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Genomic technologies in archaeology have been used to study migration patterns, origin of and genetic similarity between ancient populations. Researchers are, however, just beginning to employ these technologies to evaluate the genomic health of ancient communities. In this study we screen publicly available whole-genome sequencing data of pre-contact Caribbean individuals for the presence of pathogenic mutations causing monogenic diseases. Our results show that Caribbean communities from the Ceramic Age (3100–400 BP) had an unusually high frequency of pathogenic variants associated with three monogenic conditions, Classical Phenylketonuria, Hypohidrotic Ectodermal Dysplasia and LRRK2-Related Parkinson’s disease. The estimated frequency of these variants from the analyzed ancient samples is severalfold higher than that in contemporary populations. Three conditions classified today as rare diseases thus might have had much higher prevalence in the past. Studying the history of monogenic diseases from ancient communities will expand the list of rare diseases with larger prevalence in the past.

The present study aims to identify pathogenic/risky variants in the exomes of healthy young individuals predisposing to Alzheimer's disease (AD) by their validation in centenarian's exomes. The group of Bulgarian centenarians included 32 individuals (mean age 102.4) without AD diagnosis and the matched control group of 61 young healthy individuals (mean age 21.9). Two DNA pools were constructed with equimolar amounts of DNA from each participant and whole exome sequencing analysis (WES) was performed. We examined the WES data for pathogenic or risky SNPs predisposing to AD. Of altogether 1929 variants selected from DisGeNet database for association with AD, only 174 (9.02%) were detected in our WES data. One hundred and fifty-two (152) SNPs were present in both studied groups, 8 in centenarians and 14 in controls only. Seven variants have significantly higher frequency in young individuals or absence in centenarians. Based on sufficiently unambiguous literature data, we nominated rs63750264 in APP, rs429358 in APOE, rs1800562 in HFE variants for predisposition to AD in young individuals. To a lesser extent, the carriership of rs2070045 in SORL1, rs6265 in BDNF, rs769449 in APOE, rs4988514 in SST can increase the risk to AD development. These variants could find implication in the Alzheimer's disease estimation in young individuals before the onset of clinical symptoms.

Contemporary genetic methods have not yet solved the ‘missing heritability’ problem of complex diseases such as Alzheimer’s disease (AD). The impact of rare or less common variation on human complex diseases and traits remains to date barely investigated. In this study rare population variants detected using whole-exome sequencing were employed to examine how molecular pathways are prioritized in four groups: Alzheimer’s disease (AD) patients, Frontotemporal dementia (FTD) patients, young and healthy individuals and centenarians. The set of prioritized genes in AD patients associated with Semaphorin interactions pathways, contrasting with the results of the other groups. We identified rare pathogenic, likely pathogenic and variants of unknown significance in these prioritized genes in AD patients. The results of this study offer evidence that semaphorin pathways play a role in AD genetic etiology.

Ancient anatomically modern humans (AMHs) encountered other archaic human species, most notably Neanderthals and Denisovans, when they left Africa and spread across Europe and Asia ~60,000 years ago. They interbred with them, and modern human genomes retain DNA inherited from these interbreeding events. High quality (high coverage) ancient human genomes have recently been sequenced allowing for a direct estimation of individual heterozygosity, which has shown that genetic diversity in these archaic human groups was very low, indicating low population sizes. In this study, we analyze ten ancient human genome-wide data, including four sequenced with high-coverage. We screened these ancient genome-wide data for pathogenic mutations associated with monogenic diseases, and established unusual aggregation of pathogenic mutations in individual subjects, including quadruple homozygous cases of pathogenic variants in the PAH gene associated with the condition phenylketonuria in a ~120,000 years old Neanderthal. Such aggregation of pathogenic mutations is extremely rare in contemporary populations, and their existence in ancient humans could be explained by less significant clinical manifestations coupled with small community sizes, leading to higher inbreeding levels. Our results suggest that pathogenic variants associated with rare diseases might be the result of introgression from other archaic human species, and archaic admixture thus could have influenced disease risk in modern humans.

