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Related subjects: Ancient History, Classical History and Mythology
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Temporal range: Middle to Late Pleistocene 0.6–0.03Ma
Neanderthal skull, La Chapelle-aux-Saints
Mounted Neanderthal skeleton, American Museum of Natural History
Order: Primates
Family: Hominidae
Genus: Homo
Species: H. neanderthalensis
Homo neanderthalensis
King, 1864
Range of Homo neanderthalensis. Eastern and northern ranges may extend to include Okladnikov in Altai and Mamotnaia in Ural
H. mousteriensis
H. s. neanderthalensis
Palaeoanthropus neanderthalensis
The Neanderthals (English pronunciation /niˈændərˌθɔːlz/, /niˈændərˌtɔːlz/, /niˈændərˌtɑːlz/ or /neɪˈɑːndərˌtɑːlz/) are an extinct species or subspecies of the genus Homo which is closely related to modern humans. They are known from fossils, dating from the Pleistocene period, which have been found in Europe and parts of western and central Asia. The species is named after Neandertal ("Neander's Valley"), the location in Germany where it was first discovered. The species name is also sometimes spelled Neandertal, because that is the modern German spelling of the valley's name.
Neanderthals are classified either as a subspecies of Homo sapiens (Homo sapiens neanderthalensis) or as a separate species of the same genus (Homo neanderthalensis). The first humans with proto-Neanderthal traits are believed to have existed in Europe as early as 600,000–350,000 years ago.
When the Neanderthals went extinct is disputed. Fossils found in the Vindija Cave in Croatia have been dated to between 33,000 and 32,000 years old, and Neanderthal artefacts from Gorham's Cave in Gibraltar are believed to be less than 30,000 years ago, but a recent study has re-dated fossils at two Spanish sites as 45,000 years old, 10,000 years older than previously thought, and may cast doubt on recent dates at other sites. Cro-Magnon (early-modern-human) skeletal remains showing certain "Neanderthal traits" have been found in Lagar Velho (Portugal) and dated to 24,500 years ago, suggesting that there may have been an extensive admixture of the Cro-Magnon and Neanderthal populations in that region.
Several cultural assemblages have been linked to the Neanderthals in Europe. The earliest, the Mousterian stone tool culture, dates to about 300,000 years ago. Late Mousterian artifacts were found in Gorham's Cave on the south-facing coast of Gibraltar. Other tool cultures associated with the Neanderthals include the Châtelperronian, the Aurignacian, and the Gravettian; their tool assemblages appear to have developed gradually within their populations, rather than being introduced by new population groups arriving in the region.
Neanderthal cranial capacity is thought to have been as large as that of modern humans, perhaps larger, indicating that their brain size may have been comparable, or larger, as well. In 2008, a group of scientists created a study using three-dimensional computer-assisted reconstructions of Neanderthal infants based on fossils found in Russia and Syria. The study showed Neanderthal and modern human brains were the same size at birth, but by adulthood, the Neanderthal brain was larger than the modern human brain. They were much stronger than modern humans, having particularly strong arms and hands. Males stood 164–168 cm (65–66 in) and females about 152–156 cm (60–61 in) tall.
Genetic evidence published in 2010 suggests that Neanderthals contributed to the DNA of anatomically modern humans, probably through interbreeding between 80,000 and 50,000 years ago with the population of anatomically modern humans who had recently migrated from Africa. According to the study, by the time that population began dispersing across Eurasia, Neanderthals genes constituted as much as 1–4% of its genome.
The species is named after the site of its first discovery, about 12 km (7.5 mi) east of Düsseldorf, Germany, in the Feldhofer Cave in the river Düssel's Neander valley named for Joachim Neander, a 17th-century German pastor and hymnist. Neander's own name was a Greek translation of the German Neumann (lit. "New man"). Thal is the older spelling of Tal (both with the same pronunciation), the German word for 'valley' (cognate with English dale).
Neanderthal 1 was known as the "Neanderthal skull" or "Neanderthal cranium" in anthropological literature, and the individual reconstructed on the basis of the skull was occasionally called "the Neanderthal man". The binomial name Homo neanderthalensis – extending the name "Neanderthal man" from the individual type specimen to the entire species – was first proposed by the Anglo-Irish geologist William King in 1864 and this had priority over the proposal put forward in 1866 by Ernst Haeckel, Homo stupidus. The practice of referring to "the Neanderthals" and "a Neanderthal" emerged in the popular literature of the 1920s.
The German pronunciation of Neanderthaler and Neandertaler is [neˈandɐˌtʰaːlɐ] in the International Phonetic Alphabet. In British English, "Neanderthal" is spoken with the hard German /t/ but different vowels (IPA: /niːˈændərtɑːl/). In layman's American English, "Neanderthal" is pronounced with a /θ/ (the voiceless th as in thin) and /ɔ/ instead of the longer British /aː/ (IPA: /niːˈændərθɔːl/), although scientists typically use the hard German /t/.
Neander Valley site
The site of Kleine Feldhofer Grotte where the type specimen was unearthed by miners in the 19th century
Location of Neander Valley, Germany, with the modern federal state of North Rhine-Westphalia highlighted
Neanderthal skulls were first discovered in Engis Caves ( fr), in what is now Belgium (1829) by Philippe-Charles Schmerling and in Forbes' Quarry, Gibraltar, dubbed Gibraltar 1 (1848), both prior to the type specimen discovery in a limestone quarry of the Neander Valley in Erkrath near Düsseldorf in August 1856, three years before Charles Darwin's On the Origin of Species was published.
The type specimen, dubbed Neanderthal 1, consisted of a skull cap, two femora, three bones from the right arm, two from the left arm, part of the left ilium, fragments of a scapula, and ribs. The workers who recovered this material originally thought it to be the remains of a bear. They gave the material to amateur naturalist Johann Carl Fuhlrott, who turned the fossils over to anatomist Hermann Schaaffhausen. The discovery was jointly announced in 1857.
To date, the bones of over 400 Neanderthals have been found.
Crania: 1. Gorilla 2. Australopithecus 3. Homo erectus 4. Neanderthal (La Chapelle aux Saints)
5. Steinheim Skull 6. Euhominid
First reconstruction of a Neanderthal male
For some time, scientists have debated whether Neanderthals should be classified as Homo neanderthalensis or Homo sapiens neanderthalensis, the latter placing Neanderthals as a subspecies of H. sapiens. Some morphological studies support the view that H. neanderthalensis is a separate species and not a subspecies. Others, for example University of Cambridge Professor Paul Mellars, say "no evidence has been found of cultural interaction" and evidence from mitochondrial DNA studies have been interpreted as evidence Neanderthals were not a subspecies of H. sapiens. Since species can be defined by reproductive isolation, strong genomic evidence of interbreeding between the two races has led some scientists to incline toward classifying the Neanderthal as a subspecies of H. sapiens, but there are documented examples of fertile inter-specific hybridization and introgression, so this is not definitive.
Comparison of the DNA of Neanderthals and homo sapiens suggests that they diverged from a common ancestor between 350,000 and 400,000 years ago. This ancestor is not certain, but was probably Homo heidelbergensis (sometimes called homo rhodesiensis). Heidelbergensis originated between 800,000 and 1,300,000 years ago, and continued until about 200,000. It ranged over east and south Africa, Europe and west Asia. Between 350,000 and 400,000 years ago the African branch is thought to have started evolving towards modern humans and the European branch towards Neanderthals. Scientists do not agree when Neanderthals can first be recognised in the fossil record, with dates ranging 200,000 and 300,000 years BP.
Neanderthal fossils
Skull, found in 1886 in Spy, Belgium
Frontal bone of a neanderthal child from the cave of La Garigüela
Skull from La Chapelle aux Saints
Semi-frontal view of a neanderthal skull from Gibraltar
1829: Neanderthal skulls were discovered in Engis, in present-day Belgium.
1848: Neanderthal skull Gibraltar 1 found in Forbes' Quarry, Gibraltar. Called "an ancient human" at the time.
1856: Johann Karl Fuhlrott first recognized the fossil called "Neanderthal man", discovered in Neanderthal, a valley near Mettmann in what is now North Rhine-Westphalia, Germany.
1880: The mandible of a Neanderthal child was found in a secure context and associated with cultural debris, including hearths, Mousterian tools, and bones of extinct animals.
1886: Two nearly perfect skeletons of a man and woman were found at Spy, Belgium at the depth of 16 ft with numerous Mousterian-type implements.
1899: Hundreds of Neanderthal bones were described in stratigraphic position in association with cultural remains and extinct animal bones.
1899: Sand excavation workers found bone fragments on a hill in Krapina, Croatia called Hušnjakovo brdo. Local Franciscan friar Dominik Antolković requested Dragutin Gorjanović-Kramberger to study the remains of bones and teeth that were found there.
1905: During the excavation in Krapina more than 5 000 items were found, of which 874 residue of human origin, including bones of prehistoric man and animals, artifacts.
1908: A nearly complete Neanderthal skeleton was discovered in association with Mousterian tools and bones of extinct animals.
