New findings shake up traditional view of human genome function

An international research consortium has published a set of papers that promise to reshape our understanding of how the human genome functions. The findings challenge the traditional view of our genetic blueprint as a tidy collection of independent genes, pointing instead to a complex network in which genes, along with regulatory elements and other types of DNA sequences that do not code for proteins, interact in overlapping ways not yet fully understood.

In a group paper published in the 14 June issue of Nature and in 28 companion papers published in the June issue of Genome Research, the ENCyclopedia Of DNA Elements (ENCODE) consortium, which is organised by the US-based National  Human Genome Research Institute (NHGRI), reported results of its exhaustive, four-year effort to build a parts list of all biologically functional elements in 1% of the human genome. Carried out by 35 groups from 80 organisations around the world, the research served as a pilot to test the feasibility of a fullscale initiative to produce a comprehensive catalog of all components of the human genome crucial for biological function.

“This impressive effort has uncovered many exciting surprises and blazed the way for future efforts to explore the functional landscape of the entire human genome,” said NHGRI director Francis Collins, MD, PhD. “Because of the hard work and keen insights of the ENCODE consortium, the scientific community will need to rethink some long-held views about what genes are and what they do, as well as how the genome’s functional elements have evolved.

This could have significant implications for efforts to identify the DNA sequences involved in many human diseases.” The completion of the Human Genome Project in April 2003 was a major achievement, but the sequencing of the genome marked just the first step toward the goal of using such information to diagnose, treat and prevent disease. Having the human genome sequence is similar to having all the pages of an instruction manual needed to make the human body.

Researchers still must learn how to read the manual's language so they can identify every part and understand how the parts work together to contribute to health and disease. In recent years, researchers have made major strides in using DNA sequence data to identify genes, which are traditionally defined as the parts of the genome that code for proteins.

The proteincoding component of these genes makes up just a small fraction of the human genome – 1.5% to 2%. Evidence exists that other parts of the genome also have important functions. However, until now, most studies have concentrated on functional elements associated with specific genes and have not provided insights about functional elements throughout the genome.

The ENCODE project represents the first systematic effort to determine where all types of functional elements are located and how they are organised. In the pilot phase, ENCODE researchers devised and tested highthroughput approaches for identifying functional elements in the genome. Those elements included genes that code for proteins; genes that do not code for proteins; regulatory elements that control the transcription of genes; and elements that maintain the structure of chromosomes and mediate the dynamics of their replication.

The collaborative study focused on 44 targets, which together cover about 1% of the human genome malforsequence, or about 30 million DNA base pairs. The targets were strategically selected to provide a representative cross section of the entire human genome. All told, the ENCODE consortium generated more than 200 datasets and analysed more than 600 million data points.

“Our results reveal important principles about the organisation of functional elements in the human genome, providing new perspectives on everything from DNA transcription to mammalian evolution.

In particular, we gained significant insight into DNA sequences that do not encode proteins, which we knew very little about before,” said Ewan Birney, PhD, head of genome annotation at the European Molecular Biology Laboratory's European Bioinformatics Institute (EBI) in Hinxton, England, who led ENCODE's massive data integration and analysis effort.

The ENCODE consortium's major findings include the discovery that the majority of DNA in the human genome is transcribed into functional molecules, called RNA, and that these transcripts extensively overlap one another.

This broad pattern of transcription challenges the long-standing view that the human genome consists of a relatively small set of discrete genes, along with a vast amount of so-called junk DNA that is not biologically active.

The new data indicate the genome contains very little unused sequences and, in fact, is a complex, interwoven network. In this network, genes are just one of many types of DNA sequences that have a functional impact. “Our perspective of transcription and genes may have to evolve,” the researchers state in their Nature paper, noting the network model of the genome “poses some interesting mechanistic questions” that have yet to be answered.

The multinational initiative included researchers from academic, governmental and industry organisations located in Australia, Austria, Canada, Germany, Japan, Singapore, Spain, Sweden, Switzerland, the United Kingdom and the United States. ENCODE is a community resource project and the data is freely available online at and  


The first clinical trial to test a revolutionary treatment for blindness in children has been announced by researchers at United Kingdom-based Moorfields Eye Hospital and UCL Institute of Ophthalmology. The trial is the first of its kind and could have a significant impact on future treatments for eye disease.

The trial involves adults and children who have a condition called Leber's congenital amaurosis (LCA), which is a type of inherited retinal degeneration. This disease causes progressive deterioration in vision, due to an abnormality in a particular gene called RPE65. This defect prevents normal function of the retina, the light-sensitive layer of cells at the back of the eye.

This results in severely impaired vision from a very young age and there are currently no effective treatments available. The new technique that will be used in the trial involves inserting healthy copies of the gene into the cells of the retina to help them to function normally.

Restoring the activity in these cells should restore vision. The operation delivers the normal genes to the retina, using a harmless virus or "vector" to carry the gene into the cells. Previous work using animal models has demonstrated that this gene therapy can improve and preserve vision.

Research team leader Professor Robin Ali said: “We have been developing gene therapy for eye disease for almost 15 years, but until now we have been evaluating the technology only in the laboratory.

