3rol especificohumano y el desarrollo dela evoluciongen

8/12/2019 3rol Especificohumano y El Desarrollo Dela Evoluciongen

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Review

The Role of Human-Specific Gene Duplications During Brain Development

and Evolution

Takayuki SassaFaculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan

Abstract:One of the most fascinating questions in evolutionary biology is how traits unique to humans, such as their high cognitive

abilities, erect bipedalism, and hairless skin, are encoded in the genome. Recent advances in genomics have begun to reveal differences

between the genomes of the great apes. It has become evident that one of the many mutation types, segmental duplication, has drastically

increased in the primate genomes, and most remarkably in the human genome. Genes contained in these segmental duplications have a

tremendous potential to cause genetic innovation, probably accounting for the acquisition of human-specic traits. In this review, I begin

with an overview of the genes, which have increased their copy number specically in the human lineage, following its separation from

the common ancestor with our closest living relative, the chimpanzee. Then, I introduce the recent experimental approaches, focusing

on SRGAP2, which has been partially duplicated, to elucidate the role of SRGAP2 protein and its human-specic paralogs in human

brain development and evolution.

Keywords: brain development, gene duplication, human genome, SRGAP2

INTRODUCTION

How the human brain has acquired its cognitive abilitythrough evolution is a fundamental issue in evolutionarybiology. The brain is formed through highly coordinatedprocesses, including neurogenesis, synapse formation, andwiring of the neural circuitry. In addition to an increasein size, human brain exhibits a prolonged maturation orneoteny. Neoteny is a key feature that allows our brainto be modified through interaction with the environ-ment and probably underlies the emergence of highercognitive skills. How can we address the issue of humanbrain evolution? The genetic program for developingthe human brain to acquire the traits that are unique toor most prominent in humans must be embedded in our

genome. By taking advantage of the power of comparativegenomics, it has become possible to identify the human-specific sequences or regions in the human genome. Theeffects of such sequences or regions on brain develop-ment can then be tested experimentally utilizing variousin vitro and in vivo model systems. The purpose of thisreview is to emphasize the importance of such an evo-devo approach. In the second part, the genes duplicated

specifically in the human lineage, identified by compara-tive genomics, are introduced. In the following part, the

analysis of the role of one of such genes, SRGAP2, inbrain development, and particularly in dendritic spinematuration, is outlined.

THE ARCHITECTURE OF HUMAN

SEGMENTAL DUPLICATION

A comparison of human and chimpanzee draft genomesequences estimated approximately 1% sequence diver-gence between the two genomes (Chimpanzee Sequencingand Analysis Consortium, 2005). Moreover, orthologousproteins are highly similar, typically differing by only a

few amino acids, and approximately 29% are identical(Chimpanzee Sequencing and Analysis Consortium, 2005;King & Wilson, 1975). These initial analyses suggest thatthe differences in gene expression level or pattern, whichare coordinated by regulatory regions such as promoters,enhancers, or noncoding RNA, may be important for thephenotypic differences. However, the identification ofsegmental duplications (SDs) increased the estimate of

Received 26 February 2013; accepted 21 March 2013.Address correspondence to Takayuki Sassa, PhD, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812,

Japan. E-mail: [email protected]

J. Neurogenetics, 27(3): 8696Copyright 2013 Informa Healthcare USA, Inc.ISSN: 0167-7063 print/1563-5260 onlineDOI: 10.3109/01677063.2013.789512


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Gene Duplication and Human Brain Evolution 87

total differences between the two genomes to approxi-mately 4% (Britten, 2002; Cheng et al., 2005). Importantly,SDs often contain duplicated genes. Gene duplicationunderlies the evolution of novel biological functions; thisraises the attractive hypothesis that these recently dupli-

cated human lineage genes have significantly contributedto the evolution of human-specific phenotypic traits.

SDs are defined as duplicated DNA fragments that aremore than 90% identical and larger than 1 kb (Jiang et al.,2007; Marques-Bonet et al., 2009). Their high degreeof conservation has made it challenging to detect, map,and resolve the structure of the human-specific SDs. Forexample, in the genomes assembled using whole-genomeshotgun (WGS) sequencing, SDs are underrepresentedin comparison with the genomes assembled using BACclone-order-based approach. SDs that are larger than 15 kband have more than 97% homology are almost absent inthe genomes assembled using the WGS sequencing (She

et al., 2004). WGS sequences are not long enough to findand assign an overlapping sequence from highly similarsequences during genome assembly. Thus, the recent SDsthat are most likely to be relevant to human-specific geneduplications are the most difficult to resolve. To overcomethese problems, a computational method that identifiesSDs in an assembly-independent manner has been devel-oped (Bailey et al., 2002; Marques-Bonet et al., 2009). Inthis method, WGS sequence reads of nonhuman primatesare aligned against a human genome, which is most reli-able and used as a reference assembly. SDs are detected asan excess or shortage of WGS sequence read-depth. The

method is particularly sensitive for detecting high-identityduplications, and therefore suitable not only for compari-sons between humans and nonhuman primates but alsofor comparisons between human populations to identifydisease-associated SDs (Lupski, 1998; Sharp et al., 2006).

