonstrated that it is possible to unveil the mechanisms underlying genetic diversity and evolutionary change, by focusing on species that are not commonly used as model-organisms.

Iberian Hare by Pedro Moreira, 2009

In the age of genome analysis, most of the strategies put forth to tackle genetic diversity have focused on a very limited number of species, for which well-annotated reference genomes are available, as for instance, fruit flies and humans. However, in a recent study, published in the latest issue of PLOS Genetics, Gayral, Melo-Ferreira and colleagues overcome the traditional paradigms of genomic analysis and their potential limitations, and show that it is possible to explore a broad range of organisms for whom that information is still incomplete or unavailable, as is the case of hares, turtles, oysters or even termites.
In a time when full genome sequencing has become quite popular in well-developed countries, José Melo-Ferreira and colleagues suggest a strategy based in next-generation sequencing, which allows obtaining insightful and reliable data from new information that is largely unknown. In spite of the inevitable challenges it presents, this approach is very stimulating, as sustained by the researcher from CIBIO, who states that “it is almost like solving a puzzle without having access to the final picture. We have shown that, instead of attempting to reconstruct the genetic profile and evolutionary history of the individuals it is possible to efficiently attain that information, without having those data to begin with. This opens new opportunities for the study of the genomes of a wide range of species, which is likely to provide a deeper understanding of the evolutionary process”.

In addition to this extraordinary technological advancement, it is important to highlight the important contribution of this study for he understanding of biological diversity. A hypothesis that is now widely accepted by the research community suggests that population size is the most determining aspect of a species’ ability to retain beneficial genetic information and remove harmful information. For instance, it is though that the diversity and adaptive capacity of invertebrates, whose populations are exceedingly numerous, are above those observed in vertebrates, typically with lower population sizes. Nevertheless, this study reveals that this is not at all a straightforward issue. As José Melo-Ferreira explains, “… in a way, our results show that this line of reasoning is too simplistic. Actually, the utter discrepancy that until now was thought to exist between the adaptive capacity of vertebrates and invertebrates, is substantially lessened if we turn our attention to species that are usually not considered”. Hence, this study paves the way to new and promising perspectives on the study of major determinants of evolution, which bare significant implications for biodiversity research and the outline of conservation strategies.

NEWS : UCSD Study conducted more sense genome data

UCSD Study conducted more sense genome data:

LA JOLLA — The ever-faster methods of genome sequencing have caused a bit of data gridlock among researchers looking into the links between DNA sequences and disease: There's too much information to easily make sense of.

A team of UC San Diego researchers says it has found a way to better interpret the mountains of genomic data to track the associations. Their study was published April 25 in two papers in the journal PLOS Genetics.

The researchers have developed a statistical method to toss out the vast amounts of data likely to be irrelevant. Scientists can then focus more closely on the information likely to be related to diseases. By better understanding the disease process at its genetic roots, researchers hope to speed development of better therapies.

The study, led by UCSD professor Anders Dale, concerns one-letter variants in the DNA alphabet. These variants are called single-nucleotide polymorphisms, or SNPs. They can occur inside genes, or in the much larger stretch of DNA found outside genes. They can be found by scanning the entire genome to find variants associated with disease; these are called genome-wide association studies, or GWAS. The human genome contains about 3 billion letters, so a change of one letter is comparatively tiny.

Modern genomic technology has identified thousands of these SNPs. This discovery has turned on its head the common notion that a certain mutation occurs "for" a certain disease. Instead of just one mutation in a disease, there are most often many mutations.

Sometimes, people will have disease-associated SNPs but not develop the disease. That fact makes the genetic tests being sold commercially of questionable value in disease prediction. Also, genetic variations may be associated with more than one disease, a condition known as pleiotropy.

Add this all up and it means there's no obvious way to associate most of these variants with diseases in any reliable fashion. That's where the UCSD-led team says its method can make a difference.

"It's increasingly evident that highly heritable diseases and traits are influenced by a large number of genetic variants in different parts of the genome, each with small effects," said Dale, a professor in the departments of Radiology, Neurosciences and Psychiatry at the UCSD School of Medicine, in a statement on the studies. "Unfortunately, it's also increasingly evident that existing statistical methods, like genome-wide association studies that look for associations between SNPs and diseases, are severely underpowered and can't adequately incorporate all of this new, exciting and exceedingly rich data."

The study developed a shortcut to finding patterns of these SNPs that bunch up in certain diseases. The conclusion is made plain in the title of one of the papers, which stated in part, "All SNPs are not created equal."