1925: Francis Turville-Petre finds the ' Galilee Man' or 'Galilee Skull' in the Zuttiyeh Cave in Wadi Amud in Palestine (now Israel).
1926 Skull fragments of Gibraltar 2, a four-year-old Neanderthal girl, discovered by Dorothy Garrod.
1953–1957: Ralph Solecki uncovered nine Neanderthal skeletons in Shanidar Cave in the Kurdistan region of northern Iraq.
1975: Erik Trinkaus' study of Neanderthal feet confirmed they walked like modern humans.
1987: Thermoluminescence results from Israeli fossils date Neanderthals at Kebara to 60,000 BP and humans at Qafzeh to 90,000 BP. These dates were confirmed by electron spin resonance (ESR) dates for Qafzeh (90,000 BP) and Es Skhul (80,000 BP).
1991: ESR dates showed the Tabun Neanderthal was contemporaneous with modern humans from Skhul and Qafzeh.
1993: A 127.000 years old DNA is found on the child of Sclayn, found in Scladina ( fr), Belgium.
1997: Matthias Krings et al. are the first to amplify Neanderthal mitochondrial DNA ( mtDNA) using a specimen from Feldhofer grotto in the Neander valley.
1998: A team led by pre-history archeologist João Zilhão discovered an early Upper Paleolithic human burial in Portugal, at Abrigo do Lagar Velho, which provided evidence of early modern humans from the west of the Iberian Peninsula. The remains, a largely complete skeleton of an approximately 4-year-old child, buried with pierced shell and red ochre, is dated to ca. 24,500 years BP. The cranium, mandible, dentition, and postcrania present a mosaic of European early modern human and Neanderthal features.
2000: Igor Ovchinnikov, Kirsten Liden, William Goodman et al. retrieved DNA from a Late Neanderthal (29,000 BP) infant from Mezmaiskaya Cave in the Caucasus.
2005: The Max Planck Institute for Evolutionary Anthropology launched a project to reconstruct the Neanderthal genome.
2006: The Max Planck Institute for Evolutionary Anthropology announced it planned to work with Connecticut-based 454 Life Sciences to reconstruct the Neanderthal genome.
2009: The Max Planck Institute for Evolutionary Anthropology announced the "first draft" of a complete Neanderthal genome is completed.
2010: Comparison of Neanderthal genome with modern humans from Africa and Eurasia shows that 1–4% of modern non-African human genome might come from the Neanderthals.
2010: Discovery of Neanderthal tools far away from the influence of H. sapiens indicate that the species might have been able to create and evolve tools on its own, and therefore be more intelligent than previously thought. Furthermore, it was proposed that the Neanderthals might be more closely related to Homo sapiens than previously thought and that may in fact be a sub species of it. Evidence has more recently emerged that these artifacts are probably of H. sapiens sapiens origin.
2012: Charcoal found next to six paintings of seals in Nerja caves, Malaga, Spain, has been dated to between 42,300 and 43,500 years old. The paintings themselves will be dated in 2013, and if their pigment matches the date of the charcoal, they would be the oldest known cave paintings. José Luis Sanchidrián at the University of Cordoba, Spain believes the paintings are more likely to have been painted by Neanderthals than early modern humans.
Habitat and range
Sites where typical Neanderthal fossils have been found
Early Neanderthals lived in the Last glacial period for a span of about 100,000 years. Because of the damaging effects the glacial period had on the Neanderthal sites, not much is known about the early species. Countries where their remains are known include most of Europe south of the line of glaciation, roughly along the 50th parallel north, including most of Western Europe, including the south coast of Great Britain, Central Europe and the Balkans, some sites in Ukraine and in western Russia and east of Europe in Siberia to the Altai Mountains and south through the Levant to Indus River. It is estimated that the total Neanderthal population across this habitat range numbered at around 70,000 at its peak.
Neanderthal fossils have not been found to date in Africa, but there have been finds rather close to Africa, both on Gibraltar and in the Levant. At some Levantine sites, Neanderthal remains, in fact, date after the same sites were vacated by modern humans. Mammal fossils of the same time period show cold-adapted animals were present alongside these Neanderthals in this region of the Eastern Mediterranean. This implies Neanderthals were better adapted biologically to cold weather than modern humans and at times displaced them in parts of the Middle East when the climate got cold enough.
Homo sapiens sapiens appears to have been the only human type in the Nile River Valley during these periods, and Neanderthals are not known to have ever lived south-west of modern Israel. When further climate change caused warmer temperatures, the Neanderthal range likewise retreated to the north along with the cold-adapted species of mammals. Apparently these weather-induced population shifts took place before modern people secured competitive advantages over the Neanderthal, as these shifts in range took place well over ten thousand years before modern people totally replaced the Neanderthal, despite the recent evidence of some successful interbreeding.
A reconstruction of a Neanderthal male from the Neanderthal Museum.
There were separate developments in the human line, in other regions such as Southern Africa, that somewhat resembled the European and Western/Central Asian Neanderthals, but these people were not actually Neanderthals. One such example is Rhodesian Man ( Homo rhodesiensis) who existed long before any classic European Neanderthals, but had a more modern set of teeth, and arguably some H. rhodesiensis populations were on the road to modern H. sapiens sapiens. At any rate, the populations in Europe and West/Central Asia underwent more and more "Neanderthalization" as time went on. There is some argument that H. rhodesiensis in general was ancestral to both modern humans and Neanderthals, and that at some point the two populations went their separate ways, but this supposes that H. rhodesiensis goes back to around 600,000 years ago.
To date, no intimate connection has been found between these similar archaic people and the Western/Central Eurasian Neanderthals, at least during the same time as classic Eurasian Neanderthals, and H. rhodesiensis seems to have lived about 600,000 years ago, long before the time of classic Neanderthals. This said, some researchers think that H. rhodesiensis may have lived much later than this period, depending on the method used to date the fossils, leaving this issue open to debate. Some H. rhodesiensis features, like the huge brow ridge, may have been caused by convergent evolution. There is no evidence to date that Neanderthals knew how to construct boats or rafts, and the paucity of human fossils in North Africa west of the Nile Valley should be noted.
It appears incorrect, based on present research and known fossil finds, to refer to any fossils outside Europe or Western and Central Asia as true Neanderthals. They had a known range that possibly extended as far east as the Altai Mountains, but not farther to the east or south, and apparently not into Africa. At any rate, in North-East Africa the land immediately south of the Neanderthal range was possessed by modern humans Homo sapiens idaltu or Homo Sapiens, since at least 160,000 years before the present. 160,000 year old hominid fossils at Jebel Irhoud in Morocco were previously thought to be Neanderthal, but it is now clear that they are early modern humans.
Classic Neanderthal fossils have been found over a large area, from northern Germany to Israel and Mediterranean countries like Spain and Italy in the south and from England and Portugal in the west to Uzbekistan in the east. This area probably was not occupied all at the same time. The northern border of their range, in particular, would have contracted frequently with the onset of cold periods. On the other hand, the northern border of their range as represented by fossils may not be the real northern border of the area they occupied, since Middle Palaeolithic-looking artifacts have been found even further north, up to 60° N, on the Russian plain. Recent evidence has extended the Neanderthal range by about 1,250 miles (2,010 km) east into southern Siberia's Altai Mountains.
Neanderthal anatomy was more robust than anatomically modern humans and they had less neotenized skulls.
Facial forensic reconstruction by artist Cícero Moraes
Neanderthals made advanced tools, had a language (the nature of which is debated) and lived in complex social groups. The Molodova archaeological site in eastern Ukraine suggests some Neanderthals built dwellings using animal bones. A building was made of mammoth skulls, jaws, tusks and leg bones, and had 25 hearths inside.
While largely carnivorous, and apex predators; new studies indicate Neanderthals had cooked vegetables in their diet. In 2010, a U.S. researcher reported finding cooked vegetable matter in the teeth of a Neanderthal skull, contradicting the earlier belief they were exclusively (or almost exclusively) carnivorous and apex predators.
Early investigations concentrated on mitochondrial DNA (mtDNA), which, owing to strictly matrilineal inheritance and subsequent vulnerability to genetic drift, is of limited value in evaluating the possibility of interbreeding of Neanderthals with Cro-Magnon people.
In 1997, geneticists were able to extract a short sequence of DNA from Neanderthal bones from 30,000 years ago. The extraction of mtDNA from a second specimen was reported in 2000, and showed no sign of modern human descent from Neanderthals.
Scientist at the Max Planck Institute extracting the DNA.
In July 2006, the Max Planck Institute for Evolutionary Anthropology and 454 Life Sciences announced that they would sequence the Neanderthal genome over the next two years. This genome is expected to be roughly the size of the human genome, three-billion base pairs, and share most of its genes. It was hoped the comparison would expand understanding of Neanderthals, as well as the evolution of humans and human brains.
