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Human Gene Mutation Group

Researching the nature, mechanisms and consequences of human gene mutation.

Researching the nature, mechanisms and consequences of human gene mutation.

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.

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:

  1. the assessment of the spectrum of known genetic variation underlying human inherited disease
  2. the identification of factors determining the propensity of specific DNA sequences to undergo germline (and/or somatic) mutation
  3. the optimisation of mutational screening strategies
  4. improvements in our ability to predict the clinical phenotype from knowledge of the mutant genotype
  5. 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
  6. extrapolation toward the genetic basis of other, more complex traits and diseases
  7. improvements in our understanding of structure-function relationships at the protein level
  8. meaningful comparison between the mechanisms of mutagenesis underlying inherited disease and somatic disease (cancer)
  9. studies of human genetic diseases in their evolutionary context.


We hope that the results of our studies will:

  • 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.
  • help to optimise 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.
  • allow general rules of mutagenesis to be drawn up that will facilitate studies of gene and genome evolution.
  • lead to improvements in the accuracy of molecular phylogenetic studies by making allowance for DNA sequence-dependent mutation rates.
  • 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.

Nature and mechanisms of human gene mutation in inherited disease

Disease-causing mutations

A wide variety of different types of pathogenic mutation occur in the human genome with many diverse mechanisms being responsible for their generation. These types of mutation include single base-pair substitutions in coding, regulatory and splicing-relevant regions of human genes, as well as micro-deletions, micro-insertions, duplications, repeat expansions, combined micro-insertions/deletions (‘indels’), inversions, gross deletions and insertions, and complex rearrangements.

A major goal of molecular genetic medicine is to be able to predict the nature of the clinical phenotype through ascertainment of the genotype. However, the extent to which this is feasible in medical genetics is very much disease-, gene- and mutation-dependent.

The study of mutations in human genes is nevertheless of paramount importance for understanding the pathophysiology of inherited disorders, for optimising diagnostic testing, as well as in guiding the design of new therapeutic approaches.

DNA polymorphisms

Human DNA polymorphisms have proven extremely useful in developing linkage maps, for mapping monogenic and polygenic complex disorders, for determining the origin of aneuploidies and chromosomal abnormalities, for distinguishing normal from mutant chromosomes in genetic diagnoses, for performing forensic, paternity, and transplantation studies, for studying the evolution of the genome, the loss of heterozygosity in certain malignancies, the detection of uniparental disomy, the instability of the genome in certain tumours, recombination at the level of the genome, the study of allelic expression imbalance, and the development of haplotype maps of the genome.

However, in studying the role of a candidate gene in a given disorder, it is essential to distinguish between pathological mutations that are responsible for causing a specific clinical phenotype and the polymorphic variants of the normal genome.

Molecular mechanisms of mutation in cancer

Mutational spectra in the germline and the soma

Many genes appear to be mutated during the process of tumorigenesis. These genes include oncogenes, tumour suppressor genes, DNA repair genes, apoptotic and cell cycle regulatory genes etc. The somatic mutations may be subtle (single base-pair substitutions) or gross (loss of heterozygosity, gene amplification, translocation etc) and may serve either to alter the function of the gene product or increase, decrease or abolish the expression of these genes in the tumour tissue.

A major distinction to be made between somatic and germline mutations is that the former occur during mitosis whereas the latter are generally meiotic in origin. In addition, whilst somatic cancer-causing gene lesions come to clinical attention by conferring a growth advantage upon the affected cells or tissue, germ-line gene mutations causing inherited disease normally come to attention by conferring a disadvantage upon the individual, usually through haploinsufficiency.

Finally, whereas inherited disease usually implies the presence of only one or two pathological mutations at a specific locus, cancer is often characterised by a multitude of somatic mutations, scattered genome-wide, many of which may be a consequence rather than a cause of the disease. Despite these basic differences, mutational spectra, involving single base-pair substitutions, micro-deletions, micro-insertions and gross gene rearrangements, often appear to exhibit certain similarities between the germline and the soma.

Mutation of tumour suppressor genes in the germline and the soma

Cancer predisposition genes can exhibit either somatic or germline mutations. There is, however, one category of cancer predisposition gene, broadly termed tumour suppressors, that by virtue of their being mutated in both the germline and the soma, provides us with ideal model systems in which to study mutation of the same gene in both cell lineages.

Tumour suppressor genes have been defined as 'genes that sustain loss-of-function mutations in the development of cancer'. They are involved in the regulation of a diverse array of different cellular functions including cell cycle checkpoint control, detection and repair of DNA damage, protein ubiquitination and degradation, mitogenic signaling, cell specification, differentiation and migration, and tumour angiogenesis. They often encode proteins with a regulatory role in cell cycle progression (eg Rb) but may also encode DNA-binding transcription factors (eg p53) and inhibitors of cyclin-dependent kinases required for cell cycle progression (eg p16).

