Publications by authors named "Michael Lachmann"

43 Publications

Comparative cost-effectiveness of SARS-CoV-2 testing strategies in the USA: a modelling study.

Lancet Public Health 2021 03 5;6(3):e184-e191. Epub 2021 Feb 5.

The University of Texas at Austin, Austin, TX, USA; Santa Fe Institute, Santa Fe, NM, USA. Electronic address:

Background: To mitigate the COVID-19 pandemic, countries worldwide have enacted unprecedented movement restrictions, physical distancing measures, and face mask requirements. Until safe and efficacious vaccines or antiviral drugs become widely available, viral testing remains the primary mitigation measure for rapid identification and isolation of infected individuals. We aimed to assess the economic trade-offs of expanding and accelerating testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the USA in different transmission scenarios.

Methods: We used a multiscale model that incorporates SARS-CoV-2 transmission at the population level and daily viral load dynamics at the individual level to assess eight surveillance testing strategies that varied by testing frequency (from daily to monthly testing) and isolation period (1 or 2 weeks), compared with the status-quo strategy of symptom-based testing and isolation. For each testing strategy, we first estimated the costs (incorporating costs of diagnostic testing and admissions to hospital, and salary lost while in isolation) and years of life lost (YLLs) prevented under rapid and low transmission scenarios. We then assessed the testing strategies across a range of scenarios, each defined by effective reproduction number (R), willingness to pay per YLL averted, and cost of a test, to estimate the probability that a particular strategy had the greatest net benefit. Additionally, for a range of transmission scenarios (R from 1·1 to 3), we estimated a threshold test price at which the status-quo strategy outperforms all testing strategies considered.

Findings: Our modelling showed that daily testing combined with a 2-week isolation period was the most costly strategy considered, reflecting increased costs with greater test frequency and length of isolation period. Assuming a societal willingness to pay of US$100 000 per YLL averted and a price of $5 per test, the strategy most likely to be cost-effective under a rapid transmission scenario (R of 2·2) is weekly testing followed by a 2-week isolation period subsequent to a positive test result. Under low transmission scenarios (R of 1·2), monthly testing of the population followed by 1-week isolation rather than 2-week isolation is likely to be most cost-effective. Expanded surveillance testing is more likely to be cost-effective than the status-quo testing strategy if the price per test is less than $75 across all transmission rates considered.

Interpretation: Extensive expansion of SARS-CoV-2 testing programmes with more frequent and rapid tests across communities coupled with isolation of individuals with confirmed infection is essential for mitigating the COVID-19 pandemic. Furthermore, resources recouped from shortened isolation duration could be cost-effectively allocated to more frequent testing.

Funding: US National Institutes of Health, US Centers for Disease Control and Prevention, and Love, Tito's.
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http://dx.doi.org/10.1016/S2468-2667(21)00002-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862022PMC
March 2021

The impacts of COVID-19 vaccine timing, number of doses, and risk prioritization on mortality in the US.

medRxiv 2021 Jan 20. Epub 2021 Jan 20.

As COVID-19 vaccination begins worldwide, policymakers face critical trade-offs. Using a mathematical model of COVID-19 transmission, we find that timing of the rollout is expected to have a substantially greater impact on mortality than risk-based prioritization and adherence and that prioritizing first doses over second doses may be life saving.
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http://dx.doi.org/10.1101/2021.01.18.21250071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836125PMC
January 2021

Signalling architectures can prevent cancer evolution.

Sci Rep 2020 01 20;10(1):674. Epub 2020 Jan 20.

Santa Fe Institute, Santa Fe, NM, 87501, USA.

