Martin Pickford
email: martin.pickford@mnhn.fr.

Dominique Gommery
email: dominique.gommery@sorbonne-universite.fr.

Thomas Ingicco
email: thomas.ingicco@mnhn.fr.

MACAQUE MOLAR FROM THE RED CRAG FORMATION, WALDRINGFIELD, ENGLAND

Keywords: Mio-Pliocene, Cercopithecidae, Palaeoenvironment, Palaeoclimate, Taphonomy, East Anglia

Fossil monkeys are rare in the British palaeontological record, a few specimens having been reported from the Pleistocene, and a single specimen from the Red Crag, possibly of Late Miocene or Pliocene age. An undescribed monkey tooth from the Red Crag at Waldringfield collected circa 1908 that has remained unidentified in the collections of the Sedgwick Museum, Cambridge, is described herein. The fossil was associated with dental remains of a suid, a tapir and a deer which, taken as an assemblage, are best correlated to the Early Pliocene, being similar to specimens from Perrier, France. Because of the high latitudinal position of Waldringfield (52°N) and indications for a tropical to sub-tropical palaeoenvironment during the Late Miocene -Early Pliocene, the monkey tooth from there is of great interest.

INTRODUCTION

Until recently, the only known cercopithecid fossils from Britain were from West Runton, Hoxne, Cudmore Grove, Grays Thurrock, Purfleet, Swanscombe, Ebbsfleet and the Norfolk Forest Bed [START_REF] Hinton | Note on the discovery of a bone of a monkey in the Norfolk Forest Bed[END_REF][START_REF] Delson | Fossil Colobine Monkeys of the Circum-Mediterranean Region and the Evolutionary History of the Cercopithecidae (Primates, Mammalia)[END_REF][START_REF] Delson | Preliminary review of cercopithecid distribution in the Circum Mediterranean Region. -In: Actes du Vème Congrès du Néogène méditerranéen, Lyon, septembre 1974[END_REF], Arditoand Mottura 1987[START_REF] Stuart | Vertebrate faunas from the early middle Pleistocene of East Anglia[END_REF][START_REF] Schreve | Sedimentology, palaeontology and archaeology of late middle Pleistocene river Thames terrace deposits at Purfleet, Essex, UK[END_REF][START_REF] Roe | Differentiation of MIS 9 and MIS 11 in the continental record: vegetational, faunal, aminostratigraphic and sea-level evidence from coastal sites in Essex, UK[END_REF][START_REF] Alba | Fossil remains of Macaca sylvanus florentina (Cocchi, 1872) (Primates, Cercopithecidae) from the Early Pleistocene of Quibas (Murcia, Spain)[END_REF][START_REF] Parfitt | Mammalian biostratigraphy[END_REF]) most of which are of Pleistocene age [START_REF] Schreve | Differentiation of the British late Middle Pleistocene interglacials: The evidence from mammalian biostratigraphy[END_REF], with only one specimen from the Red Crag being potentially of Pliocene or Miocene age (the specimen thought by [START_REF] Delson | Fossil Colobine Monkeys of the Circum-Mediterranean Region and the Evolutionary History of the Cercopithecidae (Primates, Mammalia)[END_REF] to be of Early Pleistocene age, is possibly Late Miocene (this paper)). It is therefore of interest to place on record the identification of a macaque tooth (right upper molar, M1/ or M2/) recovered from Waldringfield, Suffolk, circa 1908, and presented to the Sedgwick Museum, Cambridge, by Dr Lloyd Jones. The preservation characters of the fossil indicate that it was redeposited into the Red Crag after derivation from a pre-existing body of sediment along with similarly preserved remains of tapirs, pigs, mastodonts, deer and carnivorans that indicate a Late Miocene to Early Pliocene age for the fossils, more or less equivalent to the palaeofauna from Les Etouaires, Perrier, France (MN 16: 3.9-3.4 Ma (Bout 1968), 3.6-2.4 Ma [START_REF] Steininger | European Neogene marine/continental chronologic correlations[END_REF])) from which a similar suite of mammalian species was described by Croizet and Jobert (1828).

Interestingly, while [START_REF] Delson | Fossil macaques, phyletic relationships and a scenario of deployment[END_REF] noted that all macaque fossils from the Mediterranean Basin from the Miocene up to the Late Pleistocene look alike, most of the described fossil taxa included in the genus Macaca Lacépède, 1799 were erected on the basis of specimens collected north of 48°N latitude. This was the case for Macaca pliocena Owen, 1846 from Grays Thurrock, England [START_REF] Owen | Notice sur la découverte faite en Angleterre de restes fossiles d'un quadrumane du genre Macaque, dans une formation d'eau douce appartenant au nouveau pliocène[END_REF][START_REF] Owen | A History of British Fossil Mammals, and Birds[END_REF] and Macaca suevica from the Gutenberger Höhle, Heppenloch, Germany (48°32′34″N : 31°19′03″E; Hedinger 1891). However, except for the small island endemic species Macaca majori Azzaroli, 1946from Sardinia, Italy (Azzaroli 1946) most of the fossil macaque "nominal species" are either indistinguishable from each other or may, at most, be separated at the subspecific rank, with the result that several recent authors retain Macaca sylvanus florentina [START_REF] Cocchi | Su di due Scimmie fossili italiane [On Two Italian Fossil Monkeys[END_REF] first described from the Upper Valdarno, Italy [START_REF] Cocchi | Su di due Scimmie fossili italiane [On Two Italian Fossil Monkeys[END_REF] as the only valid subspecies, even though M. s. pliocena Owen, 1846 has priority according to the International Code of Zoological Nomenclature (ICZN 1999). The subspecies M. sylvanus prisca Gervais, 1859 from the Pliocene (type locality: Montpellier, France; Ruscinian) that is of comparable age to the Waldringfield molar, has been retained as valid by [START_REF] Alba | Fossil remains of Macaca sylvanus florentina (Cocchi, 1872) (Primates, Cercopithecidae) from the Early Pleistocene of Quibas (Murcia, Spain)[END_REF][START_REF] Alba | New macaque remains from the Middle Pleistocene of Gruta da Aroeira (Almonda karst system, Portugal)[END_REF] along with M. s. pliocena. M. s. florentina is distinguished from the extant Barbary macaque, M. s. sylvanus [START_REF] Linnaeus | Systema Naturae per Regna Tria Naturae, Secundum Classes, Ordines, Genera, Species, cum Characteribus, Differentiis, Synonymis[END_REF] by its longer and broader upper molars and itsnarrower lower third molars [START_REF] Alba | Fossil remains of Macaca sylvanus florentina (Cocchi, 1872) (Primates, Cercopithecidae) from the Early Pleistocene of Quibas (Murcia, Spain)[END_REF].

Abbreviations BGSK British Geological Survey, Keyworth CAMSM Cambridge Sedgwick Museum of Earth Science,Cambridge NHMUK Natural History Museum of the United Kingdom,London GEOLOGICAL SETTING Historical background and context [START_REF] Newton | The Vertebrata of the Pliocene Deposits of Britain (Memoirs of the Geological Survey of the United Kingdom). -Eyre & Spottiswode for Her Majesty's Stationary Office[END_REF] reported that no monkey fossils had been found in the Red Crag, the only cercopithecid known from Britain at the time being the specimen called Macacus pliocenus by [START_REF] Owen | A History of British Fossil Mammals, and Birds[END_REF] from Grays in Essex ("Newer Pliocene" Brickearth) listed as Grays Thurrock by [START_REF] Delson | Fossil Colobine Monkeys of the Circum-Mediterranean Region and the Evolutionary History of the Cercopithecidae (Primates, Mammalia)[END_REF][START_REF] Delson | Preliminary review of cercopithecid distribution in the Circum Mediterranean Region. -In: Actes du Vème Congrès du Néogène méditerranéen, Lyon, septembre 1974[END_REF] and subsequent authors (fig. 1). The type locality of M. Sylvanus pliocena [START_REF] Owen | A History of British Fossil Mammals, and Birds[END_REF], is correlated to Marine Isotope Stage (MIS) 9 (Middle Pleistocene; Schreve 2001).

In part 5 of his series of papers on Suffolk geology, Spencer (1971e) reported that the "[Red Crag] …. at Newbourne and Waldringfield …. has produced a suspicious number of Pliocene species which have been accepted as indigenous Red Crag fossils, species which are poorly represented in the newer Crag". In the section on Mammalia from the Red Crag, however, [START_REF] Spencer | The Crag Mammalia[END_REF] stressed the important point that the mammal fossils from the Red Crag are of two classes, echoing the observations of previous researchers [START_REF] Owen | Report on the British Fossil Mammalia[END_REF][START_REF] Owen | Notice sur la découverte faite en Angleterre de restes fossiles d'un quadrumane du genre Macaque, dans une formation d'eau douce appartenant au nouveau pliocène[END_REF][START_REF] Owen | A History of British Fossil Mammals, and Birds[END_REF][START_REF] Owen | Description of some Mammalian Fossils from the Red Crag of Suffolk[END_REF][START_REF] Wood | On the extraneous fossils of the Red Crag[END_REF][START_REF] Lankester | On the sources of the mammalian fossils of the Red Crag, and on the discovery of a new mammal in that deposit, allied to the walrus[END_REF][START_REF] Lydekker | Notes on some Vertebrata from the Red Crag[END_REF]. The first category comprises material of diverse pre-Crag ages that were reworked from older deposits and redeposited in the Crag, including Hippariongracile, Mastodon borsoni, Mastodon longirostris andMastodon arvernensis, a tapir, various species of pigs, an axis deer (Axis pardinensis) and Cervus suttonensis, alongwith diverse whale and shark bones and teeth. The secondclass of mammal fossils comprises species that lived and diedat the time of accumulation of the Red Crag. In particular [START_REF] Spencer | The Crag Mammalia[END_REF] mentioned the presence of Equus robustus at Waldringfield which, if correctly identified, means that the Red Crag is of Pleistocene age. Hand-written labels in the Cambridge palaeontology collections reveal that Spencer was aware of the presence of tapirs, deer, fish and suids from the Red Crag at Waldringfield. The box with these labels also contains the upper molar of a cercopithecid, which is the subject of this paper (fig. 2). [START_REF] Delson | Fossil Colobine Monkeys of the Circum-Mediterranean Region and the Evolutionary History of the Cercopithecidae (Primates, Mammalia)[END_REF][START_REF] Delson | Preliminary review of cercopithecid distribution in the Circum Mediterranean Region. -In: Actes du Vème Congrès du Néogène méditerranéen, Lyon, septembre 1974[END_REF] recorded ?Mesopithecus monspessulanus (Gervais, 1849) from the Red Crag on the basis of an isolated upper third molar, but no details were available concerning the precise locality from which the fossil (NHMUK M9171) was obtained. It was purchased by the museum in January, 1905, from F. H. Butler and was included in the Pinder collection.

