Genetic signatures of exceptional longevity in humans

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.     

Biodemography of exceptional longevity: early-life and mid-life predictors of human longevity

This study explores the effects of early-life and middle-life conditions on exceptional longevity using two matched case-control studies. The first study compares 198 validated centenarians born in the United States between 1890 and 1893 to their shorter-lived siblings. Family histories of centenarians were reconstructed and exceptional longevity validated using early U.S. censuses, the Social Security Administration Death Master File, state death indexes, online genealogies, and other supplementary data resources. Siblings born to young mothers (aged less than 25 years) had significantly higher chances of living to 100 compared to siblings born to older mothers (odds ratio = 2.03, 95% CI = 1.33-3.11, p = .001). Paternal age and birth order were not associated with exceptional longevity. The second study explores whether people living to 100 years and beyond differ in physical characteristics at a young age from their shorter-lived peers. A random representative sample of 240 men who were born in 1887 and survived to age 100 was selected from the U.S. Social Security Administration database and linked to U.S. World War I civil draft registration cards collected in 1917 when these men were 30 years old. These validated centenarians were then compared to randomly selected controls who were matched by calendar year of birth, race, and place of draft registration in 1917. Results showed a negative association between "stout" body build (being in the heaviest 15 percent of the population) and survival to age 100. Having the occupation of "farmer" and a large number of children (4 or more) at age 30 increased the chances of exceptional longevity. The results of both studies demonstrate that matched case-control design is a useful approach in exploring effects of early-life conditions and middle-life characteristics on exceptional longevity.     

Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs

To move closer to understanding the mechanistic underpinnings of sex differences in human longevity, we studied pet dogs to determine whether lifetime duration of ovary exposure was associated with exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, age at death, and cause of death for a cohort of canine ‘centenarians’– exceptionally long‐lived Rottweiler dogs that lived more than 30% longer than average life expectancy for the breed. Sex and lifetime ovary exposure in the oldest‐old Rottweilers (age at death, ≥ 13 years) were compared to a cohort of Rottweilers that had usual longevity (age at death, 8.0–10.8 years). Like women, female dogs were more likely than males to achieve exceptional longevity (OR, 95% CI = 2.0, 1.2–3.3; P = 0.006). However, removal of ovaries during the first 4 years of life erased the female survival advantage. In females, a strong positive association between ovaries and longevity persisted in multivariate analysis that considered other factors, such as height, body weight, and mother with exceptional longevity. A beneficial effect of ovaries on longevity in females could not be attributed to resistance against a particular disease or major cause of death. Our results document in dogs a female sex advantage for achieving exceptional longevity and show that lifetime ovary exposure, a factor not previously evaluated in women, is associated with exceptional longevity. This work introduces a conceptual framework for designing additional studies in pet dogs to define the ovary‐sensitive biological processes that promote healthy human longevity.     

Genes encoding longevity: from model organisms to humans

Ample evidence from model organisms has indicated that subtle variation in genes can dramatically influence lifespan. The key genes and molecular pathways that have been identified so far encode for metabolism, maintenance and repair mechanisms that minimize age-related accumulation of permanent damage. Here, we describe the evolutionary conserved genes that are involved in lifespan regulation of model organisms and humans, and explore the reasons of discrepancies that exist between the results found in the various species. In general, the accumulated data have revealed that when moving up the evolutionary ladder, together with an increase of genome complexity, the impact of candidate genes on lifespan becomes smaller. The presence of genetic networks makes it more likely to expect impact of variation in several interacting genes to affect lifespan in humans. Extrapolation of findings from experimental models to humans is further complicated as phenotypes are critically dependent on the setting in which genes are expressed, while laboratory conditions and modern environments are markedly dissimilar. Finally, currently used methodologies may have only little power and validity to reveal genetic variation in the population. In conclusion, although the study of model organisms has revealed potential candidate genetic mechanisms determining aging and lifespan, to what extent they explain variation in human populations is still uncertain.     

