Professor David Cooper


School of Medicine

+44 29207 44062
Institute Of Medical Genetics
Media commentator

David N. Cooper is Professor of Human Molecular Genetics at Cardiff University.

His research interests are largely focused upon elucidating the mechanisms of mutagenesis underlying human genetic disease, but also include the study of the genotype–phenotype relationship in various inherited disorders, as well as human evolutionary and population genetics.

He has published ~500 papers in the field of human molecular genetics and has authored or edited a number of books including Human Gene Mutation (1993), Human Gene Evolution (1999), Nature Encyclopedia of the Human Genome (2003), Molecular Genetics of Lung Cancer (2005), Handbook of Human Molecular Evolution (2008) and Copy Number Variation and Disease (2009).

He curates the Human Gene Mutation Database (, a comprehensive database of mutations causing human inherited disease, which is marketed internationally through a commercial partner, Qiagen. P

rofessor Cooper is European Editor of Human Genetics and Editor of the Genetics & Disease section of Wiley’s Encyclopedia of Life Sciences. He is also a member of several Editorial Boards including the Journal of Medical Genetics and Human Mutation as well as Human Genomics.

He obtained his BSc in Biological Sciences (Hons. Zoology) from Edinburgh University in 1979 and his PhD in molecular biology from the same institution in 1983. He then held post-doctoral fellowships in Göttingen (Germany) and Lausanne (Switzerland) between 1983 and 1984. Having worked on the molecular genetics of inherited disorders of thrombosis and haemostasis at the University of London, he took up his present position in Cardiff in 1995.

Education and qualifications

1975-1979  University of Edinburgh, BSc Biological Sciences (Hons. Zoology) - First Class

1979-1982  University of Edinburgh, PhD in Molecular Biology. Medical Research Council Postgraduate Research Studentship, MRC Mammalian Genome Unit, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, UK.

Career overview

November 1995: Appointed Professor of Human Molecular Genetics, Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK

April 1995: Promoted to Reader in Molecular Genetics, Thrombosis Research Institute, National Heart & Lung Institute, Imperial College London, Manresa Road, London SW3 6LR, UK.

April 1989-March 1995: Appointed Senior Lecturer (non-clinical) in Molecular Genetics, Thrombosis Research Institute, National Heart & Lung Institute, Imperial College London, Manresa Road, London SW3 6LR, UK.

May 1987-March 1989: Appointed Lecturer (non-clinical) in Molecular Genetics, Haematology Department, King's College Hospital School of Medicine, University of London, Denmark Hill, London SE5 8RX, UK.

January 1985-April 1987: Post-Doctoral Research Fellow, Neurochemistry Department, Institute of Neurology, University College London, 1 Wakefield Street, London WC1N 1PJ, UK.

May 1984-December 1984: EMBO Long Term Fellowship, Institut de Biologie Animale, Université de Lausanne, CH-1015                                       Lausanne, Switzerland.

March 1983-April 1984:  Wissenschaftlicher Angestellter, Institut für Humangenetik, Georg-August-Universität Göttingen,                                     D-37070 Göttingen, Germany.

Researching the Nature, Mechanisms and Consequences of Human Gene Mutation

Mutation is a fundamental process in biology

Mutation of the DNA molecule is an absolutely fundamental process in biology. It occurs in all known species and serves to generate genetic variation between individuals, thereby providing the fuel for molecular evolution. In higher organisms, mutation is however also responsible for causing genetic disease. Indeed, mutations in human gene pathology and evolution can be seen as representing two sides of the same coin in that the same mutational mechanisms that have frequently been implicated in disease also appear to have been involved in potentiating evolutionary change. Consistent with their having underlying causal mechanisms in common, a remarkable parallelism often exists between the DNA sequence changes that have arisen in paralogous and orthologous gene sequences over evolutionary time and those much more recent sequence changes associated with inherited disease and cancer. It comes as no surprise to learn that this parallelism also extends to the DNA sequence changes responsible for inter-individual (polymorphic) variation. The explanation is that, although their contexts are quite different, many of these diverse types of mutation are endogenous in origin and have often arisen as a consequence of the inherent mutability of specific DNA sequences or DNA sequence motifs.

Mutation as a continuum of genetic change

Since different types of mutation in different contexts often share multiple unifying characteristics, they should be viewed as contributing to a continuum of genetic change that ultimately links molecular evolution and population genetics with molecular medicine. The consequences of each type of mutational event are however quite different in each context and it is these consequences that serve to determine whether the mutational changes in question come to clinical attention, are maintained within populations, or are fixed as species-specific differences.

Mutational spectra and what we can learn from them

The study of naturally occurring mutations is vital for understanding the genetic basis of human pathology, particularly the relationship between genotype and phenotype, and that between protein structure and function. As mentioned above, human gene mutation has turned out to be a highly sequence-specific process, irrespective of the type of lesion involved (Cooper et al. 2011). This has important implications, not only for the nature and prevalence of human genetic disease, but also for diagnostic practice in molecular medicine. Certain DNA sequences have been found to be hypermutable (mutation ‘hotspots’), thereby providing important clues as to the nature of the endogenous mechanisms underlying different types of human gene lesion, but also emphasizing the non-uniform nature of mutagenesis (Cooper et al. 2011). Hence, meta-analyses of the various different types of human gene mutation promise to facilitate the elucidation of the underlying mutational mechanisms and allow an assessment of the role of the local DNA sequence environment in promoting mutagenesis.

