Karen De La Vega-Hernández

Elise Romain

Anais Coffinet

Kajetan Bijouard

Geoffrey Gontard

Fabrice Chemla

Franck Ferreira

Olivier Jackowski

Alejandro Perez-Luna

Radical Germylzincation of -Heteroatom-Substituted Alkynes

The regio-and stereoselective addition of germanium and zinc across the C-C triple bond of nitrogen-, sulfur-, oxygen-, and phosphorous-substituted terminal and internal alkynes is achieved by reaction with a combination of R 3 GeH and Et 2 Zn.

Diagnostic experiments support a radical-chain mechanism and the -zincated vinylgermanes that show exceptional stability are characterized by NMR spectroscopy and X-ray crystallography. The unique feature of this new radical germylzincation reaction is that the C(sp 2 )-Zn bond formed remains available for subsequent in situ Cu(I)-or Pd(0)-mediated C-C or C-heteroatom bond formation with retention of the double bond geometry. These protocols offer a modular access to elaborated tri-and tetrasubstituted vinylgermanes decorated with heteroatom substituents  to germanium that are useful for the preparation of stereodefined alkenes.

INTRODUCTION

Vinylgermanes 1 are attractive synthetic building blocks that offer specific features such as increased stability towards protonolysis, 2 facile halodegermylation 3 or low toxicity, 4 which make them useful when limitations are met with the more popular group 14 homologues vinylsilanes and vinylstannanes. [START_REF] Piers | Total Synthesis of the Diterpenoid (±)-Ambliol B[END_REF] Hence, the preparation of vinylgermanes is a field of intense ongoing research. A number of approaches have proved suitable for the preparation of vinylgermanes, 1c including electrophilic substitution of vinylmetals with halogermanes, 3b,6 Pd-catalyzed germylation of vinyl halides, [START_REF] Nakamura | Biaryl Synthesis from Two Different Aryl Halides with Tri(2-furyl)germane[END_REF] hydro- 3a,8 or carbometalation [START_REF]Butyllithium Mediated Cyclization of Substituted cis-1-(Alk-4-ynyl)-2-hydroxymethyl-1-iodocyclopropanes: Synthesis of Functionalized Spiro[2.4]heptanes[END_REF] of alkynylgermanes, radical substitution of vinylsulfides, 10a -stannanes, 10a or -sulfones, 10b alkene germylation through coupling with hydrogermanes [START_REF] Furukawa | Transition Metal-Catalyzed Dehydrogenative Germylation of Olefins with Tri-n-butylgermane[END_REF] or with vinylgermanes, 12 olefination of acylgermanes, 13 or domino arylgermylation of oxanorbornadiene / retro-Diels-Alder. [START_REF] Lv | Palladium-Catalyzed Ortho-Silylation of Aryl Iodides with Concomitant Arylsilylation of Oxanorbornadiene: Accessing Functionalized (Z)-β-Substituted Vinylsilanes and Their Analogues[END_REF] Yet, the direct synthesis of vinylgermanes from alkynes by carbon-germanium bond-forming addition reactions represents the most straightforward approach and has received the greatest attention. The hydrogermylation of alkynes with hydrogermanes has been disclosed through thermal or microwave-activated, [START_REF] David-Quillot | Regio-and Stereoselective Synthesis of (Z)-Vinylgermanes by Hydrogermylation of Alkynes[END_REF] radical, 16 transition-metal-catalyzed, 3a,8d,16e,17 as well as main-group Lewis-acid-catalyzed addition processes. 18 These protocols offer high levels of regio-and stereocontrol, but a shared fundamental limitation is that they cannot provide access to derivatives having two substituents distal to the position of the alkene germyl group ( Scheme 1, top). Furthermore, only some of the aforementioned synthetic alternatives have been implemented for this purpose, 6,9,10,13b and they rely on more elaborated starting materials and are not wide-in-scope. Thus, there is no direct and general solution available for the regio-and stereoselective preparation of 1,2,2-trisubstituted or tetrasubstituted vinylgermanes. To satisfy this demand, alkyne germylmetalation, i.e. the 1,2addition of germanium-metal bonds across the carbon-carbon triple bond of alkynes, is particularly appealing as it establish-es in a single synthetic operation a C(sp 2 )-Ge bond and a C(sp 2 )-metal bond. The newly formed reactive bond can be used as linchpin for subsequent C-C bond formation in one pot following electrophilic substitution. However, in sharp contrast with the related silylmetalation and stannylmetalation reactions that are prevalent approaches for the preparation of polysubstituted vinylsilanes [START_REF] Lim | Synthesis of Vinylsilanes[END_REF] and vinylstannanes, 20 germylmetalation reactions are almost unknown. The reaction between (trimethylgermyl)copper and a terminal alkyne was reported to be low yielding. [START_REF] Piers | Reaction of (Trimethylgermyl)copper(I)-dimethyl Sulfide with Acyl Chlorides: Efficient Syntheses of Functionalized Acyltrimethylgermanes[END_REF] Also, the germylcupration of terminal acetylenes with (triethylgermyl)-and (triphenylgermyl)cuprates was disclosed: [START_REF] Oda | Regioselective Germylcupration of Acetylenes[END_REF] excellent cis stereoselectivity was observed, but regiocontrol was only achieved with the triphenylgermyl reagents. In that case however, the addition was found to be reversible and in favor of the starting materials; hence vinylgermane formation only proceeded in the presence of a proton donor and the C(sp 2 )-Cu bond formed was not available for subsequent elaboration. [START_REF] Piers | The related conjugate addition of (trimethylgermyl)cuprate reagents across alkyl-2-ynoates was also reported, but the organometallic adducts (allenoates) were not used for further functionalization[END_REF] It is also worthy of mention that protocols for the related alkyne germylstannation were developed using the oxidative addition chemistry of Ge-Sn compounds. [START_REF] Terminal Alkynes ; Nakano | Alternative Synthesis of (Z)-1-Aryl-1-(tributylstannyl)-2-(triethylgermyl)ethenes and the Unprecedented Germyl 1,2-Migration During the Destannylation of the Adducts[END_REF][START_REF] Acetylenic | Regioselective Germylation-Stannylation of α,β-Acetylenic Esters[END_REF][START_REF]Other germanium-element bonds were also added across alkynes using related oxidative addition chemistry, but the newly created C(sp 2 )-Ge and C(sp 2 )-element bonds were not suitable for orthogonal manipulation[END_REF] Nonetheless, following this approach, subsequent elaboration of the C(sp 2 )-Sn bond required an additional synthetic step. [START_REF] Kato | Synthesis of Novel Stereodefined Vinylgermanes Bearing an Allyl Group or an Allenyl Group: (E)-2-Aryl-1-germylalka-1,4-dienes and (E)-4-Aryl-5-germylpenta-1,2,4trienes[END_REF]

Scheme 1. Synthesis of Vinylgermanes from Alkynes with C-Ge bond formation (Ge = triorganogermyl)

Here we focus on -heteroatom-substituted alkynes, a substrate class that has not been considered previously for the above-described methods and that would deliver valuable heteroatom-substituted alkenes. [START_REF] Evano | Metal-Catalyzed Synthesis of Hetero-Substituted Alkenes and Alkynes[END_REF] We describe the regio-and stereoselective germylzincation of both terminal and internal nitrogen-, oxygen-, sulfur-and phosphorus-substituted alkynes by reaction with a combination of a hydrogermane and Et 2 Zn (Scheme 1, bottom). Upon hydrolysis of the C(sp 2 )-Zn bond or in situ Cu(I)-or Pd(0)-mediated functionalization, this method gives access to a variety of original di-, tri-and tetrasubstituted vinylgermanes. As part of this work, we also demonstrate the synthetic potential of this construction of orthogonally 1,2-dimetalated alkenes. Our idea, shown in Scheme 2, was to develop a radical approach similar to the one we recently applied to obtain the silylzincation of terminal -heteroatom-substituted alkynes using a combination of (Me 3 Si) 3 SiH and Et 2 Zn. 29 We reasoned that germanium-centered radicals II, produced by H-atom transfer between hydrogermanes and ethyl radical (I) (III), should add readily across the C-C triple bond of heteroatom-substituted alkynes III to provide regioselectively -heteroatom-substituted vinylic radicals IV (IIIIV). Radicals IV would then react with Et 2 Zn by homolytic substitution (S H 2) at the zinc atom (IVV) to afford -zincated vinylgermanes V along with ethyl radical I that would propagate the radical chain. For such a process to be possible, radical IV would have to undergo Zn-atom transfer (IVV) faster than competitive H-atom transfer from R 3 GeH (IVVI). Otherwise, radical hydrogermylation 16 would be the main reaction outcome and the Zn functionality would be lost. Estimation of the rate coefficients for each elementary step involved provided support for the feasibility of this radical chain, as they were all expected to be well above 10 2 M -1 s -1 , the commonly accepted lower limit for a radical chain to propagate in dilute solutions. [START_REF] Giese | Synthesis with Radicals -C-C Bond Formation via Organotin and Organomercury Compounds[END_REF] Triaryl-and trialkylgermanes undergo H-atom abstraction from alkyl radicals with rate constants in the range of 10 5 -10 6 M -1 s -1 at ca. 30 °C. [START_REF] Chatgilialoglu | Hydrogen Donor Abilities of Germanium Hydrides[END_REF] Moreover, it is also important to emphasize here that the rate for the addition of the ethyl radical across alkynes with -heteroatom substituents should be lower than ~10 5 M -1 s -1 , which is the rate for the addition of alkyl radicals across propiolates (terminal alkynes with a strong electron-withdrawing substitu-ent): [START_REF] Wille | Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems[END_REF] thus, direct ethyl radical addition leading to carbozincation products should be avoided. The rate constant for the addition of germanium-centered radicals across alkynes has not been determined, [START_REF] Wille | Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems[END_REF] but it should be of the same order of magnitude (though lower) than that for additions of silylcentered radicals [START_REF] Ingold | Absolute Rate Constants for the Reactions of Tri-n-butylgermyl and Tri-n-butylstannyl Radicals with Carbonyl Compounds, other Unsaturated Molecules, and Organic Halides[END_REF] (1 x 10 8 M -1 s -1 at 27 °C for the addition of the triethylsilyl radical across phenylacetylene). [START_REF] Wille | Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems[END_REF] While little is known about the rate for the reaction between vinyl radicals and Et 2 Zn, our previous work on radical silylzincation demonstrates that for -heteroatom-substituted vinylic radicals (IV), the rate for S H 2 at the zinc atom is suitable for chain propagation and can outcompete H-atom transfer from (Me 3 Si) 3 SiH. 29 Given that the rates for radical H-abstraction are in comparable ranges for R 3 GeH and for (Me 3 Si) 3 SiH, [START_REF] Chatgilialoglu | Hydrogen Donor Abilities of Germanium Hydrides[END_REF] a similar situation was expected here. Finally, regarding the initiation of the radical chain (not shown in the scheme), we surmised that it could occur, even in the absence of deliberately added radical initiators, through several pathways, including spontaneous-17b,34 or light [START_REF] Fuchs | Behavior of Triphenylsilane, Triphenylgermane, and Triphenyltin Hydride in the Presence of Olefins[END_REF] -induced homolysis of the Ge-H bond (as for the hydrogermylation reactions) [START_REF]Alkyne hydrogermylation reactions are characterized by very long chains and can proceed in the absence of clearly identified radical initiators[END_REF] or oxidation of diethylzinc by traces of molecular oxygen. [START_REF] Ryu | Initiation of Tin-Mediated Radical Reactions by Diethylzinc-Air[END_REF]38 Scheme 2. Anticipated Radical Approach to the Germylzincation of -Heteroatom-Substituted Alkynes