The potential of and limitations to marine population prognosis

Following the 19th century recognition and definition of basic ecological entities, functional analysis has been the highlight of this century. The synthesis of these findings enables ecological prognosis. The population as the basic functional unit has been repeatedly treated; in the marine field, fisheries management approaches developed into multi-species population analysis. As in planktology, theoretical ecology, and classic biocoenotic research, the population interactions are of increasing scientific interest. A mathematical model is suggested that combines these extrinsic and intrinsic functional relationships in order to define the fit of the ecological niche to the environment, the decisive measure of the expected population success, and thus of the probable population development needed for prognostic purposes. It is discussed in how far the orientation towards the predictive power or — with respect to the “skill” of meteorological prognoses — the “ecological prognostic skill” improvement may serve as a means to choose the best investigative strategy.     

The genetics of sun sensitivity in humans

Humans vary >100-fold in their sensitivity to the harmful effects of ultraviolet radiation. The main determinants of sensitivity are melanin pigmentation and less-well-characterized differences in skin inflammation and repair processes. Pigmentation has a high heritability, but susceptibility to cancers of the skin, a key marker of sun sensitivity, is less heritable. Despite a large number of murine coat-color mutations, only one gene in humans, the melanocortin 1 receptor (MC1R), is known to account for substantial variation in skin and hair color and in skin cancer incidence. MC1R encodes a 317-amino acid G-coupled receptor that controls the relative amounts of the two major melanin classes, eumelanin and pheomelanin. Most persons with red hair are homozygous for alleles of the MC1R gene that show varying degrees of diminished function. More than 65 human MC1R alleles with nonsynonymous changes have been identified, and current evidence suggests that many of them vary in their physiological activity, such that a graded series of responses can be achieved on the basis of (i) dosage effects (of one or two alleles) and (ii) individual differences in the pharmacological profile in response to ligand. Thus, a single locus, identified within a Mendelian framework, can contribute significantly to human pigmentary variation.     

Prospects for the genetics of human longevity

Longevity varies between and within species. The existence of species-specific limit to human life-span and its partial heritability indicate the existence of genetic factors that influence the ageing process. Insight into the nature of these genetic factors is provided by evolutionary studies, notably the disposable soma theory, which suggests a central role of energy metabolism in determining life-span. Energy is important in two ways. First, the disposable soma theory indicates that the optimum energy investment in cell maintenance and repair processes will be tuned through natural selection to provide adequate, but not excessive, protection against random molecular damages (e.g. to DNA, proteins). All that is required is that the organism remains in a sound condition through its natural expectation of life in the wild environment, where accidents are the predominant cause of mortality. Secondly, energy is implicated because of the intrinsic vulnerability of mitochondria to damage that may interfere with the normal supply of energy to the cell via the oxidative phosphorylation pathways. Oxidative phosphorylation produces ATP, and as a by-product also produces highly reactive oxygen radicals that can damage many cell structures, including the mitochondria themselves. Several lines of evidence link, on the one hand, oxidative damage to cell ageing, and on the other hand, energy-dependent antioxidant defences to the preservation of cellular homeostasis, and hence, longevity. Models of cellular ageing in vitro allow direct investigation of mechanisms, such as oxidative damage, that contribute to limiting human life-span. The genetic substratum of inter-individual differences in longevity may be unraveled by a two-pronged reverse genetics approach: sibling pair analysis applied to nonagenarian and centenarian siblings, combined with association studies of centenarians, may lead to the identification of genetic influences upon human longevity. These studies have become practicable thanks to recent progress in human genome mapping, especially to the development of microsatellite markers and the integration of genetic and physical maps.     

