MRC Human Genetics Unit
Unit profile from the MRC Network publication issued January/February 2008.
The unit is at the forefront of human genetics research, and is unparalleled in advancing our understanding of the genetic factors implicated in human disease and in normal and abnormal development.
The unit was established in 1956 as the Clinical Effects of Radiation Unit under the directorship of Professor W M Court-Brown. Following the arrival of a new Director, Professor John Evans, in 1969, the unit grew considerably in size and reputation. It is now one of the largest MRC research establishments, supporting around 220 scientists, support staff, fellows, PhD students and visiting workers.
The Director, Professor Nick Hastie (right)
The current Director, Professor Nick Hastie, arrived almost 25 years ago to take up a post as a senior group leader, becoming Director in 1994.
Nick explained: “The unit aims to gain an understanding of the molecular basis of genetic disease and normal human development, and to understand the role of nuclear and cytoplasmic organisation in regulating the flow of information from DNA to an organism. Population genetics also plays an important role, in helping to identify genetic risk factors in common disease. We’re always keen to take our work forward and to investigate opportunities for possible therapies.”
Research at the unit is organised into three sections: medical and developmental genetics, chromosomal biology, and a new section, biomedical systems analysis. Each section plays a strategic role in contributing to the overall understanding of human genetics.
Chromosome packing
Professor Wendy Bickmore leads a group investigating the three-dimensional folding of the genome, and how this controls genome function. “Working out how our cells fit so much DNA into such a tiny nucleus in a useful way is a fascinating problem,” she said. “The approach we apply is primarily visual, using fluorescence microscopy to study the spatial organisation of genes and chromosomes in humans and mice.”
Microscopy allows Wendy to zoom in on individual cells in areas where genes are being activated, then to look at the position of the genes to see how tightly packed the chromosome is, and how and when the genes open up.
Last year, the group showed that changes in chromosome packing occur in patients with ICF, a syndrome with immunodeficiency and facial abnormalities, and they think these changes may contribute to changes in expression of genes in this disease. Wendy is now developing a technique that will allow her to control and alter the position of chromosomes in the nucleus and then monitor any changes this causes in gene expression.
Germ cell development
Dr Ian Adams is busy pulling together several different strands of enquiry to investigate the molecular mechanisms involved in a germ cell’s decision to become male or female. “This decision is important for human genetics, since female germ cells tend to transmit different types of mutations to those transmitted by male germ cells,” said Ian.
Ian identified a male-specific gene, expressed only in the testis from the time the decision to become male is made, which is involved in the secretion of molecules from one cell to other cells. When this secretion of molecules from cells supporting the germ cells was blocked, the sex of the germ cell was reversed and the germ cells became female.
Ian believes that a change in the cell biology of the supporting cells is behind the sex decision process, enabling these cells to increase secretion which, in turn, allows them to communicate the sex determination decision to all other cells. The next step is to identify the molecules being secreted by the male supporting cells that are telling the germ cells to become male. “Problems with germ cell development cause problems with fertility and we hope that our work will give us an insight into the possible causes of some fertility issues as well as cancers related to germ cell development,” explained Ian.
Disorders of the human brain
Andrew Jackson is a clinical geneticist particularly interested in using human genetics to help us understand how neurological conditions occur. “My philosophy is to study genetic neurological disorders, identify the genes involved, then study how the proteins they encode work both in health and disease,” he said. Andrew works with patients suffering from disorders of human brain size, Primary Microcephaly and Seckel syndrome, and those with Aicardi Goutières syndrome, a childhood autoimmune brain disease. In Primary Microcephaly patients, the brain is reduced to a third of normal size.
Andrew has been involved in identifying genes for this condition and the related condition, Seckel syndrome. Recently, with colleagues at the MRC Genome Damage and Stability Centre in Brighton, they identified mutations in the Pericentrin gene as a cause of Seckel syndrome, which results in patients having a similar head and body size to the recently discovered Homo floresiensis. Their work has also linked DNA damage signaling to a structural protein in the centrosome, which is involved in cell division, for the first time.
Biomedical systems analysis
Recent re-structuring at HGU has led to the creation of a biomedical systems analysis section, led by Professor Richard Baldock, which reflects the growing recognition that there should be greater development of ‘dry’ computational systems biology and statistical modelling within the unit to complement and extend the ‘wet’ biomedical science.
“We want to develop a much more mathematical and computational approach to our work,” explained Richard. “The unit generates masses of data and this will expand as new sequencing and imaging technologies come online. We need to be able to data-mine for more reliable interpretations and novel associations which, in turn, will allow us to develop new and better hypotheses that we can then test.”
The section has an explicit drive to build its work on programmes of research which are linked to other groups in the unit and within the IGMM.
Population genetics
These are exciting times for population genetics research. Scientists can now use whole genome scans to identify genes and biochemical mechanisms underlying many complex diseases.
As part of an ongoing collaboration between scientists in the unit and Croatia, data and samples have been collected from over 2,000 individuals from the Dalmatian islands. The fieldwork involved measurements of basic biochemistry, such as plasma cholesterol; physiological parameters, such as blood pressure; anthropometric traits, such as height and weight; as well as more specialised clinical data.
Volunteers also completed questionnaires relating to health, family information, personality and cognitive assessments. “Analysis of our data from Vis Island is already proving successful. We’re identifying new diseaserelated genes, and we hope these might lead to new understandings of the mechanisms of common disease,” said Dr Caroline Hayward.
The project is part of the EU Framework Programme 6 EUROSPAN consortium studying similar quantitative traits in isolated populations in Scotland, Sweden, the Netherlands and Italy in order to replicate, compare and contrast results.