RESULTS AND DISCUSSION

We commenced our study by investigating the germylzincation of model terminal ynamide 1 with Ph 3 GeH, a well-established radical hydrogermylating reagent that is commercially available and easy-to-handle (Table 1). The initial conditions involving 1.3 equiv of hydrogermane and 3.0 equiv of Et 2 Zn at 0 °C in n-hexane, led to the exclusive formation of -germylenamide 2 as an E/Z = 30:70 mixture of isomers, but the reaction was not complete and only ~ 60% of 1 was consumed (Entry 1). In fact, competitive deprotonation of 1 by Et 2 Zn as well as direct hydrogermylation delivering Z-2 hampered the germylzincation process. A survey of other solvents was then carried out. While no significant improvement was observed in CH 2 Cl 2 and Et 2 O, reactions in benzene and methyl tert-butyl ether (MTBE) afforded improved conversion (~ 80%). The stereoselectivity was only modest but, by contrast with the reaction in n-hexane, often in favor of the E isomer. Furthermore, in MTBE, competitive carbozincation giving 3 was also observed. Eventually, full conversion and total stereocontrol, also in favor of the E isomer, were obtained using Me-THF and THF. Nevertheless, carbozincation of 1 occurred to some extent with the more hindered ether, and a better yield in 2 (87% vs 64%) was obtained in THF. With lower amounts of Et 2 Zn (1.8 or 1.2 equiv), the reaction also took place with high conversion and exclusive formation of 2, albeit with lower stereocontrol. The scope of this new germylzincation reaction of terminal ynamides was next considered (Scheme 3). Modification of the substitution pattern  to the nitrogen atom of the oxazolidinone ring was well tolerated and -germylenamides 4-6 were isolated in good yields and as single E isomers. 39 Here however, small amounts (10-12%) of carbozincation adducts were detected in the crude. Other hydrogermanes were also used. Trifurylgermane 40 reacted smoothly to provide stereopure E-7 in 72% yield. With nBu 3 GeH, the conversion (50%) was not complete and product 8 was obtained in a lower 40% yield along with 10% of the carbozincation adduct (3).

In this case, the rate coefficient for the reaction between alkyl radicals and the hydrogermane is around one order of magnitude lower than for triarylgermanes: 41 this makes ethyl radical addition more competitive and the propagation of the radical chain (Scheme 2, III) less efficient. Nevertheless, with higher amounts of hydrogermane (2.0 equiv) and longer reaction times, nBu 3 GeH and Et 3 GeH led respectively to 8 and 9 in high yields with very high (≥ 95:5) stereoselectivities, and no ethylzincation was observed.

Scheme 3. Reaction Scope for the Germylzincation of Terminal Ynamides

The formation of vinylzinc intermediates upon reaction with R 3 GeH / Et 2 Zn under the developed conditions was studied systematically by deuterium labeling and D-incorporation > 95% at the -position was observed in every case (Scheme 3).

It must be noted however that these experiments were complicated by the remarkably high stability towards hydrolysis of the C(sp

Germylenamides

Importantly, the germylzincation reaction was also found to be well suited for internal ynamides (Scheme 5).

Scheme 5. Reaction Scope for the Germylzincation of Internal Ynamides

For this substrate class, the best conditions for the reaction with Ph 3 GeH / Et 2 Zn involved using n-hexane as solvent at 40 °C. Here, direct hydrogermylation did not interfere with the germylzincation process, and -germylenamide E-10 was obtained from the parent Ph-substituted ynamide in 92% yield with -regioselectivity and cis-stereoselectivity. The same exquisite regio-and stereoselectivity was observed at lower temperatures and/or in THF, but conversion of the starting material was not complete. Modification of the nitrogen substituent was also well tolerated here. E-enamides 11-13 having different oxazolidinone rings were obtained in 69-86% yields from the corresponding cyclic ynamides. Importantly and by contrast with the terminal ynamides derived from the same oxazolidinones, competing ethyl radical addition was not observed, what is consistent with the lower rate coefficient for the addition of alkyl radicals to disubstituted alkynes than to monosubstituted alkynes. [START_REF] Wille | Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems[END_REF] Moreover, enamide 14 having an acyclic carbamate was produced, with full regio-and stereoselectivity, in 73% yield. The E configuration of products 12 and 14 was established by Xray crystallographic analysis. 43 Regardless of the electronic character or the position of the substituent, substitution of the phenyl ring had little impact on the reaction outcome with other aryl-substituted ynamides. Thus, 15 and 17 with para-or meta-methoxy-substituted rings, or 16 and 19 with para chloro-or ortho, ortho dichlorosubstituted rings were all obtained in similar high yields and as single E isomers. Only 18 having an ortho methoxysubstituted phenyl ring was an exception to this trend as it was delivered with low stereoselectivity. Certainly, coordination of Et 2 Zn to the MeO group influences the alkylzinc group transfer event that is the stereodiscriminating step (vide infra).

The germylzincation was not restricted to ynamides substituted at the alkyne terminus by aryl groups, as trisubstituted enamides having alkenyl (20)-, alkynyl (21)-, primary alkyl (22 and 23)-, secondary alkyl ( 24)-, and CF 3 (25)-substituents  to the nitrogen atom were prepared for the most part in good yields, even if longer reaction times were sometimes necessary. Excellent stereoselectivities were obtained in all cases, but for cyclohexyl-and CF 3 -substituted enamides 24 and 25, reversal of stereoselectivity in favor of a trans-selective germylzincation was observed. Furthermore, in the formation of the CF 3 -substituted enamide, competitive carbozincation and -selective germylzincation were detected to some extent.

The configurations of products 23 (E) and 25 (Z) were established by X-ray crystallographic analysis. 43 As demonstrated with the preparation of 26 as a single E isomer in 88% yield, (2-furyl) 3 GeH performed as well as Ph 3 GeH for the germylzincation of internal ynamides. By contrast, trialkylgermanes were not suitable because of the lack of regiocontrol, as in the case of the formation of 27.

Finally, similarly to the reactions involving terminal ynamides, D-labeled enamides (> 90% D-incorporation) were obtained on quenching the reactions with ND 4 Cl (Scheme 5), thus confirming the formation of vinylzinc intermediates upon reaction of internal ynamides with R 3 GeH / Et Hence, the rate of formation of a hypothetical germaniumzinc intermediate under these conditions was too slow to account conveniently for the germylzincation reactions. Overall, these findings provided strong support for the mechanism foreseen at the outset of our work (depicted in Scheme 2) involving the addition of germanium-centered radicals across the C-C triple bond of ynamides. The regioselectivity of the process was fully consistent with this mechanism, as previous intermolecular additions of radicals across ynamides, including the abovementioned direct hydrogermylation, occured  to the nitrogen atom both for terminal and internal ynamides. 53 Steric effects usually account for the regioselectivity of radical additions across monosubstituted alkynes, [START_REF] Wille | Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems[END_REF] and this is likely also the case for terminal ynamides. By contrast, the origin of regioslectivity for internal ynamides is not clear. Steric factors still seem important, as shown by the lack of stereocontrol with the less hindered trialkylgermanes (Scheme 5, product 27), but other elements, among which stabilization of the vinyl radical by the -nitrogen atom, or differences in reactivity of the possible regioisomeric radicals in the subsequent forward reaction (S H 2 at zinc), can also intervene and are difficult to estimate. [START_REF] Wille | Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems[END_REF] The stereochemical outcome of the germylzincation reactions was also rationalized conveniently on the basis of this scenario: the stereoselectivity of the germylzincation reaction is that of the alkylzinc group transfer (i.e. XIVVII, Scheme 7). sp 2 -Hybridized radicals XIV have a bent geometry and are considered to exist in two equilibrating diastereomeric forms with a low interconversion energy barrier. The reaction of E-XIV with Et 2 Zn provides Z-VII and that of Z-XIV produces E-VII. 54 Thus, the Z/E ratio for the formation of VII depends both on the relative stability of both isomers of XIV (K eq ), as well as the relative ease of each diastereomeric form to undergo ethylzinc group transfer (k Z vs k E ). In general terms, one would expect Z-XIV to react more promptly than E-XIV (k Z > k E ) because the Et 2 Zn/R 3 steric interaction is less demanding that the Et 2 Zn/R 3 Ge interaction. With "small" R 3 substituents (i.e. R 3 = H, primary alkyl or aryl), the Z/E equilibrium is largely in favor of the E form (K eq >> 1) and the formation of Z-VII is favored. By contrast "larger" R 3 substituents (i.e. cyclohexyl or CF 3 55 ), destabilize E-XIV (K eq becomes lower) and thus the formation of E-VII becomes more favorable.

