Publications by authors named "Benjamin Peter"

29 Publications

  • Page 1 of 1

Unearthing Neanderthal population history using nuclear and mitochondrial DNA from cave sediments.

Science 2021 05 15;372(6542). Epub 2021 Apr 15.

Department of Evolutionary Genetics, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany.

Bones and teeth are important sources of Pleistocene hominin DNA, but are rarely recovered at archaeological sites. Mitochondrial DNA (mtDNA) has been retrieved from cave sediments but provides limited value for studying population relationships. We therefore developed methods for the enrichment and analysis of nuclear DNA from sediments and applied them to cave deposits in western Europe and southern Siberia dated to between 200,000 and 50,000 years ago. We detected a population replacement in northern Spain about 100,000 years ago, which was accompanied by a turnover of mtDNA. We also identified two radiation events in Neanderthal history during the early part of the Late Pleistocene. Our work lays the ground for studying the population history of ancient hominins from trace amounts of nuclear DNA in sediments.
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http://dx.doi.org/10.1126/science.abf1667DOI Listing
May 2021

Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry.

Nature 2021 Apr 7;592(7853):253-257. Epub 2021 Apr 7.

Francis Crick Institute, London, UK.

Modern humans appeared in Europe by at least 45,000 years ago, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania and Siberia who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.
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http://dx.doi.org/10.1038/s41586-021-03335-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026394PMC
April 2021

Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes.

Elife 2021 Jan 20;10. Epub 2021 Jan 20.

Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

We generated induced excitatory neurons (iNeurons, iNs) from chimpanzee, bonobo, and human stem cells by expressing the transcription factor neurogenin-2 (NGN2). Single-cell RNA sequencing showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee and bonobo than the human cells. In accordance, during the first 2 weeks of differentiation, chimpanzee and bonobo iNs showed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length. However, the axons of human iNs were slightly longer at 5 weeks of differentiation. The timing of the establishment of neuronal polarity did not differ between the species. Chimpanzee, bonobo, and human neurites eventually reached the same level of structural complexity. Thus, human iNs develop slower than chimpanzee and bonobo iNs, and this difference in timing likely depends on functions downstream of NGN2.
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http://dx.doi.org/10.7554/eLife.59323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870144PMC
January 2021

Denisovan ancestry and population history of early East Asians.

Science 2020 10;370(6516):579-583

Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany.

We present analyses of the genome of a ~34,000-year-old hominin skull cap discovered in the Salkhit Valley in northeastern Mongolia. We show that this individual was a female member of a modern human population that, following the split between East and West Eurasians, experienced substantial gene flow from West Eurasians. Both she and a 40,000-year-old individual from Tianyuan outside Beijing carried genomic segments of Denisovan ancestry. These segments derive from the same Denisovan admixture event(s) that contributed to present-day mainland Asians but are distinct from the Denisovan DNA segments in present-day Papuans and Aboriginal Australians.
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http://dx.doi.org/10.1126/science.abc1166DOI Listing
October 2020

AuthentiCT: a model of ancient DNA damage to estimate the proportion of present-day DNA contamination.

Genome Biol 2020 09 15;21(1):246. Epub 2020 Sep 15.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103, Leipzig, Germany.

Contamination from present-day DNA is a fundamental issue when studying ancient DNA from historical or archaeological material, and quantifying the amount of contamination is essential for downstream analyses. We present AuthentiCT, a command-line tool to estimate the proportion of present-day DNA contamination in ancient DNA datasets generated from single-stranded DNA libraries. The prediction is based solely on the patterns of post-mortem damage observed on ancient DNA sequences. The method has the power to quantify contamination from as few as 10,000 mapped sequences, making it particularly useful for analysing specimens that are poorly preserved or for which little data is available.
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http://dx.doi.org/10.1186/s13059-020-02123-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490890PMC
September 2020

A high-coverage Neandertal genome from Chagyrskaya Cave.