These studies have revealed several features of humanand nonhuman primate SDs. First, large human SDs (20kb) are mostly (66%) separated by1 Mb of uniquesequences (Bailey et al., 2001; Cheng et al., 2005; Sheet al., 2004). This is in sharp contrast with the mouse, inwhich the large SDs are predominantly (88%) organizedin tandems (She et al., 2008). Second, human SDs distrib-ute nonrandomly in the genome. Most human SDs clus-

ter to form approximately 400 blocks (She et al., 2004).Each block consists of a complex mosaic of different SDs,suggesting that it has been formed by multiple rounds ofduplication (Johnson et al., 2006). These blocks map tothe euchromatic portions as well as subcentromeric andsubtelomeric regions (Linardopoulou et al., 2005; Sheet al., 2004). Third, intrachromosomal SDs tend to showhigher identity than interchromosomal SDs (She et al.,2006). Using this difference in the degree of substitution,it has been estimated that interchromosomal duplicationreached its peak around 25 million years ago (mya), whenthe ancestral human lineage separated from the Old World

monkeys, whereas intrachromosomal duplication activitypeaked around 10 mya and began to decline around 2 mya(She et al., 2006).

Global genome-wide comparison of SDs of humansand chimpanzees revealed that, of the human SDs larger

than 20 kb, 33% (26.5 Mb) are unique to the human and66% (53.4 Mb) are also duplicated in the chimpanzee(Cheng et al., 2005; Chimpanzee Sequencing and AnalysisConsortium, 2005). The chimpanzee-only SDs and copynumber differences between the shared SDs account forthe genetic difference between the two species of approxi-mately 2.7%. This difference is larger than the difference(approximately 1.2%) caused by single-base-pair substi-tutions, supporting the hypothesis that gene duplicationunderlies the evolution of phenotypic traits unique tohumans (OBleness et al., 2012; Varki et al., 2008).

GENES SPECIFICALLY DUPLICATED OREXPANDED IN THE HUMAN LINEAGE

The average length of large human-only SDs (20 kb)is 54.6 kb (Cheng et al., 2005). Thus, genes in SD can beduplicated as a whole or partially. In the study mentionedabove, the genome-wide comparison of SDs betweenhuman and chimpanzee has identified 177 genes dupli-cated in the human but not in chimpanzee (Cheng et al.,2005). About half of the gene duplications found in thestudy are partial, although the precise structure and copynumber of the duplicated genes remain unresolved.

Using array comparative genomic hybridizationagainst human cDNA array, other studies compared thehuman genome not only with that of chimpanzee but alsowith the genomes of other nonhuman primates, includingbonobo, gorilla, and orangutan (Dumas et al., 2007; Fortnaet al., 2004). This approach has identified 134 genes ascandidates for human lineage-specific gene duplications(Fortna et al., 2004). The study has found that about half ofthe genes that have an increased copy number in humansin comparison with chimpanzees have also increased theircopy number in other nonhuman primates. This findinghighlights the importance of comparing multiple speciesto identify human-specific gene duplication events.

More recently, a sequence read-depth obtained usingthe next-generation sequencing has been applied to pre-dict the copy number of duplicated genes (Sudmant et al.,2010). The study has compared 159 human genomes withthose of a gorilla, chimpanzee, and orangutan, and identi-fied 23 genes with human-specific duplications (diploidin the three nonhuman primates) as well as 30 genes withduplications in the primate lineage and further expansionsin the human lineage.

A current list of duplicated genes identified by thesegenome-wide studies is presented in Table 1 (Cheng et al.,2005; Dumas et al., 2007; Fortna et al., 2004; Sudmant


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Table 1.List of genes duplicated or expanded specifically in the human lineage.