Scheme 7. Stereoselectivity Model for the Germylzincation of Terminal and Internal Ynamides

The reversal of stereoselectivity observed between the radical trans-silylzincation of terminal ynamides with (Me 3 Si) 3 SiH / Et 2 Zn in n-hexane 29a and the present cis-stereoselective germylzincation in THF is a noteworthy point that deserves further comment. The trans selectivity for the silylzincation was attributed to the formation, in n-hexane, of a Lewis pair between Et 2 Zn and the carbonyl group on the nitrogen atom; the Zn-atom transfer step was accelerated and outcompeted Zto-E interconversion of the -amino vinylic radical that reacted only as the initially formed Z-stereomer. 56 As evidenced with in situ IR experiments, THF prevents this Lewis-pair formation during germylzincation (see supporting information). Hence, Z-to-E interconversion becomes faster than the Zn-atom transfer step; the reaction of the E-stereomer (i.e. E-XIV (R 3 =H)) is favored and the formation of Z-VII (R 3 =H) is obtained. The fact that silylzincation of terminal ynamide 1 with (Me 3 Si) 3 SiH / Et 2 Zn proceeds with exclusive cisstereoselectivity in THF, 57 provides additional evidence for this remarkable solvent effect. Having established the scope for the germylzincation reaction, we next investigated the synthetic potential of C(sp 2 )-Zn bond functionalization to provide access to vinylgermanes with two substituents  to the germanium atom. In situ Cu(I)-mediated electrophilic substitution following germylzincation occurred readily with complete stereoretention of the double bond geometry (Scheme 8). The typical procedure involved using the THF-soluble salt CuCN•2LiCl, but (commercially available) CuTC could be used alternatively with comparable results. Both protocols were equally efficient for the vinylzinc intermediates arising from the germylzincation of terminal or internal ynamides, thus giving access to diversely substituted trior tetrasubstituted vinylgermanes with defined geometry. Competent carbon and non-carbon electrophiles included allylic halides (28-30 and 34-38), acyl halides (31), alkynyl bromides (32, 40-42), methyl iodide (39) or phenyl phenylthio sulfone (33). The E configuration of product 40 was established by X-ray crystallographic analysis. 43 Scheme 8. Domino Ynamide Germylzincation / Cu(I)-Mediated Electrophilic Substitution Importantly, the domino cis-germylzincation-Cu(I)-mediated electrophilic substitution was also applicable with tosylynamides (terminal and internal) and delivered -substituted -germyl enamides 30, 37 and 38 in 77-88% yield. It must be noted that the corresponding -germyl enamides arising from protonolysis (E = H) decomposed during work-up and could not be isolated. Moreover, in situ functionalization of the C(sp 2 )-Zn bond of the germylzincation adducts was also readily achieved by means of Cu(I)-mediated 1,4-addition to enones, as illustrated with the formation of adduct 43 from 1 (Scheme 9).

Scheme 9. Domino Ynamide Germylzincation / Cu(I)-Mediated 1,4-Addition

The presence of excess Et 2 Zn required for the germylzincation step complicated in certain cases clean C(sp 2 )-Zn bond functionalization, notably for halodezincation reactions. To overcome this limitation we decided to eliminate Et 2 Zn before the electrophilic substitution step by removing the volatiles under reduced pressure. Upon elimination of Et 2 Zn, displacement of the Schlenk equilibria (Scheme 4) led to the exclusive formation of divinylzinc intermediates. In particular, the structure of compounds 44 and 45 was analyzed by X-ray crystallography and both showed similar characteristics (Figure 1). The cis geometry between zinc and germanium following germylzincation was confirmed. An almost linear arrangement of the two carbon-zinc bonds was observed, with bond lengths (1.985 to 2.009 Å) in the expected range for diorganozinc compounds. 58 Remarkably, the zinc atom was also coordinated to the oxygen atoms of the carbonyl groups and adopted an uncommon distorted seesaw shaped four-coordinate geometry. 59 The position of the phenyl rings of Ph 3 Ge is also of interest. Even though there is no Zn-C ipso contact, two of them clearly shield the Zn atom and likely confer to the divinylzinc species their unusual stability towards hydrolysis and oxidation mentioned previously. prepared in acceptable yields. Trifluoromethylation with Umemoto's reagent to deliver 49 was also accomplished. An additional asset of this protocol was that it made possible the use of catalytic amounts of Cu(I) salt, as shown for the formation of 28 in 87% yield from 1 using 10 mol% CuTC to promote the allylation step. It was also feasible to perform Pdcatalyzed Negishi-type cross-coupling reactions, and 44 reacted with 1-bromo-4-nitrobenzene to afford arylated product 50 in 56% yield. Here, 24% of product E-2 coming from the hydrolysis of unreacted 44 was also recovered. It is noteworthy, that no cross-coupling reaction occurred when 1-iodo-4nitrobenzene was used under similar conditions. carbon-carbon triple bond of sulfur-, oxygen-, and phosphorous-substituted terminal alkynes occurred at 0 °C yielding the corresponding -heteroatom-substituted vinylgermanes 54-57 with full -regioand cis-stereocontrol (Scheme 12). It was interesting to note that the heteroatom substituent had no impact on the regioselectivity, as this trend differed from that observed for certain alkyne carbometalation reactions. 60 THF was generally the solvent of choice, but in the case of 57 better yields were obtained in n-hexane. Isolated yields were in the range 37% to 70%. Likewise, tri-substituted vinylgermane 58 was delivered in 70% yield (with the same regio-and stereocontrol) from the germylzincation in n-hexane at 40 °C of an internal -phosphonate-substituted alkyne. The E configuration of product 58 was established by X-ray crystallographic analysis. 43 In all cases, D-labeling confirmed the formation of vinylzinc intermediates and the availability of the C(sp 2 )-Zn bond formed for further elaboration, as [ 2 H]-54-[ 2 H]-58 were obtained (> 90% D-incorporation) on quenching with ND 4 Cl. In the case of product 57, D-incorporation  to germanium was also observed indicating that here, germylzincation occurred on the zincated alkyne.

Scheme 12. Germylzincation of Other -Heteroatom-

Substituted Alkynes

To finish our study, we next established that the new germylzincation approach was not restricted to -heteroatomsubstituted alkynes and could also be extended to conventional alkynes (Scheme 13). At 40 °C in THF, 1-phenyl-1-propyne and diphenylacetylene yielded products 59 and 60 in respectively 40% and 49% yield in high trans-stereoselectivity consistent with a radical chain-transfer mechanism with a Znatom transfer under kinetic control. Here, the intermediate vinyl radical (sp-hybridized as the result of the conjugation with the adjacent Ph ring) was expected to be linear, and Et 2 Zn to approach from the less hindered side opposite to the bulky Ph 3 Ge group. 61 At this temperature however, the reactions did not proceed to completion, a behavior that was attributed to the shortening of the radical chains because of a less favorable radical addition step. 62 This effect was eventually corrected by adding AIBN as radical initiator and operating at 80 °C to ensure its decomposition. Products 59 and 60 were obtained in improved 66% and 67% yields within much shorter reaction times (1 h). Control experiments in the absence of AIBN gave less than 10% conversion under the same operating conditions, what underscored the decisive role played by the radical initiator and provided further support for radical character of the germylzincation. The stereoselectivity remained very high in the case of 60, but dropped for 59 as the consequence of radical induced isomerization of the intermediate zincated vinylgermanes. 63 Scheme 13. Germylzincation of 1-Phenyl-1-Propyne and Diphenylacetylene

CONCLUSIONS

In conclusion, we disclosed here the first germylzincation reaction of C-C triple bonds using a combination of a hydrogermane and diethylzinc in a radical chain process. Ready availability of the reagents, operational simplicity and excellent levels of regio-and stereocontrol are important assets of this reaction that can be performed on terminal and internal ynamides as well as on other sulfur-, oxygen-, and phosphorous-substituted alkynes. The decisive feature of this new approach is the possibility of using the C(sp 2 )-Zn bond formed as linchpin for the subsequent installation of carbon or heteroatom substituents with complete retention of configuration through in situ Cu(I)-or Pd(0)-mediated electrophilic substitution. This offers a convenient and modular route to elaborated di-, tri-and tetrasubstituted vinylgermanes decorated with heteroatom substituents  to germanium that are useful for the preparation of stereodefined alkenes and cannot be prepared using hydrogermylation chemistry or previously reported germylmetalation reactions. As part of this work, we also were able to isolate and fully characterize, including by X-ray crystallography, the -amino -germyl vinylzinc intermediates arising from the germylzincation of ynamides. These divinylzinc complexes showed exceptional stability towards oxidation and hydrolysis, probably as the result of the very uncommon seesaw coordination of zinc.