Taphonomy

As was discussed by [START_REF] Spencer | The Crag Mammalia[END_REF][START_REF] Spencer | The contemporary mammalian fossils of the Crags[END_REF]Spencer ( , 1971a[START_REF] Spencer | A contribution to the Geological History of Suffolk[END_REF] vertebrate fossils collected from the Red Crag, but derived from older deposits, are usually dark brown with glossy surfaces. The monkey tooth from Waldringfield is varicoloured but predominantly dark brown with a highly polished surface, agreeing in preservation characters with teeth of a tapir, some suids and a deer from the same deposits (figs 2, 3). There can be little doubt that the monkey molar discussed herein was originally fossilised in a pre-Crag deposit, then eroded from it and redeposited as a clast within the Red Crag. The specimen was most likely collected from the so-called Nodule Bed or Coprolite Bed, which yielded many well-preserved, highly polished vertebrate bones and teeth [START_REF] Newton | The Vertebrata of the Pliocene Deposits of Britain (Memoirs of the Geological Survey of the United Kingdom). -Eyre & Spottiswode for Her Majesty's Stationary Office[END_REF].

Geological age

The Red Crag is generally considered to have been deposited during the Pleistocene [START_REF] Spencer | The Crag Mammalia[END_REF][START_REF] Spencer | The contemporary mammalian fossils of the Crags[END_REF], 1971a[START_REF] Spencer | A contribution to the Geological History of Suffolk[END_REF][START_REF] Stuart | Vertebrate faunas from the early middle Pleistocene of East Anglia[END_REF][START_REF] Schreve | Sedimentology, palaeontology and archaeology of late middle Pleistocene river Thames terrace deposits at Purfleet, Essex, UK[END_REF][START_REF] Roe | Differentiation of MIS 9 and MIS 11 in the continental record: vegetational, faunal, aminostratigraphic and sea-level evidence from coastal sites in Essex, UK[END_REF][START_REF] King | A revised correlation of Tertiary in the British Isles and adjacent areas of NW Europe. -Special Report[END_REF][START_REF] Davies | Where does the time go? Assessing the chronostratigraphic fidelity of sedimentary geological outcrops in the Pliocene-Pleistocene Red Crag Formation, eastern England[END_REF]) but, as has been pointed out on several occasions (see above) many of the fossil mammals found in it are reworked from older deposits [START_REF] Wood | On the extraneous fossils of the Red Crag[END_REF], Prestwich 1871a, b). An examination of the proboscideans and suids reveals that there are some Late Miocene and Early Pliocene taxa in the Red Crag ranging in age from ca. 10 Ma to 3 Ma (corresponding to MN 10 to MN 16 in the European land mammal zonation; [START_REF] Steininger | European Neogene marine/continental chronologic correlations[END_REF], Pickford 2013a, b). Some of the suid fossils, in particular, were considered in the older literature to belong to Sus palaeochoerus (= Propotamochoerus palaeochoerus in more recent literature) and Sus antiquus (= Hippopotamodon antiquus in recent literature) which would suggest correlation to MN 9 and MN 10, but most of them are in fact closer in dimensions and morphology to material of Dasychoerus arvernensis, upon which basis Pickford (2013a, b) and [START_REF] Pickford | Pliocene suids from Musaitu and Dermenji, Moldova: implications for understanding the origin of African Kolpochoerus Van Hoepen & Van Hoepen[END_REF] correlated the Red Crag mammals to MN 16. The Red Crag has also yielded a few specimens of Hippopotamodon erymanthius or Hippopotamodon major (MN 11 -MN 12) [START_REF] Pickford | Late Miocene Suidae from Eurasia: The Hippopotamodon and Microstonyx problem revisited. -Münchner Geowissenschaftliche Abhandlungen[END_REF]. There is thus a degree of uncertainty about the age of the monkey tooth from Waldringfield, but its association (albeit secondary) with specimens of Dasychoerus arvernensis, Anancus arvernensis, and Tapirus sp. indicate that it is most likely to be of latest Miocene to Early Pliocene age. It is certainly older than the period of deposition of the Red Crag itself, which accumulated during the Pleistocene [START_REF] Davies | Where does the time go? Assessing the chronostratigraphic fidelity of sedimentary geological outcrops in the Pliocene-Pleistocene Red Crag Formation, eastern England[END_REF]).

Palaeoenvironment

The presence in the Red Crag faunas of mammals with close relatives that today occur in tropical and sub-tropical forested environments, such as tapirs [START_REF] Owen | Description of some Mammalian Fossils from the Red Crag of Suffolk[END_REF][START_REF] Newton | The Vertebrata of the Pliocene Deposits of Britain (Memoirs of the Geological Survey of the United Kingdom). -Eyre & Spottiswode for Her Majesty's Stationary Office[END_REF][START_REF] Spencer | The Crag Mammalia[END_REF], red pandas (Parailurus anglicus) (Boyd-Dawkins 1888, Newton 1890), rhinoceroses and warty pigs (Dasychoerus) [START_REF] Pickford | Pliocene suids from Musaitu and Dermenji, Moldova: implications for understanding the origin of African Kolpochoerus Van Hoepen & Van Hoepen[END_REF] suggests that for a time, East Anglia was warmer and more densely vegetated than it is today, likely being sub-tropical rather than fully tropical [START_REF] Gibson | Reconstructing terrestrial paleoclimates: A comparison of the Co-existence Approach, Bayesian and probability reconstruction techniques using the UK Neogene[END_REF]). The macaque fossil described herein does not contradict this inference, even though extant macaques can survive in regions with severe winters [START_REF] Alba | Fossil remains of Macaca sylvanus florentina (Cocchi, 1872) (Primates, Cercopithecidae) from the Early Pleistocene of Quibas (Murcia, Spain)[END_REF]. Nowadays in the Maghreb, Barbary macaques occur in the cedar forests of the High and Middle Atlas in Morocco and in the coastal regions of the Rif [START_REF] Fooden | Systematic review of the Barbary macaque, Macaca sylvanus (Linnaeus, 1758)[END_REF]. They feed on fruits during the summer and on seeds and bark during the winter (El Alami and Chait 2015). Thanks to this dietary flexibility [START_REF] Ménard | Behavioral responses of Barbary macaques (Macaca sylvanus) to variations in environmental conditions in Algeria[END_REF] they easily survive in high altitude zones during the winter and in the presence of snow [START_REF] Kowalski | Mammals of Algeria. -Zaklad Naradowy im[END_REF]. The relatively common occurrence of the proboscidean Anancus arvernensis in Red Crag deposits also suggests that the palaeoclimate was of sub-tropical affinities at the time that they lived in the region, although on the basis of mesowear angle analysis, [START_REF] Saarinen | Dental mesowear reflects local vegetation and niche separation in Pleistocene proboscideans from Britain[END_REF] suggested that this genus had a browse-dominated diet in a more wooded environment, opening the possibility that it could also inhabit a more boreal palaeoenvironment. Locality and geological context: Waldringfield, Suffolk, United Kingdom (52°03'10"N : 01°19'39"E).Reworked into the Red Crag Formation from a pre-existing deposit.

Description: The isolated cercopithecoid tooth from Waldringfield has a glossy surface and the roots are polished and somewhat abraded indicating that it has been reworked into the Red Crag from a pre-existing deposit. The occlusal surface is deeply worn, indicating adult status, up to stage A4 of Ingicco's ageing system [START_REF] Ingicco | A deciduous and permanent dental wear stage system for assessing the age of Trachypithecus sp. specimens (Colobinae, Primates)[END_REF]) but the crown is otherwise well preserved (fig. 4). The tooth is quadricuspidate and bilophodont with shallow buccal and lingual notches and the floor of the median transverse valley is elevated well above cervical level. The two lingual roots are coalescent; the buccal ones separated from each other. The occlusal surface is heavily worn, to the extent that dentine lakes on the protocone and hypocone have coalesced across the median transverse valley. The dentine exposures on the paracone and metacone are smaller, the one on the paracone has joined the one developed on the protocone, the one on the hypocone is isolated at the apex of the cusp. The preprotocrista runs mesiobuccally, almost reaching the mesio-buccal corner of the crown. The posthypocrista is directed disto-buccally stopping short of the disto-buccal corner of the tooth. The mesio-distal length of the tooth is 9.0 mm and its bucco-lingual breadth is 8.5 mm. Discussion: Based on its dimensions, theWaldringfield tooth is more likely to be an M2/ than an M1/ although in the bivariate diagram (fig. 5) it plots close to the zone of overlap between M1/ and M2/. Given that its measurements may be slightly underestimated due to the abrasion and polishing that the tooth has undergone (red arrow in fig. 5) the unabraded position would have been closer to the mean of M2/ of the two subspecies in the plot (M. s. florentina and M. s. sylvanus) suggesting that the Waldringfield tooth is more likely to be an M2/ than an M1/.

