Mapping the Genomic Era

Mitochondrial mutations, genomics and genome sequencing were the topics of choice for social and natural scientists, policy makers and commentators from across the globe at the Economic and Social Research Council’s three-day annual conference in Cardiff

‘Mapping the Genomic Era: Measurements and Meanings’ was organised by the Economic and Social Research Council’s (ESRC) Cesagen centre based at the Universities of Cardiff and Lancaster - part of the wider ESRC Genomic Network, established to examine the social and economic consequences surrounding the development and use of genomics.

Keynote speaker, Professor Doug Turnbull, discussed the mitochondrial genome, mutation and disease. Turnbull - Professor of Neurology at Newcastle University and an honorary consultant neurologist at Newcastle upon Tyne Hospitals NHS Foundation Trust – has a long standing interest in both clinical and basic science research aspects of mitochondrial disease. The clinical research involves developing clinical rating scales and quality of life scales for patients with mitochondrial disease, as well as trials of exercise therapy.  His more basic research involves understanding the mechanism of neurological and other clinical features, and developing methods to prevent transmission of these diseases.

The mitochondrial genome - first sequenced in the early 1980s and roughly 16,500 bases (or 37 genes) long - is maternally inherited and has therefore become important in evolutionary studies looking at the historical movement of our species. However, what is not so widely appreciated is that it is also important as a source of human disease.

Mitochondrial DNA (mtDNA) disease is being increasingly recognised, and patients may present with a wide variety of symptoms, with illness ranging from a devastating illness in early childhood to a mild disturbance of eye movement later in life. In fact, patients usually present with a variety of clinical features, and can do so at a variety of different ages, from babies in their first few hours of life to patients in their sixties and seventies.

Unlike the nuclear genome, the mitochondrial genome is mostly coding – so deletion or point mutations are more likely to have an effect on the phenotype. As any schoolchild will be able to tell you, mitochondria are the ‘batteries’ of our cells, and if they run down it can affect several different tissues, especially those with high energy demands including the central nervous system and the muscles.

Also unlike the nuclear genome, there are many thousands of copies of the mitochondrial genome in each cell, meaning, explained Turnbull, “you have a totally different sort of genetics – heteroplasmy, which is a mixture of wild type and abnormal copies, or homoplasmy where everything is abnormal.”

In other words, the load of mutation is directly related to the phenotype, and in most cases, you need high levels of mutation to get a particular phenotype. In the case of heteroplasmy, the severity of the disease is in part dependent upon the proportion of mutated to wild-type mtDNA, or at least the total amount of wild type, he added.

Amongst those with mitochondrial mutations, problems commonly occur with the heart, the beta cells in the pancreas (meaning diabetes is common) and the hearing. A diagnosis of mutations in the mitochondrial DNA is made by looking at sections from a muscle biopsy. Mutated mtDNA is missing the key enzyme cytochrome oxidase, and muscle fibres with high levels of mutation show up white instead of brown.

The mitochondrial genome is an important source of disease

mtDNA goes through a bottleneck very early in a female’s development as the primordial germ cells develop - the number of copies of mtDNA drop from tens of thousands to about 200 and then increase again. So a woman with a heteroplasmic mutation may therefore have children with widely different levels of mutation. By way of example, Turnbull reported on one set of close relatives (two sisters and a cousin) with a mutation, where one individual is unaffected, one is mildly affected, and one severely affected by the disease, with the degree of heteroplasmy ranging from 10-80% in these three cases.

As Turnbull pointed out, providing counselling for women with mtDNA mutations is complicated. Whilst the majority of these defects are rare, the frequency of these mutations is higher than was previously thought. Studies on a birth cohort of 3,000 babies, found a common mutation occurred 1 in 500. A biopsy at 12 weeks can tell if the foetus has any mutations, as can pre-implantation tests on IVF embryos.

Turnbull finished by saying that many new techniques are being considered to help prevent transmission of mtDNA mutations. It is now possible to move a pro-nucleus into another embryo with only wild type mitochondria, or, as was recently reported in work on primates, even the metaphase II spindle can be transferred. As he pointed out though, such efforts raise many ethical questions as it essentially creates a baby with two mothers.

Fellow keynote speaker, Professor Yang Huanming, Director of the Beijing Genomics Institute, took his audience - or his teachers as he referred to them - on a breathless canter through his views on genomics and genome sequencing. Barely pausing to allow for audience laughter - of which there was plenty - Huanming swept through an overview of genomics research, with nods to Darwin, Douglas Adams, Craig Venter and others too numerous to mention, before focusing on the work of his own Institute.

Applauding the celebrations of Darwin’s life and work that have been so abundant this year, Huanming suggested that “Turning Darwin’s language into the four letters ACGT is one of the greatest achievements of human science.”

Author of the Hitchhikers Guide to the Universe, Douglas Adams, wrote that the answer to the ultimate question is 42, and according to Huanming, he wasn’t too wide of the mark. “Life is in sequence” - the 4 letters of genetic code, and “life is digital”, the 2 digits of binary code which support all our information systems.

“The sequencing revolution is only at the beginning,” Huanming announced, before noting that that the cost of sequencing the human genome is reducing so rapidly that soon it could cost as little as $100. But what does it mean if ‘my genome costs less than my bike’? “I’m convinced it will bring us more good than harm,” he said. “The era of personal genomics is upon us. This will transform not only how we take care of ourselves but also what we mean by ‘personal information’.”