Cooperation between cells in multicellular organisms is preserved by an active regulation of growth through the control of cell division. Molecular signals used by cells for tissue growth are usually present during developmental stages, angiogenesis, wound healing and other processes. In this context, the use of molecular signals triggering cell division is a puzzle, because any molecule inducing and aiding growth can be exploited by a cancer cell, disrupting cellular cooperation. A significant difference is that normal cells in a multicellular organism have evolved in competition between high-level organisms to be altruistic, being able to send signals even if it is to their detriment. Conversely, cancer cells evolve their abuse over the cancer's lifespan by out-competing their neighbours. A successful mutation leading to cancer must evolve to be adaptive, enabling a cancer cell to send a signal that results in higher chances to be selected. Using a mathematical model of such molecular signalling mechanism, this paper argues that a signal mechanism would be effective against abuse by cancer if it affects the cell that generates the signal as well as neighbouring cells that would receive a benefit without any cost, resulting in a selective disadvantage for a cancer signalling cell. We find that such molecular signalling mechanisms normally operate in cells as exemplified by growth factors. In scenarios of global and local competition between cells, we calculate how this process affects the fixation probability of a mutant cell generating such a signal, and find that this process can play a key role in limiting the emergence of cancer.
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http://dx.doi.org/10.1038/s41598-020-57494-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971087PMC
January 2020

The complexity of understanding others as the evolutionary origin of empathy and emotional contagion.

Sci Rep 2019 04 8;9(1):5794. Epub 2019 Apr 8.

Santa Fe Institute, Santa Fe, New Mexico, 87501, USA.

Contagious yawning, emotional contagion and empathy are characterized by the activation of similar neurophysiological states or responses in an observed individual and an observer. For example, it is hard to keep one's mouth closed when imagining someone yawning, or not feeling distressed while observing other individuals perceiving pain. The evolutionary origin of these widespread phenomena is unclear, since a direct benefit is not always apparent. We explore a game theoretical model for the evolution of mind-reading strategies, used to predict and respond to others' behavior. In particular we explore the evolutionary scenarios favoring simulative strategies, which recruit overlapping neural circuits when performing as well as when observing a specific behavior. We show that these mechanisms are advantageous in complex environments, by allowing an observer to use information about its own behavior to interpret that of others. However, without inhibition of the recruited neural circuits, the observer would perform the corresponding downstream action, rather than produce the appropriate social response. We identify evolutionary trade-offs that could hinder this inhibition, leading to emotional contagion as a by-product of mind-reading. The interaction of this model with kinship is complex. We show that empathy likely evolved in a scenario where kin- and other indirect benefits co-opt strategies originally evolved for mind-reading, and that this model explains observed patterns of emotional contagion with kin or group members.
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http://dx.doi.org/10.1038/s41598-019-41835-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453980PMC
April 2019

Epigenetic inheritance systems contribute to the evolution of a germline.

Philos Trans R Soc Lond B Biol Sci 2016 08;371(1701)

Santa Fe Institute, Santa Fe, NM 87501, USA.

Differentiation within multicellular organisms is controlled by epigenetic markers transmitted across cell division. The process of differentiation will modify these epigenetic markers so that information that one cell type possesses can be lost in the transition to another. Many of the systems that encode these markers also exist in unicellular organisms but do not control differentiation. Thus, during the evolution of multicellularity, epigenetic inheritance systems were probably exapted for their current use in differentiation. We show that the simultaneous use of an information carrier for differentiation and transmission across generations can lead to the evolution of cell types that do not directly contribute to the progeny of the organism and ergo a germ-soma distinction. This shows that an intrinsic instability during a transition from unicellularity to multicellularity may contribute to widespread evolution of a germline and its maintenance, a phenomenon also relevant to the evolution of eusociality. The difference in epigenetic information contents between different cell lines in a multicellular organism is also relevant for the full-success cloning of higher animals, as well as for the maintenance of single germlines over evolutionary timescales.This article is part of the themed issue 'The major synthetic evolutionary transitions'.
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http://dx.doi.org/10.1098/rstb.2015.0445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958939PMC
August 2016

Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes.

Diabetologia 2016 08 7;59(8):1702-13. Epub 2016 May 7.

Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.

Aims/hypothesis: Genome-wide association studies (GWAS) have identified more than 65 genetic loci associated with risk of type 2 diabetes. However, the contribution of distorted parental transmission of alleles to risk of type 2 diabetes has been mostly unexplored. Our goal was therefore to search for parent-of-origin effects (POE) among type 2 diabetes loci in families.

Methods: Families from the Botnia study (n = 4,211, 1,083 families) were genotyped for 72 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and assessed for POE on type 2 diabetes. The family-based Hungarian Transdanubian Biobank (HTB) (n = 1,463, >135 families) was used to replicate SNPs showing POE. Association of type 2 diabetes loci within families was also tested.