ASSOCIATED CONTENT Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

Additional data and discussion, experimental details, NMR spectra for new compounds, and X-ray crystal structures (PDF)

Figure 1 .

 1 Figure 1. X-ray crystal structure of 44 and 45. Selected bond lengths and bond angles. 44: Zn-C1 = 1.995(8) Å, Zn-C26 = 1.985(8) Å, C1-Zn-C26 = 170.8(3)°, O1-Zn1-O3 = 97.8(3)°. 45: Zn-C1 = 1.989(7) Å, Zn-C27 = 2.009(7) Å, C1-Zn-C27 = 165.5(3)°, O1-Zn-O3 = 91.3(3)°. The divinylzinc intermediates arising from the germylzincation / evaporation sequence also underwent smooth Cu(I)-mediated electrophilic substitution in THF and this modified protocol offered additional possibilities for C(sp 2 )-Zn functionalization (Scheme 10). The use of halogen electrophiles was possible and -germylenamides decorated in -position with iodine (46), bromine (47) or fluorine (48) were

  Scheme 10. Ynamide Germylzincation / Cu(I)-or Pd(0)-Mediated Electrophilic Substitution via Divinylzinc Intermediate44

Table 1 . Optimization of the Germylzincation of Ynamide 1

 1

	Entry	Solvent a	Et 2 Zn [equiv]	Convers ion b,c (2/1)	d.r. 2 (E/Z) c	Yield 2 (%) d
	1	n-hexane e	3.0	62:38	30:70	nc f
	2	CH 2 Cl 2	3.0	50:50	70:30	37
	3	Et 2 O	3.0	54:46	48:52	29
	4	benzene	3.0	85:15	57:43	nc f
	5	MTBE	3.0	80:20	68:32	62 g
	6	Me-THF	3.0	>99:1	98:2	64 h
	7	THF	3.0	>99:1	>98:2	87
	8	THF	1.8	>99:1	90:10	nc f
	9	THF	1.2	89:11	76:24	nc f

a Reaction conditions: Ph 3 GeH (1.3 equiv), 0 °C, 3 h unless otherwise stated. b Only -germylated regioisomers were detected. c Determined by 1 H NMR prior to purification. d Combined yield of isolated diastereomers. e Reaction time = 6 h. f Not calculated. g 6% of 3 was observed. h 10% of 3 was observed.

  examined the influence of metalation of 1 in the reaction media(Scheme 6, a). Performing the germylzincation on D-labeled ynamide [ 2 H]-1 led exclusively to E-[ 2 H()]-2 without loss of deuterium at the -position, thus indicating that deprotonation of 1 (neither by Et 2 Zn 44 nor by vinylzinc intermediates) did not occur during germylzincation (in THF at 0 °C). It was found that Ph 3 GeH could react with 1 in the absence of Et 2 Zn (Scheme 6, b): 45 both in n-hexane and THF, after 3 h at 0 °C, the stereoselective formation of Z-2 was observed in50- 60% yield, 46 and the absence of this direct hydrogermylation in the presence of TEMPO confirmed its radical character.47 The afore-described D-labeling experiments (Scheme 3) established that germylzincation outcompetes this radical hydrogermylation in THF with excess Et 2 Zn. However, the loss of stereoselectivity observed with lower amounts of Et 2 Zn or in other solvents (Table1), can certainly by ascribed to the coexistence of the two competing processes: germylzincation that leads to the E-isomer (after work-up), and hydrogermylation that delivers the Z-isomer. It is important to note that, by contrast, with internal ynamides, no reaction with Ph 3 GeH was detected in the absence of Et 2 Zn, even at 40 °C. While these experiments lend clear evidence for the intervention of radicals in the mechanism, we could not at this point exclude a scenario wherein Et 2 Zn would react with R 3 GeH by a radical alkylzinc group-transfer process (reminiscent of that involved in the formation of [(Me 3 Si) 3 Si] 2 Zn from (Me 3 Si) 3 SiH and Et 2 Zn) 48 and provide a putative germaniumzinc intermediate IX (Scheme 6, d) that would add across the C-C triple bond of the ynamide through a polar mechanism. Notably, the reported formation of (Ph 3 Ge) 2 Zn by reaction between Et 2 Zn and Ph 3 GeH in THF required to exclude this possibility.[START_REF] Nanjo | Synthesis and Oxidation of Bis(triphenylgermyl)zinc[END_REF] Towards this end, the reaction of Ph 3 GeH / Et 2 Zn with mechanistic probe X 29a was considered (Scheme 6, e). Furthermore, we also monitored by in situ 1 H NMR the rate of depletion of Ph 3 GeH upon contact with Et 2 Zn in THF in the absence of ynamide. After 3 h at 0 °C (Scheme 6, d), 40% of the initial amount of Ph 3 GeH had disappeared.52

	The formation of cyclized products [ 2 H]-XI (33%) and [ 2 H]-
	XII (52%) (arising from competing ethyl radical addition) 50
	provided evidence for a radical 1,4-addition (leading to an
	intermediate -alkoxy radical XIII that undergoes 5-exo-dig
	ring closure) whereas no products arising from the fragmenta-
	tion of an intermediate -alkoxy anion 51 (not shown) that
	would support an alternative polar addition of IX were detect-
	ed.

2 Zn. Again, in the cases of 19 and 24, quenching with a mixture of CuTC / ND 4 Cl / D 2 O was necessary to obtain reliable values for Dincorporation. Our next efforts were directed to gain insight into the mechanism of the new germylzincation reaction. In a first set of experiments, we Scheme 6. Mechanistic Studies

The presence of TEMPO also thwarted completely the germylzincation (Scheme 6, c): no conversion was observed if amounts as low as 10 mol% were added at the beginning and only 26% of E-2 was formed upon addition after 5 min of reaction.

Table of Contents artwork

 ofartwork

Funding Sources

This work was supported by Sorbonne Université, CNRS and the Agence Nationale de la Recherche (SATRAZ Project, grant n° 2011-INTB-1015-01) which we gratefully acknowledge.

AUTHOR INFORMATION

Corresponding Author * alejandro.perez_luna@sorbonne-universite.fr

Author Contributions

All authors have given approval to the final version of the manuscript.

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT

Omar Khaled and Cédric Przyblski from IPCM are gratefully acknowledged for HRMS analysis. Aurélie Bernard and Claire Troufflard from IPCM are acknowledged for help with NMR analysis.

ABBREVIATIONS

AIBN, azobisisobutyronitrile; CuTC, Copper(I)-thiophene-2carboxylate; Me-THF, 2-methyltetrahydrofuran; MTBE, methyl tert-butyl ether; TEMPO, (2,2,6,6-tétraméthylpipéridin-1-yl)oxy; THF, tetrahydrofuran.

Involving Organozinc Reagents and -(Allyloxy)-enoates. Tetrahedron Lett. 2008, 49, 3963-3966. (52) In fact, an immediate 20% loss of Ph3GeH was observed on reagent mixing, followed by a much slower disappearance of an additional 20% over 3 h (see supporting information).

( (56) Note also that coordination of the carbonyl by a Lewis acid should decrease the electronic density of the nitrogen atom of the carbamate group and thus decrease the rate for Z-to-E interconversion of XIV.

(57) The reaction in THF (0 °C, 3 h) of 1 with (Me3Si)3SiH (1.3 equiv) in the presence of Et2Zn (3.0 equiv) afforded in 78% yield the corresponding -tris(trimethylsilyl)silyl enamide as a Z/E = 10:90 mixture (see supporting information).

(58) Jastrzebski, J. T. B. H.; Boersma, J.; Van Koten, G. Structural Organozinc Chemistry, in: Z. Rappoport (Ed.), Patai's Chemistry of Functional Groups; Organozinc Compounds (2007), John Wiley & Sons, Ltd, Chichester, 2009. (59) To the best of our knowledge there is only one previous report of a Zn complex with such geometry, see: Chu, T.; Belding, L.; Poddutoori, P. K.; van der Est, A.; Dudding, T.; Korobkov, I.; Nikonov, G. I. Unique Molecular Geometries of Reduced 4-and 5-Coordinate Zinc Complexes Stabilised by Diiminopyridine Ligand. Dalton Trans. 2016, 45, 13440-13448. (60) Nakamura, E.; Miyachi, Y.; Koga, N.; Morokuma, K. Theoretical Studies of Heteroatom-directed Carbometalation. Addition of MeCu, Me2Cu -, and MeLi to Substituted Acetylenes. J. Am. Chem. Soc. 1992, 114, 6686-6692. (61) Galli, C.; Guarnieri, A.; Koch, H.; Mencarelli, P.; Rappoport, Z. Effects of Substituents on the Structure of the Vinyl Radical: Calculations and Experiments. J. Org. Chem. 1997, 62, 4072-4077. (62) This behavior is counter-intuitive as -heteroatom-substituted alkynes are regarded as electron-rich and germanium-centered radicals nucleophilic. Nevertheless, since the inductive effect of the heteroatom substituent lowers the energy of the LUMO (see ref 60), a possible explanation is that the addition of the germyl radical benefits from a more favorable SOMO-LUMO interaction for -heteroatomsubstituted alkynes.

(63) The mechanism for the radical isomerization has not been identified but abstraction of allylic hydrogen atoms might intervene with this particular substrate, see: Shimoi, M.; Watanabe, T.; Maeda, K.; Curran, D. P.; Taniguchi, T. Radical Trans-Hydroboration of Alkynes with N-heterocyclic Carbene. Angew. Chem. Int. Ed. 2018, 57, 9485-9490.