The presence of a distoconule disto-lingual to the hypocone on the M3/ is the main character mentioned by [START_REF] Cocchi | Su di due Scimmie fossili italiane [On Two Italian Fossil Monkeys[END_REF] for erecting the taxon M. s. florentina. This small additional cusp is present in most of the fossils attributed to the species and occurs in two-thirds of the specimens from Quibas, Spain [START_REF] Alba | Fossil remains of Macaca sylvanus florentina (Cocchi, 1872) (Primates, Cercopithecidae) from the Early Pleistocene of Quibas (Murcia, Spain)[END_REF]). However, because the Waldringfield specimen is not an M3/, it is not possible to confirm its subspecies attribution on the basis of this character. Furthermore, the tooth has morphometric similarities to Macaca libyca [START_REF] Stromer | Mitteilungen über Wirbeltierreste aus dem Mittelpliocän des Natrontales (Ägypten)[END_REF] Description: The colobine upper molar from the Red Crag is dark brown, with a glossy surface and has been rolled and polished, like most of the mammalian teeth from the deposit. The tooth is quadricuspidate, with the four main cusps arranged in two transverse lophs. There is a small low basal pillar at the lingual end of the median transverse valley and a low talon cusp (distoconule) at the distal end, in the midline of the tooth, indicating that the specimen is an M3/. The buccal and lingual notches are mesiodistally wide and occlusally deep, and the floor of the median transverse valley is slightly above the cervix. The roots have been abraded off. Wear has advanced to the stage where small dentine lakes are exposed at the apices of the four main cusps, as well as the apex of the distoconule. This signifies a fully adult status, but not an aged individual. The mesio-distal length of the tooth is 7.7 mm, the breadth of the mesial loph is 7.2 mm and that of the distal loph is 6.4 mm (the original measurements prior to abrasion and polishing would have been slightly greater than these figures).

Discussion: This upper third molar from the Red Crag (fig. 6) was attributed to ?Mesopithecus monspessulanus by [START_REF] Delson | Fossil Colobine Monkeys of the Circum-Mediterranean Region and the Evolutionary History of the Cercopithecidae (Primates, Mammalia)[END_REF] but we prefer to leave it in open nomenclature as Mesopithecus sp.

GENERAL DISCUSSION

The Waldringfield macaque molar (fig. 4) differs from those of colobine monkeys (fig. 6) by the shallow buccal and lingual notches and by the floor of the median transverse valley being elevated well above the cervix. For these reasons it is attributed to the Cercopithecinae. Among cercopithecines, the tooth most closely resembles those of papionins, especially members of the genus Macaca. The dimensions of the fossil agree with a diversity of Late Miocene to Pleistocene and Recent monkeys, both colobines and cercopithecines. If the specimen is an M1/, then its dimensions accord with those of Macaca Sylvanus florentina from Quibas, Spain (Pleistocene ca. 1.8-1.1 Ma) [START_REF] Alba | Fossil remains of Macaca sylvanus florentina (Cocchi, 1872) (Primates, Cercopithecidae) from the Early Pleistocene of Quibas (Murcia, Spain)[END_REF]) and M. s. prisca/M. s. cf. prisca from Montpellier, RDB quarry, Cova Bonica and Gundersheim. If it is an M2/, then it is slightly smaller than teeth of these species. However, comparison of the Waldringfield fossil with specimens from latitudes higher than 48°N suggests that it is more likely to be an M2/ than an M1/. The tooth is compatible in dimensions with specimens of Macaca libyca from Sahabi, Libya (Late Miocene) [START_REF] Benefit | New fossil cercopithecoids from the Late Miocene of As Sahabi, Libya. -Garyounis Scientific Bulletin[END_REF] and Wadi Natrun, Egypt (Late Miocene to Early Pliocene) [START_REF] Stromer | Mitteilung über die Wirbeltierreste aus dem Mittelpliocän des Natrontales (Ägypten)[END_REF][START_REF] Pickford | A descriptive catalogue of fossils from Wadi Natrun (Mio-Pliocene) Egypt, housed in the Cairo Geological Museum and in Museums in Europe. -Münchner Geowissenschaftliche Abhandlungen[END_REF]. Macaques of similar dimensions are known from many localities in the Circum-Mediterranean region [START_REF] Delson | Fossil Colobine Monkeys of the Circum-Mediterranean Region and the Evolutionary History of the Cercopithecidae (Primates, Mammalia)[END_REF] as well as further afield in Asia in deposits ranging in age from the Late Miocene to Recent [START_REF] Ardito | An overview of the geographic and chronologic distribution of West European cercopithecids[END_REF]. Under the circumstances and given that the tooth could be either a first or second molar, the most appropriate decision is to leave the specimen in open nomenclature as Macaca sp. while recognising that it has morphometric affinities to molars of the species Macaca libyca and Macaca sylvanus. The recognition of this fossil monkey tooth in the Sedgwick Museum, Cambridge, highlights the value of re-examining old collections of fossils, in this case more than a century after the material was donated to the institution. Similar research in the old collections of the University of Tübingen, Germany, resulted in the recognition of a Miocene monkey tooth from Melchingen. The Melchingen karst infillings (Bohnerz deposits) correlate to MN 9, MN 10 and MN 13, with the monkey tooth most likely being of Turolian age. It had lain misidentified as a carnivoran in the collections since about 1902 [START_REF] Schlosser | Beiträge zur Kenntniss der Säugethierreste aus den süddeutschen Bohnerzen[END_REF][START_REF] Pickford | Miocene monkey from Melchingen[END_REF]. Each such specimen has augmented knowledge about the distribution of the species concerned, as well as yielding information about the palaeoenvironment and palaeoclimate of the locations and geological time periods concerned.

CONCLUSION

The recognition of a macaque upper molar from the Red Crag Formation at Waldringfield, England, is of interest for several reasons. Firstly, it is from 52°N latitude, and thus one of the most northerly occurrences of the genus in Europe. Secondly, it and the associated fauna indicate that the palaeoclimate was likely to have been of subtropical affinities. Thirdly, it increases the known diversity of monkeys from pre-Pleistocene contexts in the country. Macaques have long been known to occur in English Pleistocene deposits [START_REF] Owen | Notice sur la découverte faite en Angleterre de restes fossiles d'un quadrumane du genre Macaque, dans une formation d'eau douce appartenant au nouveau pliocène[END_REF] but this paper reports the first record of the genus Macaca in the Pliocene or Late Miocene, where it joins the record of Mesopithecus sp. From an unknown locality in the Red Crag [START_REF] Delson | Fossil Colobine Monkeys of the Circum-Mediterranean Region and the Evolutionary History of the Cercopithecidae (Primates, Mammalia)[END_REF]. [START_REF] Konidaris | First record of Macaca (Cercopithecidae, Primates) in the Middle Pleistocene of Greece[END_REF] pointed out that the oldest macaque fossil thus far recorded from Europe is considered to date from the Late Miocene, ca. 5.5 Ma [START_REF] Köhler | Macaca (Primates, Cercopithecidae) from the Late Miocene of Spain[END_REF][START_REF] Alba | First joint record of Mesopithecus and cf. Macaca in the Miocene of Europe[END_REF]. Even though there is doubt about the precise age of the Waldringfield specimen, it is potentially one of the older specimens from Europe, possibly somewhat older than the site of Les Etouaires, France (MN 16: 3.9-3.4 Ma -Bout 1968;3.6-2.4 Ma -Steininger et al. 1990). Few sites in Europe have yielded fossils of both Mesopithecus and Macaca [START_REF] Alba | First joint record of Mesopithecus and cf. Macaca in the Miocene of Europe[END_REF]. Even though the precise locality of the ?Mesopithecus monspessulanus tooth from the Red Crag described by [START_REF] Delson | Fossil Colobine Monkeys of the Circum-Mediterranean Region and the Evolutionary History of the Cercopithecidae (Primates, Mammalia)[END_REF] is not recorded, the possibility exists that these two genera may have coexisted in East Anglia, England during the latest Miocene or Early Pliocene. The Waldringfield macaque forms part of a small collection of vertebrate fossils donated to the Sedgwick Museum in 1908. In the same box are teeth of a tapir (Tapirus) a warty pig (Dasychoerus arvernensis) as well as a deer and there are two fish teeth and a first phalanx of an unidentified mammal. As an assemblage these fossils suggest that the palaeoenvironment was warm and humid, possibly tropical forest, and that the most likely age of the ensemble is Early Pliocene. If this interpretation is correct then it supports the results of previous researchers such as [START_REF] Newton | The Vertebrata of the Pliocene Deposits of Britain (Memoirs of the Geological Survey of the United Kingdom). -Eyre & Spottiswode for Her Majesty's Stationary Office[END_REF] who concluded that the Red Crag mammal indicated that tropical forest-like conditions prevailed in East Anglia at the time that the mammals lived there, contrasting with its present day boreal environment with marked wintersummer cycles. [START_REF] Ardito | An overview of the geographic and chronologic distribution of West European cercopithecids[END_REF], [START_REF] Alba | Dentognathic remains of Macaca (Primates, Cercopithecidae) from the late early Pleistocene of Terrassa (Catalonia, Spain)[END_REF][START_REF] Alba | Fossil remains of Macaca sylvanus florentina (Cocchi, 1872) (Primates, Cercopithecidae) from the Early Pleistocene of Quibas (Murcia, Spain)[END_REF][START_REF] Alba | First record of macaques from the early Pleistocene of Incarcal (NE Iberian Peninsula)[END_REF][START_REF] Alba | New macaque remains from the Middle Pleistocene of Gruta da Aroeira (Almonda karst system, Portugal)[END_REF][START_REF] Alba | New macaque fossil remains from Morocco[END_REF], [START_REF] Elton | Macaques at the margins: the biogeography and extinction of Macaca sylvanus in Europe[END_REF] and [START_REF] Mecozzi | Macaca ulna from new excavations at the Notarchirico Acheulean site (Middle Pleistocene, Venosa, Southern Italy)[END_REF]. The inlay at the bottom of the map shows the English localities in greater detail. Numbers correspond to localities listed in Table 1. The maximum icesheet extension refers to the last glacial.

  fig. 2. Assemblage of fossils and their labels curated in a tray at the Sedgwick Museum of Earth Sciences, Cambridge. Note the slip of paper with identifications by H.E.P.S. (Harold Spencer). a: CAMSM C.13378, mammalian first phalanx; b: CAMSM X.50379, Tapirus upper cheek tooth; c: CAMSM X.50378, Dasychoerus arvernensis m/3 distal portion; d: CAMSM X.50381, cervid upper molar; e-f: CAMSM X.50376 and X 50377, wolffish teeth (Anarhicas lupus); g: CAMSM X.50380, Macaca sp. upper molar (Photo credit -Matt Riley, Sedgwick Museum of Earth Science).