Gene Chromosome Copy number Status Full or partial Proposed function

FCGR1A 1 5.64 D Full IgG bindingRBM8A 1 3.52 D ND mRNA bindingHIST2HBF 1 5.49 D ND DNA bindingSRGAP2 1 5.36 D Partial GTPase activationNCRNA00152 2 3.88 D ND noncoding RNAPTPN20A 10 3.68 D ND Tyrosine phosphataseFRMPD2 10 3.94 D Partial phosphatidylinositol bindingGPRIN2 10 4.40 D ND Neurite outgrowthC10orf57 10 4.06 D ND UnknownCHRFAM7A 15 4.27 D Full CHRNA7-FAM7A fusion proteinARHGAP11A 15 3.55 D Partial Rho GTPase activationARHGEF5 7 5.94 D Full Guanine-nucleotide exchangeHYDIN 16 3.85 D Partial Cilia motilityGTF2H2 5 4.49 D Full Transcriptional regulationSERF1B 5 3.60 D Full UnknownSMN2 5 3.58 D Full Biogenesis of snRNPsNAIP 5 5.04 D ND Inhibition of apoptosis

DUSP22 6 3.98 D Full Dual specificity protein phosphataseGTF2IRD2 7 5.50 D Full Transcriptional regulationFAM115C 7 3.93 D ND UnknownLOC154761 7 3.94 D ND UnknownZNF322 6 3.85 D ND Transcriptional regulationWASH2P 2 20.81 E ND WAS protein family homologCROCCL1 1 10.23 E ND Ciliary proteinMSTP2 1 13.85 E ND Hepatocyte growth factor-likeAMY1A 1 9.91 E Full 1,4 alpha-glucosidaseFLJ39739 1 11.83 E Full UnknownPDE4DIP 1 7.20 E Partial Golgi/Centrosome localizationNBPF14 1 244.66 E ND Neuroblastoma breakpoint familyNCF1 7 6.43 E Full NADPH oxidaseLOC645166 1 12.50 E ND F-actin bindingGOLGA6L10 15 29.81 E ND Golgin subfamily

GIYD1 16 6.90 E ND Structure-specific endonucleaseLRRC37A4 17 16.22 E ND UnknownC2orf78 2 10.88 E ND UnknownRPL23AP53 8 27.08 E ND Ribosomal proteinLOC728323 2 19.18 E ND UnknownPOM121L4P 22 50.71 E ND NucleoporinZNF595 4 10.63 E Partial Transcriptional regulationDRD5 4 11.34 E Full Dopamine signalingLOC100272216 5 63.64 E ND UnknownGUSBL1 6 13.20 E ND Degrades glycosaminoglycansLOC100170939 5 9.73 E ND Degrades glycosaminoglycansC6orf41 6 11.48 E ND Non-protein coding RNASTAG3L1 7 8.61 E ND Meiotic chromosome pairingGTF2IP1 7 6.81 E ND Transcriptional regulationSPDYE5 7 37.77 E ND Unknown

AQP7 9 11.70 E Full Water, glycerol and urea transportKGFLP1 9 11.29 E ND Keratinocyte growth factorFAM95B1 9 16.19 E ND UnknownLOC642929 9 14.62 E ND Transcriptional regulationARHGAP15 2 ND ND ND Rho GTPase activationNBEA 13 ND ND ND A-kinase anchoringARHGAP42 11 ND ND ND Rho GTPase activationNEK2 1 ND ND ND Serine/threonine protein kinasePMP2 8 ND ND ND MyelinationSLC6A13 12 ND ND ND GABA reuptakeFGF7 15 ND ND ND Growth factorOCLN 5 ND ND Partial Cell adhesion

(Continued)


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et al., 2010). These genes are distributed on several chro-mosomes: chr1, chr2, chr5, chr7, chr9, and chr10. Thechromosomal distribution of duplicated genes is verysimilar to that of high-identity (95%) segmental dupli-cations. Each duplicated gene may undergo neofunction-alization, subfunctionalization, or degradation, or exert

a dosage effect by the virtue of its high identity withthe ancestral gene (Hurles, 2004; Lynch & Katju, 2004;Ohno, 1970). Many genes with human-specific duplica-tion or expansion could be involved in brain develop-ment, function, and diseases. HYDIN is a flagellar centralpair protein that is required for ciliary motility.HYDINmutation in mice impairs ciliary motility and results inhydrocephaly (Lechtreck et al., 2008). AncestralHYDINis located on 16q22.2 and its duplicated paralog is insertedin the 1q21.1 region, which is susceptible to microdele-tion and microduplication (Doggett et al., 2006). Notably,microdeletion and microduplication were correlated withmicrocephaly and macrocephaly, respectively, suggest-

ing that the copy number of HYDIN may regulate thebrain size (Lechtreck et al., 2008). CHRNA7 is locatedon 15q13 and encodes the 7 subunit of the nicotinicacetylcholine receptor, which is highly expressed in thenervous system. A recurrent 680-kb deletion within thisregion that encompasses CHRNA7 has been associatedwith neurodevelopmental abnormalities, including mentalretardation and seizures (Shinawi et al., 2009). Human-specific partial duplication of CHRNA7in this region hasgenerated a novel chimeric gene, CHRFAM7A, which is ahybrid between CHRNA7and FAM7A(Riley et al., 2002).Using homozygous haplotype mapping, CHRFAM7Ahas