Mitochondrial DNA variants associated with diseases are widely studied in contemporary populations, but their prevalence has not yet been investigated in ancient populations. The publicly available AmtDB database contains 1443 ancient mtDNA Eurasian genomes from different periods. The objective of this study was to use this data to establish the presence of pathogenic mtDNA variants putatively associated with mitochondrial diseases in ancient populations. The clinical significance, pathogenicity prediction and contemporary frequency of mtDNA variants were determined using online platforms. The analyzed ancient mtDNAs contain six variants designated as being “confirmed pathogenic” in modern patients. The oldest of these, m.7510T>C in theMT-TS1gene, was found in a sample from the Neolithic period dated 5800-5400 BCE. All six have well established clinical association, and their pathogenic effect is corroborated by very low population frequencies in contemporary populations. In addition, ten variants designated as possibly or likely pathogenic were detected. The oldest of these were two variants in theMT-TDgene, m.7543A>G and m.7554G>A, from Neolithic samples dated 8205-7700 BCE. A novel mutation in contemporary populations, m.4440G>A in theMT-TMgene, is established in 12 ancient mtDNA samples from different periods ranging from 2800 BCE to 920 CE. The pathogenic effect of these possibly/likely pathogenic mutations is not yet well established, and further research is warranted. All detected mutations putatively associated with mitochondrial disease in ancient mtDNA samples are in tRNA coding genes. Most of these mutations are in a mt-tRNA type (Model 2) that is characterized by loss of D-loop/T-loop interaction. Seven mutations are located in CS-Anticodon stem, 4 are located in AS-Acceptor stem, 2 in TS-TΨC stem, and single mutations are found in DL-Dihydrouridine Loop, CL-Anticodon Loop and DS-Dihydrouridine stem. Exposing pathogenic variants in ancient human populations expands our understanding of their origin.

Objectives: The aim of the present study was to evaluate the clinical relevance of mutations in tumor suppressor genes using whole-exome sequencing data from centenarians and young healthy individuals. Methods: Two pools, one of centenarians and one of young individuals, were constructed and whole-exome sequencing was performed. We examined the whole-exome sequencing data of Bulgarian individuals for carriership of tumor suppressor gene variants. Results: Of all variants annotated in both pools, 5080 (0.06%) are variants in tumor suppressor genes but only 46 show significant difference in allele frequencies between the two studied groups. Four variants (0.004%) are pathogenic/risk factors according to single nucleotide polymorphism database: rs1566734 in PTPRJ, rs861539 in XRCC3, rs203462 in AKAP10, and rs486907 in RNASEL. Discussion: Based on their high minor allele frequencies and presence in the centenarian group, we could reclassify them from pathogenic/risk factors to benign. Our study shows that centenarian exomes can be used for re-evaluating the clinically uncertain variants.

The aim of the present study was to detect copy number variations (CNVs) related to tumour progression and metastasis of urothelial carcinoma through whole-genome scanning. A total of 30 bladder cancer samples staged from pTa to pT4 were included in the study. DNA was extracted from freshly frozen tissue via standard phenol-chloroform extraction and CNV analysis was performed on two alternative platforms (CytoChip Oligo aCGH, 4x44K and Infinium OncoArray-500K BeadChip; Illumina, Inc.). Data were analysed with BlueFuse Multi software and Karyostudio, respectively. The results highlight the role of genomic imbalances in regions containing genes with metastatic and proliferative potential for tumour invasion. A high level of genomic instability in uroepithelial tumours was observed and a total of 524 aberrations, including 175 losses and 349 gains, were identified. The most prevalent genetic imbalances affected the following regions: 1p, 1q, 2q, 4p, 4q, 5p, 5q, 6p, 6q, 7q, 8q, 9p, 9q, 10p, 10q, 11q, 13q and 17q. High-grade tumours more frequently harboured genomic imbalances (n=227) than low-grade tumours (n=103). A total of 36 CNVs in high-grade bladder tumours were detected in chromosomes 1-5, 8-11, 14, 17, 19 and 20. Furthermore, five loss of heterozygosity variants containing 176 genes were observed in high-grade bladder cancer and may be used as potential targets for precision therapy. Revealing specific chromosomal regions related to the metastatic potential of uroepithelial tumours may lay a foundation for implementing molecular CNV profiling of bladder tumours as part of a routine progression risk estimation strategy, thus expanding the personalized therapeutic approach.