The synaptonemal complex and meiotic recombination in humans: new approaches to old questions

Meiotic prophase serves as an arena for the interplay of two important cellular activities, meiotic recombination and synapsis of homologous chromosomes. Synapsis is mediated by the synaptonemal complex (SC), originally characterized as a structure linked to pairing of meiotic chromosomes (Moses (1958) J Biophys Biochem Cytol 4:633–638). In 1975, the first electron micrographs of human pachytene stage SCs were presented (Moses et al. (1975) Science 187:363–365) and over the next 15 years the importance of the SC to normal meiotic progression in human males and females was established (Jhanwar and Chaganti (1980) Hum Genet 54:405–408; Pathak and Elder (1980) Hum Genet 54:171–175; Solari (1980) Chromosoma 81:315–337; Speed (1984) Hum Genet 66:176–180; Wallace and Hulten (1985) Ann Hum Genet 49(Pt 3):215–226). Further, these studies made it clear that abnormalities in the assembly or maintenance of the SC were an important contributor to human infertility (Chaganti et al. (1980) Am J Hum Genet 32:833–848; Vidal et al. (1982) Hum Genet 60:301–304; Bojko (1983) Carlsberg Res Commun 48:285–305; Bojko (1985) Carlsberg Res Commun 50:43–72; Templado et al. (1984) Hum Genet 67:162–165; Navarro et al. (1986) Hum Reprod 1:523–527; Garcia et al. (1989) Hum Genet 2:147–53). However, the utility of these early studies was limited by lack of information on the structural composition of the SC and the identity of other SC-associated proteins. Fortunately, studies of the past 15 years have gone a long way toward remedying this problem. In this minireview, we highlight the most important of these advances as they pertain to human meiosis, focusing on temporal aspects of SC assembly, the relationship between the SC and meiotic recombination, and the contribution of SC abnormalities to human infertility.The synaptonemal complex–50 years     

Synthetic genomics: potential and limitations

Technologies to synthetically assemble chromosome sized fragments of DNA as well as to enable making thousands of simultaneous changes to existing genomes are now available. These capacities are collectively termed synthetic genomics. The implications of synthetic genomics extend beyond the limited pathway and gene engineering of the past to include the engineering or whole metabolisms, regulatory networks, and even ecosystems. However, in order for those potentials to be met, certain limitations and barriers must be overcome. These barriers no longer include DNA modification and assembly, but instead are based in the limited organisms that many synthetic genomics methods function in, and the limited software for designing custom genomic sequences.     

Evidence of correlated evolution of hypsodonty and exceptional longevity in endemic insular mammals

Here, we test whether the increase in tooth height in insular endemics results from the expansion of the dietary niche under resource limitation, as widely considered, or whether it represents an investment in dental durability in response to the selection for extended longevity under low levels of extrinsic mortality. We tested these hypotheses in the extremely hypsodont fossil bovid Myotragus balearicus from the Balearic Islands, an ideal model to study the evolutionary trends on islands. Dental abrasion was significantly lower in the insular bovid than in highly hypsodont continental artiodactyls, suggesting that feeding habits are not the sole driving force behind increased crown height. However, the estimated longevity for M. balearicus based on dental durability was two times that predicted from body mass. Survivorship curves confirm that an extraordinarily large number of individuals approached the longevity of the species. Our results, hence, provide evidence that hypsodonty in insular endemics is the outcome of selection for increased durability of the permanent dentition in association with an extended lifespan. In the context of insularity, our results lend additional support to the disposable soma theory of ageing confirming the dependency of somatic maintenance and repair on lifespan, and its control by resource availability and extrinsic mortality.     

The potential role of humans in structuring the wooded landscapes of Mesolithic Ireland: a review of data and discussion of approaches

This paper has two primary aims. Firstly, we review new data demonstrating interactions between people, plants, animals and woodlands in Mesolithic Ireland (ca. 8000–4000 cal. b.c.). This includes a synthesis of evidence from archaeological fishtraps, plant macrofossils, palynological indications of disturbance, and large mammal records. Secondly, we suggest that the potential role of humans in structuring the wooded landscape of the island of Ireland has been underestimated and is a key area for future research; Ireland may be an important case study for understanding the role of hunter-gatherers in influencing ecological relationships at the landscape scale. The new data demonstrate that existing models of the role of humans in structuring the wooded landscapes of Ireland are inadequate, and we suggest that new models are required.     