been identified as one of the candidate genes associatedwith autism-spectrum disorders (Sinkus et al., 2009).It remains to be determined whether CHRFAM7A hasacquired a novel function or exerts its effect through inter-action with CHRNA7. DRD5 and SLC6A13, encodingdopamine D5 receptor and -aminobutyric acid (GABA)

transporter, respectively, are possibly involved in thedevelopment of the brain and the formation of cognitiveabilities through regulation of synaptic transmission andplasticity (Centonze et al., 2003; Hglund et al., 2005;Lemon & Manahan-Vaughan, 2006). GPRIN2 interactswith guanosine triphosphate (GTP)-bound form of G

oor

Gzin vitro, and induces neurite formation in Neuro2A cells

(Chen et al., 1999). GTF2IRD2,GTF2I, and GTF2IRD1constitute the GTF2Ifamily of putative transcription fac-tors with multiple helix-loop-helix domains known as Irepeats (Gunbin & Ruvinsky, 2013; Palmer et al., 2012).Interestingly, these three genes are all located in a nar-row region of 7q11.23. Microdeletions in this region,

including GTF2I and GTF2IRD1, are associated withthe pathogenesis of the cognitive and behavioral phe-notypes of Williams-Beuren syndrome (Makeyev et al.,2004; Porter et al., 2012). Patients with slightly largerdeletions encompassing GTF2IRD2are more cognitivelyimpaired in executive function (Porter et al., 2012).NAIPgenes encode the nucleotide-binding domain and leucine-rich repeat (NLR) protein family, which suppress apop-tosis through the inhibition of procaspase-9 activation(Davoodi et al., 2010; Mercer et al., 2000; Perrelet et al.,2002). Spinal muscular atrophy (SMA) is an autosomalrecessive neuromuscular disease in which the motor

Gene Chromosome Copy number Status Full or partial Proposed function

USP10 16 ND ND ND Ubiquitin pathwayANAPC1 2 ND ND Partial Cell cycle

PAK2 3 ND ND ND Protein kinaseCDH12 5 ND ND ND Cell adhesionFXYD2 11 ND ND ND TransportMST1 3 ND ND Full Immune responseE2F6 2 ND ND ND TranscriptionDDX11 12 ND ND Full RNA helicaseRAB6C 2 ND ND ND TraffickingABCC6 16 ND ND ND TransportGPR116 6 ND ND Partial G protein signalingEIF3A 10 ND ND ND TranslationMPPE1 18 ND ND ND GPI anchor biosynthesis

Note.Genes listed are chosen from Fortna et al. (2004) and Sudmant et al. (2010). From Fortna et al. (2004),only genes confirmed by Dumas et al. (2007), which employed essentially the same experimental approach, wereadopted. Copy number refers to total copies per diploid genome, including both ancestral and duplicated copies.

Status refers to whether the gene is duplicated specifically in the human lineage (D), i.e., after the divergence ofhuman and chimpanzee lineages, or the gene had duplicated in a common primate ancestral lineage followedby further expansion specifically in the human lineage (E). Full or Partial refers to whether the gene duplicationincludes entire exons (Full) or lacks more than one exon (Partial). Note that not all duplicated copies of a particulargene are entirely Full or Partial, and it remains to be determined whether both full duplication and partial duplicationhad occurred from one ancestral gene. NDnot determined.

Table 1.(Continued).


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neurons in the anterior horn of the spinal cord degenerate(Hamilton & Gillingwater, 2013). SMA is associated withmutations in SMN1. SMN2, a human-specific gene, is verysimilar to SMN1 and encodes a protein identical to theproduct of SMN1 (Lorson et al., 2010).However, a syn-

onymous point mutation in the coding sequence of SMN2results in the skipping of exon 7, which makes most ofthe SMN2transcripts inactive (Lorson et al., 1999). SMN2has been characterized as a modifier of SMA; an increasein SMN2copy number reduces the severity of the disease(Zheleznyakova et al., 2011). OCLNencodes a transmem-brane protein involved in the formation of tight junctions(Steed et al., 2010). Mutations in OCLNcause band-likecalcification with simplified gyration and polymicrogyria(BLC-PMG), an autosomal recessive neurological disor-der characterized by microcephaly, polymicrogyria, andgray matter calcification (ODriscoll et al., 2010). The listof genes duplicated or expanded in the human highlights

the genes related to signal transduction mediated by Rhofamily of GTPases (Ridley, 2012), including SRGAP2(ARHGAP34), ARHGAP11A, ARHGEF5, ARHGAP15,

