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DNA preserved in ice. DNA molecule strand in transparent glass, ice container. DNA storage. Frozen DNA. 3d render illustration.
π Science and technology

Fossil DNA: on the trail of human evolution

Jean-Louis Mergny
Jean-Louis Mergny
Inserm Research Director and Head of the Biology Department at IP Paris
Key takeaways
  • Since the discovery of 2% of Neanderthal genes in the Eurasian genome, science has been studying the extinction of Neanderthals and the survival of Homo sapiens.
  • Palaeogenomics allows us to observe the evolution of humanity through the genetic information of our distant ancestors.
  • Our genetic heritage bears the traces of ‘selection pressures’ (climate, predation, sexual selection, or pandemics) that have shaped our species.
  • Study of the DNA structure of Homo neanderthalensis explains its extinction by a selective disadvantage in the face of the ‘superiority’ of Homo sapiens.
  • Palaeogenomics is fraught with difficulties, notably the conservation of ancient DNA and insufficient or missing documentation.

At the end of 2016, the news hit the head­lines. Eurasians car­ry around 2% of the genes of Nean­derthals, who dis­ap­peared around 40,000 years ago. This dis­cov­ery, which was award­ed the Nobel Prize in 2022, sheds light on the links between this species and our own and even sug­gests that they may have inter­bred on sev­er­al occa­sions. Since then, new avenues have been opened up to under­stand the caus­es of Nean­derthal extinc­tion, as well as the fac­tors that favoured the sur­vival and sub­se­quent expan­sion of Homo sapi­ens in the his­to­ry of human evolution.

Ancient (or fos­sil) DNA is the key to access­ing the genet­ic infor­ma­tion of our ances­tors. This tool is used by palaeoge­nomics, a dis­ci­pline that com­bines DNA sequenc­ing tech­niques with the analy­sis of ancient bio­log­i­cal remains. By extract­ing and deci­pher­ing the DNA pre­served in bones, teeth, hair, seeds and wood, sci­en­tists can access the genet­ic infor­ma­tion of species, includ­ing that of our dis­tant ancestors.

Ancient DNA: at the roots of the evolutionary tree

One of the first to suc­ceed in ‘read­ing’ a fos­sil DNA sequence was biol­o­gist Allan Wil­son, who in the mid-1980s sequenced DNA from a quag­ga, a zebra-like equine that had been extinct since the 19th Cen­tu­ry. Biol­o­gist Svante Pääbo then went fur­ther back in time by sequenc­ing pre­served DNA from an Egypt­ian mum­my. “Even though the DNA mol­e­cule is chem­i­cal­ly more sta­ble than RNA, its con­ser­va­tion over sev­er­al mil­len­nia remained hypo­thet­i­cal. It was only after sev­er­al decades of effort that we realised we could work on such ancient DNA”, explains Jean-Louis Mergny, Inserm research direc­tor and head of the biol­o­gy depart­ment at Insti­tut Poly­tech­nique de Paris. Since then, the Swede’s work was reward­ed with a Nobel Prize in Med­i­cine (2022) and palaeoge­nomics is mak­ing giant strides. Jean-Louis Mergny empha­sis­es that the emer­gence of this dis­ci­pline “is a sci­en­tif­ic rev­o­lu­tion that enables us to go back in time to remote periods”.

This bio­chemist who is “fas­ci­nat­ed by the unusu­al con­for­ma­tions and odd­i­ties of DNA” devel­oped a pas­sion for ancient DNA “after read­ing books on Nean­derthals dur­ing lock­down and suc­ces­sive vis­its to the Musée de l’Homme”. As such, he ini­ti­at­ed a research project to look for unusu­al struc­tures in ancient genomes, first on a virus12, then on extinct human species.

The work that inspired the Juras­sic Park saga was wrong; insect DNA is not pre­served in amber.

The researcher has focused in par­tic­u­lar on Denisov­ian and Nean­derthal pop­u­la­tions, two species for which the data (DNA libraries) are “avail­able in open access and open to the sci­en­tif­ic com­mu­ni­ty”. The aim: to com­pare their metab­o­lisms with those of anatom­i­cal­ly mod­ern humans (Homo sapi­ens) and detect genom­ic vari­a­tions that could explain any selec­tive disadvantage.

The prob­lem is that fos­sil DNA is a frag­ile mate­r­i­al. Time, chem­i­cal agents, micro-organ­isms and human manip­u­la­tion degrade and con­t­a­m­i­nate it. Even Svante Pääbo, one of the lead­ing fig­ures in the dis­ci­pline, encoun­tered this dif­fi­cul­ty when work­ing on Egypt­ian mum­mies dur­ing his first attempts in the 1980s.  “He realised after­wards that what he had sequenced con­tained parts of genomes that undoubt­ed­ly belonged to peo­ple who had manip­u­lat­ed the mum­mies”, recounts Jean-Louis Mergny.