Winati Nurhayu

Sarah Nila

Arum Kanthi

Puji Widayati

Bambang Rianti

Michel Suryobroto

Raymond

Arum Widayati

Puji Rianti

Bambang Suryobroto

Michel Raymond
email: michel.raymond@umontpellier.fr

Handedness heritability in industrialized and nonindustrialized societies

come

Introduction

Since prehistoric times, both right-and left-handed individuals have been ubiquitous in human populations, exhibiting geographical frequency variations [START_REF] Dellatolas | Age and cohort effects in adult handedness[END_REF][START_REF] De Agostini | Environmental influences in hand preference: An African point of view[END_REF][START_REF] Llaurens | Why are some people left-handed? An evolutionary perspective[END_REF][START_REF] Mcmanus | The history and geography of human handedness[END_REF][START_REF] Raymond | Is there geographical variation in human handedness? Laterality Asymmetries Body[END_REF]. A polymorphism maintained in all populations of a given species can happen for a neutral trait but is easily lost by genetic drift; therefore, at least some populations lose the polymorphism.

The fact that the polymorphism of handedness is maintained in all human populations suggests that handedness is not a neutral trait and that some selective forces are maintaining this diversity. Directional selection, if acting alone, would lead to the fixation of the advantageous morph and eliminate the polymorphism. The ancient and ubiquitous polymorphism observed for handedness [START_REF] Faurie | Origins, Development, and Persistence of Laterality in Humans[END_REF] suggests that balancing selection is influencing this trait. This balancing selection could result from a situation-dependent benefit, such as a negative frequency-dependent selection [START_REF] Raymond | Frequency-dependent maintenance of left handedness in humans[END_REF]. Data have suggested that left-handedness, as the rare hand preference, could represent an important strategic advantage in fighting interactions. This notion has been largely supported by sport data [START_REF] Brooks | Sinister strategies succeed at the cricket world cup[END_REF]Faurie and Published version: https://doi.org/10.1038/s41437-019-0274-3

Raymond 2013; [START_REF] Goldstein | Evolutionary' stable strategy of handedness in major league baseball[END_REF]Loffing et al. 2012a;Loffing et al. 2012b); video experiments have shown that it is more difficult to predict the outcome of an action performed by a left-hander than it is by a right-hander, and this difference is attenuated, or even reversed, by specific training (Loffing et al. 2012b;[START_REF] Schorer | Human handedness in interactive situations: Negative perceptual frequency effects can be reversed![END_REF]). In addition, the correlation observed in traditional societies between the frequency of left-handers and the rate of homicide further suggests a frequency-dependent advantage of left-handers in violent interactions (Faurie and Raymond 2005, but see Faurie and[START_REF] Faurie | The fighting hypothesis as an evolutionary explanation for the handedness polymorphism in humans: Where are we?[END_REF][START_REF] Groothuis | The fighting hypothesis in combat: How well does the fighting hypothesis explain human left-handed minorities?[END_REF]. However, the fact that left-handedness never occurs at a frequency close to 50% (Faurie et al. 2005;[START_REF] Raymond | Is there geographical variation in human handedness? Laterality Asymmetries Body[END_REF] indicates that some evolutionary costs could be associated with lefthandedness [START_REF] Billiard | Maintenance of handedness polymorphism in humans: a frequency-dependent selection model[END_REF]. In Western societies, this cost has often been attributed to the technological environment, with asymmetrical artefacts being dangerous for left-handers [START_REF] Aggleton | Evidence for longevity differences between left handed and right handed men: An archival study of cricketers[END_REF][START_REF] Coren | Left-handedness and accident-related injury risk[END_REF][START_REF] Daniel | Accident proneness and handedness[END_REF]. However, the frequency of left-handers is also far from 50% in any traditional society, suggesting the existence of costs in non-industrialized environments as well (Faurie and Raymond 2005, see also [START_REF] Ghirlanda | Intraspecific competition and coordination in the evolution of lateralization[END_REF]).

In modern societies, the type of violence has radically changed with the introduction of modern weapons, with the consequence that no differential advantage of left-handers is expected anymore (with the exception of interactive sports, a restricted form of ritualized violence not using modern weapons). Another factor affecting handedness in industrialized societies is the extensive automation of most manual labour, including agriculture. Machines are now replacing a large part of the previous manual load, thus reducing hand usage and importance of hand specialization. Now, the majority of individuals do not use their arms and hands intensively for highly specialized tasks on an everyday basis (usage of keys, mouse, comb, hairdryer, phone, etc. do not require a very high and intense manual specialization). This general decrease of specialized and demanding manual tasks in the daily life of modern societies probably explains the secular decline of handgrip strength and, more generally, of muscular strength components, observed during the last century in countries such as the US, Canada, Denmark, and Spain [START_REF] Malina | Secular trends in growth, maturation and physical performance: A review[END_REF][START_REF] Moliner-Urdiales | Secular trends in health-related physical fitness in Spanish adolescents: The AVENA and HELENA Studies[END_REF][START_REF] Silverman | The secular trend for grip strength in Canada and the United States[END_REF]. As a result, in industrialized countries, for a given manual action, each individual shows a preference for the use of one hand, although it is not always the same hand for two different actions [START_REF] Salmaso | Problems in the assessment of hand preference[END_REF]. This notion suggests that right-or left-handed is a not general category but rather is defined as a function of the task, explaining why indexes have been often developed in industrialized countries to measure handedness, such as the one derived from the Edinburgh Handedness Inventory [START_REF] Oldfield | The assessment and analysis of handedness: The Edinburgh inventory[END_REF]. For the countries not affected by the process of extended mechanization, a higher level of hand specialization is expected. The only available comprehensive study was performed in Indonesia, where a strong correlation between the different tasks has been found, suggesting that handedness could be considered a general category [START_REF] Nurhayu | Are right-and lefthandedness relevant as general categories in a non-industrialized country?[END_REF].

Selection of handedness is thus likely to differ between traditional and modern societies. As no direct frequency-dependent advantages associated with left-handedness are known in modern societies, it is expected that the frequency of left-handedness has decreased due to its fitness cost, as homicides and violence are no longer driven by traditional weapons. Societies displaying a traditional type of violence are becoming scarce, although some were still studied during the 20 th century (e.g., [START_REF] Chagnon | Life histories, blood revenge, and warfare in a tribal population[END_REF][START_REF] Downs | Head-hunting in Indonesia. Bijdr Tot Taal-Land-En Volkenkd[END_REF][START_REF] Harrison | Four types of symbolic conflict[END_REF]. The general decrease in traditional violence during the 20th century is attributable to pacification imposed by colonization or by higher state control, particularly over remote areas, and to a shift to other types of violence through the introduction of modern weapons.

When selection is present, the relative speed of evolutionary dynamics is determined by heritability [START_REF] Falconer | Introduction to Quantitative Genetics[END_REF][START_REF] Lynch | Genetics and Analysis of Quantitative Traits[END_REF]. It has long been known that in humans, handedness is heritable. This fact has been shown in cross-fostering studies [START_REF] Carter-Saltzman | Biological and sociocultural effects on handedness: Comparison between biological and adoptive families[END_REF][START_REF] Hicks | Human handedness: A partial cross-fostering study[END_REF][START_REF] Longstreth | Human handedness: More evidence for genetic involvement[END_REF][START_REF] Saudino | Handedness, footness, eyedness and earedness, in the Colorado Adoption Project[END_REF], parent-offspring resemblance studies [START_REF] Chamberlain | The inheritance of left-handedness[END_REF][START_REF] Rife | Handedness, with special reference to twins[END_REF][START_REF] Coren | Family patterns in four dimensions of lateral preference[END_REF][START_REF] Gangestad | Parental handedness and relative hand skill: A test of the developmental instability hypothesis[END_REF][START_REF] Hicks | Human handedness: A partial cross-fostering study[END_REF][START_REF] Mckeever | A new family handedness sample with findings consistent with X-linked transmission[END_REF], twins studies [START_REF] Medland | Handedness in twins: Joint analysis of data from 35 samples[END_REF][START_REF] Medland | Genetic influences on handedness: Data from 25,732 Australian and Dutch twin families[END_REF][START_REF] Sicotte | Handedness in twins: A metaanalysis[END_REF], and a genetic association study [START_REF] Armour | Genome-wide association study of handedness excludes simple genetic models[END_REF]. The measure of heritability has been analysed several times during the last hundred years (e.g., [START_REF] Annett | Handedness in families[END_REF][START_REF] Chamberlain | The inheritance of left-handedness[END_REF][START_REF] Coren | Family patterns in four dimensions of lateral preference[END_REF][START_REF] Falek | Handedness: A family study[END_REF][START_REF] Hicks | Human handedness: A partial cross-fostering study[END_REF][START_REF] Mcgee | Population genetic analysis of human hand preference: Evidence for generation differences, familial resemblance, and maternal effects[END_REF][START_REF] Mckeever | A new family handedness sample with findings consistent with X-linked transmission[END_REF][START_REF] Merrell | Dominance of eye and hand[END_REF][START_REF] Rife | Handedness, with special reference to twins[END_REF] Published version: https://doi.org/10.1038/s41437-019-0274-3 [START_REF] Risch | Segregation analysis of human hand preference[END_REF][START_REF] Warren | Heritability and linkage analysis of hand, foot, and eye preference in Mexican Americans[END_REF], although the various resulting estimates are probably not directly comparable. First, handedness was measured differently across the studies, and some of the tasks considered, such as writing handedness, are prone to cultural influences [START_REF] Shimizu | Handedness and familial sinistrality in a Japanese student population[END_REF][START_REF] Teng | Handedness in a Chinese population: Biological, social, and pathological factors[END_REF], thus probably affecting the estimate of heritability.