In this study, we developed a method of fractional parentage analysis using microsatellite markers. We propose a method for calculating parentage probability, which considers missing data and genotyping errors due to null alleles and other causes, by regarding observed alleles as realizations of random variables which take values in the set of alleles at the locus and developing a method for simultaneously estimating the true and null allele frequencies of all alleles at each locus. We then applied our proposed method to a large sample collected from a wild population of brown trout (Salmo trutta). On analyzing the data using our method, we found that the reproductive success of brown trout obeyed a power law, indicating that when the parent-offspring relationship is regarded as a link, the reproductive system of brown trout is a scale-free network. Characteristics of the reproductive network of brown trout include individuals with large bodies as hubs in the network and different power exponents of degree distributions between males and females.

Habitat fragmentation is an increasing threat to wildlife species across the globe and it has been predicted that future biodiversity will decrease rapidly without the intervention of scientifically-based management. In this study we have applied a landscape genetics approach to suggest a network design that will maintain connectivity among populations of the endangered mountain Nyala (Tragelaphus buxtoni) in the fragmented highlands of Ethiopia. DNA was obtained non-invasively from 328 individuals and genetic population structure and gene flow were estimated using 12 microsatellite markers. In addition, a 475-bp segment of the mitochondrial control region was sequenced for 132 individuals. Potential dispersal corridors were determined from least-cost path analysis based on a habitat suitability map. The genetic data indicated limited gene flow between the sampled mountain Nyala populations of the Bale Massif and the Arsi Massif. The genetic differentiation observed among five sampling areas of the Bale Massif followed a pattern of isolation by distance. We detected no impact of habitat resistance on the gene flow. In the future, however, the current expanding human population in the highlands of Ethiopia may reduce the current mountain Nyala habitat and further limit migration. Hence, maintaining habitat connectivity and facilitating survival of stepping-stone populations will be important for the future conservation of the species. The approach used here may also be useful for the study and conservation of other wildlife species inhabiting areas of increasing human encroachment.

Many animals move among habitats, and even small-scale dispersal of individuals between habitat patches may have strong implications for population dynamics and structure. Here, we use long-term mark-recapture data combined with extensive genotyping and parentage assignment to investigate the importance of small-scale location change of resident brown trout (Salmo trutta) in a small stream (1500 m). During the first summer, juvenile fish dispersed downstream (mean displacement 200 m), with smaller juveniles dispersing longer distances. Downstream movement was also predominant dur- ing the first winter, but older fish moved little. This limited dispersal resulted in a significant isolation-by-distance structure for ages 1 and 2, but not for older age groups or for the mature fish. Individual pairwise relatedness coefficients decreased with waterway distance for mature fish during the 2002 and 2003 spawning seasons, but only weakly. Overall, between-site genetic differentiation was stronger for the younger age classes, and the signal decayed with age, indicating that the genetic structure observed in the stream is mainly driven by spatial aggregation of close relatives. Resume : De nombreux animaux se deplacent d'un habitat a l'autre et la dispersion, meme a petite echelle, d'individus en- tre differentes parcelles d'habitat peut avoir d'importantes repercussions sur la dynamique et la structure des populations. Nous utilisons des donnees de marquage-recapture a long terme combinees au genotypage et a la determination de la filia- tion de nombreux specimens pour etudier l'importance des changements d'emplacement a petite echelle de la truite de mer (Salmo trutta) dans un petit cours d'eau (1500 m). Au cours du premier ete, les poissons juveniles se sont disperses vers l'a- val (deplacement moyen de 200 m), les juveniles plus petits se dispersant sur de plus grandes distances. Les deplacements vers l'aval etaient egalement predominants durant le premier hiver, bien que les poissons plus âges se soient peu deplaces. Cette dispersion limitee s'est traduite par une structure d'isolement par la distance significative pour les groupes d'un et deux ans d'âge, mais non pour les groupes de juveniles plus âges ou les poissons matures. Les coefficients de correlation par paire individuels montraient une faible diminution en fonction de la distance le long du cours d'eau pour les poissons matures durant les periodes de frai de 2002 et 2003. Dans l'ensemble, la differentiation genetique entre emplacements etait plus forte pour les classes d'âges plus jeunes, le signal diminuant avec l'augmentation de l'âge, ce qui indique que la struc- ture genetique observee dans le cours d'eau est principalement controlee par l'agregation spatiale de parents proches. (Traduit par la Redaction)

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.