Proc Natl Acad Sci U S A 2020 06 16;117(26):15132-15136. Epub 2020 Jun 16.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany;

We sequenced the genome of a Neandertal from Chagyrskaya Cave in the Altai Mountains, Russia, to 27-fold genomic coverage. We show that this Neandertal was a female and that she was more related to Neandertals in western Eurasia [Prüfer et al., Science 358, 655-658 (2017); Hajdinjak et al., Nature 555, 652-656 (2018)] than to Neandertals who lived earlier in Denisova Cave [Prüfer et al., Nature 505, 43-49 (2014)], which is located about 100 km away. About 12.9% of the Chagyrskaya genome is spanned by homozygous regions that are between 2.5 and 10 centiMorgans (cM) long. This is consistent with the fact that Siberian Neandertals lived in relatively isolated populations of less than 60 individuals. In contrast, a Neandertal from Europe, a Denisovan from the Altai Mountains, and ancient modern humans seem to have lived in populations of larger sizes. The availability of three Neandertal genomes of high quality allows a view of genetic features that were unique to Neandertals and that are likely to have been at high frequency among them. We find that genes highly expressed in the striatum in the basal ganglia of the brain carry more amino-acid-changing substitutions than genes expressed elsewhere in the brain, suggesting that the striatum may have evolved unique functions in Neandertals.
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http://dx.doi.org/10.1073/pnas.2004944117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334501PMC
June 2020

Genetic Landscapes Reveal How Human Genetic Diversity Aligns with Geography.

Mol Biol Evol 2020 04;37(4):943-951

Department of Human Genetics, University of Chicago, Chicago, IL.

Geographic patterns in human genetic diversity carry footprints of population history and provide insights for genetic medicine and its application across human populations. Summarizing and visually representing these patterns of diversity has been a persistent goal for human geneticists, and has revealed that genetic differentiation is frequently correlated with geographic distance. However, most analytical methods to represent population structure do not incorporate geography directly, and it must be considered post hoc alongside a visual summary of the genetic structure. Here, we estimate "effective migration" surfaces to visualize how human genetic diversity is geographically structured. The results reveal local patterns of differentiation in detail and emphasize that while genetic similarity generally decays with geographic distance, the relationship is often subtly distorted. Overall, the visualizations provide a new perspective on genetics and geography in humans and insight to the geographic distribution of human genetic variation.
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http://dx.doi.org/10.1093/molbev/msz280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086171PMC
April 2020

No interactions between heparin and atacicept, an antagonist of B cell survival cytokines.

Br J Pharmacol 2019 10 15;176(20):4019-4033. Epub 2019 Oct 15.

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

Background And Purpose: The TNF family ligands, B cell activating factor of the TNF family (BAFF, also known as B lymphocyte stimulator, BLyS) and a proliferation-inducing ligand (APRIL), share the transmembrane activator and calcium-modulator and cyclophilin ligand (CAML)-interactor (TACI) as one of their common receptors. Atacicept, a chimeric recombinant TACI/IgG1-Fc fusion protein, inhibits both ligands. TACI and APRIL also bind to proteoglycans and to heparin that is structurally related to proteoglycans. It is unknown whether the portion of TACI contained in atacicept can bind directly to proteoglycans, or indirectly via APRIL, and whether this could interfere with the anti-coagulant properties of heparin.

Experimental Approach: Binding of atacicept and APRIL to proteoglycan-positive cells was measured by FACS. Activities of heparin and atacicept were measured with activated factor Xa inhibition and cell-based assays. Effects of heparin on circulating atacicept was monitored in mice.

Key Results: Atacicept did not bind to proteoglycan-positive cells, but when complexed to APRIL could do so indirectly via APRIL. Multimers of atacicept obtained after exposure to cysteine or BAFF 60-mer bound directly to proteoglycans. Atacicept alone, or in complex with APRIL, or in a multimeric form did not interfere with heparin activity in vitro. Conversely, heparin did not influence inhibition of BAFF and APRIL by atacicept and did not change circulating levels of atacicept.

Conclusions And Implications: Lack of detectable interference of APRIL-bound or free atacicept on heparin activity makes it unlikely that atacicept at therapeutic doses will interfere with the function of heparin in vivo.
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http://dx.doi.org/10.1111/bph.14811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811742PMC
October 2019

Human local adaptation of the TRPM8 cold receptor along a latitudinal cline.