In inherited cancer syndromes, the mutational inactivation of both tumour suppressor alleles is required to change the phenotype of the cell. This 'two hit hypothesis' provides the basis for a mechanistic understanding of tumour suppressor gene mutagenesis: a first (inherited) mutation in one tumour suppressor allele is followed by the somatic loss of the remaining wild-type allele via a number of different mutational mechanisms.

Whilst the inherited lesion is usually fairly subtle, the second (somatic) hit may often involve the deletional loss of the entire gene or even a substantial portion of the chromosome involved. Alternatively, in sporadic cases, both ‘hits’ may constitute somatic mutations: whatever the actual mechanism, the end result is the same – the loss or inactivation of both gene copies.

Molecular mechanisms of mutation in evolution

Mutations in human gene pathology and evolution represent two sides of the same coin in that the same mechanisms that have frequently been implicated in disease-associated mutagenesis appear also to have been involved in potentiating evolutionary change.

Indeed, the mutational spectra of germline mutations responsible for inherited disease, somatic mutations underlying tumorigenesis, polymorphisms (either neutral or functionally significant) and differences between orthologous gene sequences exhibit remarkable similarities, implying that they may often have causal mechanisms in common.

Since these different categories of mutation share multiple unifying characteristics, they should no longer be viewed as distinct entities but rather as portions of a continuum of genetic change that links population genetics and molecular medicine with molecular evolution.

Irrespective of whether the mutational changes are advantageous, disadvantageous or neutral, their putative underlying causal mechanisms are likely to be very similar. It is now clear that the gene has often been a dynamic entity over evolutionary time, not a static one.

Indeed, during vertebrate evolution, many genes have undergone gross rearrangement as a result of the action of any one of a number of mutational processes such as insertion, inversion, duplication, repeat expansion, translocation or deletion. It turns out that even relatively conserved genes do not necessarily always change by a slow incremental process of single base-pair substitutions; rather, such genes may acquire multiple nucleotide substitutions simultaneously by mechanisms such as gene conversion.

At the heart of the way in which we conceptualise the process of evolution is an apparent dichotomy: on the one hand, sequence conservation is usually held to imply functionality, on the other, the emergence of novel functions implies change.

Thus, selection may act conservatively so as to retain features of structural or functional importance (negative or purifying selection) or act so as to favour changes that confer some advantageous characteristic (positive selection). Evolution can, however, also proceed in a stochastic neutralist fashion, some features being adopted not necessarily because of any selective advantage accruing to the organism but rather owing to the vagaries of population size, structure or dynamics over an extended period of time. In practice, these diverse mechanisms are acting in different combinations and permutations at many loci simultaneously.

Selected publications

Principal Investigator

Professor David Cooper

Professor David Cooper


+44 (0)29 2074 4062

The Human Gene Mutation Database (HGMD) represents a comprehensive collection of germ-line mutations in nuclear genes, underlying or associated with human inherited disease.

HGMD includes single base-pair substitutions in coding (missense and nonsense), regulatory and splicing-relevant regions of human nuclear genes, micro-deletions and microinsertions, indels, repeat expansions, as well as gross gene lesions (deletions, insertions and duplications) and complex gene rearrangements.

Go to the HGMD

This unique resource currently contains in excess of 134,000 different germline mutations and disease-associated/functional polymorphisms, in a total of over 5,100 nuclear genes (December 2012, HGMD Professional release), causing or associated with human inherited disease.

Access to HGMD

HGMD currently provides free access to the bulk of its mutation data to over 58,000 registered academic/non-profit users worldwide. In the absence of any public funding, HGMD is maintained courtesy of a subscription-based version - HGMD Professional, distributed through BIOBASE GmbH.

HGMD Professional not only provides access to the very latest mutation data, but also contains valuable extra features, including an expanded search engine, genomic coordinates, additional literature references, Human Genome Variation Society (HGVS) nomenclature, SIFT and MutPred predictions, data on evolutionary conservation and disease ontology as well as a suite of advanced search tools that greatly enhance the utility of the database.

Together with BIOBASE, we are working toward being able to make all HGMD data and search tools available to the academic community free of charge and in a timely fashion, with the costs of up-keep being borne primarily by industry and commerce.

We believe that this funding model should not only guarantee the financial viability of HGMD, but will also allow this unique resource to be sustainable into the long term, to the benefit of the scientific community.