Svante Pääbo has tested more than 70 Neanderthal specimens. Preliminary DNA sequencing from a 38,000-year-old bone fragment of a femur found at Vindija Cave, Croatia, in 1980 showed Neanderthals and modern humans share about 99.5% of their DNA. From mtDNA analysis estimates, the two species shared a common ancestor about 500,000 years ago. An article appearing in the journal Nature has calculated the species diverged about 516,000 years ago, whereas fossil records show a time of about 400,000 years ago. A 2007 study pushes the point of divergence back to around 800,000 years ago.
Edward Rubin of the Lawrence Berkeley National Laboratory states recent genome testing of Neanderthals suggests human and Neanderthal DNA are some 99.5% to nearly 99.9% identical.
On 16 November 2006, Lawrence Berkeley National Laboratory issued a press release suggesting Neanderthals and ancient humans probably did not interbreed. Edward M. Rubin, director of the U.S. Department of Energy's Lawrence Berkeley National Laboratory and the Joint Genome Institute (JGI), sequenced a fraction (0.00002) of genomic nuclear DNA (nDNA) from a 38,000-year-old Vindia Neanderthal femur. They calculated the common ancestor to be about 353,000 years ago, and a complete separation of the ancestors of the species about 188,000 years ago.
Their results show the genomes of modern humans and Neanderthals are at least 99.5% identical, but despite this genetic similarity, and despite the two species having coexisted in the same geographic region for thousands of years, Rubin and his team did not find any evidence of any significant crossbreeding between the two. Rubin said, "While unable to definitively conclude that interbreeding between the two species of humans did not occur, analysis of the nuclear DNA from the Neanderthal suggests the low likelihood of it having occurred at any appreciable level."
In 2008 Richard E. Green et al. from Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany published the full sequence of Neanderthal mitochondrial DNA (mtDNA) and suggested "Neanderthals had a long-term effective population size smaller than that of modern humans." Writing in Nature about Green et al.'s findings, James Morgan asserted the mtDNA sequence contained clues that Neanderthals lived in "small and isolated populations, and probably did not interbreed with their human neighbours."
In the same publication, it was disclosed by Svante Pääbo that in the previous work at the Max Planck Institute that "Contamination was indeed an issue," and they eventually realized that 11% of their sample was modern human DNA. Since then, more of the preparation work has been done in clean areas and 4-base pair 'tags' have been added to the DNA as soon as it is extracted so the Neanderthal DNA can be identified.
With 3 billion nucleotides sequenced, analysis of about ⅓ showed no sign of admixture between modern humans and Neanderthals, according to Pääbo. This concurred with the work of Noonan from two years earlier. The variant of microcephalin common outside Africa, which was suggested to be of Neanderthal origin and responsible for rapid brain growth in humans, was not found in Neanderthals. Nor was the MAPT variant, a very old variant found primarily in Europeans.
However, an analysis of a first draft of the Neanderthal genome by the same team released in May 2010 indicates interbreeding may have occurred. "Those of us who live outside Africa carry a little Neanderthal DNA in us," said Pääbo, who led the study. "The proportion of Neanderthal-inherited genetic material is about 1 to 4 percent. It is a small but very real proportion of ancestry in non-Africans today," says Dr. David Reich of Harvard Medical School, who worked on the study. This research compared the genome of the Neanderthals to five modern humans from China, France, sub-Saharan Africa, and Papua New Guinea. The finding is that about 1 to 4 percent of the genes of the non-Africans came from Neanderthals, compared to the baseline defined by the two Africans.
This indicates a gene flow from Neanderthals to modern humans, i.e., interbreeding between the two populations. Since the three non-African genomes show a similar proportion of Neanderthal sequences, the interbreeding must have occurred early in the migration of modern humans out of Africa, perhaps in the Middle East. No evidence for gene flow in the direction from modern humans to Neanderthals was found. The latter result would not be unexpected if contact occurred between a small colonizing population of modern humans and a much larger resident population of Neanderthals. A very limited amount of interbreeding could explain the findings, if it occurred early enough in the colonization process.
While interbreeding is viewed as the most parsimonious interpretation of the genetic discoveries, the authors point out they cannot conclusively rule out an alternative scenario, in which the source population of non-African modern humans was already more closely related to Neanderthals than other Africans were, due to ancient genetic divisions within Africa.
Among the genes shown to differ between present-day humans and Neanderthals were RPTN, SPAG17, CAN15, TTF1 and PCD16.
Extinction hypotheses
Neanderthal fossils found in Vindija Cave in Croatia have been dated to between 32,000 and 33,000 years old, and what have been claimed as the last traces of Mousterian culture (Neanderthal artefacts but not bones) have been found in Gorham's Cave on the remote south-facing coast of Gibraltar, dated to less than 30,000 years ago. However, a recent re-examination of Neanderthal bones from two Spanish Neanderthal sites has suggested they were around 45,000 years old, 10,000 years older than previously thought. Clive Finlayson, who excavated Gorham's Cave, argues that the sites which have been re-dated are highland ones which would have been inhospitable in the approach to an ice age. However bone collagen degrades in the warmer lowland sites where Finlayson thinks Neanderthals would have survived longer, and it has yet to be determined whether the re-dating affects other Neanderthal sites with reported recent dates.
Possible scenarios for the extinction of the Neanderthals are:
Neanderthals were a separate species from modern humans, and became extinct (due to climate change or interaction with humans) and were replaced by modern humans moving into their habitat beginning around 80,000 years ago. Competition with humans probably contributed to Neanderthal extinction. Jared Diamond has suggested a scenario of violent conflict and displacement.
Neanderthals were a contemporary subspecies that bred with modern humans and disappeared through absorption ( interbreeding theory).
A Campanian ignimbrite volcanic super-eruption around 40,000 years ago, followed by a second one a few thousand years later, has been hypothesised as having contributed to the demise of the Neanderthal, based on evidence from Mezmaiskaya cave in the Caucasus Mountains of southern Russia Mitochondrial DNA (mtDNA) analysis of a specimen from Mezmaiskaya Cave is radiocarbon dated to be about 29,000 years BP and therefore from one of the latest living Neanderthal individuals. The sequence shows 3.48% divergence from the Feldhofer Neanderthal. Phylogenetic analysis places the two Neanderthals from the Caucasus and western Germany together in a clade that is distinct from modern humans, suggesting that their mtDNA types have not contributed to the modern human mtDNA pool.
mtDNA-based simulation of modern human expansion in Europe starting 1600 generations ago. Neanderthal range in light grey.
As Paul Jordan notes: "A natural sympathy for the underdog and the disadvantaged lends a sad poignancy to the fate of the Neanderthal folk, however it came about." Jordan, though, does say that there was perhaps interbreeding to some extent, but that populations that remained totally Neanderthal were probably out-competed and marginalized to extinction by the Aurignacians.
About 55,000 years ago, the weather began to fluctuate wildly from extreme cold conditions to mild cold and back in a matter of a few decades. Neanderthal bodies were well suited for survival in a cold climate—their barrel chests and stocky limbs stored body heat better than the Cro-Magnons. However, the rapid fluctuations of weather caused ecological changes to which the Neanderthals could not adapt; familiar plants and animals would be replaced by completely different ones within a lifetime. Neanderthals' ambush techniques would have failed as grasslands replaced trees. A large number of Neanderthals would have died during these fluctuations, which peaked about 30,000 years ago.
Studies on Neanderthal body structures have shown that they needed more energy to survive than any other species of hominid. Their energy needs were up to 100–350 calories more per day comparing to projected anatomically modern human males weighing 68.5 kg (151.0 lbs) and females 59.2 kg (130.5 lbs). When food became scarce, this difference may have played a major role in the Neanderthals' extinction.
Coexistence with H. sapiens sapiens
There is no longer certainty regarding the identity of the humans who produced the Aurignacian culture, even though the presumed westward spread of anatomically modern humans (AMHs) across Europe is still based on the controversial first dates of the Aurignacian. Currently, the oldest European anatomically modern Homo sapiens is represented by a robust modern-human mandible discovered at Peştera cu Oase (southwest Romania), dated to 34,000–36,000 years ago. Human skeletal remains from the German site of Vogelherd, so far regarded as the best association between anatomically modern Homo sapiens and Aurignacian culture, were revealed to represent intrusive Neolithic burials into the Aurignacian levels and subsequently all the key Vogelherd fossils are now dated to 3,900–5,000 years ago instead. As for now, the expansion of the first anatomically modern humans into Europe cannot be located by diagnostic and well-dated AMH fossils "west of the Iron Gates of the Danube" before 32,000 years ago.
Reconstruction of a Neanderthal man and woman from the Neanderthal Museum.
Consequently, the exact nature of biological and cultural interaction between Neanderthals and other human groups between 50,000 and 30,000 years ago has been contested. A new proposal strives to resolve the issue by proposing the Gravettians rather than the Aurignacians as the anatomically modern humans who contributed to the Eurasian genetic pool after 30,000 years ago. Correspondingly, the human skull fragment found at the Elbe River bank at Hahnöfersand near Hamburg was once radiocarbon-dated to 36,000 years ago and seen as possible evidence for the intermixing of Neanderthals and anatomically modern humans. It is now dated to the more recent Mesolithic.