PLoS Genet 2018 05 3;14(5):e1007298. Epub 2018 May 3.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

Ambient temperature is a critical environmental factor for all living organisms. It was likely an important selective force as modern humans recently colonized temperate and cold Eurasian environments. Nevertheless, as of yet we have limited evidence of local adaptation to ambient temperature in populations from those environments. To shed light on this question, we exploit the fact that humans are a cosmopolitan species that inhabit territories under a wide range of temperatures. Focusing on cold perception-which is central to thermoregulation and survival in cold environments-we show evidence of recent local adaptation on TRPM8. This gene encodes for a cation channel that is, to date, the only temperature receptor known to mediate an endogenous response to moderate cold. The upstream variant rs10166942 shows extreme population differentiation, with frequencies that range from 5% in Nigeria to 88% in Finland (placing this SNP in the 0.02% tail of the FST empirical distribution). When all populations are jointly analyzed, allele frequencies correlate with latitude and temperature beyond what can be explained by shared ancestry and population substructure. Using a Bayesian approach, we infer that the allele originated and evolved neutrally in Africa, while positive selection raised its frequency to different degrees in Eurasian populations, resulting in allele frequencies that follow a latitudinal cline. We infer strong positive selection, in agreement with ancient DNA showing high frequency of the allele in Europe 3,000 to 8,000 years ago. rs10166942 is important phenotypically because its ancestral allele is protective of migraine. This debilitating disorder varies in prevalence across human populations, with highest prevalence in individuals of European descent-precisely the population with the highest frequency of rs10166942 derived allele. We thus hypothesize that local adaptation on previously neutral standing variation may have contributed to the genetic differences that exist in the prevalence of migraine among human populations today.
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http://dx.doi.org/10.1371/journal.pgen.1007298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933706PMC
May 2018

Unpacking the performance of a mobile health information messaging program for mothers (MomConnect) in South Africa: .

BMJ Glob Health 2018 24;3(Suppl 2):e000583. Epub 2018 Apr 24.

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Despite calls to address broader evidence gaps in linking digital technologies to outcome and impact level health indicators, limited attention has been paid to measuring processes pertaining to the performance of programs. In this paper, we assess the program reach and message exposure of a mobile health information messaging program for mothers (MomConnect) in South Africa. In this descriptive study, we draw from system generated data to measure exposure to the program through registration attempts and conversions, message delivery, opt-outs and drop-outs. Using a logit model, we additionally explore determinants for early registration, opt-outs and drop-outs. From August 2014 to April 2017, 1 159 431 women were registered to MomConnect; corresponding to half of women attending antenatal care 1 (ANC1) and nearly 60% of those attending ANC1 estimated to own a mobile phone. In 2016, 26% of registrations started to get women onto MomConnect did not succeed. If registration attempts were converted to successful registrations, coverage of ANC1 attendees would have been 74% in 2016 and 86% in 2017. When considered as percentage of ANC1 attendees with access to a mobile phone, addressing conversion challenges bring registration coverage to an estimated 83%-89% in 2016 and 97%-100% in 2017. Among women registered, nearly 80% of expected short messaging service messages were received. While registration coverage and message delivery success rates exceed those observed for mobile messaging programs elsewhere, study findings highlight opportunities for program improvement and reinforce the need for rigorous and continuous monitoring of delivery systems.
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http://dx.doi.org/10.1136/bmjgh-2017-000583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922477PMC
April 2018

Mobile health messaging service and helpdesk for South African mothers (MomConnect): history, successes and challenges.

BMJ Glob Health 2018 24;3(Suppl 2):e000559. Epub 2018 Apr 24.

HIV/AIDS, TB and MCWH, National Department of Health, Pretoria, Gauteng, South Africa.