Second, the samples used to estimate the handedness heritability were from different places, different years or different centuries and were not always representative of the general population. Heritability is not an intrinsic property of a trait: it varies with phenotypic and additive genetic variances and thus can vary across populations and across generations [START_REF] Falconer | Introduction to Quantitative Genetics[END_REF][START_REF] Lynch | Genetics and Analysis of Quantitative Traits[END_REF]. Therefore, the interpretation of the variation in the published estimates of handedness heritability is unclear. In addition, most heritability estimates published thus far seem to concern only samples from industrialized countries.

Here, we sampled individuals from a non-industrialized area, Flores and Adonara Islands from Indonesia, where violent conflicts are relatively frequent and tribal wars were still prevalent very recently. We recorded their selfdeclared handedness and the handedness assignment of their kin members. The resulting information on pedigrees allowed the use of modern tools to estimate handedness heritability for these populations. Then, we collected all the published estimates of handedness heritability, or calculated them using raw data when available, to analyse the variability of heritability estimates as a function of the country type (industrialized or not), taking into account the Published version: https://doi.org/10.1038/s41437-019-0274-3 method of measuring handedness, the left-handedness frequency, and the sampling year.

Materials and Methods

Sampling

Sampling was performed on the islands of Flores and Adonara, Indonesia. On these islands, people generally work in traditional agriculture.

Violence is relatively frequent, either as ritualized violence, such as the whipping duel (called tjatjik) involving groups of participants, or communal battles involving entire villages to settle disagreements over land ownership and use rights (perang tanding, or land war); however, various other types of disputes are also likely to lead to violence [START_REF] Barron | Local conflict in post-Suharto Indonesia: Understanding variations in violence levels and forms through local newspapers[END_REF][START_REF] Clark | Ten Land and Natural Resource Conflict Case Studies from East Java and Flores[END_REF][START_REF] Downs | Head-hunting in Indonesia. Bijdr Tot Taal-Land-En Volkenkd[END_REF][START_REF] Erb | Uniting the bodies and cleansing the village': Conflicts over local heritage in a globalizing world[END_REF]. Although there has been a trend in recent years to find or impose other forms of conflict resolution, interpersonal violence is still present in the 21 st century. For example, over three years (2001)(2002)(2003), 227 violent conflicts were recorded in Flores, resulting in 313 cases of injuries and 117 deaths, generally facilitated by traditional weapons such as knives, machetes, stones, and sticks [START_REF] Barron | Counting Conflicts: Using Newspaper Reports to Understand Violence in Indonesia[END_REF]. This corresponds to a rate of 2.36 homicides/year for 100,000 inhabitants (taking 1,652,640 as the that self-declared by the now-focal individual: in all cases (N = 99), an exact concordance was observed. At the beginning of each interview, the participants were informed of the general aim of the study, the type of data to be collected and that the data would only be used anonymously for a scientific purpose. A written voluntary consent was obtained prior to data collection. The interviews were conducted in the Bahasa Indonesia language in the presence of an Indonesian researcher. No financial incentive was provided. Sampling was performed independently of the local proportion of left-handers, although the snowball effect resulted in a higher proportion of left-handers (left-handed neighbours were sometimes solicited by participants as soon as the purpose of the study was disclosed). These non-randomly sampled participants (N = 32) and their associated non-focal kin members (N = 487) were removed from the final sample because the frequency of the trait studied affects heritability estimate [START_REF] Lynch | Genetics and Analysis of Quantitative Traits[END_REF]. After removing individuals with incomplete data (N = 414), a final sample of 650 independent pedigrees (see Figure 1 for an example), corresponding to a total number of 11 490 individuals (focal and non-focal), was obtained. The total number of left-handed subjects was 755 (6.60%), and the total number of right-handed subjects was 10 735 (93.40%).

Among individuals of known age (i.e. focal individuals), right-handedness was significantly (Binomial regression, X 2 = 9.62 , df= 1, P = 0.002) associated with older age, with a 0.025 increase of linear unit (i.e., log of odd ratio) for each additional year. For the non-focal individuals, the variation of left-handedness was evaluated across four individual categories with different mean ages (1: grand-parents of focal; 2: parents of focal; 3: sibs of focal; 4: child of focal).

Left-handedness frequency significantly increased between categories 1 and 2, was not different between categories 2 and 3, and was marginally significantly increasing between categories 3 and 4 (Fisher exact test on 2x2 contingency table, P < 10 -5 , P = 0.63, and P = 0.044, respectively).

Heritability

The total phenotypic variance for handedness was described as:

V P =V A +V R
, where V A is the additive genetic effect and V R is the residual variance. The heritability (h 2 ) of a phenotypic trait is defined as the proportion of phenotypic variance that is attributable to additive genetic effects:

h 2 = V A /(V A +V R ) (1)
Published version: https://doi.org/10.1038/s41437-019-0274-3

Handedness (right/left-handed) was considered a threshold trait. This means that the two options are determined by an underlying continuous distribution, or 'liability' [START_REF] Falconer | Introduction to Quantitative Genetics[END_REF][START_REF] Lynch | Genetics and Analysis of Quantitative Traits[END_REF], with a threshold of sensitivity. Individuals with liabilities above the threshold are left-handed, whereas those below the threshold are right-handed. Based on this assumption, we estimated heritability for handedness using a pedigreebased animal model. The pedigree was created using the pedigreemm R package. We estimated genetic variance components of handedness with Bayesian inferences using a univariate animal model. Generalized linear mixed models were fitted with Markov Chain Monte Carlo (MCMC) techniques using the MCMCglmm R package [START_REF] Hadfield | MCMC methods for multi-response generalized linear mixed models: The MCMCglmm R Package[END_REF]. A random effect was introduced, relating individuals to their additive genetic values through the pedigree. Sex was included as a fixed effect. A binomial error structure with a probit link was used, hence V R = 1 [START_REF] Ødegård | A simple algorithm to estimate genetic variance in an animal threshold model using Bayesian inference[END_REF][START_REF] Charmantier | Heritability of short-scale natal dispersal in a large-scale foraging bird, the wandering Published version[END_REF]. Two distinct functions were used as uninformative or weakly informative prior distributions for V A : an inverse gamma (Prior1: V = 1 and ν = 0.002) or a flat improper prior (Prior2: V = 1, ν = 0), as proposed by [START_REF] Hadfield | MCMCglmm Course Notes[END_REF]. A MCMC was run for 10 7 steps and sampled every 100 steps after a burning phase of 10 000 steps.

The Heidelberg stationarity test was used to evaluate the convergence of the MCMC chain [START_REF] Heidelberger | Simulation run length control in the presence of an initial transient[END_REF]. The posterior distribution of the heritability was computed from the posterior distribution of the variance components using equation 2.16 of [START_REF] Hadfield | MCMCglmm Course Notes[END_REF]; the mean and 95% credible interval were then extracted. The presence of a maternal effect was not tested due to the limited number of cases (N = 2) in the pedigrees where maternal-only contribution could be measured, i.e. where a women had children with distinct men. Models with/without an additive genetic variance, or with/without a fixed sex effect were compared using the deviance information criterion (DIC, [START_REF] Spiegelhalter | Bayesian measures of model complexity and fit[END_REF], following [START_REF] Hadfield | MCMC methods for multi-response generalized linear mixed models: The MCMCglmm R Package[END_REF] and as implemented in MCMCglmm.

Literature data

To find primary data on heritability of handedness, we proceeded in two ways. First, we performed literature searches on accessible databases to find recent publications. Second, to find older data, we scanned cited literature. In addition, inspection of review articles and books from 1957 to 2009 ensured that no major older papers were overlooked [START_REF] Annett | A model of the inheritance of handedness and cerebral dominance[END_REF][START_REF] Clark | Left-handedness: Laterality characteristics and their educational implications[END_REF][START_REF] Llaurens | Why are some people left-handed? An evolutionary perspective[END_REF][START_REF] Mcgee | Population genetic analysis of human hand preference: Evidence for generation differences, familial resemblance, and maternal effects[END_REF][START_REF] Mcmanus | Handedness, language dominance and aphasia: a genetic model[END_REF][START_REF] Mcmanus | The Inheritance of left-handedness[END_REF][START_REF] Mcmanus | Genetic of handedness, cerebral dominance and lateralization[END_REF][START_REF] Porac | Lateral Preferences and Human Behaviour[END_REF]. Papers that classify individuals in discrete categories (usually right and left handers) and provided raw data on handedness over two generations (parents and offspring), or from which raw data could be unambiguously reconstructed, were considered for heritability computation. Cases displaying at least 100 family units were retained. When information was missing (e.g., year of sampling), authors were tentatively contacted to provide the missing information. Papers concerned with the quantification of relative hand performance or preference, e.g., the peg-moving task or handgrip, were not considered. For each estimate, the way in which handedness was measured (writing handedness, handedness for other uni-

Published version: https://doi.org/10.1038/s41437-019-0274-3 manual tasks, quantitative index, index with "any left" criterion, selfevaluation), the type of country (industrialized or not), the year of sampling, the sample size, the type of sample (student, general population), and the sample frequency of left-handedness were recorded. For one particular study [START_REF] Hicks | Human handedness: A partial cross-fostering study[END_REF], the handedness of the parent generation was measured differently than that of the offspring generation (writing handedness and index, respectively). This study was coded as using writing handedness criteria, although the other possible type of coding (index) or even removing this study did not qualitatively change the results. The university student sample described by Chaurasia and Goswami (in McManus 1985) from Bhopal, India, was considered as originating from an industrialized country. In the university student sample described by [START_REF] Singh | Hand preference and approval among Hindus and Muslims in India[END_REF] from India, individuals were allowed to ascribed the handedness of their relatives using three categories (right, left, ambidextruous), and they reported an unusual proportion of ambidextrous relatives. As the validity of ascribed ambidextry has never been evaluated, these data were not considered.

