Susceptibility to Neurodegenerative Disorders: Insights from Paleogenomic Data

Ancient human genome data that has accumulated in recent years can be employed to establish the spatiotemporal trajectories of genetic variants associated with human diseases. Such knowledge might illuminate if and how past adaptations impact contemporary human health and medicine. Scarcely any studies have yet been attempted to evaluate the genetic susceptibility to neurodegenerative disorders in ancient human communities. Using publicly available ancient human genome-wide data the present study evaluates the molecular predisposition to neurodegenerative disorders in ancient human communities. To this end we screened the ancient genome-wide data for the presence of variants unequivocally associated with neurodegenerative disorders in modern populations, and their historical and geographic prevalence was assessed. These variants are two rare variants in the LRRK2 gene associated with Mendelian Parkinson\u27s disease, a pathogenic variant in the CRH gene, associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), and a rare variant in the TREM2 gene, a possible risk modifier associated with Alzheimer\u27s disease. Our assessment of the historical and geographic prevalence indicates differing spatiotemporal frequency dynamics for these clinically significant variants. Neurodegenerative disorders are often with poorly understood pathogenesis that might be elucidated by studying the interaction of past genetic variability with ecological and evolutionary factors such as adverse environmental conditions, specific selective pressures, periods of population isolation and admixture processes. Data on molecular predisposition to neurodegenerative disorders in ancient genomes is instructive to modern medical diagnostic and therapeutic practices

Life history and demographic determinants of effective/census size ratios as exemplified by brown trout (Salmo trutta)

A number of demographic factors, many of which related to human-driven encroachments, are predicted to decrease the effective population size (Ne) relative to the census population size (N), but these have been little investigated. Yet, it is necessary to know which factors most strongly impact Ne, and how to mitigate these effects through sound management actions. In this study, we use parentage analysis of a stream-living brown trout (Salmo trutta) population to quantify the effect of between-individual variance in reproductive success on the effective number of breeders (Nb) relative to the census number of breeders (Ni). Comprehensive estimates of the Nb/N ratio were reduced to 0.16–0.28, almost entirely due to larger than binomial variance in family size. We used computer simulations, based on empirical estimates of age-specific survival and fecundity rates, to assess the effect of repeat spawning (iteroparity) on Ne and found that the variance in lifetime reproductive success was substantially higher for repeat spawners. Random family-specific survival, on the other hand, acts to buffer these effects. We discuss the implications of these findings for the management of small populations, where maintaining high and stable levels of Ne is crucial to extenuate inbreeding and protect genetic variability.publishedVersio

parentage data

The genotype data from three consecutive seasons used in the parentage assignment analyses. The columns in the dataset are as follows: trout-the identity of the individual fish, function-description whether an individual is a potential parent or an offspring in each season, distance-the distance in meters from the mouth of the stream, present-whether an individual was observed in the focal spawning season (1) or not(0), the sex, age and length of the individuals, and the genotypes for 15 microsatellite loci

Genomics of longevity: recent insights from research on centenarians

An ever larger portion of the world population survives into advanced old age, and that has been a steady trend for the last century. Despite some substantial advances in our understanding of the genomic basis of ageing in recent years, healthy ageing remains an increasingly important social task. Initially established in model organisms, many human orthologue genes and pathways associated with longevity have been identified. Ageing is a result from the declining ability of the human organism to maintain homeostatic balance and to regenerate damaged cells and tissues, and is the main risk factor for the prevalent diseases in developed countries. It could be imagined that the genome of very old individuals is purged of disease-causing variants, but recent studies have demonstrated that long-lived individuals carry the same number of disease alleles as young controls. Longevity may however also be explained by the presence of protective genetic factors against age-related phenotypes and diseases, and there is a pertinent need for these to be identified. Centenarians are the extreme phenotype of human longevity and their genomes undoubtedly contain clues about genes and pathways that are involved in longevity. Understanding the genomic basis of ageing, together with knowledge of population ecology and insights from evolutionary biology, will shed light on the biological mechanisms underlying human longevity and hence on the potential of extending healthy human life span

Data from: Mating patterns and determinants of individual reproductive success in brown trout (Salmo trutta) revealed by parentage analysis of an entire stream living population