"We hypothesize that all SNPs in a GWAS are not exchangeable, but come from pre-determinable categories with different distributions of effects," the study stated. "This implies that some categories of SNPs are enriched, i.e. are more likely to be associated with a phenotype than others."

The method also includes pleiotropic information, recognizing that diseases may share common genetic causes.

NEWS :Co-discoverer of DNA highlights the importance of knowledge for success

Co-discoverer of DNA highlights the importance of knowledge for success:


The Nobel Prize winning scientist who co-discovered the structure of DNA 60 years ago has said Ireland cannot be a success in science unless it knows as much as other nations.
Dr James Watson, 86, said the investment made in research in Ireland over the past 40 years is beginning to pay off and there are some very good scientists in the country.
He was asked about comments he made last month in San Diego, where he referred to ignorance being the curse of the Irish. Dr Watson said what he meant was that historically Irish people lacked knowledge. He said that he was not implying that Irish people were stupid.
Ireland just has to be good at technology, he said, and that takes a long time and requires a serious university system. He said it is very important to make science appealing to young people.
Dr Watson, who is now engaged in cancer research, said he is convinced genetics will not lead to the discovery of a cure for cancer, but chemistry will.
On the level of investment in cancer research, he said he does not believe that too much is being spent on it.  Dr Watson said he did not think the future of cancer research is dependent on a big burst of investment in the area. He said what is really limiting the search for a cure for cancer is ideas and intelligent people.  Dr Watson was in Dublin to unveil a new sculpture in the Botanic Gardens in Dublin marking the 60th anniversary since the discovery of the double helix structure of DNA.

NEWS: Malaria Parasite drug resistance Fingerprinting 'offers a new tool for monitoring public health threat

Malaria Parasite drug resistance Fingerprinting 'offers a new tool for monitoring public health threat :  29 April 2013


Resistance to the frontline antimalarial drug, artemisinin, can be identified and tracked by analysing the genetic fingerprint of parasite populations, a study published online today in ‘Nature Genetics’ demonstrates.
The effectiveness of this key drug is weakening, threatening hundreds of thousands of lives, and new methods of tracking resistance are vital for understanding how it could be contained.

An international team of researchers used new genetic sequencing technologies to analyse the whole genetic make-up, or genomes, of samples of the malaria-causing parasite Plasmodium falciparum. They discovered multiple strains of the parasite that seem to be rapidly expanding throughout the local parasite population in Western Cambodia, a known hotspot for drug resistance. These strains have emerged recently and are all resistant to artemisinin.

The scientists were able to characterise distinct genetic patterns, or 'fingerprints', for each of the strains, showing the approach offers a rapid and novel way to detect and track the global emergence of drug resistance. Their findings provide important insights into how resistance emerges and is maintained by certain parasite populations.

A major objective of the World Health Organization is to stop the spread of malaria parasites resistant to leading drugs. Researchers from 23 institutions across South-east Asia, Africa, the USA and the UK sequenced parasite genomes from more than 800 malaria samples from Africa and South-east Asia with the aim of investigating how the large-scale genetic monitoring of malaria could identify and track drug resistance.

"Our survey of genetic variation showed that Western Cambodian malaria parasites had a population structure that was strikingly different to those of the other countries we analysed. Different not just from countries in Africa, but also different from malaria parasite populations in neighbouring Thailand, Vietnam, and even Eastern Cambodia," says Professor Dominic Kwiatkowski, senior author of the paper from the Wellcome Trust Sanger Institute and University of Oxford.

"Initially, we thought our findings might be just an anomaly. But when we investigated further we found three distinct sub-populations of drug-resistant parasites that differ not only from the susceptible parasites but also from one another. It is as if there are different ethnic groups of artemisinin-resistant parasites inhabiting the same region."

One important benefit of this genetic approach is that, even without knowing the precise genetic causes of drug resistance, researchers are able to quickly identify resistant strains - an important step towards identifying molecular markers to enable effective worldwide surveillance.

Dr Olivo Miotto, first author of the paper from Oxford University, Mahidol University in Thailand, and the MRC Centre for Genomics and Global Health, said: "Public health authorities need rapid and efficient ways to genetically detect drug-resistant parasites in order to track their emergence and spread. Our approach allows us to identify emerging populations of artemisinin-resistant parasites, and monitor their spread and evolution in real time. This knowledge will play a key role in informing strategic health planning and malaria elimination efforts."

Western Cambodia seems to be a hotspot for the emergence of drug resistance, but it is not fully known why. Resistance to other malaria drugs, namely chloroquine and sulfadoxine/pyrimethamine, first developed in South-east Asia before spreading to Africa. This study offers new leads regarding why drug resistance arises more readily in some locations than in others, which the consortium will be pursuing.