Genetic predisposition to bilharziasis in humans: research methods and application to the study of Schistosoma mansoni infection

The development of genetic epidemiology methods using recent human genetic mapping information together with the growing availability of candidate genes has led to major advances in the identification of host genes in human schistosomiasis. Two phenotypes have been studied so far in the infection by Schistosoma mansoni: infection levels by the parasite as measured by the faecal egg counts, and the severe hepatic fibrosis caused by S. mansoni assessed by ultrasound examination. The first study was performed on Brazilian pedigrees and provided strong evidence for a major gene controlling infection levels by S. mansoni denoted as SM1 which was mapped to chromosome 5q31-q33. This region contains several candidate genes involved in the regulation of the Th1/Th2 response, and the direct role of polymorphisms located within these genes is under investigation. The second study conducted in Sudan also showed the presence of a major gene influencing the development of severe hepatic fibrosis due to S. mansoni infection denoted as SM2. This gene is not located in the 5q31-q33 region, but maps to chromosome 6q22-q23 and is closely linked to the IFN-gamma R1 gene encoding the receptor of the strongly anti-fibrogenic cytokine Interferon-gamma. These findings indicate that two distinct genetic loci control human predisposition to schistosomiasis, SM1 located in the 5q31-q33 region which is likely to play a role in the Th1/Th2 differentiation, and SM2 in 6q22-q23 influencing disease progression with a possible involvement in the regulation of IFN-gamma.     

The genetics of cell death: approaches, insights and opportunities in Drosophila

Cell death is ubiquitous in metazoans and involves the action of an evolutionarily conserved process known as programmed cell death or apoptosis. In Drosophila melanogaster, it is now uniquely possible to screen for genes that determine the fate - life or death - of any cell or population of cells during development and in the adult. This review describes these genetic approaches and the key insights into cell-death mechanisms that have been obtained, as well as the outstanding questions that these techniques can help to answer.     

Theoretical framework of population genetics with somatic mutations taken into account: application to copy number variations in humans

Traditionally, population genetics focuses on the dynamics of frequencies of alleles acquired by mutations on germ-lines, because only such mutations are heritable. Typical genotyping experiments, however, use DNA from some somatic tissues such as blood, which harbors somatic mutations at the current generation in addition to germ-line mutations accumulated since the most recent common ancestor of the sample. This common practice may sometimes cause erroneous interpretations of polymorphism data, unless we properly understand the role of somatic mutations in population genetics. We here introduce a very basic theoretical framework of population genetics with somatic mutations taken into account. It is easy to imagine that somatic mutations at the current generation simply add individual-specific variations, as errors in mutation detection do. Our theory quantifies this increment under various conditions. We find that the major contribution of somatic mutations plus errors is to very rare variants, particularly to singletons. The relative contribution is markedly large when mutations are deleterious. Because negative selection also increases rare variants, it is important to distinguish the roles of these mutually confounding factors when we interpret the data, even after correcting for demography. We apply this theory to human copy number variations (CNVs), for which the composite effect of somatic mutations and errors may not be negligible. Using genome-wide CNV data, we demonstrate how the joint action of the two factors, selection and somatic mutations plus errors, shapes the observed pattern of polymorphism.     

Reviewing the somatic genetics of melanoma: from current to future analytical approaches

Metastatic melanoma has traditionally been difficult to treat, and although molecularly based targeted therapies have shown promising results, they have yet to show consistent improvements in overall survival rates. Thus, identifying the key mutation events underlying the etiology of metastatic melanoma will no doubt lead to the improvement of existing therapeutic approaches and the development of new treatment strategies. Significant advances toward understanding the complexity of the melanoma genome have recently been achieved using next-generation sequencing (NGS) technologies. However, identifying those mutations driving tumorigenesis will continue to be a challenge for researchers, in part because of the high rates of mutation compared to other cancers. This article will review the catalog of mutations identified in melanoma through a variety of approaches, including the use of unbiased exome and whole-genome NGS platforms, as well discuss complementary strategies for identifying driver mutations. The promise of personalized medicine afforded by better understanding these mutation events should provide impetus for increased activity and rapid advances in this field.