ARHGAP42, and PAK2. SRGAP2is the first human-spe-cific duplication gene for which the precise nucleotidesequence of the duplicated copies has been determinedand the function experimentally demonstrated (see nextsection) (Charrier et al., 2012; Dennis et al., 2012).PAK2is a member of the p21 (Cdc42/Rac)-activated serine/threonine kinase family (Boda et al., 2006). Among thesix human PAKgenes, PAK3is associated with X-linkednonsyndromic forms of mental retardation, which are

characterized by the cognitive deficit (Allen et al., 1998).PAK3 preferentially binds to and is activated by Cdc42and regulates the dendritic spine morphogenesis, synapseformation, and plasticity (Boda et al., 2004; Kreis et al.,2007). PMP2(FABP8), a member of the fatty acidbind-ing protein (FABP) family (Smathers & Petersen, 2011),is expressed mainly in peripheral myelin. PMP2 is one ofthe major proteins in peripheral myelin, and immuniza-tion of rats with PMP2 induces experimental autoimmuneneuritis, an animal model of acute inflammatory demyeli-nating polyradiculoneuropathy/Guillain-Barr syndrome(Rostami et al., 1984). DUSP22 is a member of dual-specificity phosphatases that can dephosphorylate both

tyrosine and serine/threonine residues (Patterson et al.,2009). DUSP22 protein is associated with actin cytoskel-eton, dephosphorylates focal adhesion kinase (FAK) andregulates cell motility (Li et al., 2010).

Which of these duplicated genes may be involved inhuman brain evolution? One point to be considered is thecopy number stability of the duplicated gene among humanpopulations. Some of these recently duplicated genes arehighly variable in terms of copy numbers. The existenceof normal individuals having the same gene copy numberas nonhuman primates makes it less likely that such genesplayed a role in the human brain evolution. Of the genes

mentioned above, HYDIN, GTF2IRD2, SRGAP2, andARHGAP11A are almost copy numberfixed in humanpopulations and therefore may be attractive candidates forfurther experiments. Because HYDIN dosage positivelyregulates the brain size, the duplication may have con-

tributed to the expansion of the human cortex. Rho fam-ily GTPases are implicated in neuronal morphogenesis,including axon guidance and synapse formation. Thus,SRGAP2andARHGAP11Amay regulate the formation ofneural circuits and their subsequent maturation unique tothe human brain.

ROLE OF SRGAP2DUPLICATION IN

BRAIN DEVELOPMENT

As mentioned above, SRGAP2is emerging as one of thecandidate genes whose duplication may have contributed

to the human brain evolution. This has stimulated researchon the structure and function of duplicated as well as ances-tral SRGAP2(Figure 1). The results show that the humanSRGAP2has been partially duplicated thrice. One of theduplicated copies is fixed among human populations andhas acquired a novel function, i.e., antagonizing ancestralSRGAP2 protein function. Heterogeneous introductionof duplicated SRGAP2 in mouse brain induces neotenyin dendritic spine maturation, a trait observed in humanprefrontal cortex (Figure 2). Thus, the duplication ofSRGAP2is the first example that supports the hypothesisthat the human-specific gene duplication may play a key

role in human brain evolution. These results are discussedin more detail in the following paragraphs.Human-specific duplication of SRGAP2 was first

demonstrated in 2004 by Fortna et al. (Fortna et al., 2004).In that study, array-based comparative genomic hybrid-ization (aCGH) was used to perform the whole-genomecomparison of copy number variation between humansand nonhuman primates. Another work, using short-read

Figure 1.Schematic representation of SRGAP family proteins.SRGAP2A, SRGAP1, and SRGAP3 possess F-BAR, Rho-GAP,and SH3 domains. SRGAP2B and SRGAP2C are present onlyin humans and consist of truncated F-BAR domain followedby a unique VRECYGF sequence. In addition, SRGAP2B andSRGAP2C have several amino acid substitutions compared withSRGAP2A.


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mapping depth to human reference genome, has indepen-dently identified SRGAP2duplication in humans but not in

nonhuman primates (Sudmant et al., 2010). However, theposition, structure, and extent of the duplication remain tobe determined. Fluorescent in situ hybridization (FISH)has identified three SRGAP2loci on human chromosome1: 1q32.1, 1q21.1, and 1p12 (Dennis et al., 2012). In non-human primates, only one signal on 1q32.1 has been iden-tified, which has established 1q32.1 as the ancestral locus.Notably, ancestral copy of SRGAP2 (named SRGAP2A)as well as duplicated copies (SRGAP2B on 1q21.1 andSRGAP2C on 1p12) have been misassembled and con-tained sequence gaps in the human reference genome(GRCh37/hg19), suggesting that the identities between

