Trends in Genetics
ReviewPhylomedicine: an evolutionary telescope to explore and diagnose the universe of disease mutations
Section snippets
Evolutionary genomic medicine
Thousands of individuals in the general public have begun to gain access to their genetic variation profiles by using direct-to-consumer DNA tests available from commercial vendors; these tests profile hundreds of thousands of genomic markers at a cost of a few hundred dollars (Figure 1a). Through this genetic profiling individuals hope to learn about not only their ancestry but also about genetic variations underlying their physical characteristics and predispositions to diseases. In
Mendelian (monogenic) diseases
For centuries it has been known that particular diseases run in families, notably in some royal families where there was a degree of inbreeding. Once Mendel's principles of inheritance became widely known in the early 1900s it became evident from family genealogies that specific heritable diseases fit Mendelian predictions. These are termed Mendelian diseases (reviewed in [33]). Such diseases can have substantial impact on the affected individual but tend to be rare, on the order of one case
Multigenic (complex) diseases
Despite successes in identifying and mapping genes causing Mendelian diseases, it is now clear that most common diseases with significant genetic components, although they are often seen to cluster in families, do not approximate to the simple paradigm of high penetrance based on a dominant/recessive genotype. Instead, common diseases appear to result from a more complex pattern where many genes, and probably other non-genetic factors, contribute in non-additive ways, and individual monogenic
Evolutionary and biochemical constraints on disease-associated nSNVs
In addition to the evolutionary conservation of the positions in the protein, the biochemical properties of the amino acid change can also provide rich information. Not all changes at a position have an equal effect because one set of amino acid alternatives could be optimal, another set tolerable, and a third crippling to protein structure and function. Although the actual effect of a mutation is expected to be a complex function of the protein structure and its cellular milieu, many
Evolutionary diagnosis of function-altering mutations in silico
Over a decade ago, first methods were proposed to predict computationally whether a mutation will negatively affect the structure and function of a human protein 30, 66, 67, 68. These methods, now part of the PolyPhen software package, employed physical properties of the mutational change along with a multispecies alignment as a basis to evaluate mutations. This method showed promise: 69% of mutations associated with human disorders could be correctly diagnosed to be damaging to protein
Concluding remarks
The cosmic analogy used in the title of this review is intended to convey the enormity of the challenge that researchers in genomic medicine face as they attempt to decipher the functional consequences of the constellation of genomic changes carried in each personal genome. In tackling this challenge the evolutionary telescope is among a set of initial tools to generate functional predictions. Clearly, the progress made to date prompts enthusiasm, but there is an urgent need to develop better
Acknowledgments
We thank Vanessa Gray and Alicia Varma for literature searching, Maxwell Sanderford for mapping 23andMe information to the dbSNP database, and Carol Williams for edits. This work is supported by research grants from National Institutes of Health to S.K.
Glossary
- Complex disease
- refers to any disease having some genetic component of etiology that is characterized as involving the effects of many genes. Complex diseases are typically common in the population, exhibit complex patterns of inheritance, and often involve the interaction of genetic and environmental factors.
- Driver mutation
- somatic mutations implicated as having a causal role in the pathogenesis of cancer.
- Evolutionary retention
- a position-specific measure of conservation taking into account the
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