Interbreeding hypotheses
Chris Stringer's hypothesis of the family tree of genus Homo, published 2012 in Nature: Homo floresiensis originated in an unknown location from unknown ancestors and reached remote parts of Indonesia. Homo erectus spread from Africa to western Asia, then east Asia and Indonesia; its presence in Europe is uncertain, but it gave rise to Homo antecessor, found in Spain. Homo heidelbergensis originated from Homo erectus in an unknown location and dispersed across Africa, southern Asia and southern Europe (other scientist interprete fossils, here named heidelbergensis, as late erectus). Homo sapiens spread from Africa to western Asia and then to Europe and southern Asia, eventually reaching Australia and the Americans. In addition to Neanderthals and Denisovans a third gene flow in Africa is indicated at the right.
An alternative to extinction is that Neanderthals were absorbed into the Cro-Magnon population by interbreeding. This would be counter to strict versions of the Recent African Origin, since it would imply that at least part of the genome of Europeans would descend from Neanderthals.
The most vocal proponent of the hybridization hypothesis is Erik Trinkaus of Washington University. Trinkaus claims various fossils as products of hybridized populations, including the "child of Lagar Velho", a skeleton found at Lagar Velho in Portugal dated to about 24,000 years ago. In a 2006 publication co-authored by Trinkaus, the fossils found in 1952 in the cave of Peștera Muierii, Romania, are likewise claimed as descendants of previously hybridized populations.
Genetic research has confirmed that some admixture took place. The genomes of all non-Africans include portions that are of Neanderthal origin, due to interbreeding between Neanderthals and the ancestors of Eurasians in Northern Africa or the Middle East prior to their spread. Rather than absorption of the Neanderthal population, this gene flow appears to have been of limited duration and limited extent. An estimated 1 to 4 percent of the DNA in Europeans and Asians (French, Chinese and Papua probands) is non-modern, and shared with ancient Neanderthal DNA rather than with Sub-Saharan Africans (Yoruba and San probands). Nonetheless, more recent genetic studies seem to suggest that modern humans may have mated with "at least two groups" of ancient humans: Neanderthals and Denisovans.
While modern humans share some nuclear DNA with the extinct Neanderthals, the two species do not share any mitochondrial DNA, which in primates is always maternally transmitted. This observation has prompted the hypothesis that whereas female humans interbreeding with male Neanderthals were able to generate fertile offspring, the progeny of female Neanderthals who mated with male humans were either rare, absent or sterile.
The Ferrassie skull.
Neanderthal 1: Initial Neanderthal specimen found during an archaeological dig in August 1856. Discovered in a limestone quarry at the Feldhofer grotto in Neanderthal, Germany. The find consisted of a skull cap, two femora, the three right arm bones, two of the left arm bones, ilium, and fragments of a scapula and ribs.
La Chapelle-aux-Saints 1: Called the Old Man, a fossilized skull discovered in La Chapelle-aux-Saints, France, by A. and J. Bouyssonie, and L. Bardon in 1908. Characteristics include a low vaulted cranium and large browridge typical of Neanderthals. Estimated to be about 60,000 years old, the specimen was severely arthritic and had lost all his teeth, with evidence of healing. For him to have lived on would have required that someone process his food for him, one of the earliest examples of Neanderthal altruism (similar to Shanidar I.)
La Ferrassie 1: A fossilized skull discovered in La Ferrassie, France, by R. Capitan in 1909. It is estimated to be 70,000 years old. Its characteristics include a large occipital bun, low-vaulted cranium and heavily worn teeth.
Le Moustier: A fossilized skull, discovered in 1909, at the archaeological site in Peyzac-le-Moustier, Dordogne, France. The Mousterian tool culture is named after Le Moustier. The skull, estimated to be less than 45,000 years old, includes a large nasal cavity and a somewhat less developed brow ridge and occipital bun as might be expected in a juvenile.
Type Specimen, Neanderthal 1
Shanidar 1: Found in the Zagros Mountains in northern Iraq; a total of nine skeletons found believed to have lived in the Middle Paleolithic. One of the nine remains was missing part of its right arm; theorized to have been broken off or amputated. The find is also significant because it shows that stone tools were present among this tribe's culture. One was buried with flowers, showing that some type of burial ceremony may have occurred.
Bones with Neanderthal traits in chronological order. (Sorted by time)
Mixed with H. heidelbergensis traits
> 350 ka: Sima de los Huesos c. 500:350 ka ago
350–200 ka: Pontnewydd 225 ka ago.
200–135 ka: Atapuerca, Vértesszőlős, Ehringsdorf, Casal de'Pazzi, Biache, La Chaise, Montmaurin, Prince, Lazaret, Fontéchevade
Typical H. neanderthalensis traits
135–45 ka: Krapina, Saccopastore skulls, Malarnaud, Altamura, Gánovce, Denisova, Okladnikov Altai, Pech de l'Azé, Tabun 120 ka – 100±5 ka, Qafzeh9 100, Shanidar 1 to 9 80–60 ka, La Ferrassie 1 70 ka, Kebara 60 ka, Régourdou, Mt. Circeo, Combe Grenal, Erd 50 ka, La Chapelle-aux Saints 1 60 ka, Amud I 53±8 ka, Teshik-Tash.
45–35 ka: Le Moustier 45 ka, Feldhofer 42 ka, La Quina, l'Horus, Hortus, Kulna, Šipka, Saint Césaire, Bacho Kiro, El Castillo, Bñnolas, Arcy-sur-Cure.
< 35 ka: Chătelperron, Figueria Brava, Zafaraya 30 ka, Vogelherd 3?, Vindija 32,400 ± 800 14C B.P. (Vi-208 31,390 ± 220, Vi-207 32,400 ± 1,800 14C B.P.), Velika Pećina,
Homo sapiens with some neanderthal-like archaic traits
< 35 Pestera cu Oase 35 ka, Mladeč 31 ka, Pestera Muierii 30 ka (n/s), Lapedo Child 24.5 ka.
Neanderthal reconstructions
Early artistic reconstructions mostly presented Neanderthals as beastly creatures, emphasizing hairiness and rough, dark complexion.
More recent reconstructions acknowledge that due to the lineage evolution in European latitude there is reason to believe that Neanderthals were fair-skinned and probably with no more facial hair than modern man. Also, archaeological evidence exists indicating that they may have communicated by speech, used tools and engaged in artistic endeavours. Reconstructions of Neanderthal men, women and children have become much more intelligent-looking and pleasing to the modern eye.
Neanderthals have been portrayed in popular culture including appearances in literature, visual media and comedy, often in unflattering and inaccurate light.
Retrieved from " http://en.wikipedia.org/w/index.php?title=Neanderthal&oldid=545048894"


text:
Marijuana Legalization Debated By Ohio And New Mexico Gubernatorial Candidates
Democratic and Republican gubernatorial candidates in Ohio and New Mexico clashed on the issue of marijuana legalization during televised debates on Wednesday night.
In Ohio, Democrat Richard Cordray said for the first time that he would support an initiative to legalize cannabis if it were put before the state's voters.
Distancing himself from a "deeply flawed" and "monopolistic" cannabis legalization proposal that Ohioans resoundingly defeated in 2015, he said he would support placing the issue back on the ballot, would vote yes and would implement it if passed.
Republican Mike DeWine, currently the state's attorney general, took a different stance on ending prohibition, which he claimed has been an "absolute disaster" in Colorado.
"I'm against it," he said. "I will veto it."
Cordray, a former director of the federal Consumer Financial Protection Bureau, shot back, accusing his GOP opponent of "living in the past" on cannabis issues.
"Marijuana has been legalized in numerous states now and they're working through these issues," he said of DeWine's concerns about the impacts of legalization.
But the Republican criticized Cordray for at first not directly responding to the question of whether he would support ending prohibition and instead pivoting to how he would implement it if approved by voters.
"You're really a profile in courage," DeWine said. "You're not going to take a position at all on recreational marijuana? I will."
That's when Cordray revealed his personal support for legalization.
Earlier in the debate, the two candidates butted heads over a current state ballot measure going before voters in November that would reclassify some felony drug possession crimes as misdemeanors with no jail time.
Cordray said he supported "more efforts for treatment in the community and less emphasis on jailing drug users," while DeWine argued the measure would "put a star on Ohio and every drug dealer in the country will come here."