allelic and paralogous copies were too high to distinguishthem in the process of genome assembly. Dennis et al. haveresolved this problem by constructing a bacterial artificialchromosome (BAC) library covering a haploid genome(Dennis et al., 2012). From this BAC library, sequencecontigs corresponding to ancestral and duplicated copieshave been unambiguously generated. Moreover, a fourthcopy (SRGAP2D), not found in the reference genome, hasbeen identified in the BAC library and mapped by FISHon 1p21.1, proximal to SRGAP2B (Dennis et al., 2012).Charrier et al. also succeeded in generating BAC contigscorresponding to SRGAP2A, SRGAP2B, and SRGAP2Cby identifying BAC clones that covered the regions miss-

ing in the reference genome (Charrier et al., 2012). Thesestudies, together with an additional method to obtainhaplotype-resolved genome information (Kitzman et al.,2011), present a strategy applicable to other genes thathave undergone human-specific duplication or expansion.Combining multiple-sequence alignment, phylogeneticanalysis, and FISH, Dennis et al. revealed essentially thewhole picture of SRGAP2duplication events during humanevolution (Dennis et al., 2012). The first event duplicatedthe promoter and the first nine exons of SRGAP2A to1q21.1 for generating SRGAP2B around 3.4 mya. Twolarger duplications copied the entire SRGAP2Band adjacent

regions to 1p12 (SRGAP2C) and 1q21.1 (SRGAP2D)approximately 2.4 and 1 mya, respectively. SRGAP2Dwas later made nonfunctional by a 115-kb deletion includ-ing exons 2 and 3. The copy number of SRGAP2C isfixed at a diploid copy of 2, whereas that of SRGAP2B

is variable. Moreover, the identification of normal indi-viduals with homozygous deletions of SRGAP2Bhas leftSRGAP2Cas the only candidate.

What is the function of SRGAP2C? Before address-ing this question, it is necessary to overview the functionof ancestral SRGAP2. Mammalian SRGAP family con-sists of three members, SRGAP13(Figure 1). SRGAP1has been originally identified as Rho GTPase-activatingprotein (GAP) that may participate in the Slit-Robosignaling pathway involved in axon guidance and cellmigration (Wong et al., 2001). SRGAPs are expresseddynamically during the development of various regionsof nervous system, including the neocortex (Bacon et al.,

2009; Guerrier et al., 2009). SRGAP protein is composedof three domains from the N-terminus to C-terminus:F-BAR (Bin, Amphiphysin, Rvs) domain (Frost et al.,2009), GAP domain, and Src homology 3 (SH3) domain(Figure 1). F-BAR domains of SRGAPs form homodim-ers or heterodimers and can regulate membrane defor-mation and filopodia formation in vitro (Coutinho-Buddet al., 2012). The GAP domain of SRGAP2 and SRGAP3is specific for Rac1 (Guerrier et al., 2009; Soderlinget al., 2002). Accumulating evidence indicates that ances-tral SRGAP2 plays a pivotal role in brain development.SRGAP2is highly enriched in the neuritis. Overexpression

of mouse SRGAP2in radially migrating neocortical neu-rons induces the formation of highly dynamic neurites andbranches, which destabilize the leading process and impairdirectional cell body translocation (Guerrier et al., 2009).F-BAR domain of SRGAP2 is necessary and sufficientfor this effect, suggesting that the ability of this domainto induce membrane protrusions is required for appropri-ate neuronal migration and morphogenesis. Consistentlywith the overexpression analysis results, knockdown ofSRGAP2 reduces branching in the leading process andaccelerates neuronal migration (Guerrier et al., 2009).

High-level expression of SRGAP2 continues at thelater stages of brain development such as the synapse

formation (Bacon et al., 2009; Charrier et al., 2012;Guerrier et al., 2009). Endogenous SRGAP2 is a postsyn-aptic protein accumulated in the heads of dendritic spines(Charrier et al., 2012). Analysis of SRGAP2-knockout(KO) mice has demonstrated that SRGAP2 promotesspine maturation and limits spine density (Charrier et al.,2012) (Figure 2). Notably, these changes are dosagedependent; the phenotypes of heterozygous individuals isintermediate between wild-type and KO phenotype. Thus,at low SRGAP2 levels, spine maturation is neotenic, i.e.,its duration is extended; the adult neurons form immaturespines with a longer neck. These changes possibly have

Figure 2.Schematic representation of changes in dendritic spinemorphology induced by expression of SRGAP2C in mouseneocortical pyramidal neurons in vivo. SRGAP2A localizes indendritic spines and promotes spine maturation (its activity isshown in red). SRGAP2C forms dimers with SRGAP2A andantagonizes its spine maturation activity, which results in higherdensity of spines with longer necks and smaller heads.