Reproductive success and its determinants are difficult to infer for wild populations of species with no parental care where behavioral observations are difficult or impossible. In this study, we characterized the breeding system and provide estimates of individual reproductive success under natural conditions for a stream-resident, semi-isolated brown trout (Salmo trutta) population. We inferred parentage using a full probability Bayesian model that combines genetic (microsatellite) with phenotypic data. We had tried to exhaustively sample all individuals from a population, including large sib-ship families from three consecutive offspring cohorts. This allowed us to make inferences about the parental genotypes that had produced these families, and thus to augment the parent file with the inferred parental genotypes in cases where large families had unsampled parents. We observed both polygamous and monogamous matings and large reproductive skew for both sexes, but particularly so in males. We found no impact of individual neutral genetic variation or between-partners genetic similarity on reproductive success. Combining parentage analysis with sib-ship reconstruction allows for more precise inference on variance of family sizes and more definite statements on the determinants of reproductive success

Incidence of ancient variants associated with oncological diseases in modern populations

AbstractPublicly available genome-wide data, sequenced from 2730 ancient human samples were analyzed for genetic predisposition to malignancy. The temporal and spatial incidence of risk variants for cancer diseases in ancient genomes was recorded, allowing for estimates of their frequencies in ancient human communities. We identified 55 risk alleles associated with oncological conditions in the screened ancient samples. For further analysis, we selected three variants conclusively deemed to entail pathogenic effect, the VHL gene’s rs28940298, the TP53 gene’s rs78378222 and the BRCA2 gene’s rs11571833. The contemporary population frequency of these three variants is lower, or similar, to their estimated frequency in ancient human communities, indicating that they might have been subject to negative selection. This is also suggested by their temporal dynamics during the last 10000 years, which show an overall temporal decrease in population frequency. The oldest samples in which these three variants were established testify their ancient origin, including the presence of TP53 gene’s rs78378222 variant in 50000 BP old Neanderthal and Denisovan genomes. Our results demonstrate the presence of cancer-causing mutations in ancient human communities and suggest that they differed in frequency among ancient populations as they do among contemporary ones. Data on germline mutations in tumour suppressor genes in ancient human genomes are scarce and their historic prevalence gives insights into the evolution of predisposition to cancer disease and hence helps advance paleogenomic medicine

Data from: Genetic parentage analysis confirms a polygynandrous breeding system in the European grayling (Thymallus thymallus)

Knowing the breeding system of a species is important in order to understand individual variation in reproductive success. Large variation in reproductive success and thus reproductive skew strongly impacts on the effective number of breeders and thus the long-term effective population size (Ne). Fishes, in particular species belonging to the salmonid family, exhibit a wide diversity of breeding systems. In general, however, breeding systems are rarely studied in detail in the wild. Here we examine the breeding system of the spring-spawning European grayling Thymallus thymallus from a small Norwegian stream using parentage assignment based on the genotyping of 19 polymorphic microsatellite loci. In total 895 individual grayling fry and 154 mature grayling (57 females and 97 males) were genotyped. A total of 466 offspring were assigned a father, a mother, or a parent pair with a confidence of 90% or higher. Successfully reproducing males had on average 11.9 ± 13.3 (SD) offspring with on average 2.1 ± 1.2 partners, whereas successful females had on average 9.5 ± 12.8 offspring and 2.3 ± 1.5 partners. Parents with more partners also produced more offspring. Thus the grayling breeding system within this small stream revealed a polygynandrous breeding system, similar to what has been observed for many other salmonid fish species. The present study thus unambiguously corroborates a polygynadrous breeding system in the European grayling. This knowledge is critical for managing populations of this species, which has suffered significant local population declines throughout its range over the last several decades

parentage data

The genotype data from three consecutive seasons used in the parentage assignment analyses. The columns in the dataset are as follows: trout-the identity of the individual fish, function-description whether an individual is a potential parent or an offspring in each season, distance-the distance in meters from the mouth of the stream, present-whether an individual was observed in the focal spawning season (1) or not(0), the sex, age and length of the individuals, and the genotypes for 15 microsatellite loci