Worse still, oth­er less scrupu­lous teams sub­se­quent­ly pub­lished erro­neous results based on DNA sup­pos­ed­ly extract­ed from insects pre­served in amber – the work that inspired the Juras­sic Park saga. “We now know that DNA is poor­ly pre­served in amber, and cer­tain­ly not over tens of mil­lions of years… sci­ence pro­gress­es through its mis­takes!” smiles Jean-Louis Mergny.

In addi­tion to the risk of con­t­a­m­i­na­tion, which has now been part­ly brought under con­trol thanks to strin­gent lab­o­ra­to­ry hygiene stan­dards, mul­ti-mil­len­nia-old DNA sequences are dam­aged and present them­selves to sci­en­tists in high­ly frag­ment­ed form.What is an obsta­cle is also an oppor­tu­ni­ty, because, as the bio­chemist reveals, « we can more eas­i­ly recog­nise what is old and unsta­ble, and sep­a­rate it from more recent con­t­a­m­i­nat­ing sequences that remain intact”.

On Darwin’s shoulders: selection pressures and immune variations

Tak­ing a jour­ney through our genet­ic her­itage, shows that it bears traces of the “selec­tion pres­sures” that have shaped our species over the course of its his­to­ry. These pres­sures are linked to changes in cli­mate, the unavail­abil­i­ty of cer­tain resources, pre­da­tion, sex­u­al selec­tion, par­a­sites, and the emer­gence of pathogens. These con­straints have ‘pushed’ our species to adapt and mutate its allele fre­quen­cies over the gen­er­a­tions. In the cat­a­logue of these selec­tion pres­sures, palaeo­ge­neti­cists are par­tic­u­lar­ly inter­est­ed in the impact of major pan­demics on the evo­lu­tion of our immune system.

In this con­text, sci­en­tists sug­gest­ed in 20223 that Euro­pean pop­u­la­tions pos­i­tive­ly select­ed cer­tain immune sys­tem genes that respond­ed bet­ter to Yersinia pestis, the bac­teri­um that caused the Black Death and dec­i­mat­ed at least 50 mil­lion peo­ple in the 16th Cen­tu­ry. Genet­ic mark­ers of this episode are still present in Euro­peans, unlike pop­u­la­tions in Asia or Africa, where the Black Death did not occur.

More broad­ly, in 2023, biol­o­gists Gas­pard Kern­er and Lluís Quin­tana-Mur­ci (Insti­tut Pas­teur, Col­lège de France) pub­lished the results of a colos­sal palaeoge­nom­ic study, which com­pared 503 mod­ern Euro­pean genomes with more than 2,300 ancient genomes found on the con­ti­nent and span­ning the last 10 mil­len­nia. The sci­en­tists iden­ti­fied selec­tion muta­tions in almost 90 dif­fer­ent genes, includ­ing those cod­ing for lac­tase (which enables milk to be digest­ed), skin pig­men­ta­tion (explain­ing the lighter skin colour of Euro­peans), and the immune response to cer­tain infec­tious dis­eases (such as the Black Death).

Their work shows that these genet­ic muta­tions have a dou­ble-edged effect. They are pos­i­tive in terms of resis­tance to infec­tious dis­eases, but neg­a­tive in terms of the risk of devel­op­ing autoim­mune or chron­ic inflam­ma­to­ry dis­eases, such as dia­betes or Crohn’s dis­ease. This phe­nom­e­non, known as antag­o­nis­tic pleiotropy, illus­trates the evo­lu­tion­ary com­pro­mise that each liv­ing species makes to opti­mise its selec­tive value.

The hidden structures of Neanderthal DNA

Let’s go back to Nean­derthal. Jean-Louis Mergny has used this abil­i­ty to deter­mine the impact of selec­tion pres­sures on the genet­ic her­itage of a species as the basis for his cur­rent research. The bio­chemist has analysed Nean­derthal mito­chon­dr­i­al DNA for genet­ic mark­ers of evo­lu­tion and links with Sapiens.

Remem­ber that our researcher prefers non-con­form­ing and ‘rebel­lious’ DNA to ‘the canon­i­cal dou­ble-helix struc­ture’. This is why he focused on orig­i­nal genet­ic sequences locat­ed in the G‑quadruplexes (G4). “These are four-strand­ed sec­ondary struc­tures that form nodes in the genome”, he explains. How­ev­er, the Nean­derthal mito­chon­dr­i­al node “is much more ‘com­pli­cat­ed’ than ours”, which would make repli­ca­tion of its mito­chon­dria more dif­fi­cult, “at least in the Homo sapi­ens con­text that we know”. Since these organelles are con­sid­ered to be the ener­gy pow­er­hous­es of cells, their poor repro­duc­tion is a pri­ori a selec­tive dis­ad­van­tage for this species… “Unless Nean­derthal had more effi­cient enzymes for unwind­ing these knots”, he adds.