"While we have not yet identified the precise mechanism of action or resistance to artemisinin, this research represents substantial progress in that direction. It also provides an important insight into why antimalarial drug resistance (previously to chloroquine and antifols, and now to artemisinin) arises in Western Cambodia," said Professor Nicholas White, Director of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme in Thailand.

"Artemisinin resistance is an emergency which could derail all the good work of global malaria control in recent years. We desperately need methods to track it in order to contain it, and molecular fingerprinting provides this."

In the longer term, the findings provide an important resource for exploring the underlying mechanisms of resistance. Several genetic variations were discovered in genes that are suspected to play a part in drug resistance, notably those that code transporter proteins and those implicated in DNA repair. These findings provide a rich resource for researchers investigating the molecular mechanism of drug resistance.

"This research demonstrates the value of collaborative working to survey the genetic landscape of malaria across the globe," added Dr Abdoulaye Djimdé from the Malaria Research and Training Centre, University of Science, Techniques and Technologies of Bamako, Mali and the Sanger Institute. "Continuing global genetic surveillance and investigation will help us to identify the emergence of further resistant strains and improve our understanding of how they arise and spread."

There were an estimated 219 million cases of malaria in 2010 and an estimated 660 000 deaths. The World Health Organization Global Plan for Artemisinin Resistance Containment is a call to action that outlines measures to protect the value of artemisinin-based combination therapies for Plasmodium falciparum malaria.


Image caption: A gene map of the malaria genome. Credit: Wellcome Library, London.

"There is no choice for you according to the ACMG (American College of Medical Genetics)

"There is no choice for you according to the ACMG (American College of Medical Genetics)

The American College of Medical Genetics (ACMG) has recently published recommendations for reporting incidental findings (IFs) in clinical exome and genome sequencing. These recommendations advocate actively searching for a set of specific IFs unrelated to the condition under study. For example, a two-year-old child may have his (and his parents’) exome sequenced to explore a diagnosis for intellectual disability and at the same time will be tested for a series of cancer and cardiac genetic variants. The ACMG feel it is unethical not to look for a series of incidental conditions while the genome is being interrogated, conditions that the patient or their family may be able to take steps to prevent. This flies in the face of multiple international guidelines that advise against testing children for adult onset conditions. The ACMG justify this as “a fiduciary duty to prevent harm by warning patients and their families.” They conclude that “this principle supersedes concerns about autonomy,” i.e. the duty of the clinician to perform opportunistic screening outweighs the patients right not to know about other genetic conditions and their right to be able to make autonomous decisions about testing. Family have exome sequencing to determine son’s diagnosis

There is strength in the above argument if opportunistic genetic screening did indeed reveal an established predisposition to a treatable and preventable condition where steps could be taken to protect the individual or their family. But this isn’t the case with some of the conditions the ACMG insist on testing for. There are many apparently ‘disease causing’ variants that appear in healthy people with no evidence of disease, and in the absence of a strong family history it will be difficult to interpret some results. It is not too far fetched to imagine that, in the hands of a health professional who doesn’t understand the limitations of the testing, that a supposed BRCA1 gene fault will be identified in a women who is then advised to have preventative surgery to remove her ovaries and breasts. And yet in the absence of a family history, it is impossible to tell whether the BRCA1 gene fault is fully penetrant and whether there are any modifying genes at play.

The ACMG acknowledge “there are insufficient data on clinical utility to fully support these recommendations… and… insufficient evidence about benefits, risks and costs of disclosing incidental findings to make evidence-based recommendations”. Yet, they clearly felt the need to draw a line in the sand and create a starting point. This is a bold and fearless move. The result is that a set of conditions, genes and variants are listed, many of which will reveal uncertain pathogenicity in the absence of a family history. Moreover, in many cases, there is no screening program available (what should be offered to a child with a P53 mutation? There is no universal agreement on whether screening for rhabdomyosarcoma is appropriate). The intent was to identify “disorders where preventative measures and/or treatments were available” but the reality falls short somewhat.

Finally, the ACMG “Working Group encourages prospective research on incidental or secondary findings and the development of a voluntary national patient registry to longitudinally follow individuals and their families who receive incidental or secondary findings as part of clinical sequencing and document the benefits, harms and costs that may result.” In effect, what they are saying is that we don’t really know what the impact of this technology will be, and only time will tell whether our risk predictions are correct. Given such uncertainty and also the fact that many of the families and individuals who will be accessing this technology are incredibly vulnerable (by virtue of their desperate need for a diagnosis for example, for a developmental disorder), it strikes us that this all should actually be part of a research project and not offered as a clinical service. Under the guise of ‘research’ this makes much more sense. What do you think? If you want to contribute to other discussions about ethics and genomics, see our survey.

