[Show abstract][Hide abstract] ABSTRACT: Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.
PLoS ONE 08/2015; 10(8):e0134548. DOI:10.1371/journal.pone.0134548 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The transcription factor FOXP2 has been linked to severe speech and language impairments in humans. An analysis of the evolution of the FOXP2 gene has identified two amino acid substitutions that became fixed after the split of the human and chimpanzee lineages. Studying the functional consequences of these two substitutions in the endogenous Foxp2 gene of mice revealed alterations in dopamine levels, striatal synaptic plasticity, neuronal morphology and cortico-striatal dependent learning. In addition, ultrasonic vocalizations (USVs) of pups had a significantly lower average pitch than control littermates. To which degree adult ultrasonic vocalizations would be affected in mice carrying the "humanized" Foxp2 variant remained unclear. In the present study, we analyzed USVs of 68 adult male mice uttered during repeated courtship encounters with different females. Mice carrying the Foxp2(hum/hum) allele did not differ significantly in the number of call elements, their element structure, or in their element composition from control littermates. We conclude that neither the structure nor usage of USVs in adult mice is affected by the two amino acid substitutions that occurred in FOXP2 during human evolution. The reported effect for pup vocalization thus appears to be transient. These results are in line with accumulating evidence that mouse USVs are hardly influenced by vocal learning. Hence, the function and evolution of genes that are necessary, but not sufficient for vocal learning in humans must be either studied at a different phenotypic level in mice or in other organisms.
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Genes Brain and Behavior 08/2015; DOI:10.1111/gbb.12237 · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neanderthals are thought to have disappeared in Europe approximately 39,000-41,000 years ago but they have contributed 1-3% of the DNA of present-day people in Eurasia. Here we analyse DNA from a 37,000-42,000-year-old modern human from Peştera cu Oase, Romania. Although the specimen contains small amounts of human DNA, we use an enrichment strategy to isolate sites that are informative about its relationship to Neanderthals and present-day humans. We find that on the order of 6-9% of the genome of the Oase individual is derived from Neanderthals, more than any other modern human sequenced to date. Three chromosomal segments of Neanderthal ancestry are over 50 centimorgans in size, indicating that this individual had a Neanderthal ancestor as recently as four to six generations back. However, the Oase individual does not share more alleles with later Europeans than with East Asians, suggesting that the Oase population did not contribute substantially to later humans in Europe.
[Show abstract][Hide abstract] ABSTRACT: The Protoaurignacian culture is pivotal to the debate about the timing of the arrival of modern humans in western Europe and
the demise of Neandertals. However, which group is responsible for this culture remains uncertain. We investigated dental
remains associated with the Protoaurignacian. The lower deciduous incisor from Riparo Bombrini is modern human, based on its
morphology. The upper deciduous incisor from Grotta di Fumane contains ancient mitochondrial DNA of a modern human type. These
teeth are the oldest human remains in an Aurignacian-related archaeological context, confirming that by 41,000 calendar years
before the present, modern humans bearing Protoaurignacian culture spread into southern Europe. Because the last Neandertals
date to 41,030 to 39,260 calendar years before the present, we suggest that the Protoaurignacian triggered the demise of Neandertals
in this area.
[Show abstract][Hide abstract] ABSTRACT: 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 3 10 29 to 0.6 3 10 29 per site per year, a Y chromosomal mutation rate of 0.7 3 10 29 to 0.9 3 10 29 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 3 10 28 to 3.2 3 10 28 per site per year based on the age of the bone.
[Show abstract][Hide abstract] ABSTRACT: The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2(hum)), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2(hum/hum) mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2(hum/hum) mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.
Proceedings of the National Academy of Sciences 09/2014; 111(39). DOI:10.1073/pnas.1414542111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: RUNX2, a gene involved in skeletal development, has previously been shown to be potentially affected by positive selection during recent human evolution. Here we have used antibody-based proteomics to characterize potential differences in expression patterns of RUNX2 interacting partners during primate evolution. Tissue microarrays consisting of a large set of normal tissues from human and macaque were used for protein profiling of 50 RUNX2 partners with immunohistochemistry. Eleven proteins (AR, CREBBP, EP300, FGF2, HDAC3, JUN, PRKD3, RUNX1, SATB2, TCF3 and YAP1) showed differences in expression between humans and macaques. These proteins were further profiled in tissues from chimpanzee, gorilla and orangutan, and the corresponding genes were analyzed with regard to genomic features. Moreover, protein expression data was compared with previously obtained RNA sequencing data from six different organs. One gene (TCF3) showed significant expression differences between human and macaque at both the protein and RNA level, with higher expression in a subset of germ cells in human testis compared to macaque. In conclusion, normal tissues from macaque and human showed differences in expression of some RUNX2 partners that could be mapped to various defined cell types. The applied strategy appears advantageous to characterize the consequences of altered genes selected during evolution.
