Michael Dannemann

The complete genome sequence of a Neanderthal from the Altai Mountains

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.

The genomic landscape of Neanderthal ancestry in present-day humans

Genomic studies have shown that Neanderthals interbred with modern humans, and that non-Africans today are the products of this mixture. The antiquity of Neanderthal gene flow into modern humans means that genomic regions that derive from Neanderthals in any one human today are usually less than a hundred kilobases in size. However, Neanderthal haplotypes are also distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci. We systematically infer Neanderthal haplotypes in the genomes of 1,004 present-day humans. Regions that harbour a high frequency of Neanderthal alleles are enriched for genes affecting keratin filaments, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African environments. We identify multiple Neanderthal-derived alleles that confer risk for disease, suggesting that Neanderthal alleles continue to shape human biology. An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals. Genes that are more highly expressed in testes than in any other tissue are especially reduced in Neanderthal ancestry, and there is an approximately fivefold reduction of Neanderthal ancestry on the X chromosome, which is known from studies of diverse species to be especially dense in male hybrid sterility genes. These results suggest that part of the explanation for genomic regions of reduced Neanderthal ancestry is Neanderthal alleles that caused decreased fertility in males when moved to a modern human genetic background.

Transcriptional neoteny in the human brain

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.

PatMaN: Rapid alignment of short sequences to large databases

Summary: 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. Contact: pruefer@eva.mpg.de Supplementary information: Supplementary data are available at Bioinformatics online.

Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals

Denisovan DNA retained in Melanesians Modern humans carry remnants of DNA from interbreeding events with archaic lineages, such as Neandertals. However, people from Oceania also retain genes from a second ancient lineage, the Denisovans. Vernot et al. surveyed archaic genomic sequences in a worldwide sample of modern humans, including 35 individuals from the Melanesian Islands. All non-African genomes surveyed contained Neandertal DNA, but a significant Denisovan component was found only in the Melanesians. Reconstruction of this genetic history suggests that Neandertals bred with modern humans multiple times, but Denosivans only once, in ancestors of modern-day Melanesians. Science, this issue p. 235 Neandertal and Denisovan DNA live on in modern day Melanesians. Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression.

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

Significance The human form of forkhead box P2 (FOXP2) is the leading genetic candidate for human speech and language proficiency. We demonstrate that the introduction of the amino acid changes that occurred during human evolution into murine Foxp2 (Foxp2hum) profoundly affects learning and striatal neuroplasticity. Foxp2hum/hum mice learn stimulus–response associations more rapidly than WT mice when declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could interfere with one another. Dopamine levels, gene expression patterns, and synaptic physiology are oppositely affected in the striatal districts underpinning these learning forms, paralleling the behavioral change. We hypothesize that the human FOXP2 evolution led to differential tuning of corticostriatal systems involved in declarative and procedural learning and thus contributed to adapting the human brain for speech and language acquisition. 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 (Foxp2hum), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2hum/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 Foxp2hum/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.

Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors

Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. Here we document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neandertal genome, and the third haplotype is most similar to the Denisovan genome. The Toll-like receptors are key components of innate immunity and provide an important first line of immune defense against bacteria, fungi, and parasites. The unusually high allele frequencies and unexpected levels of population differentiation indicate that there has been local positive selection on multiple haplotypes at this locus. We show that the introgressed alleles have clear functional effects in modern humans; archaic-like alleles underlie differences in the expression of the TLR genes and are associated with reduced microbial resistance and increased allergic disease in large cohorts. This provides strong evidence for recurrent adaptive introgression at the TLR6-TLR1-TLR10 locus, resulting in differences in disease phenotypes in modern humans.

Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations

Summary Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli—ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus—and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.