Consider the ACMG guidelines with the following fictitious case study in mind….

CASE STUDY

Bobby is a severely disabled six-year-old. He has a learning disability and hyperactivity, and is incontinent.  Numerous paediatricians have seen the family over many years, but existing tests haven’t led to a diagnosis. Bobby’s parents are anxious to have a name for his condition. Without an actual diagnosis it is more challenging to access the educational and respite care he needs.

At their latest paediatric review, Bobby’s parents are given the first glimmers of hope: there is a new test, an exome sequence, that will explore the subtle changes in Bobby’s genes to (hopefully) reveal previously undetected genetic causes for his condition. However, there is a catch — the testing comes in a package where other conditions are also explored at the same time. The parents aren’t interested in anything else and they are confused when the paediatrician tells them Bobby will be tested for a whole set of adult-onset cancers as well as cardiac conditions. The paediatrician explains that these latter conditions are likely to be totally unrelated (‘incidental’) to Bobby’s condition, may not be relevant until Bobby grows up and also it may not be possible to tell with any certainty what the actual risks are of developing them. The parents are surprised — isn’t this a paediatric clinic? Why is a paediatrician talking to them about adult conditions completely outside her area of expertise?

The paediatrician explains that this is just the same as having a full blood count done or an X-ray; there is always the chance of picking up something unexpected. But, the lab will be specifically searching for a set of additional conditions, there doesn’t seem to be much that is ‘incidental’ about this. ‘Call it opportunistic screening’ says the paediatrician’; however, what shocks Bobby’s parents is the fact there is no choice. In order to access the exome sequencing technology they have to receive information on a set list of conditions, there is no opt-out only an opt-in. So, they have to proceed.

Some months later they receive a telephone call from their paediatrician, the exome did not reveal an obvious genetic diagnosis for Bobby’s disabilities however, after several weeks of additional exploratory work by the laboratory staff, they reported a change in a gene called ‘P53’ that is ‘likely’ to given him an increased risk of cancer. The lab had spent a long time looking through the medical literature. Although the gene change looked as if it should be significant in that cancer was possible, the fact that no-one in the family had already had cancer (and the family was large with many people living well into old age), it was difficult to know what this actually meant for Bobby and his parents, and whether cancer screening would be necessary or not. Bobby’s parents are stunned, they proceeded with testing that they had no choice about and now have to deal with uncertain results together with an uncertain plan of action. Should they be worrying about this result or not?  Does it have implications for other members of the family? The paediatrician isn’t sure.