First, heritability on the observed scale (h 2 _obs) was estimated from parent-offspring regression. The classical formula proposed by [START_REF] Dempster | Heritability of threshold characters[END_REF] to compute heritability on the liability scale was not used, as it leads to overestimates when the left-handed frequency is low (typically lower than 0.25, which is the case for 93% of the present samples), and to larger overestimates when the heritability if large (48% of the samples have h2_latent >0.2, see below), as shown by [START_REF] Vleck | Estimation of heritability of threshold characters[END_REF]. For comparison purpose,

Published version: https://doi.org/10.1038/s41437-019-0274-3 heritability on the liability scale (h2_l) was computed using the same method as for the Flores sample, using a pedigree-based animal model. As this method necessitates a large amount of precise pedigrees, pedigrees of simple families were generated for each study, keeping constant the observed left-hander frequency (pobs) and h 2 obs. For one estimate, 500 parent-offspring pedigrees were generated. RR, RL, and LL parents were in proportion of (1 -pobs)², 2pobs

(1-pobs), and pobs², respectively, and each had 10 offspring. The probability, for each offspring, to be left-handed was (1 -h 2 obs)pobs + h 2 obs(pp), where pp is the left-handedness frequency in parents (0, 0.5, and 1, for RR, RL, and LL parents, respectively). From these pedigrees, heritability on the liability scale was estimated as described above using the MCMCglmm R package. For each study, this process was performed 30 times, and the mean and variance of these 30 estimates were computed. When the true heritability value was close to zero, some MCMC did not converge, and the corresponding estimates were not considered, providing an overall slight overestimate of the mean. To reduce such cases, the number of pedigrees and the number of offspring per family were increased (up to 700 pedigrees, and 30 offspring per family). In order to verify that no bias were introduced, heritability on the observed scale was computed from each set of pedigrees, and compared to the original h 2 _obs value. The correlation between the two values was 0.999.

A linear regression was used to assess how estimates of heritability vary according to the type of country (qualitative variable, two modalities: industrial, non-industrial), controlling for the year of sampling (quantitative Published version: https://doi.org/10.1038/s41437-019-0274-3 variable, centred), the frequency of left-handedness (quantitative variable, centred), and the type of handedness measure (qualitative variable, four modalities: writing, other uni-manual tasks, quantitative index, index with "any left" criterion, self-evaluation). Variances of heritability estimates were used as a weight variable. Some studies provided several estimates of handedness heritability using the same dataset; thus, study identity was introduced as a random-effect variable and linear mixed models were used (function lmer of lmerTest v3.1-0 R package). The significance of an independent variable was calculated by removing it from the full model and comparing the resulting variation in deviance using a X² test (function Anova of the car v3.0-2 R package).

Result

Among the 11 490 individuals sampled from Flores and Adonara islands, 755 were left-handers, or 6.6 % (Table 1). This proportion remained similar (4.6-8.2%) for the various classes of individuals (parents, child, sibs and spouse's family), suggesting that no sampling bias occurred. The only exception were the focal individuals, with an excess of left-handers (14.6%), and the grand-parents, with a deficit of left-handers (2.3%).

Pedigree data from Flores and Adonara Islands were used to estimate handedness heritability using a pedigree-based generalized linear mixed model.

The DIC from each model with/without an additive genetic variance and with/ without a fixed sex effect were not different for both Prior1 and Prior2, suggesting that the results seem to be prior independent. Models incorporating sex and maternal effect were not retained, as models including only animal as a random effect and sex as a fixed effect were associated with the lowest DIC value (DIC = 3,873.9 for Model 2; DIC = 3,873.2 for Model 2a, see Table 2).

These models generated a converging chain, as confirmed by the Heidelberg stationarity test of convergence (P = 0.73 for Model 2; P = 0.44 for Model 2a), with an effective sample size of the mean at 3,160 (Model 2 and Model 2a).

The traces and density of the posterior distribution of both Prior1 and Prior2

were not different, and the posterior distributions were relatively symmetrical and unimodal (Figure 2). From Model 2 and Model 2a, heritability estimates were h 2 = 0.556 (95 credible interval from 0.472 to 0.645) and h 2 = 0.556 (95% credible interval from 0.471 to 0.643), respectively. When focal individuals were excluded from the pedigrees to partially control for a residual sampling bias, the heritability estimates were h 2 = 0.582 (95% credible interval from 0.481 to 0.677) and h 2 = 0.565 (95% credible interval from 0.477 to 0.672), for Prior1 and Prior2, respectively.

A total of 18 papers describing 24 studies displayed handedness data over two generations that was sufficient to compute an estimate of heritability.

On the overall data set (including the current Flores estimate), heritability on the liability scale ranged from 0.04 to 0.56 (Table 3). This variability was explained by the type of country, with non-industrialized countries (i.e. Flores) displaying a higher heritability value (P = 1.1 × 10 -2 , Table 4). The weighted mean estimate was h 2 = 0.20 (SEM = 0.026) for industrialized countries and h 2

Published version: https://doi.org/10.1038/s41437-019-0274-3 = 0.56 (95% credible interval from 0.47 to 0.64) for the only non-industrialized country. The variability in heritability estimates was also explained by the year of sampling (Figure 3), with a decrease of heritability of 0.04 (SE = 0.012) per decade. The type of handedness measure, and the frequency of left-handedness had non-significant effect (P = 0.960, and P = 0.761, respectively, Table 4).

Discussion

The overall analysis of the available data shows that the heritability of direction of handedness is higher in a non-industrialized society compared to that in industrialized countries. The type of handedness measurement and the left-handedness frequency had no significant influence on the heritability estimate.

A relatively high heritability estimate of handedness was found in Flores and Adonara Islands. Indonesia is now categorized as an NIC (newly industrialized country), although most industries are located on Java Island, and the economy of Flores and Adonara is still based on traditional agriculture.

Indonesia has recently extended the road and electric networks in Flores, with increasing market integration as a result. Nevertheless, manual work is still intense, and during the sampling sessions, we saw people building houses without the help of any mechanized tools, constructing fishing boats from tree trunks with axes and traditional manual tools, practising fully manual agriculture, manual weaving, etc. Thus, Flores and Adonara could still be considered non-industrialized areas. This is the first time that handedness

Published version: https://doi.org/10.1038/s41437-019-0274-3 heritability has been measured in populations where traditional violence is still prevalent or has been prevalent very recently. One frequent type of violence in Flores concerns land disputes [START_REF] Clark | Ten Land and Natural Resource Conflict Case Studies from East Java and Flores[END_REF]), leading to warfare involving only men. The annual homicide rate in Flores is estimated to be approximately 39 homicides per 100,000 inhabitants [START_REF] Barron | Counting Conflicts: Using Newspaper Reports to Understand Violence in Indonesia[END_REF], one of the highest rates recorded among countries worldwide (United Nations Office of Drugs and Crime 2011; 2013). This rate is also higher than the rate calculated for Indonesia as a whole (less than 1 annual homicide per 100,000 inhabitants over the period 2000-2012; United Nations Office of Drugs and Crime 2013).

Several factors could possibly bias the estimate towards higher values, such as an inflated left-hander frequency in the sample. All identified individuals sampled non-randomly (mainly left handers) were removed from the analysis, although it is possible that some were missed during the recording process in field conditions. To control for such a possible residual effect, the analysis was also performed by removing all focal individuals from the pedigrees, although this removal did not lowered the heritability estimate, suggesting that a sampling bias is probably not generating an overestimate.

Finally, a drastic procedure was performed: all left-handed focal individuals were removed, along with all their associated pedigrees, with a resulting heritability estimate of h 2 ≃ 0.53 (95% credible interval from 0.42 to 0.65).

This value could thus be seen as a conservative minimum, underestimating the true value as it is computed from a sample from which the frequency of lefthandedness has been artificially decreased. Nevertheless, this minimal value is significantly higher than the weighted mean estimate from industrialized countries (h 2 = 0.20, SEM = 0.026).

The sampling year had a negative influence on the estimate of heritability of handedness, suggesting a decrease in the value of heritability over the 20 th century in industrialized societies. This decrease of heritability is not resulting from a decrease of left-handedness frequency, as the lefthandedness frequency was controlled for in the model. In addition, heritability on the liability scale is independent from the frequency of the observed trait (here left-handedness). The evolution of left-handedness frequency could not be properly studied using the present sample, as some studies in Table 3 did not consider randomly sampled individuals and samples rich in left-handers were sometimes considered (e.g., [START_REF] Chamberlain | The inheritance of left-handedness[END_REF], Annet 1973[START_REF] Mckeever | A new family handedness sample with findings consistent with X-linked transmission[END_REF]. No maternal effect on handedness inheritance could be evaluated in Indonesia. This was due to the limited number of cases (N = 2) in the pedigrees where maternal-only contribution could be measured, i.e. where a women had children with distinct men. A maternal effect on offspring handedness was previously proposed; there was a higher prevalence of left-handedness in children when the mother was left handed compared to the prevalence when the father was left handed in a family unit with discordant handedness (see [START_REF] Mcmanus | Genetic of handedness, cerebral dominance and lateralization[END_REF] for a review). Whether the maternal effect is geographically variable, or it varies with the type of handedness measure is not known. Most studies reporting a maternal effect used writing as a measure of handedness (e.g., [START_REF] Annett | Handedness in families[END_REF][START_REF] Ashton | Handedness: An alternative hypothesis[END_REF][START_REF] Chamberlain | The inheritance of left-handedness[END_REF][START_REF] Spiegler | Incidence of left-handed writing in a college population with reference to family patterns of hand preference[END_REF], although it was also reported when quantitative indexes (e.g., [START_REF] Falek | Handedness: A family study[END_REF][START_REF] Harkin | Evidence for a maternal effect on infant handuse preferences[END_REF][START_REF] Risch | Segregation analysis of human hand preference[END_REF], or "any left" criterion (McGee and Cozad 1980) indexes were used. As this maternal effect seems strong enough to be detected despite the variability of the handedness measurements, it may represent a genuine effect in industrialized countries, possibly mediated by still unidentified cultural or genetic factors.

Whether or not these factors are also operating in non-industrialized countries remains to be established.

The genetics of handedness have not yet been fully deciphered (e.g., [START_REF] Ocklenburg | Handedness: a neurogenetic shift of perspective[END_REF][START_REF] Brandler | The genetic relationship between handedness and neurodevelopmental disorders[END_REF][START_REF] Shore | The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts[END_REF][START_REF] Güntürkün | Ontogenesis of Lateralization[END_REF]. Major gene models, even when considering various dominance or penetrance levels (e.g., [START_REF] Trankell | Aspects of genetics in psychology[END_REF][START_REF] Annett | A model of the inheritance of handedness and cerebral dominance[END_REF][START_REF] Levy | A model for the genetics of handedness[END_REF][START_REF] Mcmanus | The Inheritance of left-handedness[END_REF][START_REF] Armour | Genome-wide association study of handedness excludes simple genetic models[END_REF], were found insufficient to account for the inheritance data, suggesting that several interacting genes contribute to the trait. Most of the genetic analyses for lateral preference have been performed in industrialized countries, where the environmental conditions are generally not favourable for the expression of general handedness at the individual level. It is possible that the penetrance of the genes affecting handedness has been modified in industrialized countries, where arm or hand specialization is less needed. The new environmental conditions thus affect the former expression of the trait, although the details of this change in expression are not clear. For example, writing corresponds to a culturally important task in modern societies compared to traditional ones.

Writing handedness is prone to cultural influences [START_REF] Bryden | Handedness in native Amazonians[END_REF][START_REF] Mandal | Cultural difference in hand preference: Evidence from India and Japan[END_REF][START_REF] Shimizu | Handedness and familial sinistrality in a Japanese student population[END_REF][START_REF] Teng | Handedness in a Chinese population: Biological, social, and pathological factors[END_REF] In conclusion, the data are consistent with a decrease in handedness heritability following the industrialization process and/or the associated decrease in violence using traditional weapons. The difference in heritability between industrialized and non-industrialized countries suggests that selection of handedness is thus likely to differ between traditional and modern societies.

Additional data from other non-industrialized countries, and possibly from areas that do not use modern weapons to settle interpersonal or inter-group disagreements, are required to further evaluate this hypothesis. As the handedness heritability in Flores is at the same level as in industrial countries at the beginning of the XXth century, it will be interesting to follow in the future how this value evolves according to social changes in Flores, particularly those affecting hand usage [START_REF] Schaafsma | Handedness in a nonindustrial society challenges the fighting hypothesis as an evolutionary explanation for left-handedness[END_REF]).

Flores

  population size in 2002, Baron 2005), a value on the upper decile of the world distribution of communal and organized armed conflict where none of the parties is the government (UCDP Non-State Conflict Dataset, version 18.1, https://ucdp.uu.se/downloads/#d 7 ). Three sampling sessions were performed Published version: https://doi.org/10.1038/s41437-019-0274-3 (2015, N = 204; 2016, N = 302; and 2017, N = 301) in 174 locations from most regencies (kabupaten) on the islands. Focal individuals were analysed for manual specialization in 2015 and 2016 by Nurhayu et al. (2018), with the conclusion that self-declaration is a reliable and sufficient measure of handedness in Flores and Adonara Islands. In addition to providing their selfdeclared handedness, focal individuals declared the handedness of their close kin and other family members, resulting in a sample of 10 849 non-focal individuals. When a non-focal individual was later sampled as a focal individual, the handedness attributed by the focal individual was compared to

  It has been suggested that left-hander frequency in England decreased in the 19 th century and then increased during the last century based on the comparison of arm waving in Victorian English films(1897 and 1913) and Google images from the modern population[START_REF] Mcmanus | Declining left-handedness in Victorian England seen in the films of Mitchell and Kenyon[END_REF]. Arm waving is not a complex task requiring hand specialization, such as writing or throwing, and has not been considered previously in the various studies on handedness. The way in which arm waving handedness correlates with the other classical measures of handedness, including self-declaration, is currently unknown. It has been suggested that historical and geographical variations in lefthandedness frequency are primarily genetic in origin, rather that due to differences in direct social pressures[START_REF] Mcmanus | The history and geography of human handedness[END_REF]. However, the recent Published version: https://doi.org/10.1038/s41437-019-0274-3 evolution of the left-handedness frequency remains a debatable subject due to the variability of methods used to assess handedness and the variability of results concerning the correlation between the various tasks considered (for example,[START_REF] Milenkovic | Modification of the Edinburgh Handedness Inventory: A replication study[END_REF] versus Briggs and Nebes 1975[START_REF] White | Handedness assessment inventory[END_REF]. It is thus possible that the different measures of handedness are not measuring the same phenomenon. To better understand that situation, the various handedness studies over the last century should be considered in order to evaluate the evolution of left-handedness frequency for each measure of handedness. This aspect seems less important for the estimation of heritability, as the variability of the various estimates was not explained by the method of measuring handedness.

Figure 1 .

 1 Figure 1. Example of a pedigree from Flores. Females are represented with a circle, and males are represented with a square. Left-handers are represented by filled symbols, and right-handers are represented by open symbols. 'Focal' designates the sampled individual. Performed with the R package kinship2.

Figure 2 .

 2 Figure 2. Heritability posterior distributions of Model2 (with Prior1) and Model2a (with Prior2). (a) Traces of the posterior values along the Markov chain for each prior (black line: Prior1; grey line: Prior2). (b) Density of posterior distribution for Prior1 (black curve) and Prior2 (grey curve). Vertical lines indicate the means.

Figure 3 .

 3 Figure 3. Heritability estimates from industrialized and non-industrialized countries. Each circle represents an estimate from a study, or the mean of several estimates from a same study. The regression line for industrialized countries is shown (dotted line).

  Published version: https://doi.org/10.1038/s41437-019-0274-3 forgotten) or overestimate (left-handers are conspicuous and more often remembered) the left-handedness frequency and how this modified lefthandedness frequency affects heritability estimates. Third, paternity uncertainty could be a possible bias, introducing errors in the pedigrees. We are not aware of non-paternity estimates from Indonesia and specifically from Flores or Adonara Islands. However, the proportion of extra-pair paternity in human populations is very low[START_REF] Larmuseau | Cuckolded fathers rare in human populations[END_REF]; thus, paternity uncertainty is probably not a strong bias, even if it remains a noisy parameter.

	, thus increasing the
	environmental variance; the resulting effect is a low estimate of the heritability
	of writing handedness or a lower heritability estimate when the writing hand
	contributes to the measure of handedness. Without proper knowledge of the
	genetics of handedness, it is difficult to infer the various existing environmental
	interactions and to understand how handedness correlations for various tasks
	partially decrease in industrialized countries. As a consequence, it is difficult to
	decide which handedness measure would be rationally valid among single tasks
	or among various ways to compute indexes from several tasks.
	This study presents several limitations. First, it provides only one
	heritability estimate from a relatively violent and non-industrialized country.
	The relatively high value could not be unambiguously attributed to a particular
	variable, such as intense and specialized manual labour. Only additional data
	from other non-industrialized areas with variable degrees of violence involving
	only traditional weapons will allow us to form conclusions. Second, the
	constructed pedigrees relied largely on the collection of indirect data. Although
	the quality of these indirect data were controlled when non-focal individuals
	were also sampled as focal individuals (and a 100% concordance was found),
	some misattribution of handedness for non-focal individuals was still possible,
	as only 0.91% of non-focal individuals were verified. Removing focal

individuals did not decrease the heritability estimate, suggesting that this possible bias remains minimal. It is difficult to assess whether some misattribution will underestimate (left-handers are a minority and more often

Table 1 .

 1 Handedness composition of the members of the pedigrees, relatively to focal individuals.

	Individuals	R	L	All	Left-Handedness frequency
	Focal	598	102	700	0.146
	Parents	1251	85	1336	0.064
	Grand-parents	974	23	997	0.023
	Child	1393	125	1518	0.082
	Sibs	2663	167	2830	0.059
	Spouse and spouse'family	828	40	868	0.046
	Others (uncles. aunts. cousins. etc.)	3028	213	3241	0.066
	All	10735	755	11490	0.066

Acknowledgements

We are grateful to the Programme Magister Menuju Doktor untuk Sarjana Unggul (PMDSU) 2015 for providing funding to

Data archiving

The data and R scripts for generating Tables 1,2, 4, and Fig. 3, are available from the Zenodo open-access repository at https://doi.org/10.5281/zenodo.3460771.

Published version: https://doi.org/10.1038/s41437-019-0274-3 BS, to PHC -Nusantara grant # 41100 WC, to Bernard Godelle for advice, to Jacques David and Anne Charmantier for advice on heritability estimates using

Conflict of interest

The authors declare that they have no conflict of interest.

Model

Prior

Fixed effect Random effect DIC Left-hander: any left for ten tasks 6.51 x 10 -3

Chaurasia & Goswami, unpublished (data in [START_REF] Mcmanus | Handedness, language dominance and aphasia: a genetic model[END_REF] Indonesia (Flores and Adonara) Self-reported handedness 2.32 x 10 -2 a. When the year of sampling was not indicated, the year of paper submission was used as a proxy.