Results: Three loci showed nominal POE, including the previously reported variants in KCNQ1, for type 2 diabetes in families from Botnia (rs2237895: p POE  = 0.037), which can be considered positive controls. The strongest POE was seen for rs7578597 SNP in the THADA gene, showing excess transmission of the maternal risk allele T to diabetic offspring (Botnia: p POE  = 0.01; HTB p POE  = 0.045). These data are consistent with previous evidence of allelic imbalance for expression in islets, suggesting that the THADA gene can be imprinted in a POE-specific fashion. Five CpG sites, including those flanking rs7578597, showed differential methylation between diabetic and non-diabetic donor islets.

Conclusions/interpretation: Taken together, the data emphasise the need for genetic studies to consider from which parent an offspring has inherited a susceptibility allele.
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http://dx.doi.org/10.1007/s00125-016-3973-9DOI Listing
August 2016

Human adaptation and population differentiation in the light of ancient genomes.

Nat Commun 2016 Mar 18;7:10775. Epub 2016 Mar 18.

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

The influence of positive selection sweeps in human evolution is increasingly debated, although our ability to detect them is hampered by inherent uncertainties in the timing of past events. Ancient genomes provide snapshots of allele frequencies in the past and can help address this question. We combine modern and ancient genomic data in a simple statistic (DAnc) to time allele frequency changes, and investigate the role of drift and adaptation in population differentiation. Only 30% of the most strongly differentiated alleles between Africans and Eurasians changed in frequency during the colonization of Eurasia, but in Europe these alleles are enriched in genic and putatively functional alleles to an extent only compatible with local adaptation. Adaptive alleles--especially those associated with pigmentation--are mostly of hunter-gatherer origin, although lactose persistence arose in a haplotype present in farmers. These results provide evidence for a role of local adaptation in human population differentiation.
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http://dx.doi.org/10.1038/ncomms10775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802047PMC
March 2016

Selective Strolls: Fixation and Extinction in Diploids Are Slower for Weakly Selected Mutations Than for Neutral Ones.

Genetics 2015 Dec 23;201(4):1581-9. Epub 2015 Oct 23.

Santa Fe Institute, Santa Fe, New Mexico 87501.

In finite populations, an allele disappears or reaches fixation due to two main forces, selection and drift. Selection is generally thought to accelerate the process: a selected mutation will reach fixation faster than a neutral one, and a disadvantageous one will quickly disappear from the population. We show that even in simple diploid populations, this is often not true. Dominance and recessivity unexpectedly slow down the evolutionary process for weakly selected alleles. In particular, slightly advantageous dominant and mildly deleterious recessive mutations reach fixation slightly more slowly than neutral ones (at most 5%). This phenomenon determines genetic signatures opposite to those expected under strong selection, such as increased instead of decreased genetic diversity around the selected site. Furthermore, we characterize a new phenomenon: mildly deleterious recessive alleles, thought to represent a wide fraction of newly arising mutations, on average survive in a population slightly longer than neutral ones, before getting lost. Consequently, these mutations are on average slightly older than neutral ones, in contrast with previous expectations. Furthermore, they slightly increase the amount of weakly deleterious polymorphisms, as a consequence of the longer unconditional sojourn times compared to neutral mutations.
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http://dx.doi.org/10.1534/genetics.115.178160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676532PMC
December 2015

Genome sequence of a 45,000-year-old modern human from western Siberia.

Nature 2014 Oct;514(7523):445-9

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

We present the high-quality genome sequence of a ∼45,000-year-old modern human male from Siberia. This individual derives from a population that lived before-or simultaneously with-the separation of the populations in western and eastern Eurasia and carries a similar amount of Neanderthal ancestry as present-day Eurasians. However, the genomic segments of Neanderthal ancestry are substantially longer than those observed in present-day individuals, indicating that Neanderthal gene flow into the ancestors of this individual occurred 7,000-13,000 years before he lived. We estimate an autosomal mutation rate of 0.4 × 10(-9) to 0.6 × 10(-9) per site per year, a Y chromosomal mutation rate of 0.7 × 10(-9) to 0.9 × 10(-9) per site per year based on the additional substitutions that have occurred in present-day non-Africans compared to this genome, and a mitochondrial mutation rate of 1.8 × 10(-8) to 3.2 × 10(-8) per site per year based on the age of the bone.
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http://dx.doi.org/10.1038/nature13810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753769PMC
October 2014

Neanderthal ancestry drives evolution of lipid catabolism in contemporary Europeans.