NEWS: Tempering the genetic revolution

Tempering the genetic revolution

We may not be fully aware of it, but future generations will likely consider our era truly historic. Never before has mankind been able to understand the functioning of cells, tissues and organs, the precise molecular mechanisms of evolution, and where and how our species originated and spread throughout the world.
The technology that allows us to unravel cellular and subcellular processes and mechanisms, identify the causes of diseases and develop more specific and effective treatments, and determine who is biologically related to us and to what degree combines knowledge from biology, computer sciences, information technology and material sciences. 
As might be expected, such a revolution in knowledge must also have a significant societal impact, requiring answers to questions that, until recently, were considered pure science fiction.
Today, it is technically possible to sequence the 2.4 metres of DNA – present in the nucleus of every cell of our body – in only a few days. And, just as the speed of reliable sequencing continues to increase, the price of sequencing has dropped precipitously, and will soon amount to just a few hundred dollars. 
Once the function of every fragment of DNA is known, nothing will stand in the way of routine sequencing.
Already, variations in the composition of about 500,000 DNA building blocks (SNPs or Single Nucleotide Polymorphisms), spread over the total length of the DNA and shown to correlate with particular physical and behavioural characteristics or susceptibility to diseases, are being analysed routinely. 
Major errors in DNA composition that are responsible for about 3,000 of the 7,000 known genetic diseases can be visualized, and efforts are underway to identify the causes of the remaining 4,000.
Meanwhile, a growing number of companies are offering a new commercial service: direct-to-consumer analysis of DNA for genealogical or medical purposes. 
While their activities and clientele are steadily increasing, many of the results currently are of only limited value for determining physical and behavioural characteristics or risks of common diseases such as hypertension, cardiovascular diseases, diabetes, and depression.
Some people, however, claim the right to know all information pertaining to them, including even the slightest elevated risk for these diseases. Some are even willing to undergo preventive measures or modify their behaviour to decrease or control this risk. 
Others must cope with results showing that they carry defects that significantly increase their risk of developing a hereditary form of cancer or dementia, or of transmitting a defect to their children that could, in turn, cause a serious defect in their grandchildren.
Some people – so far still a minority – are fascinated by this new knowledge, and take the results for granted. But more research is needed before we can understand the results of sequencing correctly and apply this knowledge appropriately in risk calculations. 
For example, more than 97% of our DNA contains no information for the synthesis of proteins – that is, it contains no genes – but nonetheless interacts with our genes to increase, decrease, or inhibit the production of proteins.
We also know that even if our DNA is somewhat responsible for increased risks for common diseases, and in some cases is fully responsible for inherited diseases, the environment in which this DNA functions can be as important as the composition of the DNA itself. 
Indeed, from fertilisation on, the environment in which the fertilised egg develops – for example, what the mother eats, whether she smokes or drinks alcohol, and whether she develops diseases or infections – places so-called epigenetic marks on the DNA or on the proteins surrounding it, affecting its function.
This conditioning effect continues and increases after birth, leading to different degrees of epigenetic marking in different organs. Individual differences in susceptibility to diseases can be the consequence. This is nicely illustrated in identical twins, who show as they age increasing differences in the way that their identical DNA is marked by the environment.
Nonetheless, the dangers implied by recent technological progress have become increasingly obvious. For example, it is now possible to analyse the DNA of an unborn child from the blood of its mother and determine its risk for diseases later in life. This opens the way to full-blown eugenics – the selection (by parents, authorities, or others) of children with characteristics considered “appropriate”.
We must take care that we do not become more fascinated by the composition of DNA and what characteristics and risks it carries than we are by the human qualities of less-than-perfect individuals, which we all are. 
This does not mean that there are no applications of our knowledge that are not important, life-saving, and even necessary. But they are more limited in number and scope than many seem to believe. Now is a time not only to advance current research, but also to reflect and to tread cautiously. Project Syndicate

***  Jean-Jacques Cassiman is professor of human genetics at the Center for Human Genetics at the Catholic University of Leuven, Belgium.

NEWS:The newly discovered genes can treat childhood arthritis

The newly discovered genes can treat childhood arthritis

Scientists from The University of Manchester have identified 14 new genes which could have important consequences for future treatments of childhood arthritis.

Scientists Anne Hinks, Joanna Cobb and Wendy Thomson, from the University’s Arthritis Research UK Epidemiology Unit, whose work was published in Nature Genetics, looked at DNA extracted from blood and saliva samples of 2,000 children with childhood arthritis and compared these to healthy people.

Principal Investigator Thomson, who also leads the Inflammatory Arthritis in Children theme at the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit, said: “This study brought together an international group of scientists from around the world and is the largest investigation into the genetics of childhood arthritis to date.”

Childhood arthritis affects one in 1,000 in the UK. It is caused by a combination of genetic and environmental risk factors, however until recently very little was known about the genes that are important in developing this disease– only three were previously known.

Hinks, joint lead author of the study, said the findings were a significant breakthrough for understanding more about the biology of the disease and this might help identify novel therapies for the disease. "Childhood arthritis, also known as juvenile idiopathic arthritis (JIA), is a specific type of arthritis quite separate from types found in adults and there's been only a limited amount of research into this area in the past,” she said. "This study set out to look for specific risk factors. To identify these 14 genetic risk factors is quite a big breakthrough. It will help us to understand what's causing the condition, how it progresses and then to potentially develop new therapies.”

The study may help to predict which children need specific treatment earlier and allow health workers to better control their pain management, quality of life and long-term outcome. Currently 30 percent of children with the disease continue to suffer from arthritis in adulthood.

Cobb, joint lead author, added: “There are lots of different forms of childhood arthritis so identifying the markers will help us understand a little bit more about the disease process. It will also help to categorize children with JIA into sub-types dependent on which genes they have and allow us to determine the best course of treatment.”

The study, which took two years to complete, will ultimately help clinicians to better manage children with the disease and give potential to develop new therapies. 

Alan Silman, medical director of Arthritis Research UK who partly funded the work, said: “We have known for some time that there is a strong genetic contribution to a child’s risk of developing JIA, however previously only three genetic risk factors had been identified. This study is the largest genetic investigation of JIA to date and has identified 14 new risk regions, adding a significant amount to our knowledge of the genetic basis of this disorder. Further work is now required to investigate each of these regions in more detail, to enable us to understand how they are involved in disease development and identify potential new therapeutic targets.”