MomConnect is a flagship programme of the South African National Department of Health that has reached over 1.5 million pregnant women. Using mobile technology, MomConnect provides pregnant and postpartum women with twice-weekly health information text messages as well as access to a helpdesk for patient queries and feedback. In just 3 years, MomConnect has been taken to scale to reach over 95% of public health facilities and has reached 63% of all pregnant women attending their first antenatal appointment. The helpdesk has received over 300 000 queries at an average of 250 per day from 6% of MomConnect users. The service is entirely free to its users. The rapid deployment of MomConnect has been facilitated by strong government leadership, and an ecosystem of mobile health implementers who had experience of much of the content and technology required. An early decision to design MomConnect for universal coverage has required the use of text-based technologies (short messaging service and Unstructured Supplementary Service Data) that are accessible via even the most basic mobile phones, but cumbersome to use and costly at scale. Unlike previous mobile messaging services in South Africa, MomConnect collects the user's identification number and facility code during registration, enabling future linkages with other health and population databases and geolocated feedback. MomConnect has catalysed additional efforts to strengthen South Africa's digital health architecture. The rapid growth in smartphone penetration presents new opportunities to reduce costs, increase real-time data collection and expand the reach and scope of MomConnect to serve health workers and other patient groups.
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http://dx.doi.org/10.1136/bmjgh-2017-000559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922496PMC
April 2018

A longitudinal cline characterizes the genetic structure of human populations in the Tibetan plateau.

PLoS One 2017 27;12(4):e0175885. Epub 2017 Apr 27.

Department of Human Genetics, University of Chicago, Chicago, IL, United States of America.

Indigenous populations of the Tibetan plateau have attracted much attention for their good performance at extreme high altitude. Most genetic studies of Tibetan adaptations have used genetic variation data at the genome scale, while genetic inferences about their demography and population structure are largely based on uniparental markers. To provide genome-wide information on population structure, we analyzed new and published data of 338 individuals from indigenous populations across the plateau in conjunction with worldwide genetic variation data. We found a clear signal of genetic stratification across the east-west axis within Tibetan samples. Samples from more eastern locations tend to have higher genetic affinity with lowland East Asians, which can be explained by more gene flow from lowland East Asia onto the plateau. Our findings corroborate a previous report of admixture signals in Tibetans, which were based on a subset of the samples analyzed here, but add evidence for isolation by distance in a broader geospatial context.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175885PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407838PMC
September 2017

Chimpanzee genomic diversity reveals ancient admixture with bonobos.

Science 2016 10 27;354(6311):477-481. Epub 2016 Oct 27.

Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.

Our closest living relatives, chimpanzees and bonobos, have a complex demographic history. We analyzed the high-coverage whole genomes of 75 wild-born chimpanzees and bonobos from 10 countries in Africa. We found that chimpanzee population substructure makes genetic information a good predictor of geographic origin at country and regional scales. Multiple lines of evidence suggest that gene flow occurred from bonobos into the ancestors of central and eastern chimpanzees between 200,000 and 550,000 years ago, probably with subsequent spread into Nigeria-Cameroon chimpanzees. Together with another, possibly more recent contact (after 200,000 years ago), bonobos contributed less than 1% to the central chimpanzee genomes. Admixture thus appears to have been widespread during hominid evolution.
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http://dx.doi.org/10.1126/science.aag2602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546212PMC
October 2016

Recent advances in the study of fine-scale population structure in humans.

Curr Opin Genet Dev 2016 Dec 20;41:98-105. Epub 2016 Sep 20.

Department of Human Genetics, University of Chicago, IL 60636, United States.

Empowered by modern genotyping and large samples, population structure can be accurately described and quantified even when it only explains a fraction of a percent of total genetic variance. This is especially relevant and interesting for humans, where fine-scale population structure can both confound disease-mapping studies and reveal the history of migration and divergence that shaped our species' diversity. Here we review notable recent advances in the detection, use, and understanding of population structure. Our work addresses multiple areas where substantial progress is being made: improved statistics and models for better capturing differentiation, admixture, and the spatial distribution of variation; computational speed-ups that allow methods to scale to modern data; and advances in haplotypic modeling that have wide ranging consequences for the analysis of population structure. We conclude by outlining four important open challenges: the limitations of discrete population models, uncertainty in individual origins, the incorporation of both fine-scale structure and ancient DNA in parametric models, and the development of efficient computational tools, particularly for haplotype-based methods.
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http://dx.doi.org/10.1016/j.gde.2016.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291306PMC
December 2016

Admixture, Population Structure, and F-Statistics.