Nat Commun 2014 Apr 1;5:3584. Epub 2014 Apr 1.

1] CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai 200031, China [2] Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig 04103, Germany.

Although Neanderthals are extinct, fragments of their genomes persist in contemporary humans. Here we show that while the genome-wide frequency of Neanderthal-like sites is approximately constant across all contemporary out-of-Africa populations, genes involved in lipid catabolism contain more than threefold excess of such sites in contemporary humans of European descent. Evolutionally, these genes show significant association with signatures of recent positive selection in the contemporary European, but not Asian or African populations. Functionally, the excess of Neanderthal-like sites in lipid catabolism genes can be linked with a greater divergence of lipid concentrations and enzyme expression levels within this pathway, seen in contemporary Europeans, but not in the other populations. We conclude that sequence variants that evolved in Neanderthals may have given a selective advantage to anatomically modern humans that settled in the same geographical areas.
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http://dx.doi.org/10.1038/ncomms4584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988804PMC
April 2014

The complete genome sequence of a Neanderthal from the Altai Mountains.

Nature 2014 Jan 18;505(7481):43-9. Epub 2013 Dec 18.

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

We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.
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http://dx.doi.org/10.1038/nature12886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031459PMC
January 2014

When unreliable cues are good enough.

Am Nat 2013 Sep 15;182(3):313-27. Epub 2013 Jul 15.

Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ 85721, USA.

In many species, nongenetic phenotypic variation helps mitigate risk associated with an uncertain environment. In some cases, developmental cues can be used to match phenotype to environment-a strategy known as predictive plasticity. When environmental conditions are entirely unpredictable, generating random phenotypic diversity may improve the long-term success of a lineage-a strategy known as diversified bet hedging. When partially reliable information is available, a well-adapted developmental strategy may strike a balance between the two strategies. We use information theory to analyze a model of development in an uncertain environment, where cue reliability is affected by variation both within and between generations. We show that within-generation variation in cues decreases the reliability of cues without affecting their fitness value. This transpires because the optimal balance of predictive plasticity and diversified bet hedging is unchanged. However, within-generation variation in cues does change the developmental mechanisms used to create that balance: developmental sensitivity to such cues not only helps match phenotype to environment but also creates phenotypic diversity that may be useful for hedging bets against environmental change. Understanding the adaptive role of developmental sensitivity thus depends on a proper assessment of both the predictive power and the structure of variation in environmental cues.
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http://dx.doi.org/10.1086/671161DOI Listing
September 2013

On the role of resonance in drug failure under HIV treatment interruption.

Theor Biol Med Model 2013 Jul 11;10:44. Epub 2013 Jul 11.

Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, Leipzig, Germany.

Background: The application of highly active antiretroviral therapy (HAART) against HIV can reduce and maintain viral load below detection limit in many patients. Continuous HAART, however, can have severe side effects. In this context, structured treatment interruptions (STI) were considered to be a promising strategy. However, using CD4 cell count to guide intermittent therapy starting and stopping points, the SMART study (strategies for management of antiretroviral therapy), revealed that STI were associated with increased risk of AIDS and other complications. Additionally, short-term periodic (e.g. one week on / one week off) interruption therapies have shown virus rebound exceeding a given "failure threshold", without any evidence for the evolution of drug resistance. Currently, the only hypothesis explaining the failure of STI is the "resonance hypothesis", which posits that treatment failure is due to a resonance effect between the drug treatment and the viral population. In the present study we used a mathematical model to analyse the parameters affecting the output of drug treatment interruption and the premises of the resonance hypothesis.

Methods: We used a population dynamic model of HIV infection. Simulations and analytical approximations of deterministic and stochastic versions of the model were studied.