  . Given the scarcity of material, it is preferable to leave it in open nomencature, and to refer to it as Macaca sp.

	Mesopithecus sp.
	fig. 6
	Material: NHMUK PV M9171, left M3/ in light wear.
	Geological context and age: Redeposited into the Red Crag, England, from a pre-existing
	deposit (precise locality unknown). The age is uncertain but possibly Late Miocene or Early
	Pliocene.
	Subfamily Colobinae Blyth, 1863
	Genus Mesopithecus Wagner, 1839

Table 1 .

 1 Late Miocene to Late Pleistocene localities in Europe, the Near East and North Africa that have yielded fossil macaques corresponding to locations in fig. 1. Distribution of fossil macaques in Europe and Northern Africa. Waldringfield is the red star. Data from

	1
	2
	3
	4
	5
	6
	7
	8
	9
	10
	11
	12
	13
	14
	15
	16
	17
	18
	19
	20
	21
	22
	23
	24
	25
	26
	27
	28
	29
	30
	31
	32
	33
	34
	35
	36
	37
	38
	39
	40
	41
	42
	43
	44
	45
	46
	47
	48
	49
	50
	51
	52
	53

ACKNOWLEDGEMENTS

Thanks to Matt Riley at the Sedgwick Museum of Earth Sciences, University of Cambridge, for providing access to the collections, and to Simon Jackson (Ipswich Museum) for alerting us to the presence of Red Crag fossil mammals in the Sedgwick Museum. We thank Eric Delson and Brenda Benefit for literature and comments about fossil macaques. Rachel Ives and Spyridoula Pappa located the colobine fossil in the NHMUK and helped with curatorial information about the Mesopithecus-like tooth from the Red Crag. David Alba and George Konidaris kindly suggested modifications to the paper which have led to its improvement.


Antoine M Dujon
email: antoine.dujon@yahoo.fr

Orsolya Vincze

Jean-François Lemaître

Catherine Lemaître

Pascal Alix-Panabières

Mathieu Pujol

Beata Giraudeau

Frédéric Ujvari

Thomas

Jean-François Lemaitre

Catherine Alix-Panabières

Pascal Pujol

Mathieu Giraudeau

Beata Ujvari

Frédéric Thomas

The effect of placentation type, litter size, lactation and gestation length on cancer risk in mammals

Keywords: Evolution Subject Areas: ecology, evolution, health and disease and epidemiology neoplasm, life history traits, evolution of cancer defences, comparative analysis

scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Cancer is a group of diseases, widespread across the tree of life, in which cells break cellular collaboration and proliferate abnormally [START_REF] Aktipis | Cancer across the tree of life: cooperation and cheating in multicellularity[END_REF][START_REF] Albuquerque | From humans to hydra: patterns of cancer across the tree of life[END_REF]. It is increasingly suggested that oncogenic processes have been influencing the evolutionary ecology of their hosts since the dawn of multi-cellularity, approximately 1 billion years ago [START_REF] Aktipis | Evolutionary foundations for cancer biology[END_REF][START_REF] Thomas | The importance of cancer cells for animal evolutionary ecology[END_REF]. Tumoral cells, especially malignant ones, can be detrimental to the host by directly or indirectly imposing fitness costs on them, reducing for instance their survival and/or their reproductive potential [START_REF] Thomas | The importance of cancer cells for animal evolutionary ecology[END_REF][START_REF] Dujon | Cancer susceptibility as a cost of reproduction and contributor to life history evolution[END_REF][START_REF] Boutry | Tumors (re)shape biotic interactions within ecosystems: experimental evidence from the freshwater cnidarian Hydra[END_REF][START_REF] Russell | Oncogenesis as a selective force: adaptive evolution in the face of a transmissible cancer[END_REF]. These effects have in return promoted the evolution of defence mechanisms in hosts [START_REF] Harris | Evolution of cancer defense mechanisms across species[END_REF], as well as compensatory adaptations [START_REF] Thomas | The evolution of resistance and tolerance as cancer defences[END_REF]. For example, tumour-bearing females in Drosophila melanogaster reproduce earlier compared with healthy ones to buffer the fitness costs of tumours [START_REF] Arnal | Cancer brings forward oviposition in the fly Drosophila melanogaster[END_REF]. In the Tasmanian devils (Sarcophilus harrisii) affected by a lethal transmissible cancer (the devil facial tumour disease), which killed more than 80% of individuals in certain areas since 1996, females are now reproducing earlier in their life, before they are infected and killed by the transmissible cancer cells [START_REF] Jones | Life-history change in diseaseravaged Tasmanian devil populations[END_REF]. In parallel, reproduction, notably the pregnancy process in humans and other mammals, exacerbates the progression of existing tumors in females as the energy gets primarily allocated in reproduction at the expense of anticancer defences, which promotes the evolution of additional defences such as possibly menopause [START_REF] Thomas | Can postfertile life stages evolve as an anticancer mechanism[END_REF]. Like several other biological processes detrimental to health, malignant dynamics can also be embedded in the antagonistic pleiotropy theory [START_REF] Williams | Pleiotropy, natural selection, and the evolution of senescence[END_REF]. For example, in the fish Xiphophorus cortezi, males carrying the Xmrk melanoma-promoting oncogene grow larger body sizes and have higher mating success compared with noncarriers, but at the cost of developing lethal melanoma at an increased frequency later in their life, following reproduction [START_REF] Fernandez | A cancer-causing gene is positively correlated with male aggression in Xiphophorus cortezi[END_REF][START_REF] Fernandez | Mate choice for more melanin as a mechanism to maintain a functional oncogene[END_REF]. Another example are SPANX genes present in primates that are under strong positive selection and are involved both in spermatogenesis and in melanoma progression by promoting cancer cell growth [START_REF] Kleene | Sexual selection, genetic conflict, selfish genes, and the atypical patterns of gene expression in spermatogenic cells[END_REF]. Understanding the evolutionary trade-off between reproduction and oncogenic processes is complex and remains only partially understood, despite its importance in diverse research areas such as population dynamics, conservation biology, epidemiology and public health [START_REF] Dujon | Identifying key questions in the ecology and evolution of cancer[END_REF][START_REF] Dujon | On the need for integrating cancer into the One Health perspective[END_REF].