Most human germline mutations are of endogenous origin

Most, if not all, germline mutations in human genes are thought to represent errors of endogenous error-prone processes involving either chemical, physical or enzymatic mechanisms (Cooper et al. 2011). Since the efficiency of these processes is DNA-sequence dependent, it is not surprising that both the spectrum and spatial distribution of mutations exhibit biases that reflect the influence of the local DNA sequence environment upon germline mutability. This influence is at its most dramatic for the ‘CpG mutation hotspot’, characterized by high-frequency C>T and G>A transitions arising from the propensity of methylated CpG dinucleotides to deaminate to yield either TpG or CpA. The influence of DNA sequence context on mutability is however also important for other types of pathological mutation e.g. non-CpG-located single base-pair substitutions, as evidenced by the finding that nucleotide substitution rates differ, and are a function of the nature and sequence of the 5' and 3' flanking oligonucleotides. Further, we and others have shown that DNA sequence repetitivity, manifesting itself in the presence of direct or inverted repeats or ‘symmetric elements’, predisposes DNA to both deletion- and insertion-type mutational events.

Using the Human Gene Mutation Database (HGMD) as a research tool

Many of the above insights into the in vivo mechanisms underlying human germline mutagenesis have been obtained from the meta-analysis of mutation data logged in HGMD ( ). However, it should be appreciated that a major difficulty in utilizing disease-associated mutations as a research tool arises from the fact that such lesions have to pass through several stages of selection before coming to clinical attention. For example, most single base-pair substitutions in HGMD have either caused an amino acid replacement or introduced a termination codon. The changes ensuing at the RNA/protein level must have been severe enough to give rise to a disease phenotype but, at the same time, cannot have been subject to negative pre-clinical selection. This implies that the spectrum of single base-pair substitutions, as well as that of other types of mutational lesion included in HGMD, is heavily biased by the phenotypic consequences of the mutations. In addition, the retrospective nature of the HGMD data allows mutation rates to be estimated only in relative terms. We have developed a series of mathematical methods that seek to allow for, and correct, these biases.

Why study human gene mutation?

The sequencing of the human genome is now essentially complete and its functional annotation well underway. However, in relation to understanding the etiology of inherited disease and disease predisposition, full exploitation of the mutation data now emerging from multiple genome sequencing projects is likely to be hampered by our ignorance of the basic processes underlying inter-individual, inter-population and inter-species genetic diversity (Cooper et al. 2011). At the population level, such an understanding is seen as essential for any meaningful interpretation of the prevalence/incidence patterns observed for diseases with a genetic basis. Within families, it is a prerequisite for being able to explain how inter-individual variation arises and how variable phenotypic expression can be associated with identical gene lesions. Thus, for human genome sequence data to be useful in the context of molecular medicine, they must eventually be related to the DNA sequence variants responsible for human genetic disease (Cooper et al. 2011). To this end, the meta-analysis of pathological germline mutations in human genes should facilitate:

  • the assessment of the spectrum of known genetic variation underlying human inherited disease,
  • the identification of factors determining the propensity of specific DNA sequences to undergo germline (and/or somatic) mutation,
  • the optimization of mutational screening strategies,
  • improvements in our ability to predict the clinical phenotype from knowledge of the mutant genotype,
  • the identification of disease states that exhibit incomplete mutational spectra, prompting the search for, and detection of, novel gene lesions associated with different clinical phenotypes,
  • extrapolation toward the genetic basis of other, more complex traits and diseases,
  • improvements in our understanding of structure-function relationships at the protein level,
  • meaningful comparison between the mechanisms of mutagenesis underlying inherited disease and somatic disease (cancer),
  • studies of human genetic diseases in their evolutionary context.

Potential Value of Research

We hope that the results of our studies will:

  1. Lead to a better understanding of the mutational mechanisms underlying specific types of gene lesion, thereby providing meaningful explanations for the mutational spectra associated with particular diseases and/or genes.
  2. Help to optimize mutation search strategies in molecular diagnostic medicine and serve as a guide to the potential location of hypermutable sites in genes whose mutational spectra are incompletely known.
  3. Allow general rules of mutagenesis to be drawn up that will facilitate studies of gene and genome evolution.
  4. Lead to improvements in the accuracy of molecular phylogenetic studies by making allowance for DNA sequence-dependent mutation rates.
  5. Lead to the development of further research avenues since new ideas arising will have to be tested not only by statistical techniques but ultimately also by biochemical studies.


Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H. (2013) Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum. Genet. 132: 1077-1130.

Cooper DN, Bacolla A, Férec C, Vasquez KM, Kehrer-Sawatzki H, Chen JM. (2011) On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum Mutat. 32:1075-99

Cooper DN, Chen JM, Ball EV, Howells K, Mort M, Phillips AD, Chuzhanova N, Krawczak M, Kehrer-Sawatzki H, Stenson PD. (2010) Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics. Hum. Mutat. 31:631-655.

Areas of expertise