Ohio's medical marijuana growers will have to start their first plants illegally: Capitol Letter
'Budtenders,' edibles chefs among fastest-growing jobs in multi-billion dollar legal cannabis industry
San Francisco has moved to ban e-cigarettes. Juul has a backup plan
Most U.S. Pot Users Think They Can Get Away With Driving High
Suicide rates among America's young people continue to soar, study shows
Meth In The Morning, Heroin At Night: Inside The Seesaw Struggle of Dual Addiction
E-Cigarette Exploded in a Teenager's Mouth, Damaging His Jaw
SPF-PFS

redpajama_set_name: RedPajamaCommonCrawl


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text:
Methylation-driven genes and their prognostic value in cervical squamous cell carcinoma
Jinhui Liu#, Sipei Nie#, Siyue Li#, Huangyang Meng, Rui Sun, Jing Yang, Wenjun Cheng
Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Contributions: (I) Conception and design: J Liu; (II) Administrative support: W Cheng; (III) Provision of study materials or patients: J Yang; (IV) Collection and assembly of data: R Sun; (V) Data analysis and interpretation: S Nie, S Li; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
#These authors contributed equally to this work.
Correspondence to: Wenjun Cheng. Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Email: wenjunchengdoc@163.com.
Background: Abnormal gene methylation is crucial for tumor progression. This study explored a cluster of methylation-driven genes involved in cervical squamous cell carcinoma (CESC).
Methods: The data on RNA expression, methylation and clinical outcomes of CESC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Protein-protein interaction (PPI) network was constructed. Gene Ontology (GO) and KEGG analyses were performed to identify the biological functions of methylation-driven genes, and univariable and multivariate Cox analyses to screen out the key prognostic genes. A risk signature was established and its predictive value was evaluated with Kaplan-Meier and ROC curves. The key genes were further investigated by Cox regression analyses, gene set enrichment analysis (GSEA), and methylation site analysis. Additionally, "rms" package was used for establishing nomogram and calibrate curve.
Results: We found 144 differentially expressed methylation-driven genes. A risk model was constructed with three key prognostic genes (ITGA5, HHEX and S1PR4). The risk score was an independent risk factor for CESC prognosis. Lowly-expressed and hypermethylated ITGA5, highly-expressed and hypomethylated HHEX and S1PR4 were associated with better CESC prognosis. The methylation sites and biological functions enriched in ITGA5, HHEX and S1PR4 were uncovered. Additionally, the nomogram also validated the performance of risk model.
Conclusions: Methylation-driven ITGA5, HHEX and S1PR4 are associated with CESC development. The three genes might serve as potential targets in the treatment of CESC.
Keywords: Methylation-driven genes; cervical squamous cell carcinoma (CESC); bioinformatic analysis; prognosis; biomarkers
Submitted Dec 23, 2019. Accepted for publication Jun 12, 2020.
doi: 10.21037/atm-19-4577
Cervical cancer is prevalent in women, causing 530,000 new cases and 270,000 deaths worldwide annually (1). Cervical squamous cell carcinoma (CESC) is the most common histological subtype of cervical cancer. The prognosis of CESC remains poor due to its high metastasis and recurrence. Cervical cancer has a wide spectrum of high-risk factors are multiple, like human papilloma virus infection and unprotected sex (2). New molecular technology has been used to dig out an increasing number of CESC-related oncogenes, such as PTE (3), MYC (4) and TP53 (5). However, no effective therapeutic drugs have been developed based on these target genes.
DNA methylation has been proved to regulate carcinogenesis-associated cellular processes (6), which provides a possibility to find therapeutic targets through assessing their DNA methylation. In recent years, increasing evidence has shown that the occurrence and progression of CESC are modulated by diverse mechanisms, including the methylation of CESC-associated genes (7).
Bioinformatic analysis is widely used to explore the molecular mechanism and candidate biomarkers in cancers. The Cancer Genome Atlas (TCGA) database (http://cancergenome.nih.gov/publications/, publication guidelines) provides genetic and epigenetic profiles. The MethylMix algorithm is used to screen out disease-specific methylation-driven genes based on a β-mixed model (8,9). In the present study, we screened out the methylation-driven genes and assessed their prognostic value in CESC.
We downloaded the expression profiles of mRNAs (level 3) in 309 cases (306 tumor tissues and 3 normal tissues), the methylation data (level 3) in 312 cases (309 tumor tissues and 3 normal tissues) from TCGA database (http://cancergenome.nih.gov/). The sequenced data were obtained from Illumina HiSeqRNASeq and Illumina Human Methylation 450 platform. The corresponding clinical information of EC patients was also downloaded from TCGA database and showed in Table S1. First of all, these data were normalized and differentially expressed genes (DEGs) and aberrant methylated genes were screened out using LIMMA package (10). Next, the correlation between gene methylation and gene expression was computed via MethylMix algorithm. We identified DEGs in CESC and the CESC-specific methylation-driven genes through the β-mixed model.
Table S1 Clinical information of CESC patients in TCGA database
Functional annotations of methylation-driven genes
The biological functions of these methylation-driven genes were further investigated based on The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 (http://david.abcc.ncifcrf.gov/) (11). The Gene Ontology (GO) enrichment analysis results were plotted in the GOplot R package (https://cran.r-project.org/web/packages/GOplot/) (12). In addition, we used ConsensusPathDB (http://cpdb.molgen.mpg.de/) online software to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis (13). P<0.05 was set as the cutoff criterion in GO and KEGG analyses.
Construction of protein–protein interaction (PPI)
To evaluate the interrelationships among these methylation-driven genes, we uploaded them onto the Search Tool for the Retrieval of Interacting Genes (STRING) database (http://string-db.org/) to construct a PPI network (14).
Construction of risk model
To further screen out prognosis-related methylation-driven genes of CESC, we performed univariable and multivariate Cox analyses, and then constructed a linear risk model (15). The prognostic score = expRNA1×βRNA1+expRNA2×βRNA2+expRNA3×βRNA3+..expRNAn×βRNAn (expRNA is the expression level of each methylation-driven gene, and βRNA is the regression coefficient calculated by the multivariate Cox regression analysis). The patients were divided into two groups (high-risk and low-risk) according to the median risk value. The Kaplan-Meier survival analysis was conducted to compare the overall survival rate of the two groups in survival R package (the log-rank P<0.05). A 5-year-dependent receiver operating characteristic (ROC) curve was further plotted to evaluate the predictive value of the risk model. In addition, univariate and multivariate Cox regression analyses were used to determine whether the candidate driver genes were independent risk factors. Meanwhile, the stratification analysis was operated based on clinicopathological features such as patient's age, tumor grade, stage and histological type.
Survival analysis of candidate driver genes and mapping of methylation sites
Using Survival R package, a survival analysis was performed to explore the correlation between the methylation and expression of key prognosis-associated genes in CESC. We extracted relevant methylated sites of key genes from the CESC methylation data. |Cor| >0.35 was used as cutoff criterion (16).
Gene set enrichment analysis (GSEA) and pathways enriched analysis
In TCGA set validation, 306 CESC samples were divided into highly-expressed and lowly-expressed groups according to the median expression level of identified genes. The biological functions of the key methylation-driven genes were clarified with GSEA (http://software.broadinstitute.org/gsea/index.jsp) (17). Annotated gene sets of c2.cp.kegg.v6.0.symbols.gmt in Molecular Signatures Database (MSigDB, http://software.broadinstitute.org/gsea/msigdb/index.jsp) were chosen as the references in GSEA software (18). The Nom. P<0.0001 and the enrichment score (ES) ≥0.70 were chosen as the cutoff criterion.
Construction and validation of the nomogram
A nomogram and a calibrate curve were plotted by the "rms" package on R. The accuracy of the nomogram was examined using the consistency between the actual and the predicted outcomes. Then, we submitted these outcomes to the calibration curve to visualize the performance of the nomogram. The 45° line represented the best prediction (19).
Aberrant methylation-driven genes in CESC
The gene expression data of 309 samples (306 CESC samples and 3 normal samples) and the methylation data of 312 samples (309 CESC samples and 3 normal samples) were downloaded from TCGA. The genes with abnormal expression were found out based on the LIMMA software package. The correlation between methylation level and expression level of each gene was investigated based on the MethylMix package. In the Wilcoxon rank test, the differential methylation was defined with |log Fold change (FC)| >0 and adjusted P<0.05, |Cor| >0.45. As a result, 144 CESC-related methylation-driven genes were screened out, and the heat maps of these aberrant methylation-driven genes were shown in Figure 1.
Figure 1 Heatmaps of cervical squamous cell carcinoma (CESC)-related aberrant methylation-driven genes. (The color from green to red shows a progression from hypomethylation to hypermethylation).
Annotations and pathways associated with methylation-driven genes in CESC
We performed GO and KEGG analyses by using DAVID and ConsensusPathDB online software, respectively. GO analysis revealed that in the aspect of BP, the genes were significantly enriched in "Transcription, DNA-templated and regulation of transcription, DNA-templated". In the aspect of MF group, the genes were mainly involved in "Nucleic acid binding, Metal ion binding, Transcription factor activity, sequence-specific DNA binding, DNA binding and RNA polymerase II core promoter proximal region sequence-specific DNA binding". In the aspect of CC, the genes were mainly enriched in "Nucleus" (Figure 2). KEGG pathway analysis showed that the genes were mainly enriched in "Generic transcription pathway, RNA polymerase II transcription, Gene expression (Transcription), The human immune response to tuberculosis, Apoptosis, Induction of apoptosis through dr3 and dr4/5 death receptors and TRAIL signaling" (Figure 3).