Reproductive success and its determinants are difficult to infer for wild populations of species with no parental care where behavioural observations are difficult or impossible. In this study, we characterized the breeding system and provide estimates of individual reproductive success under natural conditions for an exhaustively sampled stream-resident brown trout (Salmo trutta) population. We inferred parentage using a full probability Bayesian model that combines genetic (microsatellite) with phenotypic data. By augmenting the potential parents file with inferred parental genotypes from sib-ship analysis in cases where large families had unsampled parents, we could make more precise inference on variance of family size. We observed both polygamous and monogamous matings and large reproductive skew for both sexes, particularly in males. Correspondingly, we found evidence for sexual selection on body size for both sexes. We show that the mating system of brown trout has the potential to be very flexible and we conjecture that environmental uncertainty could be driving the evolution and perhaps select for the maintenance of plasticity of the mating system in this species.

Adaptability depends on the presence of additive genetic variance for important traits. Yet few estimates of additive genetic variance and heritability are available for wild populations, particularly so for fishes. Here, we estimate heritability of length-at-age for wild-living brown trout (Salmo trutta), based on long-term mark-recapture data and pedigree reconstruction based on large-scale genotyping at 15 microsatellite loci. We also tested for the presence of maternal and paternal effects using a Bayesian version of the Animal model. Heritability varied between 0.16 and 0.31, with reasonable narrow confidence bands, and the total phenotypic variance increased with age. When introducing dam as an additional random effect (accounting for c. 7% of total phenotypic variance), the level of additive genetic variance and heritability decreased (0.12–0.21). Parental size (both for sires and for dams) positively influenced length-at-age for juvenile trout – either through direct parental effects or through genotype-environment correlations. Length-at-age is a complex trait reflecting the effects of a number of physiological, behavioural and ecological processes. Our data show that fitness-related traits such as length-at-age can retain high levels of additive genetic variance even when total phenotypic variance is high.

Published version of an article in the journal: Ecology and Evolution. Also available from the publisher at: http://dx.doi.org/10.1002/ece3.1044 Open Access Reaction norms are a valuable tool in evolutionary biology. Lately, the probabilistic maturation reaction norm approach, describing probabilities of maturing at combinations of age and body size, has been much applied for testing whether phenotypic changes in exploited populations of fish are mainly plastic or involving an evolutionary component. However, due to typical field data limitations, with imperfect knowledge about individual life histories, this demographic method still needs to be assessed. Using 13 years of direct mark-recapture observations on individual growth and maturation in an intensively sampled population of brown trout (Salmo trutta), we show that the probabilistic maturation reaction norm approach may perform well even if the assumption of equal survival of juvenile and maturing fish does not hold. Earlier studies have pointed out that growth effects may confound the interpretation of shifts in maturation reaction norms, because this method in its basic form deals with body size rather than growth. In our case, however, we found that juvenile body size, rather than annual growth, was more strongly associated with maturation. Viewed against earlier studies, our results also underscore the challenges of generalizing life-history patterns among species and populations.

The effective population size (Ne) is notoriously difficult to accurately estimate in wild populations as it is influenced by a number of parameters that are difficult to delineate in natural systems. The different methods that are used to estimate Ne are affected variously by different processes at the population level, such as the life-history characteristics of the organism, gene flow, and population substructure, as well as by the frequency patterns of genetic markers used and the sampling design. Here, we compare Ne estimates obtained by different genetic methods and from demographic data and elucidate how the estimates are affected by various factors in an exhaustively sampled and comprehensively described natural brown trout (Salmo trutta) system. In general, the methods yielded rather congruent estimates, and we ascribe that to the adequate genotyping and exhaustive sampling. Effects of violating the assumptions of the different methods were nevertheless apparent. In accordance with theoretical studies, skewed allele frequencies would underestimate temporal allele frequency changes and thereby upwardly bias Ne if not accounted for. Overlapping generations and iteroparity would also upwardly bias Ne when applied to temporal samples taken over short time spans. Gene flow from a genetically not very dissimilar source population decreases temporal allele frequency changes and thereby acts to increase estimates of Ne. Our study reiterates the importance of adequate sampling, quantification of life-history parameters and gene flow, and incorporating these data into the Ne estimation.