A high-coverage Neandertal genome from Vindija Cave in Croatia

Revelations from a Vindija Neandertal genome Neandertals clearly interbred with the ancestors of non-African modern humans, but many questions remain about our closest ancient relatives. Prüfer et al. present a 30-fold-coverage genome sequence from 50,000- to 65,000-year-old samples from a Neandertal woman found in Vindija, Croatia, and compared this sequence with genomes obtained from the Altai Neandertal, the Denisovans, and ancient and modern humans (see the Perspective by Bergström and Tyler-Smith). Neandertals likely lived in small groups and had lower genetic diversity than modern humans. The findings increase the number of Neandertal variants identified within populations of modern humans, and they suggest that a larger number of phenotypic and diseaserelated variants with Neandertal ancestry remain in the modern Eurasian gene pool than previously thought. Science, this issue p. 655; see also p. 586 A second deep-sequenced Neandertal genome reveals more about Neandertals and their relationships with ancient humans. To date, the only Neandertal genome that has been sequenced to high quality is from an individual found in Southern Siberia. We sequenced the genome of a female Neandertal from ~50,000 years ago from Vindija Cave, Croatia, to ~30-fold genomic coverage. She carried 1.6 differences per 10,000 base pairs between the two copies of her genome, fewer than present-day humans, suggesting that Neandertal populations were of small size. Our analyses indicate that she was more closely related to the Neandertals that mixed with the ancestors of present-day humans living outside of sub-Saharan Africa than the previously sequenced Neandertal from Siberia, allowing 10 to 20% more Neandertal DNA to be identified in present-day humans, including variants involved in low-density lipoprotein cholesterol concentrations, schizophrenia, and other diseases.

Palaeoproteomic evidence identifies archaic hominins associated with the Châtelperronian at the Grotte du Renne

Significance The displacement of Neandertals by anatomically modern humans (AMHs) 50,000–40,000 y ago in Europe has considerable biological and behavioral implications. The Châtelperronian at the Grotte du Renne (France) takes a central role in models explaining the transition, but the association of hominin fossils at this site with the Châtelperronian is debated. Here we identify additional hominin specimens at the site through proteomic zooarchaeology by mass spectrometry screening and obtain molecular (ancient DNA, ancient proteins) and chronometric data to demonstrate that these represent Neandertals that date to the Châtelperronian. The identification of an amino acid sequence specific to a clade within the genus Homo demonstrates the potential of palaeoproteomic analysis in the study of hominin taxonomy in the Late Pleistocene and warrants further exploration. In Western Europe, the Middle to Upper Paleolithic transition is associated with the disappearance of Neandertals and the spread of anatomically modern humans (AMHs). Current chronological, behavioral, and biological models of this transitional period hinge on the Châtelperronian technocomplex. At the site of the Grotte du Renne, Arcy-sur-Cure, morphological Neandertal specimens are not directly dated but are contextually associated with the Châtelperronian, which contains bone points and beads. The association between Neandertals and this “transitional” assemblage has been controversial because of the lack either of a direct hominin radiocarbon date or of molecular confirmation of the Neandertal affiliation. Here we provide further evidence for a Neandertal–Châtelperronian association at the Grotte du Renne through biomolecular and chronological analysis. We identified 28 additional hominin specimens through zooarchaeology by mass spectrometry (ZooMS) screening of morphologically uninformative bone specimens from Châtelperronian layers at the Grotte du Renne. Next, we obtain an ancient hominin bone proteome through liquid chromatography-MS/MS analysis and error-tolerant amino acid sequence analysis. Analysis of this palaeoproteome allows us to provide phylogenetic and physiological information on these ancient hominin specimens. We distinguish Late Pleistocene clades within the genus Homo based on ancient protein evidence through the identification of an archaic-derived amino acid sequence for the collagen type X, alpha-1 (COL10α1) protein. We support this by obtaining ancient mtDNA sequences, which indicate a Neandertal ancestry for these specimens. Direct accelerator mass spectometry radiocarbon dating and Bayesian modeling confirm that the hominin specimens date to the Châtelperronian at the Grotte du Renne.