Figure 2 Results of Gene Ontology (GO) enrichment analysis of 144 methylation-driven genes. (A) GO analysis divided methylation-driven genes into three functional groups: biological process (BP), cellular component (CC), molecular function (MF); (B) GO enrichment significance items of methylation-driven genes in different functional groups; (C) distribution of methylation-driven genes for different GO-enriched functions.
Figure 3 The significant enriched pathways of methylation-driven gene (notes: node size: the number of genes; node color: P value; edge width: percentage of shared genes; Edge color: genes from input).
Construction of PPI network
The PPI network contained 124 nodes and 74 edges (Figure S1).
Figure S1 Protein-protein interaction (PPI) network shown in STRING database, which contained 144 methylation-driven genes, 124 nodes and 74 edges.
Prognostic risk model based on CESC methylation-driven genes
Through univariable and multivariate Cox regression analyses, we screened out prognosis-associated methylation-driven genes (Table S2). Then, we further performed a multivariate Cox proportional hazards regression analysis based on the top five most associative genes (ITGA5, SPRY4, HHEX, BIN2 and S1PR4). The results showed that the risk score calculated by three genes (ITGA5, HHEX and S1PR4) could be used as an independent indicator of CESC prognosis. The risk score = (0.334 × ITGA5) + (−0.326 × HHEX) + (−0.308 × S1PR1) (Figure S2). Moreover, according to their median values, a total of 302 CESC samples with corresponding clinical samples were divided into a high-risk group (151 samples) and a low-risk group (151 samples). And the results of Kaplan-Meier survival analysis showed that the overall survival rate in the low-risk group was significantly higher than that in the high-risk group (Figure 4A). The 5-year overall survival ROC curve showed the area under curve (AUC) was 0.749 (Figure 4B). It suggested that this model was reliable to evaluate 5-year overall survival of patients with CESC. Meanwhile, the risk scores, survival time, and expression levels indicated by the three genes for each patient were showed in Figure 4C,D,E. The expression levels of the three genes in low-risk and high-risk groups were shown in Figure S3A. The heatmap showed the expression of the three genes in high- and low-risk patients. We observed significant differences in histological type (P<0.01) and tumor status (P<0.001) between the high- and low-risk groups (Figure S3B).
Table S2 The top 5 significant prognostic genes revealed by univariate Cox regression
Figure S2 Results of multivariate Cox proportional hazards regression analysis.
Figure S3 Gene expressions and clinicopathological features of low- amd high-risk group. (A) Expression of the three genes in low- and high-risk groups (TCGA dataset); (B) the heatmap shows the distribution of clinicopathological features was compared between the low- and high-risk groups.
Figure 4 A linear risk model based on five methylation-driven genes. (A) Kapla-Meier survival curve of overall survival between high-risk group and low-risk group; (B) 5-year survival time dependent receiver operating characteristic (ROC) curve. Area under curve (AUC) of our five-gene signature reached was 0.749; (C,D,E) the distributions of the five-gene signature, survival status, and expression profiles of the five genes of patients in the training data set.
Moreover, we further performed univariate and multivariate Cox regression analyses of the 3-generiskscore, stage (stage I & stage II vs. stage III & stage IV), grade (G1 & G2 vs. G3), and age (≤50 vs. >50). As shown in Tables 1,2, tumor stage (HR =2.338, 95% CI: 1.013–5.392, P value =0.046) and the risk score (HR =1.342, 95% CI: 1.214–1.483, P value =0.000) were found as independent prognostic factors for CESC patients. ITGA5 (HR =1.012, 95% CI: 1.002–1.022, P value =0.019) and S1PR4 (HR =0.787, 95% CI: 0.657–0.944, P value =0.010), stage (HR =2.454, 95% CI: 1.065–5.655, P value =0.035) were also identified as independent prognostic factors by further univariable and multivariable analyses of the tumor stage, grade, and expression of three candidate driving gene.
Table 1 Results of univariable and multivariable analyses of the tumor stage, grade, age and the histological type on CESC patients
Table 2 Results of univariable and multivariable analyses of the tumor stage, grade, histological type, age and 3 candidate driving genes on CESC patients
Survival analysis and mapping of methylation sites
Through a joint Kaplan-Meier survival analysis, we found that the patients with lowly-expressed and hyper-methylated ITGA5 presented a better prognosis than those with highly-expressed and hypo-methylated ITGA5. Conversely, those with highly-expressed and hypomethylated HHEX and S1PR4 presented higher overall survival rate than those with lowly-expressed and hypermethylated HHEX and S1PR4 (Figure 5). In addition, the association between the methylation and the expression of the three genes was shown in Figure 6.
Figure 5 Kaplan-Meier survival curves for the joint survival analysis. (A) The combination of gene ITGA5 methylation and expression; (B) the combination of gene HHEX methylation and expression; (C) the combination of gene S1PR4 methylation and expression.
Figure 6 The methylation sites and gene expression. (A-D) The correlation of methylation sites and gene ITGA5 expression; (E-L) the correlation of methylation sites and gene HHEX expression; (M-S) the correlation of methylation sites and gene S1PR4 expression.
Enriched biological processes and pathways of key methylation-driven genes
GSEA was conducted to explore the biological functions enriched in each gene. ITGA5 was mostly enriched in "Glycosaminoglycan biosynthesis chondroitin sulfate, ECM receptor interaction and Focal adhesion" (Figure S4A,B,C); HHEX in "Allograft rejection, Asthma, Primary immunodeficiency, Type I diabetes mellitus and Intestinal immune network for IgA production" (Figure S4D,E,F,H); S1PR4 in "Allograft rejection, Autoimmune thyroid disease, Graft versus host disease, Type I diabetes mellitus, Intestinal immune network for IgA production, Primary immunodeficiency, Asthma, antigen processing and presentation, Hematopoietic cell lineage, Viral myocarditis and Leishmania infection" (P<0.0001) (Figure S4I-S).
Figure S4 Gene set enrichment analysis (GSEA) results of three key driver genes (ITGA5, HHEX and S1PR4). (A-C) Three enriched gene sets of ITGA5; (D-H) five enriched gene sets of HHEX; (I-S) 11 enriched gene sets of S1PR4.
Accuracy of nomogram
We created a nomogram to estimate the 1-, 3- and 5-year OS. The five independent prognostic factors included stage, age, histological type, grade and risk score (Figure 7A). The 45° line represented the best prediction. Calibration plots suggested that the nomogram performed well to predict the 1-year OS (Figure 7B,C,D). ROC curve analysis showed that the AUC value of the risk model was 0.730, much significantly higher than that of clinical stage (AUC =0.651), grade (AUC =0.621), age (AUC =0.573) and histological type (AUC =0.512). The nomogram was also efficient in predicting 3- and 5-year OS (Figure 7E,F,G).
Figure 7 Accuracy of nomogram. (A) The nomogram for predicting proportion of patients with 1-, 3‐ or 5‐year OS. (B-D) The calibration plots for predicting patient 1-, 3‐ or 5-year OS. Nomogram‐predicted probability of survival is plotted on the x‐axis; actual survival is plotted on the y‐axis. (E-G) The relationship between hub genes signature and different clinical features of 1-, 3‐ or 5-year OS.
Prognostic value and clinical utility of hub genes
The stratification analysis was performed based on grade, age, stage and histological type. The patients were stratified into grade I/II subgroups, stage I/II and stage III/IV subgroups. As shown in Figure 8A, the prognosis of high-risk patients was significantly worse than that of low-risk patients in the grade I/II, stage I/II and stage III/IV subgroups (Figure 8B,C). We also assessed the prognostic ability of risk signature combined with age and histological type. The patients were also stratified into >50 years subgroup and ≤50 years subgroups. Interestingly, we found that high-risk patients in two subgroups were inclined to unfavorable OS (Figure 8D,E). The similar trend was also observed in the squamous cancer subgroup (Figure 8F).
Figure 8 The stratification analysis was performed based on age, grade, histological type and stage. (A) Prognosis of high-risk patients was significantly worse than that of low risk patients in the grade 1–2 subgroup; (B) prognosis of high-risk patients was significantly worse than that of low risk patients in the stage I/II subgroup; (C) prognosis of high-risk patients was significantly worse than that of low risk patients in the stage III/IV subgroup; (D) high risk patients in subgroup with age >50 years old were inclined to have unfavorable OS; (E) high-risk patients in subgroup with age ≤60 years old were inclined to have unfavorable OS; (F) high risk patients in subgroup with squamous were inclined to have unfavorable OS.
CESC can be caused by abnormal genetic and epigenetic changes (20). Recently, increasing methylation-driven genes have been identified as candidate biomarkers in cancers, such as esophageal squamous cell carcinoma, lung squamous cell carcinoma and renal clear cell carcinoma (21-23). In the present study, we screened out methylation-driven genes associated with CESC.