Journal of Proteome Research 06/2014; 13(8). DOI:10.1021/pr500045f · 4.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ancient DNA sequencing has recently provided high-coverage archaic human genomes. However, the evolution of epigenetic regulation
along the human lineage remains largely unexplored. We reconstructed the full DNA methylation maps of the Neandertal and the
Denisovan by harnessing the natural degradation processes of methylated and unmethylated cytosines. Comparing these ancient
methylation maps to those of present-day humans, we identified ~2000 differentially methylated regions (DMRs). Particularly,
we found substantial methylation changes in the HOXD cluster that may explain anatomical differences between archaic and present-day
humans. Additionally, we found that DMRs are significantly more likely to be associated with diseases. This study provides
insight into the epigenetic landscape of our closest evolutionary relatives and opens a window to explore the epigenomes of
[Show abstract][Hide abstract] ABSTRACT: Author Summary
Physiological processes that maintain our tissues' functionality involve the generation of multiple products and intermediates known as metabolites—small molecules with a weight of less than 1,500 Daltons. Changes in concentrations of these metabolites are thought to be closely related to changes in phenotype. Here, we assessed concentrations of more than 10,000 metabolites in three brain regions and two non-neural tissues (skeletal muscle and kidney) of humans, chimpanzees, macaque monkeys, and mice using mass spectrometry-based approaches. We found that the evolution of the metabolome largely reflects genetic divergence between species and is not greatly affected by environmental factors. In the human lineage, however, we observed an exceptional acceleration of metabolome evolution in the prefrontal cortical region of the brain and in skeletal muscle. Based on additional behavioral tests, we further show that metabolic changes in human muscle seem to be paralleled by a drastic reduction in muscle strength. The observed rapid metabolic changes in brain and muscle, together with the unique human cognitive skills and low muscle performance, might reflect parallel mechanisms in human evolution.
[Show abstract][Hide abstract] ABSTRACT: We present the DNA sequence of 17,367 protein-coding genes in two Neandertals from Spain and Croatia and analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia. Comparisons with present-day humans from Africa, Europe, and Asia reveal that genetic diversity among Neandertals was remarkably low, and that they carried a higher proportion of amino acid-changing (nonsynonymous) alleles inferred to alter protein structure or function than present-day humans. Thus, Neandertals across Eurasia had a smaller long-term effective population than present-day humans. We also identify amino acid substitutions in Neandertals and present-day humans that may underlie phenotypic differences between the two groups. We find that genes involved in skeletal morphology have changed more in the lineage leading to Neandertals than in the ancestral lineage common to archaic and modern humans, whereas genes involved in behavior and pigmentation have changed more on the modern human lineage.
Proceedings of the National Academy of Sciences 04/2014; 111(18). DOI:10.1073/pnas.1405138111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inter-individual differences in many behaviors are partly due to genetic
differences, but the identification of the genes and variants that influence
behavior remains challenging. Here, we studied an F2 intercross of two outbred
lines of rats selected for tame and aggressive behavior towards humans for more
than 64 generations. By using a mapping approach that is able to identify
genetic loci segregating within the lines, we identified four times more loci
influencing tameness and aggression than by an approach that assumes fixation
of causative alleles, suggesting that many causative loci were not driven to
fixation by the selection. We used RNA sequencing in 150 F2 animals to identify
hundreds of loci that influence brain gene expression. Several of these loci
colocalize with tameness loci and may reflect the same genetic variants.
Through analyses of correlations between allele effects on behavior and gene
expression, differential expression between the tame and aggressive rat
selection lines, and correlations between gene expression and tameness in F2
animals, we identify the genes Gltscr2, Lgi4, Zfp40 and Slc17a7 as candidate
contributors to the strikingly different behavior of the tame and aggressive
[Show abstract][Hide abstract] ABSTRACT: Research into when and where modern humans originated and how they differ from, and interacted with, other now-extinct forms of human has so far been the realm of archaeologists and paleoanthropologists. However, over the past decade, molecular geneticists have begun to study genomes of extinct humans. Here, I discuss where we stand today with respect to understanding how modern humans came to differ from Neandertals and other human forms that existed until about 30,000 years ago.
[Show abstract][Hide abstract] ABSTRACT: Induced pluripotent stem cells (iPSCs) are regarded as a central tool to understand human biology in health and disease. Similarly, iPSCs from non-human primates should be a central tool to understand human evolution, in particular for assessing the conservation of regulatory networks in iPSC models. Here, we have generated human, gorilla, bonobo and cynomolgus monkey iPSCs and assess their usefulness in such a framework. We show that these cells are well comparable in their differentiation potential and are generally similar to human, cynomolgus and rhesus monkey embryonic stem cells (ESCs). RNA sequencing reveals that expression differences among clones, individuals and stem cell type are all of very similar magnitude within a species. In contrast, expression differences between closely related primate species are three times larger and most genes show significant expression differences among the analyzed species. However, pseudogenes differ more than twice as much, suggesting that evolution of expression levels in primate stem cells is rapid, but constrained. These patterns in pluripotent stem cells are comparable to those found in other tissues except testis. Hence, primate iPSCs reveal insights into general primate gene expression evolution and should provide a rich source to identify conserved and species-specific gene expression patterns for cellular phenotypes.
Stem Cell Research 02/2014; 12(3):622-629. DOI:10.1016/j.scr.2014.02.001 · 3.69 Impact Factor