Reproduction is a costly process, especially for females that allocate substantial amounts of energy and nutrients to support the growth of their offspring [START_REF] Speakman | The physiological costs of reproduction in small mammals[END_REF]. For example, in mammals, as the litter size increases so does the costs of gestation and lactation [START_REF] Speakman | The physiological costs of reproduction in small mammals[END_REF][START_REF] Sikes | Considerations of optimal litter size in mammals[END_REF]. Those high physiological costs could exacerbate the progression of existing tumours but not necessarily to a point at which they would result in an increase mortality risk. Indeed, species are expected to have evolved over evolutionary times anti-cancer defences to at least partially counter those negative effects on their health [START_REF] Dujon | Cancer susceptibility as a cost of reproduction and contributor to life history evolution[END_REF][START_REF] Thomas | Can postfertile life stages evolve as an anticancer mechanism[END_REF]. Placentation is also a key feature of mammalian reproduction. Like metastasis, placentation can be seen as an invasive process that involves the transplantation of cells into new environments [START_REF] Souza | Malignant cancer and invasive placentation: a case for positive pleiotropy between endometrial and malignancy phenotypes[END_REF]. Both invasive placentation and metastasis share common cellular and molecular mechanisms, e.g. angiogenesis, including the degradation of the extra-cellular matrix and expression of specialized adhesion molecules check, or avoidance of the immune system [START_REF] Souza | Malignant cancer and invasive placentation: a case for positive pleiotropy between endometrial and malignancy phenotypes[END_REF][START_REF] Lala | Human placental trophoblast as an in vitro model for tumor progression[END_REF][START_REF] Costanzo | Exploring the links between cancer and placenta development[END_REF][START_REF] Lala | A crossroad between placental and tumor biology: what have we learnt?[END_REF]. Consequently, the existence of mechanistic and evolutionary links between the placentation and cancer metastasis has been suggested [START_REF] Souza | Malignant cancer and invasive placentation: a case for positive pleiotropy between endometrial and malignancy phenotypes[END_REF][START_REF] Lala | Human placental trophoblast as an in vitro model for tumor progression[END_REF]. For instance, it has been proposed that tumours reactivate similar genes and molecular pathways involved in invasive placentation types to increase their own invasiveness [START_REF] Souza | Malignant cancer and invasive placentation: a case for positive pleiotropy between endometrial and malignancy phenotypes[END_REF][START_REF] Lala | Human placental trophoblast as an in vitro model for tumor progression[END_REF]. However, we must distinguish between different types of placentation. Based on the number of tissues separating maternal from fetal blood, placentas are classified as epitheliochorial, endotheliochorial or haemochorial [START_REF] Carter | Comparative aspects of trophoblast development and placentation[END_REF]. Epitheliochorial placentation is considered non-invasive with no penetration of the maternal tissue by fetal cells (e.g. in pangolins, whales and hoofed mammals). Endotheliochorial placentation is considered partially invasive with a uterine epithelium that is eroded, and the trophoblast located next to intact maternal blood vessels (e.g. sloths, elephants). Finally, haemochorial placentation is considered highly invasive, with the trophoblast in direct contact with the maternal blood (e.g. in primates, rodents) [START_REF] Wagner | The coevolution of placentation and cancer[END_REF]. Haemochorial placentation is also considered the ancestral type for placental mammals from which the two others evolved [START_REF] Wildman | Evolution of the mammalian placenta revealed by phylogenetic analysis[END_REF]. In female placental mammals, the possession of invasive trophoblasts and/or reproductive tissues that are more easily invaded by them is likely to promote fertility, as it favours the implantation of the embryo and its ability to extract resources from the maternal body [START_REF] Aktipis | The cheating cell: how evolution helps us understand and treat cancer[END_REF]. However, those attributes can make a more fertile female more vulnerable to metastatic cancers. Therefore, it has been proposed that species with a highly invasive placentation and long gestation periods or maternal care are under increased risk of lethal cancer. This link between placentation and cancer risk has been investigated in a few empirical studies, but their results remain equivocal. Boddy et al. [START_REF] Boddy | Lifetime cancer prevalence and life history traits in mammals[END_REF] used data on 37 mammalian species from the San Diego Zoo and found no difference in cancer prevalence between species with different placentation types but detected a positive relationship between litter size and the risk of cancerrelated mortality. Conversely, D'Souza & Wagner [START_REF] Souza | Malignant cancer and invasive placentation: a case for positive pleiotropy between endometrial and malignancy phenotypes[END_REF] used data from 12 United States and Canadian colleges of veterinary medicine on cows, horses, cats and dogs and showed that species with less invasive placentation have lower rates of metastatic cancer compared with those with invasive ones. While valuable, those studies were performed on data with a relatively limited number of species. Furthermore, these studies did not consider that species with highly invasive placentas should have selected for powerful anti-cancer defences in return, as has been proposed in the Peto paradox with the evolution of large sizes [START_REF] Vincze | Cancer risk across mammals[END_REF]. In this study, we therefore used newly published data on 191 mammal species encompassing species with very diverse life histories and placenta types from zoos around the world [START_REF] Vincze | Cancer risk across mammals[END_REF]. The high quality of this unique dataset allows to decipher the complex links between cancer mortality risk, placentation type, litter size and lactation length.

Methods (a) Data collection

To quantify cancer mortality risk, we extracted the data on mammal species provided as supplementary material by Vincze et al. [START_REF] Vincze | Cancer risk across mammals[END_REF]. The authors of this study used data from Species360 and the Zoological Information Management System (ZIMS), an international non-profit organization that maintains a real-time and centralized database of animals under human care (regrouping information from over 1200 zoos worldwide). They relied on the high probability of body retrieval of deceased zoo animals and post-mortem pathological records, which allows to detect and document cancer-related mortality (although with lower probability in case of liquid tumours, early stage cancers or small, but lethal tumours; see the original publication for details). Cancer is only registered in this database for deceased animals and only if the inspecting veterinary pathologist considered it to be a factor that contributed to the individual's death. Only species in which post-mortem pathological records were available for at least 20 adult individuals, irrespective of the cause of death, were included in their analyses. Vincze et al. also excluded all species that were subject to domestication as well as their wild ancestors, as domestication is widely regarded as a major contributing factor to inbreeding depression and higher risk of developing cancer [START_REF] Thomas | Rare and unique adaptations to cancer in domesticated species: an untapped resource?[END_REF]. In addition, cancer mortality risks provided by Vincze et al. were calculated by pooling both male and female data.

Vincze et al. calculated two measures of cancer risk, namely the cancer mortality risk (CMR) and incidence of cancer mortality (ICM). They estimated the cancer mortality risk as the royalsocietypublishing.org/journal/rspb Proc. R. Soc. B 290: 20230940 ratio between the number of cancer-related deaths and the total number of individuals whose post-mortem pathological records were entered in the database. Incidence of cancer mortality, which is a metric of cancer risk eliminating potential biases due to disregarding left-truncation (that is, cancer before individuals enter the study) and right-censoring (individuals alive, thus with unknown fate at data extraction), was computed using a Kaplan-Meier estimator (see [START_REF] Vincze | Cancer risk across mammals[END_REF] for full details on the calculation of this metric). Finally, Vincze et al. considered species to have cancer if at least one individual with post-mortem pathological record was diagnosed with cancer, a classification we used in our study too.

As classically done, we classified the placentation type of each mammalian species (n = 191) into three categories based on their invasiveness (see Introduction and [START_REF] Grosser | Frühentwicklung, eihautbildung und placentation des Menschen und der säugetiere[END_REF][START_REF] Elliot | Placental invasiveness and brain-body allometry in eutherian mammals[END_REF][START_REF] Dudley | Uterine cellular changes during mammalian pregnancy and the evolution of placentation[END_REF]): epitheliochorial placentation (n = 84), endotheliochorial placentation (n = 64) and haemochorial placentation (n = 43).

We obtained data on average litter size (number of offspring, n = 187), gestation length (in days, n = 187) and lactation length (in days, n = 137) from the PanTHERIA [START_REF] Jones | PanTHERIA: a species-level database of life history, ecology, and geography of extant and recently extinct mammals[END_REF], Animal Diversity Web (https://animaldiversity.org/), and Animal Ageing and Longevity databases (https://genomics.senescence.info/) [START_REF] Tacutu | Human ageing genomic resources: integrated databases and tools for the biology and genetics of ageing[END_REF].

Vincze et al. showed that a diet of primarily vertebrate by mammals increased their cancer mortality risk and thus should be considered as a potential confounding variable. Here we consider that diet is part of the cancer risk landscape of animals in which multiple risk factors increase the probability of developing cancer during their lifetime (see [START_REF] Dujon | Cancer risk landscapes: a framework to study cancer in ecosystems[END_REF]). We therefore re-used Vincze et al.'s classification, in which each mammal species is binary classified as primary eating vertebrate or not, as initially proposed by Kissling et al. [START_REF] Kissling | Establishing macroecological trait datasets: digitalization, extrapolation, and validation of diet preferences in terrestrial mammals worldwide[END_REF] (n = 190). Missing information on diet for one species, the Californian sea lion (Zalophus californianus, classified as primarily eating vertebrates and in which cancer was detected [START_REF] Weise | Temporal variability in ocean climate and California sea lion diet and biomass consumption: implications for fisheries management[END_REF]), was manually added to the dataset.

(b) Phylogenetic analyses

We used phylogenetic generalized least-squares (PGLS) regressions to quantify the effect of the placentation type, litter size, gestation length, lactation length and diet on the cancer mortality of mammal species following a two-step protocol (first using binary PGLS then continuous PGLS). We first investigated the potential effect of those risk factors on the probability of detecting cancer in mammal species and then quantified their effect on the cancer mortality risk in a species. Here we used binary PGLS models in order to investigate whether cancer was more likely to be detected in species with a more invasive placentation, longer gestation length, longer lactation length or larger litter size. Because of the high cost of reproduction, we hypothesize those variables will be positively associated with cancer risk. Vincze et al. [START_REF] Vincze | Cancer risk across mammals[END_REF] showed that the probability of detecting cancer in a species depended of the number of animals with a pathological record (i.e. the sample size) and observed a non-significant trend in the body size or lifetime expectancy. Peto's paradox predicts that cancer risk does not scale with body size because species evolved anti-cancer defences to reduce the risk of developing malignancies when the number of cells is large. Because of senescence, lifetime expectancy is predicted to be positively associated with cancer risk, especially in zoos in which it is extended [START_REF] Vincze | Cancer risk across mammals[END_REF][START_REF] Peto | Cancer and ageing in mice and men[END_REF]. We ensured those two last variables had no effect on the probability of detecting cancer by including them in our analyses and model selection procedures.

To quantify the effect of the various risk factors on the probability of detecting cancer, we applied a purposeful selection of covariates to build parsimonious risk factors models. This approach retains confounders at a larger rate than other selection procedures when the response variable is binary (see [START_REF] Bursac | Purposeful selection of variables in logistic regression[END_REF]). We therefore started by fitting univariate binary PGLS models, using each potential risk factor in separate models on species in which cancer was detected (n = 144 species). Then risk factors with significant effect sizes in univariate models were combined into a multivariate binary PGLS to quantify their simultaneous effect on the cancer mortality risk of mammals. When needed we also tested for potential two-way interactions between placentation types and other life-history traits.

To investigate the effect of risk factors on the CMR and ICM of mammals, we applied the model selection protocol from Zuur et al. [START_REF] Zuur | Mixed effects models and extensions in ecology with R[END_REF]. We started by fitting a univariate PGLS model using either CMR or ICM as response variable for each potential risk factor (using a restricted maximum-likelihood estimator, REML). The risk factors with a significant trend were then combined into a series of multivariate PGLS models (using a maximum-likelihood estimator, ML), and the performance of those models were compared using the Akaike's information criterion (AIC), ΔAIC and AIC weights [START_REF] Symonds | A brief guide to model selection, multimodel inference and model averaging in behavioural ecology using Akaike's information criterion[END_REF]. Once the best model was identified (lowest AIC, highest AIC weight), we refitted it using a REML estimator to interpret effect sizes.