Results And Conclusion: The present study examines the roles of the most important parameters affecting the viral rebound, responsible for drug failure. We related these findings to the resonance hypothesis, and showed that the degree of sustainability of damping oscillations present in the model after the acute phase is strongly linked to their amplitude, which determines the resonance level. Stochastic simulations of the same model even revealed sustained oscillations in virus population for small virus population sizes. Given that pronounced viral load oscillations have not been observed in HIV-1 patients, the link between oscillations and resonance level suggests that treatment failure due to a resonance effect is not plausible. Moreover, the failure threshold is attained before the virus population crosses the set point while growing. As the maximum virus population is reached even after the set point is crossed, the role of resonance effects in the context of treatment interruptions cannot explain drug failure.
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http://dx.doi.org/10.1186/1742-4682-10-44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718686PMC
July 2013

Great ape genetic diversity and population history.

Nature 2013 Jul 3;499(7459):471-5. Epub 2013 Jul 3.

Institut de Biologia Evolutiva, CSIC-Universitat Pompeu Fabra, PRBB, Doctor Aiguader 88, Barcelona, Catalonia 08003, Spain.

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.
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http://dx.doi.org/10.1038/nature12228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822165PMC
July 2013

Inferring the history of population size change from genome-wide SNP data.

Mol Biol Evol 2012 Dec 10;29(12):3653-67. Epub 2012 Jul 10.

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

Dense, genome-wide single-nucleotide polymorphism (SNP) data can be used to reconstruct the demographic history of human populations. However, demographic inferences from such data are complicated by recombination and ascertainment bias. We introduce two new statistics, allele frequency-identity by descent (AF-IBD) and allele frequency-identity by state (AF-IBS), that make use of linkage disequilibrium information and show defined relationships to the time of coalescence. These statistics, when conditioned on the derived allele frequency, are able to infer complex population size changes. Moreover, the AF-IBS statistic, which is based on genome-wide SNP data, is robust to varying ascertainment conditions. We constructed an efficient approximate Bayesian computation (ABC) pipeline based on AF-IBD and AF-IBS that can accurately estimate demographic parameters, even for fairly complex models. Finally, we applied this ABC approach to genome-wide SNP data and inferred the demographic histories of two human populations, Yoruba and French. Our results suggest a rather stable ancestral population size with a mild recent expansion for Yoruba, whereas the French seemingly experienced a long-lasting severe bottleneck followed by a drastic population growth. This approach should prove useful for new insights into populations, especially those with complex demographic histories.
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http://dx.doi.org/10.1093/molbev/mss175DOI Listing
December 2012

The bonobo genome compared with the chimpanzee and human genomes.

Nature 2012 Jun;486(7404):527-31

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

Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other.
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http://dx.doi.org/10.1038/nature11128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498939PMC
June 2012

'maskBAD'--a package to detect and remove Affymetrix probes with binding affinity differences.

BMC Bioinformatics 2012 Apr 16;13:56. Epub 2012 Apr 16.

Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany.

Background: Hybridization differences caused by target sequence differences can be a confounding factor in analyzing gene expression on microarrays, lead to false positives and reduce power to detect real expression differences. We prepared an R Bioconductor compatible package to detect, characterize and remove such probes in Affymetrix 3'IVT and exon-based arrays on the basis of correlation of signal intensities from probes within probe sets.

Results: Using completely mouse genomes we determined type 1 (false negatives) and type 2 (false positives) errors with high accuracy and we show that our method routinely outperforms previous methods. When detecting 76.2% of known SNP/indels in mouse expression data, we obtain at most 5.5% false positives. At the same level of false positives, best previous method detected 72.6%. We also show that probes with differing binding affinity both hinder differential expression detection and introduce artifacts in cancer-healthy tissue comparison.

Conclusions: Detection and removal of such probes should be a routine step in Affymetrix data preprocessing. We prepared a user friendly R package, compatible with Bioconductor, that allows the filtering and improving of data from Affymetrix microarrays experiments.
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http://dx.doi.org/10.1186/1471-2105-13-56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439685PMC
April 2012

Analysis of human accelerated DNA regions using archaic hominin genomes.

PLoS One 2012 7;7(3):e32877. Epub 2012 Mar 7.

Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

Several previous comparisons of the human genome with other primate and vertebrate genomes identified genomic regions that are highly conserved in vertebrate evolution but fast-evolving on the human lineage. These human accelerated regions (HARs) may be regions of past adaptive evolution in humans. Alternatively, they may be the result of non-adaptive processes, such as biased gene conversion. We captured and sequenced DNA from a collection of previously published HARs using DNA from an Iberian Neandertal. Combining these new data with shotgun sequence from the Neandertal and Denisova draft genomes, we determine at least one archaic hominin allele for 84% of all positions within HARs. We find that 8% of HAR substitutions are not observed in the archaic hominins and are thus recent in the sense that the derived allele had not come to fixation in the common ancestor of modern humans and archaic hominins. Further, we find that recent substitutions in HARs tend to have come to fixation faster than substitutions elsewhere in the genome and that substitutions in HARs tend to cluster in time, consistent with an episodic rather than a clock-like process underlying HAR evolution. Our catalog of sequence changes in HARs will help prioritize them for functional studies of genomic elements potentially responsible for modern human adaptations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032877PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296746PMC
August 2012

MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain.

Genome Res 2010 Sep 20;20(9):1207-18. Epub 2010 Jul 20.

Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species' life spans. We find that few gene expression changes are unique to aging. Instead, the vast majority of miRNA and gene expression changes that occur in aging represent reversals or extensions of developmental patterns. Surprisingly, many gene expression changes previously attributed to aging, such as down-regulation of neural genes, initiate in early childhood. Our results indicate that miRNA and transcription factors regulate not only developmental but also post-developmental expression changes, with a number of regulatory processes continuing throughout the entire life span. Differential evolutionary conservation of the corresponding genomic regions implies that these regulatory processes, although beneficial in development, might be detrimental in aging. These results suggest a direct link between developmental regulation and expression changes taking place in aging.
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http://dx.doi.org/10.1101/gr.106849.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928499PMC
September 2010

Targeted investigation of the Neandertal genome by array-based sequence capture.

Science 2010 May;328(5979):723-5

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

It is now possible to perform whole-genome shotgun sequencing as well as capture of specific genomic regions for extinct organisms. However, targeted resequencing of large parts of nuclear genomes has yet to be demonstrated for ancient DNA. Here we show that hybridization capture on microarrays can successfully recover more than a megabase of target regions from Neandertal DNA even in the presence of approximately 99.8% microbial DNA. Using this approach, we have sequenced approximately 14,000 protein-coding positions inferred to have changed on the human lineage since the last common ancestor shared with chimpanzees. By generating the sequence of one Neandertal and 50 present-day humans at these positions, we have identified 88 amino acid substitutions that have become fixed in humans since our divergence from the Neandertals.
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http://dx.doi.org/10.1126/science.1188046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140021PMC
May 2010

A draft sequence of the Neandertal genome.

Science 2010 May;328(5979):710-722

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

Neandertals, the closest evolutionary relatives of present-day humans, lived in large parts of Europe and western Asia before disappearing 30,000 years ago. We present a draft sequence of the Neandertal genome composed of more than 4 billion nucleotides from three individuals. Comparisons of the Neandertal genome to the genomes of five present-day humans from different parts of the world identify a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. We show that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.
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http://dx.doi.org/10.1126/science.1188021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100745PMC
May 2010

The fitness value of information.

Oikos 2010 Feb;119(2):219-230

Max Planck Inst. for Evol. Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany.

Communication and information are central concepts in evolutionary biology. In fact, it is hard to find an area of biology where these concepts are not used. However, quantifying the information transferred in biological interactions has been difficult. How much information is transferred when the first spring rainfall hits a dormant seed, or when a chick begs for food from its parent? One measure that is commonly used in such cases is fitness value: by how much, on average, an individual's fitness would increase if it behaved optimally with the new information, compared to its average fitness without the information. Another measure, often used to describe neural responses to sensory stimuli, is the mutual information-a measure of reduction in uncertainty, as introduced by Shannon in communication theory. However, mutual information has generally not been considered to be an appropriate measure for describing developmental or behavioral responses at the organismal level, because it is blind to function; it does not distinguish between relevant and irrelevant information. In this paper we show that there is in fact a surprisingly tight connection between these two measures in the important context of evolution in an uncertain environment. In this case, a useful measure of fitness benefit is the increase in the long-term growth rate, or the fold increase in number of surviving lineages. We show that in many cases the fitness value of a developmental cue, when measured this way, is exactly equal to the reduction in uncertainty about the environment, as described by the mutual information.
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http://dx.doi.org/10.1111/j.1600-0706.2009.17781.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384894PMC
February 2010

The effects of probe binding affinity differences on gene expression measurements and how to deal with them.

