| 1. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 2. |
- Gattepaille, Lucie M., et al.
(författare)
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Inferring population size changes with sequence and SNP data : lessons from human bottlenecks
- 2013
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Ingår i: Heredity. - : Springer Science and Business Media LLC. - 0018-067X .- 1365-2540. ; 110:5, s. 409-419
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Forskningsöversikt (refereegranskat)abstract
- Reconstructing historical variation of population size from sequence and single-nucleotide polymorphism (SNP) data is valuable for understanding the evolutionary history of species. Changes in the population size of humans have been thoroughly investigated, and we review different methodologies of demographic reconstruction, specifically focusing on human bottlenecks. In addition to the classical approaches based on the site-frequency spectrum (SFS) or based on linkage disequilibrium, we also review more recent approaches that utilize atypical shared genomic fragments, such as identical by descent or homozygous segments between or within individuals. Compared with methods based on the SFS, these methods are well suited for detecting recent bottlenecks. In general, all these various methods suffer from bias and dependencies on confounding factors such as population structure or poor specification of the mutational and recombination processes, which can affect the demographic reconstruction. With the exception of SFS-based methods, the effects of confounding factors on the inference methods remain poorly investigated. We conclude that an important step when investigating population size changes rests on validating the demographic model by investigating to what extent the fitted demographic model can reproduce the main features of the polymorphism data.
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| 3. |
- Günther, Torsten, et al.
(författare)
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Genes mirror migrations and cultures in prehistoric Europe - a population genomic perspective
- 2016
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Ingår i: Current Opinion in Genetics and Development. - : Elsevier BV. - 0959-437X .- 1879-0380. ; 41, s. 115-123
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Forskningsöversikt (refereegranskat)abstract
- Genomic information from ancient human remains is beginning to show its full potential for learning about human prehistory. We review the last few years' dramatic finds about European prehistory based on genomic data from humans that lived many millennia ago and relate it to modern-day patterns of genomic variation. The early times, the Upper Paleolithic, appears to contain several population turn-overs followed by more stable populations after the Last Glacial Maximum and during the Mesolithic. Some 11 000 years ago the migrations driving the Neolithic transition start from around Anatolia and reach the north and the west of Europe millennia later followed by major migrations during the Bronze Age. These findings show that culture and lifestyle were major determinants of genomic differentiation and similarity in pre-historic Europe rather than geography as is the case today.
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| 4. |
- Hollfelder, Nina, et al.
(författare)
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The deep population history in Africa
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 30:R1, s. R2-R10
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Forskningsöversikt (refereegranskat)abstract
- Africa is the continent with the greatest genetic diversity among humans and the level of diversity is further enhanced by incorporating non-majority groups, which are often understudied. Many of today's minority populations historically practiced foraging lifestyles, which were the only subsistence strategies prior to the rise of agriculture and pastoralism, but only a few groups practicing these strategies remain today. Genomic investigations of Holocene human remains excavated across the African continent show that the genetic landscape was vastly different compared to today's genetic landscape and that many groups that today are population isolate inhabited larger regions in the past. It is becoming clear that there are periods of isolation among groups and geographic areas, but also genetic contact over large distances throughout human history in Africa. Genomic information from minority populations and from prehistoric remains provide an invaluable source of information on the human past, in particular deep human population history, as Holocene large-scale population movements obscure past patterns of population structure. Here we revisit questions on the nature and time of the radiation of early humans in Africa, the extent of gene-flow among human populations as well as introgression from archaic and extinct lineages on the continent.
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| 5. |
- Li, Junrui, et al.
(författare)
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Joint analysis of demography and selection in population genetics : where do we stand and where could we go?