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a profound impact on neuronal connectivity and synap-tic input integration (Bourne & Harris, 2007; Matsuzakiet al., 2004; Yuste, 2011).

SRGAP2C is predicted to encode a protein of459 amino acids (a.a.) (Figure 1). The first 452 a.a. of

SRGAP2C correspond to the first 452 a.a. of the F-BARdomain of SRGAP2A (a.a. 1501) and the remaining 7a.a. are derived from intron 9. Thus, SRGAP2C consistsof a truncated F-BAR domain. SRGAP2C can eitherheterodimerize with SRGAP2A or homodimerize withSRGAP2C. Whereas expression of SRGAP2A in COS7cells induces filopodia, SRGAP2C expression does not(Charrier et al., 2012; Guerrier et al., 2009). Interestingly,coexpression of SRGAP2C and SRGAP2A efficientlyinhibits the ability of SRGAP2A to induce filopodia(Charrier et al., 2012). There can be two explanations forthe observed effects based on the two differences betweenSRGAP2C and SRGAP2A (Figure 1). First, SRGAP2C is

C-terminally truncated by 49 a.a. residues compared withthe F-BAR domain of SRGAP2A. Second, SRGAP2C hasseveral amino acid substitutions in its truncated F-BARdomain. Whereas some of these substitutions are the samein different human individuals, others are variable (Denniset al., 2012). Thus, SRGAP2C differs from SRGAP2A, inup to five residues in the corresponding region. To testthe relative contribution of these two types of mutationsto the inhibitory effect on SRGAP2A-mediated filopo-dia induction, two individual mutants of the ancestralF-BAR domain were generated: F-BAR-D49, which lacksthe C-terminal 49 a.a. residues, and F-BAR-D5R, which

has five amino acid substitutions (all to arginine) cor-responding to the most varied form of SRGAP2C. Bothmutants lose the ability to induce filopodia. However,only F-BAR-D49 exhibited the ability to antagonizeSRGAP2A-mediated filopodia induction (Charrier et al.,2012). Thus, SRGAP2C is able to interact with and inhibitthe ancestral SRGAP2A, primarily due to its truncatedform of F-BAR domain. These results are interesting fromthe evolutionary point of view: if the duplication had beenslightly larger and included a few more exons, then theF-BAR domains of the duplicated paralog would not haveacquired such an inhibitory property.

The expression of SRGAP2C in the developing

mouse cortex essentially phenocopied the SRGAP2defi-ciency. The introduction of SRGAP2C into the mouseneocortex by in utero electroporation reduces the leadingprocess branching and accelerates neuronal migration.This phenomenon is very similar to the changes observedin shRNA-mediated knockdown of endogenousSRGAP2(Charrier et al., 2012). Such an increase in the rateof neuronal migration may be beneficial to the devel-opment of human neocortex. In the human brain, thepostmitotic neurons have to travel a longer distancebefore reaching the final destination, as the neocortexis substantially thicker than in nonhuman primates or

rodents (Dehay & Kennedy, 2007; Rakic, 2009; Sidman& Rakic, 1973).

Charrier et al. introduced SRGAP2C by in uteroelectroporation in the mouse cortex and examined thetransfected neurons during the juvenile period, after the

completion of neuronal migration. During this period,in SRGAP2C-expressing neurons, the spine maturationslows down; the spine head is smaller and the neck longer,and the density increases (Figure 2) (Charrier et al., 2012).In adult animals, SRGAP2C-expressing neurons attain aspine head width similar to that in controls, but the spineneck length and the density remain at the juvenile level.Thus, the human-specific paralog of SRGAP2 function-ally antagonizes the ancestral SRGAP2and induces neo-teny during spine maturation. These morphological andtemporal changes induce in the mouse dendritic spinesthe characteristics observed in human dendritic spines(Benavides-Piccione et al., 2002; Elston et al., 2001;

Petanjek et al., 2011). Since dendritic spines undergo mor-phological changes to increase the connectivity, isolate theinputs from each other, and enable input-specific plastic-ity (Bloodgood & Sabatini, 2005; Bourne & Harris, 2008;Matsuzaki et al., 2004; Yuste, 2011; Yuste & Bonhoeffer,2001), it will be particularly interesting to investigatewhether the properties or functions of neural circuits arechanged in the presence of duplicated SRGAP2.

IMPLICATIONS OF HUMAN-SPECIFIC

GENE DUPLICATION AND THE FUTURE

PROSPECTS

The development of new methods for genome analysis,such as hybridization-based microarray and sequencing-based computational approaches, is largely responsiblefor the current advances in the evolutionary biology field(Alkan et al., 2011). The list of genes that have undergonehuman-specific duplication or expansion is continuouslymodified to accommodate new biological annotations aswell as the discovery of new genes.

