Clinical classification of sequence variants identified in hereditary disease genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch Syndrome genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist variant classification, and recognized by microattribution. The scheme was refined by multidisciplinary expert committee review of clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants not obviously protein-truncating from nomenclature. This large-scale endeavor will facilitate consistent management of suspected Lynch Syndrome families, and demonstrates the value of multidisciplinary collaboration for curation and classification of variants in public locus-specific databases.

Increased spontaneous mutation is associated with increased cancer risk. Here, by using a model system, we show that spontaneous mutation can be increased several hundred-fold by a simple imbalance between the first two enzymes involved in DNA base excision repair. The Saccharomyces cerevisiae MAG1 3-methyladenine (3MeA) DNA glycosylase, when expressed at high levels relative to the apurinic͞apyrimidinic endonuclease, increases spontaneous mutation by up to Ϸ600-fold in S. cerevisiae and Ϸ200-fold in Escherichia coli. Genetic evidence suggests that, in yeast, the increased spontaneous mutation requires the generation of abasic sites and the processing of these sites by the REV1͞REV3͞REV7 lesion bypass pathway. Comparison of the mutator activity produced by Mag1, which has a broad substrate range, with that produced by the E. coli Tag 3MeA DNA glycosylase, which has a narrow substrate range, indicates that the removal of endogenously produced 3MeA is unlikely to be responsible for the mutator effect of Mag1. Finally, the human AAG 3-MeA DNA glycosylase also can produce a small (Ϸ2-fold) but statistically significant increase in spontaneous mutation, a result which could have important implications for carcinogenesis.Mutation is a characteristic of all living organisms and can arise from a variety of sources. DNA is chemically unstable and its replication imperfect; such instability and infidelity can generate mutations. In addition, a variety of endogenous metabolites and exogenous physical and chemical agents can generate potentially mutagenic DNA adducts. Despite these threats organisms maintain a relatively low mutation rate, due in part to a diverse group of DNA repair pathways (1). Defects in several kinds of DNA repair are known to elevate spontaneous mutation (2, 3), and certain mammalian DNA repair defects that influence spontaneous mutation result in remarkably increased cancer risk (4).Subtly altered DNA bases, such as deaminated, oxidized, and alkylated bases, are repaired by the highly conserved base excision repair pathway (5, 6). The first step of this multistep pathway involves the release of a modified DNA base by a specific DNA glycosylase. The resulting abasic site represents another form of DNA damage that is potentially cytotoxic and mutagenic (7,8). Abasic sites are processed, in most cases, by apurinic͞ apyrimidinic (AP) endonucleases that cleave DNA 5Ј to the abasic site, generating a single strand break that cannot be ligated. The abasic sugar residue is removed by deoxyribophosphodiesterase, the gap filled by DNA polymerase, and the remaining nick sealed by DNA ligase (5).In S. cerevisiae, the 3MeA DNA glycosylase encoded by MAG1 (9) is the major activity for removing alkylated bases. Mag1 releases a variety of bases from DNA in vitro, including 3MeA, 7-methylguanine, 7-methyladenine, 3-methylguanine (9, 10), 7-hydroxyethylguanine, 7-chloroethylguanine (11), 1,N 6 -ethenoadenine (12), and hypoxanthine (deaminated adenine) (13). The abasic sites generated by Mag1 are processed norm...

Oxidative phosphorylation is an indispensable resource of ATP in tissues with high requirement of energy. If the ATP demand is not met, studies suggest that this will lead to senescence and cell death in the affected tissue. The term reserve respiratory capacity or spare respiratory capacity is used to describe the amount of extra ATP that can be produced by oxidative phosphorylation in case of a sudden increase in energy demand. Depletion of the reserve respiratory capacity has been related to a range of pathologies affecting high energy requiring tissues. During aging of an organism, and as a result of mitochondrial dysfunctions, the efficiency of oxidative phosphorylation declines. Based on examples from the energy requiring tissues such as brain, heart, and skeletal muscle, we propose that the age-related decline of oxidative phosphorylation decreases the reserve respiratory capacity of the affected tissue, sensitizes the cells to surges in ATP demand, and increases the risk of resulting pathologies.

Accurate methods to assess the pathogenicity of mutations are needed to fully leverage the possibilities of genome sequencing in diagnosis. Current data-driven and bioinformatics approaches are, however, limited by the large number of new variations found in each newly sequenced genome, and often do not provide direct mechanistic insight. Here we demonstrate, for the first time, that saturation mutagenesis, biophysical modeling and co-variation analysis, performed in silico, can predict the abundance, metabolic stability, and function of proteins inside living cells. As a model system, we selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than inherent loss of function, and accordingly our in silico modeling data accurately identifies disease-causing mutations and outperforms the traditionally used genetic disease predictors. Thus, in conclusion, in silico biophysical modeling should be considered for making genotype-phenotype predictions and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases.

The 20th century saw an unprecedented increase in average human lifespan as well as a rapid decline in human fertility in many countries of the world. The accompanying worldwide change in demographics of human populations is linked to unanticipated and unprecedented economic, cultural, medical, social, public health and public policy challenges, whose full implications on a societal level are only just beginning to be fully appreciated. Some of these implications are discussed in this commentary, an outcome of Cultures of Health and Ageing, a conference co-sponsored by the University of Copenhagen (UCPH) and the Center for Healthy Ageing at UCPH, which took place on 20–21 June 2014 in Copenhagen, Denmark. Questions discussed here include the following: what is driving age-structural change in human populations? how can we create ‘age-friendly’ societies and promote ‘ageing-in-community’? what tools will effectively promote social engagement and prevent social detachment among older individuals? is there a risk that further extension of human lifespan would be a greater burden to the individual and to society than is warranted by the potential benefit of longer life?