- 2012
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Ingår i: Molecular Ecology. - 0962-1083 .- 1365-294X. ; 21:1, s. 28-44
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Forskningsöversikt (refereegranskat)abstract
- Teasing apart the effects of selection and demography on genetic polymorphism remains one of the major challenges in the analysis of population genomic data. The traditional approach has been to assume that demography would leave a genome-wide signature, whereas the effect of selection would be local. In the light of recent genomic surveys of sequence polymorphism, several authors have argued that this approach is questionable based on the evidence of the pervasive role of positive selection and that new approaches are needed. In the first part of this review, we give a few empirical and theoretical examples illustrating the difficulty in teasing apart the effects of selection and demography on genomic polymorphism patterns. In the second part, we review recent efforts to detect recent positive selection. Most available methods still rely on an a priori classification of sites in the genome but there are many promising new approaches. These new methods make use of the latest developments in statistics, explore aspects of the data that had been neglected hitherto or take advantage of the emerging population genomic data. A current and promising approach is based on first estimating demographic and genetic parameters, using, e.g., a likelihood or approximate Bayesian computation framework, focusing on extreme outlier regions, and then using an independent method to confirm these. Finally, especially for species where evidence of natural selection has been limited, more experimental and versatile approaches that contrast populations under varied environmental constraints might be more successful compared with species-wide genome scans in search of specific signatures.
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| 6. |
- Nielsen, Rasmus, et al.
(författare)
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Tracing the peopling of the world through genomics
- 2017
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 541:7637, s. 302-310
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Forskningsöversikt (refereegranskat)abstract
- Advances in the sequencing and the analysis of the genomes of both modern and ancient peoples have facilitated a number of breakthroughs in our understanding of human evolutionary history. These include the discovery of interbreeding between anatomically modern humans and extinct hominins; the development of an increasingly detailed description of the complex dispersal of modern humans out of Africa and their population expansion worldwide; and the characterization of many of the genetic adaptions of humans to local environmental conditions. Our interpretation of the evolutionary history and adaptation of humans is being transformed by analyses of these new genomic data.
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| 7. |
- Niiranen, Laura, et al.
(författare)
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Epigenomic Modifications in Modern and Ancient Genomes
- 2022
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Ingår i: Genes. - : MDPI. - 2073-4425 .- 2073-4425. ; 13:2
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Forskningsöversikt (refereegranskat)abstract
- Epigenetic changes have been identified as amajor driver of fundamentalmetabolic pathways. More specifically, the importance of epigenetic regulatory mechanisms for biological processes like speciation and embryogenesis has beenwell documented and revealed the direct link between epigenetic modifications and various diseases. In this review, we focus on epigenetic changes in animals with special attention on human DNA methylation utilizing ancient and modern genomes. Acknowledging the latest developments in ancient DNA research, we further discuss paleoepigenomic approaches as the only means to infer epigenetic changes in the past. Investigating genome-wide methylation patterns of ancient humans may ultimately yield in a more comprehensive understanding of how our ancestors have adapted to the changing environment, and modified their lifestyles accordingly. We discuss the difficulties of working with ancient DNA in particular utilizing paleoepigenomic approaches, and assess new paleoepigenomic data, which might be helpful in future studies.
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| 8. |
- Pemberton, Trevor J., et al.
(författare)
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Sequence determinants of human microsatellite variability
- 2009
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 10, s. e612-
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Forskningsöversikt (refereegranskat)abstract
- BackgroundMicrosatellite loci are frequently used in genomic studies of DNA sequence repeats and in population studies of genetic variability. To investigate the effect of sequence properties of microsatellites on their level of variability we have analyzed genotypes at 627 microsatellite loci in 1,048 worldwide individuals from the HGDP-CEPH cell line panel together with the DNA sequences of these microsatellites in the human RefSeq database.ResultsCalibrating PCR fragment lengths in individual genotypes by using the RefSeq sequence enabled us to infer repeat number in the HGDP-CEPH dataset and to calculate the mean number of repeats (as opposed to the mean PCR fragment length), under the assumption that differences in PCR fragment length reflect differences in the numbers of repeats in the embedded repeat sequences. We find the mean and maximum numbers of repeats across individuals to be positively correlated with heterozygosity. The size and composition of the repeat unit of a microsatellite are also important factors in predicting heterozygosity, with tetra-nucleotide repeat units high in G/C content leading to higher heterozygosity. Finally, we find that microsatellites containing more separate sets of repeated motifs generally have higher heterozygosity.ConclusionsThese results suggest that sequence properties of microsatellites have a significant impact in determining the features of human microsatellite variability.
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| 9. |
- Schroeder, Kari B., et al.