SRGAP2is the first gene for which the significance ofits duplication in human brain evolution has been experi-mentally examined (Charrier et al., 2012; Dennis et al.,

2012). SRGAP2C protein modulates spine maturationthrough inhibition of SRGAP2A (Figure 2). Dendriticspines receive most of the excitatory presynaptic inputin the cortex. Spines are heterogeneous in their morphol-ogy, stability, and density; those with large heads aremature and stable, and contribute to strong synaptic con-nections, whereas the spines with small heads and longnecks are immature, motile, and unstable, and contributeless to synaptic connections (Kasai et al., 2003; Yuste,2011). The spines are initially overproduced and subse-quently selectively stabilized or eliminated in an activity-dependent manner. In the human prefrontal cortex, this


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process continues beyond adolescence and throughout thethird decade of life (Petanjek et al., 2011). The produc-tion of SRGAP2C and induction of neoteny during spinematuration may prevent the human brain from becom-ing hard-wired, and allow the embedded neural circuits

to be diverged and modified by experience. This processundoubtedly contributes to our higher cognitive abilitiessuch as language acquisition and creativity.

Many of the genes that have undergone human-specific duplication or expansion, including SRGAP2, areassociated with neurological diseases or other disorders.A de novo balanced translocation t(1;9)(q32;q13), whichdisrupts SRGAP2on 1q32, has been reported in a patientwith early infantile epileptic encephalopathy and severepsychomotor disability, suggesting that SRGAP2 has aconserved role in the human brain development (Saitsuet al., 2011). Another balanced de novo translocationt(X;3)(p11.2;p25), which disrupts SRGAP3 on 3p25,

has been reported in a patient with hypotonia and severemental retardation (Endris et al., 2002). Although theinvolvement of genes other than SRGAPs in the patho-genesis of these two cases remains possible, SRGAP2andSRGAP3 may play essential and nonoverlapping rolesin human brain development in a dosage-sensitive man-ner. This is consistent with the observation that intellec-tual disability is most consistently associated with spinedysgenesis (van Bokhoven, 2011). We can conclude thateven subtle changes in the dosage of genes encoding thekey molecules in spine morphogenesis and function canbe either beneficial or detrimental. The copy number of

most duplicated genes varies considerably, indicating thecontinuing genomic gain and loss among human popula-tions (Sudmant et al., 2010). It is possible that a particularcopy number may change as a result of positive, neutral,or negative selection depending on whether its effect isadvantageous, neutral, or harmful. A gain or loss of dupli-cates beyond a certain threshold may manifest itself as adisease or creation.

A model of evolution by gene duplication proposedby Ohno assumes whole-gene duplication, i.e., the dupli-cated gene is at first identical to the original, then acquiresa novel function over time by accumulating mutations(Lynch & Katju, 2004; Ohno, 1970). Alternatively, as

exemplified by SRGAP2C, partial gene duplication canimmediately confer a novel function.

Testing the role of duplicated genes in human braindevelopment and evolution requires analyses at multiplelevels, including biochemical, cell biology, and behav-ioral approaches. The functionality and expression ofthe duplicated gene must be carefully examined becausepartial gene duplication may miss some elements such aspromoters, enhancers, or exons encoding indispensabledomains. Although the mouse is evolutionarily moredistant from the human than nonhuman primates, itwill remain an important experimental model animal.

Examining the phenotype of transgenic mice that har-bor duplicated genes is one of the most straightforwardapproaches to obtain insights into the in vivo role of dupli-cated genes in the human brain development and func-tion. Another promising strategy is the use of embryonic

stem (ES) cells and induced pluripotent stem (iPS) cellsderived from human and nonhuman primates as well asrodents (Liu et al., 2008; Takahashi et al., 2007; Thomsonet al., 1998; Yamanaka & Blau, 2010). Induced differen-tiation of ES or iPS cells into cells or tissues forming thebrain will provide an invaluable source of new informa-tion (Eiraku et al., 2011; Gaspard et al., 2008; Han et al.,2011). Gene targeting of the duplicated genes in ES oriPS cells will enable to test the function of the duplicatesdirectly (Zou et al., 2009).

Future studies of the effect of human-specific geneduplications on normal brain development and pathologi-cal conditions will provide a wealth of insights into the

evolutionary genetic basis of what makes us human.

ACKNOWLEDGMENTS

I would like to thank Dr. Kaumudi Joshi for the commentson the initial version of the manuscript. I would like tothank Enago for the English language review.

Declaration of interest: The author reports no conflictsof interest. The author alone is responsible for the contentand writing of the paper.

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3rol especificohumano y el desarrollo dela evoluciongen

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