To account for the lack of independence between species, we re-used the phylogenetic tree from Vincze et al. [START_REF] Vincze | Cancer risk across mammals[END_REF] in all the models we fitted in this study. This tree was created by obtaining a rooted consensus from a sample of 1000, equally plausible phylogenetic trees published by Upham et al. [START_REF] Upham | Inferring the mammal tree: species-level sets of phylogenies for questions in ecology, evolution, and conservation[END_REF]. Since the precision of the cancer mortality estimates is affected by the sample size used to compute them, we included the log of the number of animals with a necropsy record available as an explanatory variable in the binary PGLS, and also used that number to weight each species in univariate and multivariable continuous PGLS. In addition, we logit transformed cancer mortality values prior to fitting models, to ensure model residual normality and homogeneity of variance (on the link-function) [START_REF] Warton | The arcsine is asinine: the analysis of proportions in ecology[END_REF]. When required we computed the models' marginal effects to visualize how a variable affected the cancer mortality of mammals [START_REF] Mize | A general framework for comparing predictions and marginal effects across models[END_REF].

All analyses were performed using R [START_REF] Core | R: a language and environment for statistical computing[END_REF] (v. 4.0.2). Phylogenetic analyses were computed using the 'nlme' and 'ape' packages [START_REF] Paradis | Ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R[END_REF][START_REF] Pinheiro | nlme: Linear and Nonlinear Mixed Effects Models[END_REF].

Results

(a) Probability of detecting cancer in mammal species

Cancer was detected in 144 out of 191 species. As previously observed, the number of animal necropsies (mean: 62.0 ± 54.7 s.d. individuals, range: 20-413, n = 191 species) was the primary driver of the probability of detecting cancer in mammal species (binary PGLS p < 0.001, figure 1). We found no significant differences in the probability of detecting cancer between the three different placentation types (n = 191 species, binary PGLS, p > 0.05, figure 1a). Based on model selection approach, gestation length (mean: 160.5 ± 88.6 s.d. days, range: 16.7-455.3, n = 187 species), body mass (mean: 74.3 ± 159.6 s.d. kg, range: 0.02-1499.5, n = 191 species), life expectancy (mean: 3664.4 ± 1814.2 s.d. days, range: 402.2-11 385.0, n = 191 species), and the consumption of vertebrates (n = 191 species) had no effect on the probability of detecting at least one cancer-related death (binary PGLS, p > 0.05, see electronic supplementary material for detailed results for the model selection approach). However, cancer mortality was more likely to be detected in species with large litter sizes (β = 1.12 ± 0.44 s.e., mean litter size: 1.9 ± 1.4 s.d., range: 0.9-11.3, n = 187, figure 1b) and species with a longer lactation length (β = 0.0071 ± 0.0022 s.e., mean lactation length: 183.8 ± 213.1 s.d., range: 5.0-1670.5, n = 136, figure 1c). Cancer mortality was detected in nearly all mammal species with a litter size of at least six offspring or a lactation length superior to 1000 days (a royalsocietypublishing.org/journal/rspb Proc. R. Soc. B 290: 20230940 length that decreased as the number of animals necropsied for a given species increased, figure 1). We found no significant interaction terms between placentation type and litter size or lactation length in the models we tested (binary PGLS, p > 0.05, see electronic supplementary material S1).

(b) Cancer mortality risk in mammal species

Based on the model selection approach, gestation length, body mass, life expectancy, litter size and lactation length had no significant effect on cancer mortality risk of mammals (based on univariate continuous PGLS model, p > 0.05, electronic supplementary material S2). The placentation type was the only variable retained in the model and we found that species with an endothelial placentation had a significantly higher CMR compared with species with epitheliochorial (twice as large) and haemochorial placentation, (half larger) which are not significantly different from each other (figure 2). One species had an unusually large cancer mortality risk (the kowari, Dasyuroides byrnie, cancer mortality = 57%) and was therefore excluded from the models. Removing that species from the dataset had little effect on the results and the effect of placentation remained significant (see electronic supplementary material S2). Similarly, based on the model selection, we found a significant interaction between diet and placentation type, with endotheliochorial and haemochorial species eating vertebrates being more at risk of dying of cancer compared with epitheliochorial species (continuous PGLS, p < 0.05, see electronic supplementary material S2).

(c) Incidence mortality risk in mammal species

We found that mammals with an endothelial placentation had the highest ICM, on average 1.9 times larger compared with 3). Like the CMR, including or excluding the kowari from the analyses had little effect on the results. We found no strong evidence that the other risk factors we tested affected the ICM of mammal species (see electronic supplementary material S3).

Discussion

Mammals with large litter sizes and long lactation lengths had a higher probability to have at least one cancer-related death registered irrespective of the type of their placentation. These results suggest that species whose allocation per reproductive episode is high, may, all else being equal, have a lower ability to prevent and/or eliminate oncogenic processes leading to the formation of tumours [START_REF] Thomas | Can postfertile life stages evolve as an anticancer mechanism[END_REF]. Reproduction is one of the most energetically demanding life-history stages, with the lactation length being typically more costly than gestation itself [START_REF] Clutton-Brock | Fitness costs of gestation and lactation in wild mammals[END_REF]. Therefore, breeding individuals are expected to experience trade-offs, where energy is diverted away from self-maintenance (cell repair, immune function) towards reproduction, favouring the development of tumours [START_REF] Dujon | Cancer susceptibility as a cost of reproduction and contributor to life history evolution[END_REF][START_REF] Thomas | Can postfertile life stages evolve as an anticancer mechanism[END_REF]. However, the effect on the fitness may be small, as the cancer mortality risk of species did not scale with litter size and lactation length. It is likely that those oncogenic processes do not systematically impact the survival, or other fitness-related parameters in their hosts (see for instance [START_REF] Folkman | Cancer without disease[END_REF]). Our results thus support the hypothesis that cancer defence mechanisms in animals are most often adjusted to align reproductive lifespan with the mortality pattern of ageing individuals (see also [START_REF] Thomas | Can postfertile life stages evolve as an anticancer mechanism[END_REF][START_REF] Boutry | Ecological and evolutionary consequences of anticancer adaptations[END_REF]). Our results are consistent with Boddy et al.'s [START_REF] Boddy | Lifetime cancer prevalence and life history traits in mammals[END_REF], which detected a positive association between litter size and cancer prevalence. They, however, found no evidence for an association between placental depth and malignancy prevalence as we observed in our study. The present analysis covers 191 species (n = 11 840 animals with pathological records), 144 in which cancer was observed (n = 9769 animals with pathological records) compared with 37 species and a total of 800 individuals in Boddy et al.'s study. Compared with the latter, our study relies on a wider taxonomic range and larger number of individuals for each species, thus offering a more reliable estimation of the role of reproduction in oncogenesis. Moreover, the trend observed by Boddy et al. could have been biased by the inclusion of some species in their study with a relatively high cancer prevalence, but unreliably small sample size (e.g. the prairie dog Cynomys ludovicianus, the Tasmanian devil Sarcophilus harrisii or the Virginia opossum Didelphis virginiana). Our results confirm the general trends observed in the two studies. The incidence of cancer mortality was the highest in mammals with an endothelial placentation compared with the two other placentation types (a pattern also observed at least partially in the cancer mortality risk data with endothelial placentation having higher cancer mortality risk compared with the two other types). Thus, contrary to what might have been predicted, the risk of developing metastatic cancer is not highest in species with the most invasive placentas. royalsocietypublishing.org/journal/rspb Proc. R. Soc. B 290: 20230940

The risk of dying from cancer was also decreased with longer gestation length for all three placentation types, suggesting a protective role of long gestation length. We argue here that a likely explanation for these apparently paradoxical results is the same as that of Peto's paradox for size [START_REF] Vincze | Cancer risk across mammals[END_REF], namely that the species most at risk of cancer death, here because of a high cellular invasive potential, are also those that have developed the strongest anti-cancer defences to counteract this vulnerability. Thus, our results are on average consistent with the hypothesis that malignant cells activate the same molecular and physiological pathways used during placenta formation to become more invasive (see for instance [START_REF] Souza | Malignant cancer and invasive placentation: a case for positive pleiotropy between endometrial and malignancy phenotypes[END_REF][START_REF] Costanzo | Exploring the links between cancer and placenta development[END_REF][START_REF] Lala | A crossroad between placental and tumor biology: what have we learnt?[END_REF][START_REF] Wagner | The coevolution of placentation and cancer[END_REF]), but that only species that have developed strong anti-cancer defences have been able to maintain over evolutionary times haemochorial placentas. Endotheliochorial placentation evolved from the more invasive haemochorial placentation at least twice in the evolutionary history of mammals [START_REF] Wildman | Evolution of the mammalian placenta revealed by phylogenetic analysis[END_REF]. It has been suggested that the evolution of less invasive placentation is an adaptation that reduces the risk of female offspring conflict during gestation [START_REF] Garratt | Diversification of the eutherian placenta is associated with changes in the pace of life[END_REF]. In the light of our results, we argue here that the risk of developing early lethal cancers may also have acted as a selective force favouring a transition to endotheliochoroid placentation, when selection for potent anti-cancer defences was not possible.