Bioinformatics 2009 Nov 18;25(21):2772-9. Epub 2009 Aug 18.

Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

Motivation: When comparing gene expression levels between species or strains using microarrays, sequence differences between the groups can cause false identification of expression differences. Our simulated dataset shows that a sequence divergence of only 1% between species can lead to falsely reported expression differences for >50% of the transcripts-similar levels of effect have been reported previously in comparisons of human and chimpanzee expression. We propose a method for identifying probes that cause such false readings, using only the microarray data, so that problematic probes can be excluded from analysis. We then test the power of the method to detect sequence differences and to correct for falsely reported expression differences. Our method can detect 70% of the probes with sequence differences using human and chimpanzee data, while removing only 18% of probes with no sequence differences. Although only 70% of the probes with sequence differences are detected, the effect of removing probes on falsely reported expression differences is more dramatic: the method can remove 98% of the falsely reported expression differences from a simulated dataset. We argue that the method should be used even when sequence data are available.

Contact: lachmann@eva.mpg.de

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btp492DOI Listing
November 2009

The Neandertal genome and ancient DNA authenticity.

EMBO J 2009 Sep 6;28(17):2494-502. Epub 2009 Aug 6.

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

Recent advances in high-thoughput DNA sequencing have made genome-scale analyses of genomes of extinct organisms possible. With these new opportunities come new difficulties in assessing the authenticity of the DNA sequences retrieved. We discuss how these difficulties can be addressed, particularly with regard to analyses of the Neandertal genome. We argue that only direct assays of DNA sequence positions in which Neandertals differ from all contemporary humans can serve as a reliable means to estimate human contamination. Indirect measures, such as the extent of DNA fragmentation, nucleotide misincorporations, or comparison of derived allele frequencies in different fragment size classes, are unreliable. Fortunately, interim approaches based on mtDNA differences between Neandertals and current humans, detection of male contamination through Y chromosomal sequences, and repeated sequencing from the same fossil to detect autosomal contamination allow initial large-scale sequencing of Neandertal genomes. This will result in the discovery of fixed differences in the nuclear genome between Neandertals and current humans that can serve as future direct assays for contamination. For analyses of other fossil hominins, which may become possible in the future, we suggest a similar 'boot-strap' approach in which interim approaches are applied until sufficient data for more definitive direct assays are acquired.
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http://dx.doi.org/10.1038/emboj.2009.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725275PMC
September 2009

Linkage disequilibrium extends across putative selected sites in FOXP2.

Mol Biol Evol 2009 Oct 16;26(10):2181-4. Epub 2009 Jul 16.

Polymorphism data in humans suggest that the gene encoding the transcription factor FOXP2, which influences speech and language development, has been subject to a selective sweep within the last 260,000 years. It has been proposed that one or both of two substitutions that occurred on the human evolutionary lineage and changed amino acids were the targets for selection. In apparent contradiction to this is the observation that these substitutions are present in Neandertals who diverged from humans maybe 300,000-400,000 years ago. We have collected polymorphism data upstream and downstream of the substitutions. Contrary to what is expected, following a selective sweep, we find that the haplotypes extend across the two sites. We discuss possible explanations for these observations. One of them is that the selective sweep reflected in FOXP2 polymorphism data was not associated with the two amino acid substitutions.
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http://dx.doi.org/10.1093/molbev/msp143DOI Listing
October 2009

Transcriptional neoteny in the human brain.

Proc Natl Acad Sci U S A 2009 Apr 23;106(14):5743-8. Epub 2009 Mar 23.

Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.