Testing it for the first time in patients is very important and exciting, and represents a huge step towards establishing gene therapy for the treatment of many different eye conditions.”

Breast cancer

A new hereditary breast cancer gene has been discovered by scientists at the Lundberg Laboratory for Cancer Research and the Plastic Surgery Clinic at the Sahlgrenska Academy in Sweden.

The researchers found that women with a certain hereditary deformity syndrome run a nearly 20 times higher risk of contracting breast cancer than expected. Several research teams around the world have long been searching for new hereditary breast cancer genes, but thus far few have been found.

“Our findings are extremely important, providing new knowledge of hereditary cancer genes and how they can cause breast cancer. The discovery also makes it possible to uncover breast cancer in women who have a predisposition for Saethre-Chotzen malformation syndrome," said researcher Göran Stenman.

By detailed mapping of families with Saethre- Chotzen syndrome, the Göteborg scientists have now found that women with this syndrome have an elevated risk of contracting breast cancer.

Saethre- Chotzen is a syndrome that primarily involves malformations of the skull, face, hands, and feet. The syndrome is caused by mutations in a gene called TWIST1. “Our findings show that women with this syndrome run a nearly 20 times greater risk of contracting breast cancer than expected. Moreover, many of the women were young when they were affected by breast cancer," said Stenman.

The findings of the study show that women with this syndrome should receive early mammograms in order to discover breast cancer at an early stage. “We have already started to use this new knowledge in our work with patients and now recommend regular mammograms for young women with this syndrome.

Several early cases of breast cancer have already been uncovered with mammography," says Pelle Sahlin, chief physician at the Plastic Surgery Clinic.

Heart attack

A common genetic variation on chromosome 9p21 is linked to a substantial increase in risk for heart attack, according to a new international research study.

The findings are published in the 3 May online edition of Science. Researchers found individuals with the variation have a 1.64-fold greater risk of suffering a myocardial infarction and a 2.02-fold greater risk of suffering a heart attack early in life (before age 50 for men and before age 60 for women) than those without the variation.

Approximately 21% of individuals of European descent carry two copies of the genetic variation (one from each parent), found on chromosome 9p21.

“The gene variant we have linked to heart attack points us to a major biological mechanism that substantially increases the risk,” explained Emory University cardiologist Arshed Quyyumi, MD, one of the study authors.

“Discoveries like this one greatly heighten our understanding of the role genetics plays in heart disease.”


A key aspect of how embryos create the cells which secrete insulin is revealed in a new study published 18 May in the Journal of Biological Chemistry.

The researchers hope that their findings will enable the development of new therapies for diabetes, a condition caused by insufficient levels of insulin.

The research reveals that glucose plays a key role in enabling healthy beta cells, which secrete insulin, to develop in the pancreas of an embryo. Glucose prompts a gene called Neurogenin3 to switch on another gene, known as NeuroD, which is crucial for the normal development of beta cells.

If glucose levels are low this gene is not switched on. Insulin is the principal hormone that regulates the uptake of glucose and if the beta cells are unable to produce sufficient insulin, this can cause diabetes.

The scientists, from Imperial College London and an INSERM Unit at Necker Hospital, Paris, hope that understanding how to switch on the gene that produces beta cells could eventually enable researchers to create these cells from stem cells. They could then transplant beta cells into patients with type 1 diabetes.


The genes that make up the immune system of the Aedes aegypti mosquito which transmits deadly viral diseases, such as yellow fever and dengue, to humans have been identified in new research published in the 22 June 2007 issue of Science.

The immune system of this mosquito is of great importance as scientists believe it plays a key role in controlling the transmission of viruses that cause yellow and dengue fevers – diseases that infect over 50 million people worldwide every year.

This study is the first of its kind on the newlysequenced genome of the Aedes aegypti mosquito. The researchers identified over 350 genes which are involved in the Aedes mosquito's immune system, and discovered that they evolve much faster than the rest of the genes in the genome.

Identifying which of these key genes are implicated in the transmission of viral diseases is an area of future research that could lead to new ways of combating these diseases. One possibility would be to affect the activity of the genes and therefore help the mosquitoes fight off the viruses more effectively, preventing transmission to humans.

Dr George Christophides of UK-based Imperial College’s Division of Cell and Molecular Biology, senior author on the paper, explained: “Our study has revealed the genetic 'landscape' made by parts of this mosquito's newly-sequenced genome which are involved with immunity. By working to understand as much as possible about these genes, and the way they interact with specific pathogens, we hope to gain a more complete understanding of the mechanisms by which a pathogen either survives inside the insect body, or is killed by the insect's defences.”

The international research team, led by Imperial PhD student Robert Waterhouse, focused on comparing the immunity genes of the Aedes mosquito with similar groups of genes in the harmless fruit fly and the Anopheles mosquito that transmits malaria. When comparing the two different mosquitoes, the scientists found some similarities in the genes controlling their respective immune systems, but also numerous differences.

The team aims to discover which of these genetic differences could explain why one type of mosquito transmits dengue and yellow fevers, while the other transmits malaria. Beyond the present descriptive work, functional studies will be needed to clarify exactly how this happens. Reference: Evolutionary dynamics of immune-related genes and pathways in disease vector mosquitoes, Science, 22 June 2007.

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