Collecting lifelong cancer data on wildlife species remains a difficult task and a key challenge. This is especially important as wildlife species is increasingly exposed to a range cancer risk factors directly linked to human activities [START_REF] Dujon | Cancer risk landscapes: a framework to study cancer in ecosystems[END_REF][START_REF] Giraudeau | Human activities might influence oncogenic processes in wild animal populations[END_REF]. The dataset used in this study, while relatively large compared with previous studies (e.g. [START_REF] Boddy | Lifetime cancer prevalence and life history traits in mammals[END_REF]) has some limitations. For instance, female and male data are pooled. Similarly, the CMR and ICM values are calculated based by aggregating data collected on different tumour types and we cannot completely exclude the presence of biases which cannot be tested using Vincze et al.'s data [START_REF] Vincze | Cancer risk across mammals[END_REF]. Differential vulnerability between cancer types has been well documented in humans [START_REF] Rubin | Sex differences in cancer mechanisms[END_REF][START_REF] Sung | Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[END_REF] but global data are lacking for most mammalian species. A possible consequence of including males in our study is an underestimation of the cancer risk associated with different placentation types across mammals. Said differently, including only female data would be likely to lead to a larger effect size than we have quantified. As the size of the datasets collected on zoo animals steadily increases, we encourage scientists to revisit our study to account of those potential biases. In addition, the data we used in this study are limited to species kept in captivity and for which there are enough available data in the Species 360 database. Certain very large species with a long lifespan such as whales or elephants were not included in our analysis. Thus, cautiousness should be applied when translating the findings to wildlife species [START_REF] Hamede | The ecology and evolution of wildlife cancers: applications for management and conservation[END_REF].

In conclusion, our study highlights the value of collecting data on a relatively large number of species to test key eco-evolutionary hypotheses related to cancer. This type of approaches will improve our understanding of how trade-off shaped anti-cancer defences and potentially to design strategies to mitigate the negative effects of cancer on species, ecosystems and human populations. Finally, this work also confirms that the logic behind the Peto's paradox can probably be applied to other traits that increase the risk of cancer mortality.

Figure 1 .

 1 Figure 1. (a) Effect of the placentation type and the number of necropsied animals on the probability of detecting cancer mortality in mammal species. The differences between placentation types are not statistically significant. (b) Effect of the litter size or (c) the lactation length and the number of animals with available post-mortem pathological record on the probability of detecting cancer in mammal species. For a given number of necropsied animals, the probability of detecting cancer significantly increases with litter size and weaning age. The vertical grey line indicates a litter size of six in (b) and a lactation length of 1000 days in (c).

Figure 2 .

 2 Figure 2. Cancer mortality risk of mammals in function of their placentation type and their diet. p-values were obtained by comparing the average cancer mortality risk for the relevant groups using PGLS models for each subset of the data. Placentation types are sorted from least to most invasive. The kowari, Dasyuroides byrnie, an outlier, was excluded from this plot.

Downloaded from https://royalsocietypublishing.org/ on 16 February 2024

Data accessibility. Data used for this paper are provided as electronic supplementary material [START_REF] Dujon | The effect of placentation type, litter size, lactation and gestation length on cancer risk in mammals[END_REF].

Authors' contributions. A.M.D.: conceptualization, data curation, formal analysis, investigation, methodology, software, validation, visualization, writing-original draft, writing-review and editing; O.V.: data curation, validation, writing-original draft, writing-review and editing; J.-F.L.: methodology, validation, writing-original draft, writing-review and editing; C.A.-P.: validation, writingreview and editing; P.P.: validation, writing-review and editing; M.G.: writing-review and editing; B.U.: funding acquisition, project administration, resources, writing-review and editing; F.T.: conceptualization, funding acquisition, project administration, resources, supervision, validation, writing-original draft, writing-review and editing.

All authors gave final approval for publication and agreed to be held accountable for the work performed therein.

Conflict of interest declaration. We declare we have no competing interests.


Julien Pigeon

Bassem A Hassan
email: bassem.hassan@icm-institute.org

Timing neurogenesis: a clock or an algorithm?

Emerging evidence supports the existence of dedicated molecular mechanisms under evolutionary selection to control time during neurogenesis. Here, we briefly review these mechanisms and discuss a potentially useful conceptual framework inspired by Computer Science to think about how these biological mechanisms operate during brain development and evolution.

Main text

In a fundamental sense, time represents the continuous progression of existence and events. It unfolds moment by moment and permits a structured chronology where events occur in a specific sequence, not randomly or all at once. This framework allows events to be ordered from the past through the present into the future, which in turn helps us understand causal chains where causes precede effects.

In developmental biology, the concept of time is closely intertwined with the pace of embryonic development. This connection can be viewed in at least two ways: the specific sequence of events that occur in a particular chronological order as well as the total amount of time this sequence occupies. Both of these dimensions are found in one of the most studied and evolutionarily conserved biological mechanisms, neurogenesis, the generation of neurons from neural progenitor cells (NPCs). Not only are different neuronal subtypes generated at different time points in a specific order, but the total amount of time dedicated to neurogenesis is itself a species-feature of brain development. Intriguingly, while the sequential stages of brain development share ancestral blueprints, the temporal dynamics can diverge considerably among species. The human brain, for example, undergoes a particularly extended period of neurogenesis compared to rodents and even other primates, allowing for a disproportional increase in the number of neurons, especially in the cerebral neocortex [START_REF] Rakic | Evolution of the neocortex: Perspective from developmental biology[END_REF], [START_REF] Vanderhaeghen | Developmental mechanisms underlying the evolution of human cortical circuits[END_REF]. Thus, there is a correlation between differences in timing and brain size, presumably intimately linked to differences in cognitive capabilities. This review will discuss the temporal dynamics of neurogenesis and the factors that drive neural progenitor cells (NPCs) to their transition into post-mitotic neurons. We will explore a conceptual framework for understanding how and why changes in timing arose during evolution and what this framework predicts as possible future experimental avenues.



Time in cell state transitions and its control through intrinsic and extrinsic cues

Classical analyses using immunohistochemistry and, more recently, single-cell transcriptomics have revealed that distinct cellular states are associated with specific gene expression patterns. Therefore, the acquisition of a specific cellular identity requires a remodeling of these gene regulatory networks (GRNs) that underlie cell state-specific expression patterns. Studies across species and neural tissue types, from fruit flies to human in vitro models, have shown that the commitment of a NPC to neurogenesis is influenced by internal and external cellular cues that act on its GRN to determine whether it will continue to self-renew as a progenitor or differentiate into a neuron. One of the causal molecular mechanisms of this dynamic equilibrium between the progenitor and neuron states is mediated by feedback regulation between the Notch signaling pathway and a class of basic Helix-Loop-Helix (bHLH) transcription factors called proneural proteins [START_REF] Bertrand | Proneural genes and the specification of neural cell types[END_REF]. When the proneural protein is maintained and stabilized in a NPC, it will overcome the antidifferentiation signal of the Notch pathway and promote neurogenesis ([3]- [START_REF] Guillemot | Beyond proneural: emerging functions and regulations of proneural proteins[END_REF]). Additionally, in the local environment of these NPCs, many secreted morphogens by specific brain regions and the NPCs themselves with their neuronal progeny will weigh on this balance. For example, WNT, FGF, and Shh, play a significant role in maintaining progenitors' selfrenewal through different processes to repress proneural genes (reviewed in [START_REF] Tiberi | Cortical neurogenesis and morphogens: diversity of cues, sources and functions[END_REF]). In other words, controlling the temporal dynamics of the expression and activity of transcription factors by intrinsic and extrinsic cues can significantly impact the timing of the switch from progenitor self-renewal to differentiation and, thus, the time available for neurogenesis. There is also evidence that more stable or longer-lived proneural proteins correlate with [START_REF] Zhang | Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum[END_REF] and can cause [11*] an increase in neuronal production.

Emerging evidence also causally implicates mitochondrial metabolism in the NPC-neuron fate decision [START_REF] Iwata | Mitochondria metabolism sets the species-specific tempo of neuronal development[END_REF]. Whether this is mechanistically linked to changes in transcription factor activity or stability remains unclear. Interestingly, however, stem cell programming into neurons by Neurogenin2 overexpression results in large-scale remodeling of cellular organelles and proteomes, suggesting that a link may also exist during normal neurogenesis the operant mechanisms discovered so far are highly conserved across eukaryotes. Although mitochondrial homeostasis and metabolism or protein turnover seem to be slower in humans than in mice, for example, there is no evidence that the highly conserved enzymes that carry out these reactions have intrinsically slower substrate processing rates. Finally, given that all these mechanisms appear to converge on the activity of transcription factors that are also themselves highly conserved, the conundrum seems even more perplexing. One way to think about the problem from a broader perspective is to shift from a mechanistic view to a theoretical view in order to provide a general framework into which the currently understood mechanisms would fit. This would guide future hypotheses that could be tested with mechanistic approaches. What might such a theoretical framework look like?

Time from Computer Science to Biology

Perhaps our human conception of time as something to be measured with clocks misleads our understanding of developmental time. In Computer Science, time is a measure of computational complexity. It describes the number of elementary operations an algorithm uses to process a set of input data. Interestingly, this measurement, known as time complexity, characterizes how the execution time of an algorithm increases as a function of the size of the input. The larger the input data set, the longer an algorithm will take to complete its processing.