All that remains now is to analyse the ‘nodes’ of its nuclear DNA: if the Nean­derthal genome is now avail­able, it was at the cost of titan­ic efforts. There was a great deal of selec­tion pres­sure on this species and many hypothe­ses have been put for­ward as to the caus­es of its dis­ap­pear­ance. For exam­ple, Homo nean­derthalen­sis did not die out as a result of a cas­cade of food poi­son­ing, poor tol­er­ance of smoke inhala­tion, an insuf­fi­cient­ly var­ied diet or exces­sive can­ni­bal­ism. It is even less true that his cog­ni­tive abil­i­ties were too weak; he was undoubt­ed­ly very cre­ative. But he had to con­tend with Homo sapi­ens, a “super-effi­cient” human­i­ty as described by archae­ol­o­gist Ludovic Sli­mak, who rushed to occu­py the spaces left vacant by Neanderthal.

Nean­derthal is not the Homo stu­pidus we have long imagined

“Palaeoge­nomics shows that Nean­derthals were not the Homo stu­pidus we have long imag­ined, quite the con­trary,” main­tains Jean-Louis Mergny. We now know that they had the same genet­ic pre­dis­po­si­tion to lan­guage as Homo sapi­ens (the FOXP2 gene has been iden­ti­fied, includ­ing in its pro­mot­er regions); that, by prac­tis­ing patrilo­cal­i­ty4, they avoid­ed inbreed­ing as much as pos­si­ble; and that they not only cohab­it­ed with Sapi­ens, but also assim­i­lat­ed (hybridised) with him. Chil­dren were born of this hybridi­s­a­tion, and humans of Euro­pean ori­gin today retain a vis­i­ble trace of it in their genet­ic her­itage, with an aver­age of 2% Nean­derthal DNA.

Many research teams around the world are now pay­ing close atten­tion to this her­itage. Recent stud­ies have shown that Nean­derthal alle­les have had an influ­ence on our species in terms of immune response5, sus­cep­ti­bil­i­ty to Covid-196, skin pig­men­ta­tion7 for UV resis­tance, the sleep cycle8 and lipid catab­o­lism9 (the break­down of lipids to pro­duce energy).

Palaeoge­nomics sheds light on the evo­lu­tion of humankind and its immune sys­tem. But this dis­ci­pline comes up against a major obsta­cle: the con­ser­va­tion of ancient DNA. This depends on the cli­mate of the regions where the human remains were dis­cov­ered. Tem­per­ate or cold areas of Europe are more favourable than trop­i­cal and humid zones, where oth­er species or human lin­eages that have now dis­ap­peared prob­a­bly lived. “This skews our per­cep­tion of human­i­ty », stress­es Jean-Louis Mergny, espe­cial­ly in Africa, the cra­dle of our species. Final­ly, he stress­es that palaeoge­nomics only makes sense “if it is com­bined with oth­er dis­ci­plines such as archae­ol­o­gy and palaeon­tol­ogy”. It is dif­fi­cult, for exam­ple, to date a bone pre­cise­ly unless it has been dis­cov­ered dur­ing rig­or­ous exca­va­tions, which are absolute­ly nec­es­sary but extreme­ly time-con­sum­ing. Unfor­tu­nate­ly, most of the sam­ples we have come from rel­a­tive­ly old exca­va­tions, with insuf­fi­cient or miss­ing doc­u­men­ta­tion. The prox­im­i­ty of two bones does not nec­es­sar­i­ly indi­cate that they are con­tem­po­rary – hun­dreds or even thou­sands of years may have elapsed between the two deaths. But extreme­ly rig­or­ous analy­ses can some­times answer this question.

New tech­ni­cal advances will undoubt­ed­ly reveal new frag­ments of human­i­ty’s genet­ic her­itage… or of these plur­al human­i­ties. “If I had dis­cov­ered this uni­verse at the age of 20, you would prob­a­bly have inter­viewed me on an exca­va­tion site,” con­cludes Jean-Louis Mergny.

Samuel Belaud
2Homo sapi­ens a par exem­ple cohab­ité avec le virus de l’hépatite B pen­dant dix mil­lé­naires, comme l’ont mon­tré des travaux parus dans la revue en 2021. Jean-Louis Mergny a repris ces don­nées, pour mon­tr­er que chez ce virus qui provoque des infec­tions chroniques, le con­tenu en motifs inhab­ituels avait con­vergé au cours de l’évo­lu­tion avec celui de son hôte, comme une sorte de « cam­ou­flage géné­tique » pour éviter ain­si d’être recon­nu comme matériel étranger. Ses travaux ont été pub­liés dans la revue Nucle­ic Acids Research en 2023.
4The oppo­site of matrilo­cal­i­ty, where a cou­ple lives in the man’s fam­i­ly.

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