Firstly, 144 methylation-driven genes were identified. GO analysis revealed that these genes were mostly associated with "Nucleic acid binding, Transcription, DNA-templated and Regulation of transcription, DNA-templated". KEGG analysis showed that they were mainly involved in the pathways including "Generic transcription pathway, RNA polymerase II transcription, Gene expression (Transcription)". The gene expression programs are governed by thousands of transcriptional factors and chromatin regulators. The mutations and epigenetic modification of these regulators contribute to tumorigenesis. Our findings indicated that most of these methylation-driven genes might regulate the transcription and expression of oncogenes/anti-oncogene in CESC. In addition, through performing univariable and multivariate Cox analyses, three candidate driver genes (ITGA5, HHEX and S1PR4) were identified as CESC prognostic-related genes and used to construct a risk model. We divided the CESC samples into two groups. Significant difference was showed in the overall survival between the two groups, suggesting that the risk model was effective in predicting the prognosis of CESC patients. The AUC of 5-year overall survival ROC curve was 0.749, suggesting that the risk model is accurate in predicting the prognosis of CESC patients. These findings were also validated by our nomogram. We further found that the three-genes-based risk score and the TNM stage might be independent prognostic factors. However, further studies are needed to support our findings.
ITGA5, as a member of integrin family, has been reported to mediate the initial adhesion process in cancers, such as the ovarian cancer (24), and colorectal cancer (25). In recent years, the role of integrins in cancers has been illustrated. Various integrin inhibitors have proved their efficacy in resisting cancer progression (26). However, we found that hyper-methylated and lowly-expressed ITGA5 was associated with a better prognosis of CESC, which is consistent with the finding of Fang et al., in that ITGA5 expression was down-regulated in invasive breast cancer cells by increasing methylation in the promotor of ITGA5 (27). HHEX is down-regulated in multiple malignancies (28). Down-regulation of HHEX suppresses the development of breast cancer, thyroid cancer and hepatocellular carcinoma (29-31). In our present study, we also found hypermethylation and low-expression of HHEX were associated with a poor prognosis in CESC.S1PRs family was found highly-expressed in multiple cancers, and associated with poor prognosis of cancers in a previous study (32). Inversely, we found that the hypermethylation and low-expression of gene S1PR4 was associated with a poor prognosis of CESC, suggesting that S1PR4 might restrain the progression of CESC. However, up to date, all the performances of three genes have not been experimentally validated. GSEA further revealed the biological functions of ITGA5, HHEX and S1PR4. Thus, we speculated that ITGA5 might participate in the progression of CESC by mediating pathways, including glycosaminoglycan biosynthesis chondroitin sulfate, ECM receptor interaction and Focal adhesion. HHEX and S1PR4 were mostly associated with autoimmune processes. The relationship between tumorigenesis and autoimmunity has been confirmed in recent years, especially in paraneoplastic syndromes (33), indicating that immunotherapy might be effective in treating cancers.
In conclusion, our study defined three methylation-driven genes (ITGA5, HHEX and S1PR4) associated with CESC development and built a 3-gene risk signature for predicting cancer prognosis. However, biofunctions of these genes remain to be unveiled with more in-depth research. The three genes might serve as potential prognostic biomarkers and therapeutic targets in the treatment of CESC.
Funding: National Natural Science Foundation (81472442, 81872119) and Jiangsu province medical innovation team (CXTDA2017008) supported our study.
Peer Review File: Available at http://dx.doi.org/10.21037/atm-19-4577
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-19-4577). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The statement of ethics approval and the informed consent were not necessary in this study, because our present study was a bioinformatics analysis based on TCGA database, and all the sample information was downloaded from open databases.
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Cite this article as: Liu J, Nie S, Li S, Meng H, Sun R, Yang J, Cheng W. Methylation-driven genes and their prognostic value in cervical squamous cell carcinoma. Ann Transl Med 2020;8(14):868. doi: 10.21037/atm-19-4577
Peer Review File


text:
Everlane Wants You to Buy Less
By Alexandria Symonds
ABOVE: MICHAEL PREYSMAN (FAR RIGHT) WITH DEVENDRA BANHART AND ANA KRAS AT EVERLANE'S FIRST-BIRTHDAY PARTY, AT CITY GRIT. IMAGE COURTESY OF BILLY FARRELL/BFANYC.COM
To get a sense for the values Michael Preysman hopes to espouse with the fashion brand he founded a year ago, Everlane, you need only visit its website. Its design is minimal, orderlyâ??no clutter on the pageâ??but inviting, with handsome typography and a large photo carousel highlighting Scottish wool scarves and fine silk blouses. Blurbs tell you what you need to know, but don't overload you with information; it's a controlled experience. There's no room for chaos in the Everlane universe.
Everlane's offerings share a similar aesthetic. The collection, thus far, is small: one style of cashmere sweater, one tee, one men's button-down, etc., all designed by perfectionists and available at surprisingly affordable price points. The brand was born when Preysman, then working in finance, discovered the margin of markup employed by most major luxury brands: up to 800%. He set out to create a line that would source the very best materials from all the same factories as those brandsâ??but would operate solely online, cutting out the overhead costs posed by brick-and-mortar stores.
In its first year, Everlane has gained a half-million registered users; but Preysman's just getting started. This week, the brand will launch a pop-up for the holidays, the Everlane Workshop, where guests can try on Everlane designs and create custom productsâ??with workshops including cashmere elbow patches, tie making, and belt designâ??all week.
ALEXANDRIA SYMONDS: You started in financeâ??what happened to make you want to switch to clothing design?
MICHAEL PREYSMAN: I spent like three years in private equity, and we looked at Facebook, and we looked at Yelp, and investing in these companies, and it was totally rad. And then I sort of looked at everyone in the industry and I was like, "I do not want to be any of you." On a personal level, I have tons of friends who are still in the industry, and I know they're not happy. I sort of made that realization that there's more to life. It was crazy for meâ??it was this one weekend where I forced myself to write down the people that I admired in the world, and not a single one of them was in finance, and I was like, "I cannot go through life not trying to be the kind of person that I admire."
SYMONDS: Do you remember some of the people who were on that list?
PREYSMAN: Oh, my God, it's going to be so corny. It was everybody from Michael Eisner to Mickey Drexler. There were people like my dad, who had started two companies and moved from Russia when he was 25 with nothingâ??they literally had, when they came here, I think $100â??just got a job and made it work in the end. I really wish I had my original listâ??I think the names are probably different, because I know more about the world today than I did two years ago.
And so for me it was like, "I'm leaving a job, what am I going to do, I'm going to go try to start something." And I really saw this opportunity at the timeâ??not just a fashion brand, but an idea that online retail, or just retail in general, is so broken. There have been so many industries that have been transformed over the past 10 yearsâ??you know it, with online versus offline journalism, to Amazon.com, to Facebook, to Googleâ??the number of the web has transformed the way we work and the way we think is really magnificent, and I think it hasn't done that much on the fashion or design side of the world.
That was what we started with, and it took us a year to get to launching our first set of products and figuring out that that was the right thing to do: to try to build a brand online only, without any of the traditional costs of retail; and one that sort of pushes forward this idea of minimalism and transparency in a way that I don't think others are doing right now.
SYMONDS: Did you have contacts in the fashion or design world when you first started? How did you find your designers?
PREYSMAN: I had a few friends that like, I made friends with this guy who ran a button-down shirt [line], and then he introduced me to a couple others, and then slowly, piece by piece, I made friends with people in the industry.
SYMONDS: You source from the exact same factories and mills as a lot of leading luxury brands, a discovery process you've compared to spying. Can you tell me about it?
PREYSMAN: We have these scarves that are made in old Scottish millsâ??of the top five brands in the world, they work with two of them. I was in a store and I saw this beautiful scarf, and I asked who it was made by, and it was made by this Scottish mill. So we literally went on Google and looked up this factory, and I found the person who runs it in Scotland, and I found the person who runs the US operations, and then I used an e-mail verifier to find the structure of their e-mail addresses. It was like an hour and a half of Googling. We e-mailed them and told them the story of who we are and that we're super excited that we've got the opportunity to work with youâ??and then we're in the factory.
And the way we did it with our silk blouses is we literally said, "Okay, who makes really beautiful silk blouses?" There's also this really great service called Panjivaâ??technology nowadays allows you to see so much more into the world than you did before. You can look up any brand and any factory and see who they work with. Now, we're making enough friends that it becomes easier and easier, so the hunt becomes faster.
SYMONDS: It seems like in that respect, Everlane is a very "of this moment" kind of company. Even two or three years ago, it seems like it would have been impossible or much, much harder to create the kind of company that you've created. Do you think that's true?
PREYSMAN: There's a number of things you could do nowadays but you couldn't do five years ago, like finding these factories, the way we communicate. The number of people we Skype with is incredible overseas. And the web has allowed things to propagate and spread much faster than they ever would. You know, a viral video can get the attention of seven million people in like two days. And so today we can build a company with so little time [spent] on major advertising campaigns, and instead we rely on people like you and me to tell their friends and that's like a totally different thing than five years ago.
