Wellcome Trust Research Round-Up: 4/8/14

Our fortnightly look at research from around the Wellcome Trust community…

8.2% of our DNA is ‘functional’

Only 8.2% of human DNA is likely to be doing something important – or ‘functional’ – say Oxford University researchers funded by the Wellcome Trust and the MRC.

This figure is very different from one given in 2012, when some scientists involved in the ENCODE (Encyclopaedia of DNA Elements) project stated that 80% of our genome has some biochemical function.

That 80% claim has been controversial, with many in the field arguing that the biochemical definition of ‘function’ was too broad, and that just because an activity on DNA occurs, it does not necessarily have a consequence. They said that for true functionality you need to demonstrate that an activity matters.

To reach the new figure, the Oxford University group took advantage of the ability of evolution to discern which activities matter and which do not. They identified how much of our genome has avoided accumulating changes over 100 million years of mammalian evolution – a clear indication that this DNA matters, with functionality that needs to be retained.

“This is in large part a matter of different definitions of what is “functional” DNA,” says joint senior author Professor Chris Pointing of the MRC Functional Genomics Unit at Oxford University. “We don’t think our figure is actually too different from what you would get looking at ENCODE’s bank of data using the same definition for functional DNA.

“But this isn’t just an academic argument about the nebulous word “function”. These definitions matter. When sequencing the genomes of patients, if our DNA was largely functional, we’d need to pay attention to every mutation. In contrast, with only 8% being functional, we have to work out the 8% of the mutations detected that might be important. From a medical point of view, this is essential to interpreting the role of human genetic variation in disease.”

The researchers Chris Rands, Stephen Meader, Chris Ponting and Gerton Lunter report their findings in the journal PLOS Genetics.

New malaria vaccine targets found in large-scale study of patients in Kenya

Researchers have discovered new vaccine targets that could help in the battle against malaria. Taking a new, large-scale approach to this search, researchers tested a library of proteins from the Plasmodium falciparum parasite with antibodies produced by the immune systems of a group of infected children.

The tests measured which proteins the children’s immune systems responded to, revealing antigens that had not previously been identified, that could be used as possible vaccine targets. They also gained new insights into the ways antigens could be used in combination to increase protection.

“Resistance to malaria drugs is an increasing problem so vaccines are desperately needed to battle the Plasmodium falciparum parasite before it has a chance to make people sick,” says Dr Faith Osier, first author of the study, from the KEMRI-Wellcome Trust Research Programme. “This study presents us with a large number of new vaccine candidates that offer real hope for the future.”

A group of children infected with malaria were followed over a six-month period by scientists at KEMRI-Wellcome. While some patients became sick, others were protected by naturally occurring antibodies that stopped the malaria parasite from penetrating their red blood cells during the blood stage of the disease, which produces severe symptoms such as fever and anaemia.

Researchers used samples taken from these children to identify combinations of antibodies that provided up to 100 per cent protection against clinical episodes of malaria.

The study used a library of parasite proteins employing an approach that was developed at the Wellcome Trust Sanger Institute by Dr Gavin Wright and Dr Julian Rayner. These researchers had previously developed a new approach to express large panels of correctly folded, full-length proteins from the Plasmodium falciparum parasite, targeting proteins involved in the invasion of human red blood cells. In this study, published in Science Translational Medicine, Sanger Institute scientists collaborated with colleagues in Kenya to see which of them the children’s immune systems had developed antibodies against.

Brain scans examine response to food in genetically obese and normal weight

People who have the most common genetic mutation linked to obesity respond differently to pictures of appetising foods than overweight or obese people who do not have the genetic mutation, according to a new study by researchers at the Wellcome Trust-MRC Institute of Metabolic Science at Addenbrooke’s Hospital in Cambridge.

Obesity typically results from a combination of eating too much, getting too little physical activity, and genetics. Foods such as chocolate trigger signals in the brain that give a feeling of pleasure and reward, and these cravings can contribute to overeating. Reward signals are processed in specific areas of the brain, where sets of neurons release chemicals such as dopamine. However, very little is known about whether the reward centres of the brain work differently in some people who are overweight or obese.

The most common genetic cause of obesity involves mutations in the melanocortin 4 receptor (MC4R), which occur in about 1% of obese people and contribute to weight gain from an early age.

The researchers compared three groups of people: eight people who were obese due to a problem in the MC4R gene, 10 people who were overweight or obese without the gene mutation, and eight people who were normal weight. They performed functional Magnetic Resonance Imaging (fMRI) scans to look at how the reward centres in the brain were activated by pictures of appetising food such as chocolate cake, compared to bland food such as rice or broccoli, and non-food items such as staplers.

“In our study, we found that people with the MC4R mutation responded in the same way as normal weight people, while the overweight people without the gene problem had a lower response,” said lead researcher Dr Agatha van der Klaauw. “In fact the brain’s reward centres light up when people with the mutation and normal weight people viewed pictures of appetising foods. But overweight people without the mutation did not have the same level of response.”

The study is published in the Journal of Clinical Endocrinology & Metabolism.

In other news…

Scientists at the University of Sussex are beginning a £4 million project to develop an innovative new drug for treating the devastating psychiatric condition, schizophrenia. The project is funded by a Wellcome Trust Seeding Drug Discovery award.

Two new papers in the New England Journal of Medicine by Professor Nicholas White at the Wellcome Trust-funded Mahidol Oxford Tropical Medicine Research Unit have shown that malaria resistance has spread across Southeast Asia, but also that a new antimalarial drug in development at Novartis has shown some promising results.

Image credits: DNA by Peter Artymiuk, Wellcome Images; Kenyan Children by Brad Ruggles on Flickr, CC-BY-NC-SA; Chocolate cake by Ron Paul on Flickr, CC-BY-NC-SA; Broccoli by keithloaf1961 on Flickr, CC-BY-ND.