Authors:
Benjamin M Peter

Genetics 2016 Apr 8;202(4):1485-501. Epub 2016 Feb 8.

Department of Human Genetics, University of Chicago, Chicago, Illinois 60637

Many questions about human genetic history can be addressed by examining the patterns of shared genetic variation between sets of populations. A useful methodological framework for this purpose isF-statistics that measure shared genetic drift between sets of two, three, and four populations and can be used to test simple and complex hypotheses about admixture between populations. This article provides context from phylogenetic and population genetic theory. I review how F-statistics can be interpreted as branch lengths or paths and derive new interpretations, using coalescent theory. I further show that the admixture tests can be interpreted as testing general properties of phylogenies, allowing extension of some ideas applications to arbitrary phylogenetic trees. The new results are used to investigate the behavior of the statistics under different models of population structure and show how population substructure complicates inference. The results lead to simplified estimators in many cases, and I recommend to replace F3 with the average number of pairwise differences for estimating population divergence.
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http://dx.doi.org/10.1534/genetics.115.183913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905545PMC
April 2016

Phylogenomics at the tips: inferring lineages and their demographic history in a tropical lizard, Carlia amax.

Mol Ecol 2016 Mar 1;25(6):1367-80. Epub 2016 Mar 1.

Research School of Biology, The Australian National University, Acton, Act, 2601, Australia.

High-throughput sequencing approaches offer opportunities to better understand the evolutionary processes driving diversification, particularly in nonmodel organisms. In particular, the 100-1000's of loci that can now be sequenced are providing unprecedented power in population, speciation and phylogenetic studies. Here, we apply an exon capture approach to generate >99% complete sequence and SNP data across >2000 loci from a tropical skink, Carlia amax, and exploit these data to identify divergent lineages and infer their relationships and demographic histories. This is especially relevant to low-dispersal tropical taxa that often have cryptic diversity and spatially dynamic histories. For C. amax, clustering of nuclear SNPs and coalescent-based species delimitation analyses identify four divergent lineages, one fewer than predicted based on geographically coherent mtDNA clades (>9.4% sequence divergence). Three of these lineages are widespread and parapatric on the mainland, whereas the most divergent is restricted to islands off the northeast Northern Territory. Tests for population expansion reject an equilibrium isolation-by-distance model for two of the three widespread lineages and infer refugial expansion sources in the relatively mesic northeast Top End and northwest Kimberley. The latter is already recognized as a hotspot of endemism, but our results also suggest that a stronger focus on the northeast Top End, and adjacent islands is warranted. More generally, our results show how genome-reduction methods such as exon capture can yield insights into the pattern and dynamics of biodiversity across complex landscapes with as yet poorly understood biogeographic history and how exon data can link between population and phylogenetic questions.
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http://dx.doi.org/10.1111/mec.13546DOI Listing
March 2016

Estimating the Ages of Selection Signals from Different Epochs in Human History.

Mol Biol Evol 2016 Mar 5;33(3):657-69. Epub 2015 Nov 5.

Department of Human Genetics, University of Chicago

Genetic variation harbors signatures of natural selection driven by selective pressures that are often unknown. Estimating the ages of selection signals may allow reconstructing the history of environmental changes that shaped human phenotypes and diseases. We have developed an approximate Bayesian computation (ABC) approach to estimate allele ages under a model of selection on new mutations and under demographic models appropriate for human populations. We have applied it to two resequencing data sets: An ultra-high depth data set from a relatively small sample of unrelated individuals and a lower depth data set in a larger sample with transmission information. In addition to evaluating the accuracy of our method based on simulations, for each SNP, we assessed the consistency between the posterior probabilities estimated by the ABC approach and the ancient DNA record, finding good agreement between the two types of data and methods. Applying this ABC approach to data for eight single nucleotide polymorphisms (SNPs), we were able to rule out an onset of selection prior to the dispersal out-of-Africa for three of them and more recent than the spread of agriculture for an additional three SNPs.
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http://dx.doi.org/10.1093/molbev/msv256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009997PMC
March 2016

Effect of Ankle Positioning During Hamstring Stretches for Improving Straight Leg Hip Flexion Motion.

Clin J Sport Med 2016 Mar;26(2):167-71

*School of Kinesiology and Recreation, Illinois State University, Normal, Illinois; and †Hillsdale College, Hillsdale, Michigan.

Objective: To compare the effects of stretching the hamstrings with the ankle in either a plantar-flexed (PF) or dorsiflexed (DF) position for improving straight leg hip flexion range of motion (ROM) over a 4-week period.

Design: Randomized, single-blinded, pretest, posttest design.

Setting: Athletic training facility.

Participants: Each limb of 34 asymptomatic individuals (15 males, 19 females) was randomly assigned to one of the 3 groups. Twenty-four limbs received hamstring stretches with the ankle in DF, 24 limbs received hamstring stretches with the ankle in PF, and 20 limbs received no stretch (control).

Independent Variables: Ankle position (PF, DF) during hamstring stretching.

Main Outcome Measures: We measured pretest and posttest passive straight leg hip flexion ROM with the test ankle in a neutral position. For the intervention groups, the test limb was passively stretched with the ankle held in end range DF or PF for their respective group. Each stretch was held for 30 seconds for a total of 3 applications. Two treatment sessions were completed per week for a total of 4 weeks. The control limbs received no stretching during the 4-week period. We conducted 1-way analyses of covariance to determine significant changes in ROM between groups (P < 0.05).

Results: There was no significant difference between treatment groups (P = 0.90), but a significant difference was found for both the PF (P = 0.04) and DF (P = 0.01) groups when compared with the control group.

Conclusions: Our findings indicate that both stretching the hamstrings in either PF or DF improve straight leg hip ROM compared with a control group.

Clinical Relevance: The results of this study should be considered by clinicians when determining the optimal stretching techniques aimed at increasing hamstring length.
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http://dx.doi.org/10.1097/JSM.0000000000000211DOI Listing
March 2016

The effective founder effect in a spatially expanding population.

Evolution 2015 Mar 10;69(3):721-34. Epub 2015 Mar 10.

Department of Integrative Biology, University of California, Berkeley, California, 94720; Current address: Department of Human Genetics, University of Chicago, Chicago, Illinois, 60637.

The gradual loss of diversity and the establishment of clines in allele frequencies associated with range expansions are patterns observed in many species, including humans. These patterns can result from a series of founder events occurring as populations colonize previously unoccupied areas. We develop a model of an expanding population and, using a branching process approximation, show that spatial gradients reflect different amounts of genetic drift experienced by different subpopulations. We then use this model to measure the net average strength of the founder effect, and we demonstrate that the predictions from the branching process model fit simulation results well. We further show that estimates of the effective founder size are robust to potential confounding factors such as migration between subpopulations. We apply our method to data from Arabidopsis thaliana. We find that the average founder effect is approximately three times larger in the Americas than in Europe, possibly indicating that a more recent, rapid expansion occurred.
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http://dx.doi.org/10.1111/evo.12609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104172PMC
March 2015

Surfing waves of data in San Diego: sophisticated analyses provide a broad view of human genetic diversity.

Genome Biol 2014 Dec 17;15(12):562. Epub 2014 Dec 17.

A report on the 64th annual American Society of Human Genetics meeting held in San Diego, USA, 18-22 October, 2014.
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http://dx.doi.org/10.1186/s13059-014-0562-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318178PMC
December 2014

A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations.

Am J Hum Genet 2014 11 23;95(5):584-589. Epub 2014 Oct 23.

Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 3QG, UK; Estonian Biocentre, Tartu 51010, Estonia. Electronic address:

Arctic populations live in an environment characterized by extreme cold and the absence of plant foods for much of the year and are likely to have undergone genetic adaptations to these environmental conditions in the time they have been living there. Genome-wide selection scans based on genotype data from native Siberians have previously highlighted a 3 Mb chromosome 11 region containing 79 protein-coding genes as the strongest candidates for positive selection in Northeast Siberians. However, it was not possible to determine which of the genes might be driving the selection signal. Here, using whole-genome high-coverage sequence data, we identified the most likely causative variant as a nonsynonymous G>A transition (rs80356779; c.1436C>T [p.Pro479Leu] on the reverse strand) in CPT1A, a key regulator of mitochondrial long-chain fatty-acid oxidation. Remarkably, the derived allele is associated with hypoketotic hypoglycemia and high infant mortality yet occurs at high frequency in Canadian and Greenland Inuits and was also found at 68% frequency in our Northeast Siberian sample. We provide evidence of one of the strongest selective sweeps reported in humans; this sweep has driven this variant to high frequency in circum-Arctic populations within the last 6-23 ka despite associated deleterious consequences, possibly as a result of the selective advantage it originally provided to either a high-fat diet or a cold environment.
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http://dx.doi.org/10.1016/j.ajhg.2014.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225582PMC
November 2014

Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4).

PLoS Genet 2014 Oct 16;10(10):e1004681. Epub 2014 Oct 16.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

Interferon lambda 4 gene (IFNL4) encodes IFN-λ4, a new member of the IFN-λ family with antiviral activity. In humans IFNL4 open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-λ4 and turns IFNL4 into a polymorphic pseudogene. Functional IFN-λ4 has antiviral activity but the elimination of IFN-λ4 through pseudogenization is strongly associated with improved clearance of hepatitis C virus (HCV) infection. We show that functional IFN-λ4 is conserved and evolutionarily constrained in mammals and thus functionally relevant. However, the pseudogene has reached moderately high frequency in Africa, America, and Europe, and near fixation in East Asia. In fact, the pseudogenizing variant is among the 0.8% most differentiated SNPs between Africa and East Asia genome-wide. Its raise in frequency is associated with additional evidence of positive selection, which is strongest in East Asia, where this variant falls in the 0.5% tail of SNPs with strongest signatures of recent positive selection genome-wide. Using a new Approximate Bayesian Computation (ABC) approach we infer that the pseudogenizing allele appeared just before the out-of-Africa migration and was immediately targeted by moderate positive selection; selection subsequently strengthened in European and Asian populations resulting in the high frequency observed today. This provides evidence for a changing adaptive process that, by favoring IFN-λ4 inactivation, has shaped present-day phenotypic diversity and susceptibility to disease.
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http://dx.doi.org/10.1371/journal.pgen.1004681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199494PMC
October 2014

Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.

Nature 2014 Aug 2;512(7513):194-7. Epub 2014 Jul 2.

1] BGI-Shenzhen, Shenzhen 518083, China [2] Department of Integrative Biology, University of California, Berkeley, California 94720 USA [3] Department of Statistics, University of California, Berkeley, California 94720, USA [4] Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.

As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.
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http://dx.doi.org/10.1038/nature13408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134395PMC
August 2014

Detecting range expansions from genetic data.

Evolution 2013 Nov 27;67(11):3274-89. Epub 2013 Aug 27.

Department of Integrative Biology, University of California, Berkeley, California, 94720.

We propose a method that uses genetic data to test for the occurrence of a recent range expansion and to infer the location of the origin of the expansion. We introduce a statistic ψ (the directionality index) that detects asymmetries in the 2D allele frequency spectrum of pairs of population. These asymmetries are caused by the series of founder events that happen during an expansion and they arise because low frequency alleles tend to be lost during founder events, thus creating clines in the frequencies of surviving low-frequency alleles. Using simulations, we show that ψ is more powerful for detecting range expansions than both FST and clines in heterozygosity. We also show how we can adapt our approach to more complicated scenarios such as expansions with multiple origins or barriers to migration and we illustrate the utility of ψ by applying it to a data set from modern humans.
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http://dx.doi.org/10.1111/evo.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282923PMC
November 2013

Distinguishing between selective sweeps from standing variation and from a de novo mutation.

PLoS Genet 2012 11;8(10):e1003011. Epub 2012 Oct 11.

Department of Integrative Biology, University of California Berkeley, Berkeley, California, USA.

An outstanding question in human genetics has been the degree to which adaptation occurs from standing genetic variation or from de novo mutations. Here, we combine several common statistics used to detect selection in an Approximate Bayesian Computation (ABC) framework, with the goal of discriminating between models of selection and providing estimates of the age of selected alleles and the selection coefficients acting on them. We use simulations to assess the power and accuracy of our method and apply it to seven of the strongest sweeps currently known in humans. We identify two genes, ASPM and PSCA, that are most likely affected by selection on standing variation; and we find three genes, ADH1B, LCT, and EDAR, in which the adaptive alleles seem to have swept from a new mutation. We also confirm evidence of selection for one further gene, TRPV6. In one gene, G6PD, neither neutral models nor models of selective sweeps fit the data, presumably because this locus has been subject to balancing selection.
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http://dx.doi.org/10.1371/journal.pgen.1003011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469416PMC
March 2013

Investigation into the use of short message services to expand uptake of human immunodeficiency virus testing, and whether content and dosage have impact.

Telemed J E Health 2012 Jan-Feb;18(1):18-23. Epub 2011 Dec 8.

Cell-Life, CPUT BARC Building, Cape Town, South Africa.

Objective: South Africa has one of the highest human immunodeficiency virus (HIV) prevalence rates in the world, but despite the well-established benefits of HIV counseling and testing (HCT), there is low uptake of HCT. The study aimed to investigate the effectiveness of using short message services (SMSs) to encourage HCT while interrogating the impact of altering SMS content and dosage (the number of SMSs).

Materials And Methods: About 2,533 participants were recruited via an SMS sent to 24,000 mobiles randomly sampled from a pre-existing database. Recruits were randomly allocated to four intervention groups that received 3 or 10 informational (INFO) or motivational (MOTI) SMSs, and a control group. After the intervention, participants were prompted to go for HCT, and postintervention assessment was done after 3 weeks.

Results: In comparison with the control, receipt of 10 MOTI messages had the most impact on uptake of HCT with a 1.7-fold increased odds of testing (confidence interval 95%; p=0.0036). The lack of efficacy of three SMSs indicates a threshold effect, that is, a minimum number of MOTI SMSs is required. INFO SMSs, whether 3 or 10 were sent, did not have a statistically significant effect. The cost can be calculated for the marginal effect of the SMSs, that is, the cost to get people to test over and above those who were likely to test without the intervention. Use of 10 MOTI SMSs yielded a cost-per-tester of $2.41.

Conclusions: While there are methodological issues apparent in our study, the results demonstrate the potential of SMSs to influence the uptake of HCT, the importance of appropriate content, and the need to determine a threshold for SMS-based interventions. These results indicate a potential for SMSs to be used more generally for interventions encouraging people to take health-related actions, and the need for further research in this field. The reasonable cost-per-tester is promising for the scale-up of such an intervention.
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http://dx.doi.org/10.1089/tmj.2011.0058DOI Listing
June 2012

Distinguishing between population bottleneck and population subdivision by a Bayesian model choice procedure.

Mol Ecol 2010 Nov 23;19(21):4648-60. Epub 2010 Aug 23.

Computational and Molecular Population Genetics (CMPG), Institute of Ecology and Evolution, University of Bern, Baltzerstrasse 6, CH-3012 Bern, Switzerland.

Although most natural populations are genetically subdivided, they are often analysed as if they were panmictic units. In particular, signals of past demographic size changes are often inferred from genetic data by assuming that the analysed sample is drawn from a population without any internal subdivision. However, it has been shown that a bottleneck signal can result from the presence of some recent immigrants in a population. It thus appears important to contrast these two alternative scenarios in a model choice procedure to prevent wrong conclusions to be made. We use here an Approximate Bayesian Computation (ABC) approach to infer whether observed patterns of genetic diversity in a given sample are more compatible with it being drawn from a panmictic population having gone through some size change, or from one or several demes belonging to a recent finite island model. Simulations show that we can correctly identify samples drawn from a subdivided population in up to 95% of the cases for a wide range of parameters. We apply our model choice procedure to the case of the chimpanzee (Pan troglodytes) and find conclusive evidence that Western and Eastern chimpanzee samples are drawn from a spatially subdivided population.
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http://dx.doi.org/10.1111/j.1365-294X.2010.04783.xDOI Listing
November 2010