In development, timing is of the utmost importance, and the timing of developmental processes often changes as organisms evolve. In human evolution, developmental retardation, or neoteny, has been proposed as a possible mechanism that contributed to the rise of many human-specific features, including an increase in brain size and the emergence of human-specific cognitive traits. We analyzed mRNA expression in the prefrontal cortex of humans, chimpanzees, and rhesus macaques to determine whether human-specific neotenic changes are present at the gene expression level. We show that the brain transcriptome is dramatically remodeled during postnatal development and that developmental changes in the human brain are indeed delayed relative to other primates. This delay is not uniform across the human transcriptome but affects a specific subset of genes that play a potential role in neural development.
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http://dx.doi.org/10.1073/pnas.0900544106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659716PMC
April 2009

PatMaN: rapid alignment of short sequences to large databases.

Bioinformatics 2008 Jul 8;24(13):1530-1. Epub 2008 May 8.

Max-Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany.

Unlabelled: We present a tool suited for searching for many short nucleotide sequences in large databases, allowing for a predefined number of gaps and mismatches. The commandline-driven program implements a non-deterministic automata matching algorithm on a keyword tree of the search strings. Both queries with and without ambiguity codes can be searched. Search time is short for perfect matches, and retrieval time rises exponentially with the number of edits allowed.

Availability: The C++ source code for PatMaN is distributed under the GNU General Public License and has been tested on the GNU/Linux operating system. It is available from http://bioinf.eva.mpg.de/patman.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btn223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718670PMC
July 2008

Human and chimpanzee gene expression differences replicated in mice fed different diets.

PLoS One 2008 Jan 30;3(1):e1504. Epub 2008 Jan 30.

Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Although the human diet is markedly different from the diets of closely related primate species, the influence of diet on phenotypic and genetic differences between humans and other primates is unknown. In this study, we analyzed gene expression in laboratory mice fed diets typical of humans and of chimpanzees. The effects of human diets were found to be significantly different from that of a chimpanzee diet in the mouse liver, but not in the brain. Importantly, 10% of the genes that differ in their expression between humans and chimpanzee livers differed also between the livers of mice fed the human and chimpanzee diets. Furthermore, both the promoter sequences and the amino acid sequences of these diet-related genes carry more differences between humans and chimpanzees than random genes. Our results suggest that the mouse can be used to study at least some aspects of human-specific traits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001504PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2200793PMC
January 2008

Patterns of damage in genomic DNA sequences from a Neandertal.

Proc Natl Acad Sci U S A 2007 Sep 21;104(37):14616-21. Epub 2007 Aug 21.

Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany.

High-throughput direct sequencing techniques have recently opened the possibility to sequence genomes from Pleistocene organisms. Here we analyze DNA sequences determined from a Neandertal, a mammoth, and a cave bear. We show that purines are overrepresented at positions adjacent to the breaks in the ancient DNA, suggesting that depurination has contributed to its degradation. We furthermore show that substitutions resulting from miscoding cytosine residues are vastly overrepresented in the DNA sequences and drastically clustered in the ends of the molecules, whereas other substitutions are rare. We present a model where the observed substitution patterns are used to estimate the rate of deamination of cytosine residues in single- and double-stranded portions of the DNA, the length of single-stranded ends, and the frequency of nicks. The results suggest that reliable genome sequences can be obtained from Pleistocene organisms.
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http://dx.doi.org/10.1073/pnas.0704665104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976210PMC
September 2007

FUNC: a package for detecting significant associations between gene sets and ontological annotations.

BMC Bioinformatics 2007 Feb 6;8:41. Epub 2007 Feb 6.

Max-Planck-Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany.

Background: Genome-wide expression, sequence and association studies typically yield large sets of gene candidates, which must then be further analysed and interpreted. Information about these genes is increasingly being captured and organized in ontologies, such as the Gene Ontology. Relationships between the gene sets identified by experimental methods and biological knowledge can be made explicit and used in the interpretation of results. However, it is often difficult to assess the statistical significance of such analyses since many inter-dependent categories are tested simultaneously.

Results: We developed the program package FUNC that includes and expands on currently available methods to identify significant associations between gene sets and ontological annotations. Implemented are several tests in particular well suited for genome wide sequence comparisons, estimates of the family-wise error rate, the false discovery rate, a sensitive estimator of the global significance of the results and an algorithm to reduce the complexity of the results.

Conclusion: FUNC is a versatile and useful tool for the analysis of genome-wide data. It is freely available under the GPL license and also accessible via a web service.
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http://dx.doi.org/10.1186/1471-2105-8-41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1800870PMC
February 2007