To translate this concept to biology, one needs to begin by defining what constitutes an algorithm and what constitutes the source of data. We propose that an operationally useful way of thinking about this is to consider the sum of all cellular biological reactions as the algorithm. After all, during development, various proteins literally "process" input in the shape of other biomolecules or metabolites to produce a cell state transition as a phenotypic output. More importantly, the genome is the only source of biological data for which we have evidence supporting a causal role in generating evolutionary change. As we have argued above, and as decades of molecular genetic mechanistic studies have shown, the biochemistry of fundamental cellular processes, that is to say, the algorithm in this metaphor, is highly conserved. What is changing is the data in the shape of evolutionary innovations in the content of genomic information. A particularly striking example in the context of neurogenesis and neuronal differentiation comes from the transplantation of human cortical pyramidal neurons into the neonatal mouse brain, which develops much faster than the human brain. What these studies show is that the maturation of the human neurons in the mouse brain takes up to a year [START_REF] Espuny-Camacho | Pyramidal Neurons Derived from Human Pluripotent Stem Cells Integrate Efficiently into Mouse Brain Circuits In Vivo[END_REF], [START_REF] Linaro | Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits[END_REF] suggesting that the mechanisms underlying the developmental timing are cell intrinsic and encoded by the human genome. A last important angle to consider is the processing modality of the cellular algorithm. Most, if not all, cellular interaction networks are partially promiscuous. This is referred to as "many-to-many" interaction networks, and they are very prevalent in ligand-receptor and transcription factor dimerization networks, for example, including for key neurogenesis pathways such as WNT, Notch and the proneural proteins. It has recently been argued that such networks are both more robust and have greater computational power [16*] than highly specific, one-to-one interaction networks, likely explaining why they have been favored by evolution. Furthermore, just like for an algorithm, several biological processes run in parallel but converge on a terminal step that induces the transition to the next state, such as proneural protein levels and activity in NPCs (see next paragraph). This terminal step acts as a coincidence detecting gatekeeper ensuring that different aspects of cellular metabolism are all compatible with the impeding state transition.

In summary, a potentially helpful way to think about how the temporal dynamics of biological processes operate is to assume that a highly conserved algorithm of flexible biochemical interactions processes a variable amount of data encoded by the genome. In this conception, the differences in developmental timing would arise principally from differences in the amount of information encoded by the genome.



Sources of differences in the amount of genomic information

One important source of increase in genomic information during evolution is gene duplication, a major evolutionary driving force [START_REF] Ohno | Gene duplication and the uniqueness of vertebrate genomes circa 1970-1999[END_REF]. Interestingly, in Drosophila, where proneural genes were discovered, there are 58 bHLH genes whereas there are 39 in C. elegans and 125 in humans [START_REF] Simionato | Origin and diversification of the basic helix-loop-helix gene family in metazoans: insights from comparative genomics[END_REF], [START_REF] Baker | All in the family: proneural bHLH genes and neuronal diversity[END_REF]. Moreover, these transcription factors induce the expression of Notch ligands such as Delta and Serrate in flies. Here again, we observe an evolutionary change in the number of proteins. In flies, there are two ligands of Notch, Delta and Serrate, while in vertebrates there are 5 known ligands: Delta like DLL1, DLL3, DLL4 and the Jagged family composed of Jagged1 and Jagged2. In addition, the number of Notch receptors has been multiplied. In flies, there is a single Notch receptor, while in humans, there are 4 (Notch1-4) [START_REF] Pierfelice | Notch in the Vertebrate Nervous System: An Old Dog with New Tricks[END_REF]. These ligands and receptors are expressed in complex overlapping spatiotemporal patterns. Altogether, these duplications of many genes multiply the possible interactions between ligands and receptors. The increased complexity in these ligand-receptor interactions carrying both activation and inhibition signals can create delays in signal interpretation into a specific pattern of effector activation [START_REF] Kuintzle | Diversity in Notch ligand-receptor signaling interactions[END_REF]. Furthermore, different ligands can transmit opposing patenting information [START_REF] Nandagopal | Dynamic Ligand Discrimination in the Notch Signaling Pathway[END_REF] and thus their co-expression would also require more time for that information to be resolved into a fate decision. Finally, many molecular interactions, especially ligand-receptor interactions and gene activation by proneural proteins, are quantitative in that they depend on the absolute amount of active protein. Because levels of any biomolecule at any time are subject to variation due to both stochastic and random noise, the greater the number of proteins in an interaction network, the more noise in the network and, thus, the longer it may take for efficient signal transmission [START_REF] Ladbury | Noise in cellular signaling pathways: causes and effects[END_REF]. Having a single Notch receptor and a single ligand makes the signal transmission direct.

As discussed above, gene duplication in humans appears to have been taken to a new level with entire families of rapidly evolving genes dedicated to the attenuation of neurogenic signals, as in the example of Noch2NL [24**].

Other potential sources of increase in information are gene regulatory elements, notably highly conserved enhancer/repressor sequences that have been subject to variation only in the human lineage called Human Accelerated Regions (HARs). Interestingly, more than half of these regions tested in vitro displayed enhancer activity, specifically in NPCs [START_REF] Whalen | Machine learning dissection of human accelerated regions in primate neurodevelopment[END_REF]- [START_REF] Girskis | Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions[END_REF] such as HAR5 that enhances WNT signaling through FZD8 to promote NPCs self-renewal [START_REF] Boyd | Human-Chimpanzee Differences in a FZD8 Enhancer Alter Cell-Cycle Dynamics in the Developing Neocortex[END_REF].

Another source of quantitative regulation of protein levels is post-transcriptional control by noncoding RNAs, considered as another driver of brain evolution. They represent 10 to 15% of the human genome [START_REF] Geschwind | Cortical Evolution: Judge the Brain by Its Cover[END_REF]. There is almost twice the number of miRNAs in humans than in mice and six times that in Drosophila [START_REF] Berezikov | Evolution of microRNA diversity and regulation in animals[END_REF]. For example, the miR-2115, a great ape-specific miRNA, promotes NPCs proliferation by targeting the ancient gene ORC4 mutations which cause the Meier-Gorlin microcephalic syndrome [31*], [START_REF] Guernsey | Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome[END_REF]. Furthermore, a primate lncRNA mediates Notch signaling during neuronal development by sequestering miRNA, promoting NPCs self-renewal [START_REF] Rani | A Primate lncRNA Mediates Notch Signaling during Neuronal Development by Sequestering miRNA[END_REF]. The increase in the number of quantitative post-transcriptional inhibitors of neurogenic proteins would be expected to delay the accumulation of these proteins to functional levels and thus delay cell state transitions that depend on these proteins.

In summary, the combination of gene duplication and increase in the number of regulators increases both the total amount of information the cellular algorithm must processes as well as the amount of noise in this information. The combined effect is to lengthen processing time and thus delay the time interval of cell state transitions during neurogenesis.

 Time, robustness, and size

Why would natural selection have favored these temporal delays over evolutionary time, in the primate and specifically human lineage for example? Needless to say, evolution does not have a plan to produce humans. It must, therefore, be that such a delay in neurogenesis confers a selective advantage for the fitness of the organism. One argument for which there is both experimental and theoretical evidence is that the increase in the number of genes, the promiscuity of protein interactions, and the stochastic noise in molecular processes all confer greater robustness on cell state transitions and developmental patterning [16*], [START_REF] Ladbury | Noise in cellular signaling pathways: causes and effects[END_REF] in this scenario, the principal selection pressure is on robustness and the increase in neurogenic time is an unintended but inevitable consequence; an exaptation [START_REF] Gould | Exaptation-A Missing Term in the Science of Form[END_REF] in the "Gouldian" sense, rather than an adaptation. However, it can also be argued that increasing the amount of time a neural progenitor remains in a progenitor state increases the number of neurons it can generate, and this, in turn, results in increasing the brain's adaptative cognitive capabilities. In this scenario, the random accident of gene duplication, for example, gave rise to time delay, which gave rise to an increase in brain size with increased cognitive capabilities, and it is this that confers the selective advantage [START_REF] Boddy | Evidence of a Conserved Molecular Response to Selection for Increased Brain Size in Primates[END_REF]. The truth most probably is that both views are correct. Exaptation and adaptation are synergetic, and both processes can be seen at work at organismal, cellular, and subcellular levels in evolutionary history [START_REF] Frenkel-Pinter | Adaptation and Exaptation: From Small Molecules to Feathers[END_REF].

Conclusion

In this review, we hypothesized that the amount, rather than the type, of information encoded by the genome controls developmental time, with a focus on neurogenesis and its mechanisms as an example. Using a concept borrowed from computer science, we suggest that fundamental cellular metabolism, the type of information in this metaphor, constitutes a conserved algorithm that processes information at a conserved pace. In contrast, the total amount of molecules and their interactions constitute the data that this algorithm must process, and the amount of this data dictates the time necessary for a developmental process like neurogenesis to be completed. The emerging evidence that conserved processes and genes can have different effects on neurogenesis in different species [8**], [9**] by altering time is testament to the key importance of temporal regulation in brain evolution. If the genomic changes that drive brain evolution have the main effect of altering developmental time, it can be reasonably argued that temporal patterning is the main feature of the genetic code, and it is related to the total amount of "data" encoded by the genome. To test this idea, future experiments and modeling efforts should be directed towards greater accuracy in the measurement of time in molecular processes at high resolution during cell state transitions and deciphering the causal effects of quantitative changes in protein levels on the timing, size and complexity of neurogenic processes.

[

  13*]. Overall, these examples support the view that the temporal dynamics of neurogenesis is controlled mainly by cell-intrinsic mechanisms that appear to converge on regulating the expression and activity levels of transcription factors and that these mechanisms operate on different time scales in different species. However, this only pushes the question from why the phenotypes (i.e. neurogenesis) emerge on different time scales to why the intrinsic cellular mechanisms operate on different time scales. This question is particularly intriguing because

Acknowledgments:

We thank members of the Hassan team for stimulating discussions. Work relevant to this review has been funded by the Paris Brain Institute-ICM core funding, the Agence Nationale de la Recherche (ANR, 21-CE13-0041-01), Fondation Neuro Glia (2003009NA), Fondation France Alzheimer (2112002NA) and the Roger De Spoelberch Prize.

Author contributions: J.P. and B.A.H conceived of and wrote the manuscript. J.P. came up with the idea of comparing biological processes to an algorithm.

Competing interest:

The authors declare no competing interests.



Bibliography: