Short Report

The Cognitive Ability of Extinct Hominins: Bringing Down the Hierarchy UsingGenomic Evidences

VANESSA R. PAIX~AO-CORTES,1 LUCAS HENRIQUES VISCARDI,1,2 FRANCISCO MAURO SALZANO,1 MARIA C�ATIRA BORTOLINI,1

AND T�ABITA H €UNEMEIER1*1Departamento de Gen�etica, Instituto de Biociencias, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil2Laborat�orio de Ensino e Pesquisa em Antropologia e Arqueologia, Instituto de Ciencias Humanas e da Informac~ao, Universidade Federal doRio Grande, Rio Grande, RS, Brazil

Background: The availability of the full genomes of Homo sapiens, Homo neanderthalensis, and Denisovans, aswell as modern bioinformatic tools, are opening new possibilities for the understanding of the differences and similar-ities present in these taxa.

Methods: We searched for cognitive genes, examined their status in the genomes of these three entities. All substitu-tions present among them were retrieved.

Results: We found 93 nonsynonymous substitutions in 51 cognitive genes, in which the derived allele was present inarchaic and modern humans and the ancestral allele in other nonhuman primates.

Conclusions: The general picture obtained is of similarity in cognitive genes between extinct and extant humans.Am. J. Hum. Biol. 25:702–705, 2013. VC 2013 Wiley Periodicals, Inc.

Despite sharing most of their genetic background,humans are remarkably different from other great apes(Noonan, 2010). The most striking differences are the cog-nitive skills acquired by Homo sapiens, and the fact thatthe knowledge had been accumulated and refinedthroughout its evolution as a species (Varki and Altheide,2005). Within the genus Homo these differences may notbe as striking. Homo sapiens, Neandertals, and Deniso-vans coexisted, probably interacting with each other inthe same ecological niche (Mellars, 2004; Noonan, 2010;Reich et al., 2010). Many assumptions have been madeabout the reasons for the replacement of archaic by mod-ern humans in Eurasia, many of them related to thecognitive differences among them. Some of these assump-tions are based on archeological record, pointingto a lower sophistication in the cultural traits of thearchaic humans (Henshilwood, and Marean, 2003;Mellars, 2004).

Recently, with the publication of the genomes of thesetwo extinct Homo species (Neandertal, Green et al., 2010;Denisovans, Reich et al., 2010) new discoveries have con-tributed to a better understanding of the level of cognitivedevelopment of Neandertals (for instance, speech ability,Krause et al., 2007).

In this study we investigated the variability in 162 cog-nition genes present in the genomes of these three Homospecies, in an attempt to verify the variants that mayhave played an important role in cognitive abilitiesdevelopment.

MATERIALS AND METHODS

Genes directly related to cognitive ability were searchedusing AmiGO database (GO:0050890; cognition: http://amigo.geneontology.org/cgi-bin/amigo/browse.cgi). Genedetails were obtained from GeneCards (http://www.gene-cards.org/). All nonsynonymous changes in these geneswhich were different in modern humans and chimpanzeeswere retrieved in the gorilla, orangutan, Rhesus, marmo-set, tarsier, mouse lemur, and bushbaby, as well as in theNeandertal and Denisova specimen genomes using theUSCS browser (http://genome.ucsc.edu/cgi-bin/hgBlat?

org5human). We considered the allele as ancestral everytime it was present in chimpanzee and in other nonhu-man primates, while a derived allele is that present onlyin Homo. Any allele could only be considered as exclusiveif it was present in only one of the primates studied.Nucleotide differences considering theses 162 genes, aswell as in other relevant regions (e.g enhancer) werechecked using the track “variant calls from high-coveragegenome sequence of an archaic Denisovan individual(hg19)” and “Neandertal Assembly and Analysis (hg18)”.The Grantham score (Grantham, 1974) was then used tocategorize all the corresponding amino acid changes intoclasses of chemical similarity. They were classified as con-servative (0–50), moderately conservative (51–100), mod-erately radical (101–150), or radical (>150).

RESULTS AND DISCUSSION

The ontology search allowed the selection of 162 genesrelated to cognitive processes. We found 93 non-synonymous substitutions in 51 cognitive genes, in whichthe derived allele was present in humans (archaic and/ormodern) and the ancestral allele in nonhuman primates(Table 1). It is noteworthy that the TANC1 gene has 8nonsynonymous changes (Fig. 1). This gene is associatedto visual learning, referring to any process in an organismin which a change in behavior occurs in response to

Additional Supporting Information may be found in the online versionof this article.

Contract grant sponsor: Conselho Nacional de DesenvolvimentoCient�ıfico e Tecnol�ogico (CNPq), Fundac~ao de Amparo �a Pesquisa doEstado do Rio Grande do Sul (FAPERGS), and Programa de Apoio aN�ucleos de Excelencia (PRONEX).The first two authors contributed equally to this work.

*Correspondence to: T�abita H€unemeier, Programa de P�os-Graduac~aoem Gen�etica e Biologia Molecular, Departamento de Gen�etica, Instituto deBiociencias, Universidade Federal do Rio Grande do Sul, Caixa Postal15053, 91501-970 Porto Alegre, RS, Brazil. E-mail: hunemeier@gmail.com

Received 6 February 2013; Revision received 3 June 2013; Accepted 11June 2013

DOI: 10.1002/ajhb.22426Published online 1 August 2013 in Wiley Online Library

(wileyonlinelibrary.com).

VC 2013 Wiley Periodicals, Inc.

AMERICAN JOURNAL OF HUMAN BIOLOGY 25:702–705 (2013)

repeated exposure to a visual cue. Remarkably, 95% of theNeandertal positions retrieved have the same allele foundin sapiens, in 2% the locus was in heterozygosis for ances-tral and derived alleles, and 3% showed new variants. Inthe Denisova specimen just two positions were recoveredwith an ancestral allele and one locus in heterozygosis.From the 93 substitutions, 49% were classified as conserv-ative, 38% as moderately conservative, 12% as moderatelyradical, and 1 as radical (Supporting Information TableS1). Thirty three of the 93 (35%) were not fixed in Nean-dertal or H. sapiens and the additional alleles found inour species besides those listed in Supporting InformationTable S1 occur in all continents (Supporting InformationTable S2).

According to Green et al. (2010), some genes associatedwith diseases that affect cognitive capacities present thederived alleles in modern human noncoding regions. Theauthors hypothesized that these genes involved in cogni-

tive development were positively selected during the earlyhistory of anatomically modern humans.

Meyer et al. (2012) suggested that Denisovans had dif-ferent cognitive abilities from extant humans based onunique modern human nonsynonymous changes found innine genes associated with brain function or nervous sys-tem development.

Our analysis with coding regions point in another direc-tion, since H. sapiens, Neandertals, and Denisova are vir-tually equal when the molecular aspects involved in thecognitive processes considered here are compared. Somerecent studies are in accordance with our results. A previ-ous work from our group (Paix~ao-Cortes et al., 2012) iden-tified four genes involved in neurogenesis and cognition(ASPM, MCPH1, AHI1, and KLK8) that had acceleratedevolutionary rates along the lineages leading to Homosince there were no differences between H. sapiens andthe extinct humans. Furthermore, Montgomery and

TABLE 1. Number of cognition genes, of their non-synonymous substitutions, and their functions as ascertained in the Gene Ontology database

N� of changes N� of genes Gene Gene ontologya

1 27 AAAS, ADNP, CASP1, CHST10, CLN8, DRD3, FABP7,FOXP3, GIP, GLP1R, GRM7, HMGCR, HTR1A,MAOA, MEF2A, MUSK, NGF, OXTR, PAFAH1B1,PPT1, RAB3GAP1, RGS14, SLC24A2, SLC11A2,SRF, STS, TAC1

GO:0007612: learning; GO:0007614: Short-term mem-ory; GO:0007613: Memory; GO:0008306: Associativelearning; GO:0008542: Visual Learning;GO:0007611: Learning or memory; GO:0007612:Learning

2 16 APBB1IP, CHRNA4, CYP7B1, CYP8B1, DRD4, FOXP2,GALR2, IL1RN, ITGA8, OXT, PDE1B, PJA2,RASGRF1, SERPINF1, STRA6, VLDLR

GO:0008542: Visual learning; GO:0050890: Cognition;GO:0008355: Olfactory learning; GO:0042297: Vocallearning; GO:0007611: Learning or memory;GO:0007613: Memory; GO:0007616: Long-termmemory; GO:0007614: Short-term memory

3 3 GRIN2A, SLC6A4, RELN GO:0008542: Visual learning: GO:0007613: Memory;GO:0007611: Learning or memory; GO:0007613:Memory; GO:0007616: Long -term memory;GO:0008306: Associative learning

4 3 CHL1, PDCL, HRH1, GO:0050890: Cognition5 1 AFF2 GO:0007611: Learning or memory8 1 TANC1 GO:0008542: Visual learning

aAt least one of these categories is associated with one of the genes indicated in the previous column. Specific information can be supplied on request.

Fig. 1. Phylogenetic tree of four nonhuman and three hominin species considering the 93 nonsynonimous mutations in genes presumablydirectly related to cognitive ability, as well as the constitution of their different regulatory regions. SRGAP2, SLIT-ROBO RHO GTPase activat-ing protein 2; HARS, human accelerated regions; AUST2, autism susceptibility candidate 2; HACNS1, human accelerated conserved noncodingsequence 1; KLK8, kallikrein-related peptidase 8. ND, No data. [Color figure can be viewed in the online issue, which is available atwileyonlinelibrary.com.]

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Mundy (2012) suggested that positive selection in geneslinked to human microcephaly was associated with theevolution of primate brain size and suggested that themajority of phenotypic and developmental traits associ-ated with the evolution of the human brain are conservedacross primates.

Charrier et al. (2012) demonstrated that the SRGAP2gene passed through two partial duplication processes inthe human lineage that led to a difference in its regula-tion by copies that are present in both Homo neandertha-lensis and Homo sapiens. Important implications forcognition, learning, and memory were proposed andenabled them to better understand the ways that led tothe Homo encephalization by changes in regulatoryprocesses.

Regarding noncoding regions, special attention shouldbe given to the study of Oksenberg et al. (2013). Theystudied the candidate enhancer sequences of AUTS2 thatcontains the most significant positively selected genomicregions differentiating sapiens from Neandertals (Greenet al., 2010). Six of the enhancers tested in mice were acti-vated in brain development and/or sensorial tissues, andtwo of them are human accelerated regions (HARs;HAR31, and HACNS369). These authors showed that fourof the six enhancers have variants shared by sapiens andneanderthalensis. We found these variants in Denisova(Supporting Information Table S3).

Green et al. (2010) already indicated that Neandertalscarried the derived state at 91.4% of HARs positions;while Burbano et al. (2012) estimated that at least onearchaic hominin allele existed for 84% of all HARs posi-tions. Additionally, H€unemeier et al. (2010), studyingchanges in a specific HAR (HACNS1; which acts as anenhancer of gene expression influencing important traitssuch as opposable thumbs, manual dexterity, and bipedalwalking) obtained evidence that they were fixed due topositive selection in some period of the hominid evolution-ary history. Supporting Information Table S4 presentsdata from the seven aforementioned regulatory regions inthe three hominin species considered, informing about thesites where they are located, the anatomical regions influ-enced, and the frequencies of the ancestral allele found inthe three hominin species. The prevalences observed aresimilar, with no indication of heterogeneity.

Additionally, we investigated all differences betweenthe human reference genome (Hg19), Denisova and 11modern humans from distinct geographic groups, consid-ering the 162 cognitive genes (Supporting InformationTable S5). The number of total differences is similar, butthe Denisova present 12,332 exclusive alleles, while theSan and Mbuti Pygmy showed 6,461 and 3,692, respec-tively. Other modern humans present a lower number ofvariants, with a clear gradient from Africa. Excluding the93 nonsynonymous substitutions, we can assume that thegreat majority of this variation is represented by synony-mous and intronic variations. Rather than functionalimplications these results can indicate demographic sce-narios where more ancient populations (Denisova, San,and Pygmy) present a larger number of exclusive allelesand/or relatively large populations. The Denisova datawere recently confirmed by preliminary results fromother authors (http://www.sciencemag.org/content/340/6134/799.full).

Together, important coding and regulatory changes forspecific cognitive traits seem to have predated Homo sapi-

ens emergence (Fig. 1). Further analyses must be per-formed to understand how these changes would haveinfluenced the establishment of Homo specific abilities.However, considering our results, if there were cognitivedifferences related to a loss of competitive ability ofextinct humans when compared to anatomic modernhumans, these differences left no striking mark in thecoding genetic background in the studied genes, suggest-ing that other possibilities, as cultural particularities, canbe raised. Our findings are in agreement with new archeo-logical record associated with Neandertal symbolic mate-rial culture. These studies revealed that these homininsmight have shared more behavioral traits with modernhumans than it used to be believed (Caron et al., 2011;Shipman, 2008; Zilh~ao et al., 2009).

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