SYMONDS: The prevalence of fast-fashion luxury collaborations over the last few yearsâ??Margiela for H&M, Jason Wu for Targetâ??has done a good job at starting a conversation about the idea of democratizing fashion. But my impression of Everlane is you're doing something similar, but in almost completely the opposite way.
PREYSMAN: Totally. I think those things are a great way for Rodarte, Jason Wu, Margiela or Missoni to get to a different customer base while still not diluting the brand in a way, we're not anti-fast fashionâ??but we kind of are. We're building things that we want to last a long time. I'm sure we both read the same article about Zara and the company does so much revenue every year and people now buy things and just throw them away. We're trying to push ourselves away from that.
Somebody asked me, "What do you think has really changed over the past 10 to 20 years?" In fashion, I think one of the biggest things is it's hard to tell quality anymore. People are so good at making that product look amazing, but you never know how it's going to wear. We are trying to go a little bit counter to that and say, "Hey, let's make something that lasts you a long time, and if it doesn't, we've done a poor job." There are brands that do that very well, but they're generally not fashion brands.
SYMONDS: I don't know if you've read any of the articles about how organizations that are working on Sandy relief are just turning away clothing donations nowâ??and there's a larger narrative that has been reported in the last year or so, that places like Goodwill and the Salvation Army have too many clothing donations, because people just buy too much clothing.
PREYSMAN: I mean, it's weirdâ??we're selling a product, at the end of the day, but in a lot of ways, we're selling a product and we're trying to get people to buy less.
SYMONDS: Right, which is so antithetical to how it normally works.
PRESYMAN: I'd hope people just buy a few button-downs, a few silk blouses, a few of this; buy the essential pieces you need. Peter Menzel went around the country and photographed how different people live, in the '90s, and it's crazy to see how much Americans own. I wish he did that 10 years later, because it's got to be so much more.
SYMONDS: Presumably you want the brand to keep expanding, and you're introducing new products, so how do you keep that growth manageable? How are you balancing it with the kind of essential company ethos of sticking to the very best of the basics?
PREYSMAN: My goodness, this is a challenging question. We don't know yet, is the answer. What we're trying to do, we don't release too many colors, we don't offer a ton of choice. A guy needs a blazer at some point, a button down, a belt, shoes, so the way we think about it is slowly building up those collections of pieces. We have a weekend bag, a backpack, and a tote. The idea is not offering eight different weekend bags. It's creating that one essential piece, and then moving on to the next thing.
THE EVERLANE WORKSHOP IS AT 74 GANSEVOORT STREET FROM NOVEMBER 30 THROUGH DECEMBER 9. FOR MORE INFORMATION, VISIT THE BRAND'S WEBSITE.
Sean (left) wears Necklace by G. Sherman Jewels. Ring Ben's own.
Adult Film Star Sean Ford Wants to Make Intimacy Sexy Again


With a variety of potential uses, the wicker games table offers a square top sized to accommodate four chairs. Set it up for dining in smaller spaces, place it in a sunroom for gatherings as a wicker cards table or add it on a protected patio or use it as a wicker porch table for serving beverages. Protect it with glass if desired and turn it into a craft or work table when space is limited. Classic basket weaving across the top offers durable surfacing matched by a simple arching apron and rattan wrapped legs. Add an optional acrylic coating to any of the finishes for extra weather resistance. Make it bright with country reds and coastal greens or tone down a little with antiqued neutrals and darker shades.


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New Funding to Promote Value-Based Payment and Care Recommendations for Transition
The National Alliance to Advance Adolescent Health has received funding from the Lucile Packard Foundation for Children's Health to develop a strategic dissemination plan to increase the use of value-based payment (VBP) and care delivery recommendations by payers for pediatric-to-adult health care transition. See more →
Transition to Adult Care, Insurance CoverageDaniel Beck April 24, 2019 Policy Communications
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by Donna L. Spencer, Margaret McManus, Kathleen Thiede Call, Joanna Turner, Christopher Harwood, Patience White, and Giovann Alarcon, March 2018
This article from the Journal of Adolescent Health examines changes to health insurance coverage and access to health care among children, adolescents, and young adults since the implementation of the Affordable Care Act. The report shows significant improvements in coverage among children, adolescents, and young adults since 2010. See more →
Insurance CoverageDaniel Beck March 30, 2018 Research
Comments to the Social Security Administration on Strategies to Improve Adult Outcomes for Youth Receiving Social Security Income (SSI)
Comments to the Social Security Administration regarding its Request for Information on Strategies to Improve Adult Outcomes for Youth Receiving Social Security Income (SSI), focusing particular attention to the distinct needs of transition-age youth and young adults, ages 14 to 25. See more →
Insurance Coverage, Transition to Adult CareDaniel Beck February 23, 2018 Policy Communications
Letter to House of Representatives on Proposed Bill on Mental Health and Substance Use Services under CHIP
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Mental Health Services, Insurance CoverageSarah Dohl July 20, 2017 Policy Communications
Lack of Comparability Between CHIP and ACA Qualified Health Plans
by Margaret A. McManus and Harriette B. Fox, July 2014.
This fact sheet provide a detailed examination of comparability between separate CHIP programs and child-only qualified health plans in Colorado, Georgia, Oregon, Texas, and West Virginia for children with family incomes between 134% to 300% FPL. It examines cost-sharing requirements, including deductibles, copayments and coinsurance, and out-of-pocket limits, and benefit coverage and treatment limitations in 28 benefit categories. Implications for CHIP reauthorization are also discussed. See more →
Insurance CoverageSarah Dohl July 1, 2014 Research
Many Low Income Older Adolescents Likely to Remain Uninsured in 2014
by Harriette B. Fox, Margaret A. McManus, and Annalia G. Michelman, October 2013.
This fact sheet identifies the states in which adolescents ages 19 and 20 living at or below the poverty level are likely to remain without health insurance protection in January 2014, despite the passage of the Affordable Care Act. It examines several avenues to state Medicaid coverage: optional Medicaid eligibility for "Ribicoff Children" up to age 21, Section 1115 demonstration waivers covering childless adults, and the ACA's optional Medicaid expansion for uninsured individuals ages 19 through 64. It also describes the obstacles these older adolescents confront in securing private health insurance coverage through employment and in exchanges. See more →
Insurance CoverageSarah Dohl October 1, 2013 Research
Private Coverage Under California's Affordable Care Act: Benefit and Cost-Sharing Requirements Affecting Children and Adolescents With Special Health Care Needs
by Margaret McManus and Harriette Fox, May 2013.
This issue brief examines the extent to which California's essential health benefits benchmark plan meets the needs of children and adolescents, including those with special needs. It also examines the cost-sharing requirements that will be used by health insurance plans sold in California's Health Insurance Exchange. It identifies potential issues of concern in the benchmark's essential health benefits, with special attention to families' out-of-pocket cost liabilities within all five levels of coverage, including subsidized coverage. See more →
Insurance CoverageSarah Dohl May 1, 2013 Research
Comments to HHS on Proposed Rule on Medicaid, CHIP, and Exchanges
Comments from The National Alliance to the Centers for Medicare and Medicaid Services on the Proposed Rule on Medicaid, Children's Health Insurance Programs, and Exchanges, issued on January 22, 2013, to implement provisions of the Affordable Care Act (ACA) and the Children's Health Insurance Program Reauthorization Act (CHIPRA). See more →
Insurance CoverageSarah Dohl February 13, 2013 Policy Communications
State EPSDT Policies for Adolescent Preventive Care
by Harriette B. Fox, Katherine K. Rogers, and Margaret A. McManus, September 2011.
This fact sheet presents findings from an analysis of state policy documents that establish guidelines for providers delivering EPSDT preventive services to adolescents. It examines state Medicaid policies including the EPSDT periodicity schedule; comprehensive health history and developmental assessments; physical examinations, laboratory tests, and immunizations; health education; and referrals. Particular emphasis is given to the early identification of problems related to nutritional health, mental health, sexual behavior, substance use, and violence and injury potential and to health education for key topics under Bright Futures. Also examined are state policies regarding adolescents' private time with providers. See more →
Adolescent-Centered Care, Insurance CoverageSarah Dohl September 1, 2011 Research
Health Reform and Adolescents
by Harriette B. Fox and Margaret A. McManus, June 2009.
This issue brief documents the significant health risks and conditions of adolescents and the financing and delivery system barriers that affect their access to appropriate care. It urges Congress to consider coverage expansions under Medicaid and CHIP, benefit and payment improvements, grant programs to support interdisciplinary models of primary care, and funds to improve training for adolescent health providers. See more →
Insurance CoverageSarah Dohl June 1, 2009 Research
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The National Alliance to Advance Adolescent Health has received funding from the WITH Foundation to improve the transition for young adults with intellectual and developmental disabilities (IDD) from pediatric to adult health care. The National Alliance will partner with The HSC Health Care System in Washington, DC to implement this first-of-its-kind transition value-based payment model. See more →
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