(författare)
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Haplotypic background of a private allele at high frequency in the Americas
- 2009
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 26:5, s. 995-1016
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Forskningsöversikt (refereegranskat)abstract
- Recently, the observation of a high-frequency private allele,the 9-repeat allele at microsatellite D9S1120, in all sampledNative American and Western Beringian populations has been interpretedas evidence that all modern Native Americans descend primarilyfrom a single founding population. However, this inference assumedthat all copies of the 9-repeat allele were identical by descentand that the geographic distribution of this allele had notbeen influenced by natural selection. To investigate whetherthese assumptions are satisfied, we genotyped 34 single nucleotidepolymorphisms across 500 kilobases (kb) around D9S1120 in 21Native American and Western Beringian populations and 54 otherworldwide populations. All chromosomes with the 9-repeat alleleshare the same haplotypic background in the vicinity of D9S1120,suggesting that all sampled copies of the 9-repeat allele areidentical by descent. Ninety-one percent of these chromosomesshare the same 76.26 kb haplotype, which we call the "AmericanModal Haplotype" (AMH). Three observations lead us to concludethat the high frequency and widespread distribution of the 9-repeatallele are unlikely to be the result of positive selection:1) aside from its association with the 9-repeat allele, theAMH does not have a high frequency in the Americas, 2) the AMHis not unusually long for its frequency compared with otherhaplotypes in the Americas, and 3) in Latin American mestizopopulations, the proportion of Native American ancestry at D9S1120is not unusual compared with that observed at other genomewidemicrosatellites. Using a new method for estimating the timeto the most recent common ancestor (MRCA) of all sampled copiesof an allele on the basis of an estimate of the length of thegenealogy descended from the MRCA, we calculate the mean timeto the MRCA of the 9-repeat allele to be between 7,325 and 39,900years, depending on the demographic model used. The resultssupport the hypothesis that all modern Native Americans andWestern Beringians trace a large portion of their ancestry toa single founding population that may have been isolated fromother Asian populations prior to expanding into the Americas.
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| 10. |
- Silva, Antero Vieira, et al.
(författare)
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A probabilistic approach to evaluate the risk of decreased total triiodothyronine hormone levels following chronic exposure to PFOS and PFHxS via contaminated drinking water
- 2020
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Ingår i: Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 128:7, s. 1-11
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Extensive exposure to per-and polyfluoroalkyl substances (PFAS) have been observed in many countries. Current deterministic frame-works for risk assessment lack the ability to predict the likelihood of effects and to assess uncertainty. When exposure exceeds tolerable intake levels, these shortcomings hamper risk management and communication. OBJECTIVE: The integrated probabilistic risk assessment (IPRA) combines dose-response and exposure data to estimate the likelihood of adverse effects. We evaluated the usefulness of the IPRA for risk characterization related to decreased levels of total triiodothyronine (T3) in humans following a real case of high exposure to PFAS via drinking water. METHODS: PFAS exposure was defined as serum levels from residents of a contaminated area in Ronneby, Sweden. Median levels were 270 ng=mL [perfluorooctane sulfonic acid (PFOS)] and 229 ng=mL [perfluorohexane sulfonic acid (PFHxS)] for individuals who resided in Ronneby 1 y before the exposure termination. This data was integrated with data from a subchronic toxicity study in monkeys exposed daily to PFOS. Benchmark dose modeling was employed to describe separate dose–effect relationship for males and females, and extrapolation factor distributions were used to estimate the corresponding human benchmark dose. The critical effect level was defined as a 10% decrease in total T3. RESULTS: The median probability of critical exposure, following a combined exposure to PFOS and PFHxS, was estimated to be [2.1% (90% CI: 0:4%–13:1%)]. Gender-based analysis showed that this risk was almost entirely distributed among women, namely [3.9% (90% CI: 0:8%–21:6%)]. DISCUSSION: The IPRA was compared with the traditional deterministic Margin of Exposure (MoE) approach. We conclude that probabilistic risk characterization represents an important step forward in the ability to adequately analyze group-specific health risks. Moreover, quantifying the sour-ces of uncertainty is desirable, as it improves the awareness among stakeholders and will guide future efforts to improve accuracy. https://doi.org/10.1289/EHP6654.
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