Human Molecular Genetics, 2000, Vol. 9, No. 3 421-430
© 2000 Oxford University Press
A polymorphic L1 retroposon insertion in the centromere of the human Y chromosome
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK, 1Institut für Rechtsmedizin, Humboldt-Universität zu Berlin, Berlin, Germany, 2Unit of Human Genetics, School of Biochemistry and Genetics, La Trobe University, Bundoora, Victoria 3083, Australia, 3Auckland Cancer Research Centre, Faculty of Medicine and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand, 4Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, India, 5Dipartimento di Biologia Animale e dell’Uomo, Università ‘La Sapienza’, Roma, Italy, 6Department of Cell Biology, University of Calabria, Rende, Italy, 7Biomedical and Genetic Engineering Laboratories, PO Box 2891, Islamabad, Pakistan, 8Forensic Laboratory for DNA Research, MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, PO Box 9503, 2300 RA Leiden, The Netherlands
Received 18 October 1999; Revised and Accepted 30 November 1999.
DDBJ/EMBL/GenBank accession nos AF207859 and AF189307.
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ABSTRACT |
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We have identified a novel polymorphic L1 retroposon insertion, designated LY1, in the centromeric alphoid array of the human Y chromosome. The element belongs to the transpositionally active Ta subset and its presence is compatible with normal centromere function. It was found at highest frequency in China, where it accounts for 23% of the Han sample, and was present at low frequencies in the surrounding areas, but was not found at all outside Asia. Chromosomes carrying LY1 show considerable microsatellite diversity, suggesting an ancient origin for the lineage at ~10 000 years ago (with wide confidence limits), but only limited subsequent migration.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The Y chromosome has a unique role in human population genetics with several properties that distinguish it from all other segments of the genome (1,2). The major portion, ~60 million base pairs (3), is transmitted exclusively from father to son. It is haploid, so there are no recombination events. It therefore makes up the largest DNA segment in the human genome where variation can only accumulate due to mutations. The number of Y chromosomes in the population is generally one quarter of the number of each autosome. This reduced effective population size and male behaviour, where marriage customs and migration can differ from female behaviour, are likely to influence the way in which Y diversity is distributed among human populations.
Some early surveys of Y variation (4) emphasized the paucity of DNA polymorphisms, but subsequently the use of more efficient methods for detecting variation and the inclusion of Y chromosomes from distinct geographical regions has yielded many variants. These include slowly evolving markers, mainly SNPs (5–12); in addition, several rapidly evolving Y microsatellite loci have been discovered and found to display high variability (5,13–16).
Since there are few genes on the Y and most polymorphisms lie in non-coding DNA, patterns of Y variation in distinct populations are usually considered to result from neutral processes such as mutation and random genetic drift. However, because of the absence of recombination, the occurrence of a mutation in coding sequences or other sequence structures could lead to a selective sweep affecting all polymorphisms on the Y by a hitchhiking effect (17). These processes, whether neutral or selective, have led to high levels of geographical clustering of Y variants and a correlation with language (9,10,12,18–20). This makes the Y a very useful tool for investigations of human population genetics, but leads to the requirement of a large number of polymorphic markers, including ones ascertained from each population and arising at different historical and pre-historical times.
Among slowly evolving markers, retrotransposon insertion polymorphisms are particularly useful because their ancestral state (the absence of the insertion) is known, recurrent insertion at the same position is unlikely, and there is no mechanism known for specific deletion (21). Most retroposons have resulted from very ancient insertion events and can be used in phylogenetic analysis between species (22). However, some retroposon insertions have happened more recently, after speciation, and can reveal intra-specific polymorphisms. Some autosomal polymorphic retroposons have been found in the human genome (21). In addition, the only reported retroposon insertion on the human Y chromosome, the Y Alu polymorphism YAP (7), has been widely used in human evolutionary studies. It is found at high frequency in Africa and in parts of Asia and Europe and the geographical distribution of its variants has led to the novel suggestion that most African Y chromosomes have been replaced by Asian ones within the last ~30 000 years (23,24).
We now describe a polymorphic L1 retroposon element on the human Y chromosome. The insertion occurred in the alphoid DNA of the Y centromere, where it appears to be compatible with normal centromere function and is now found in a substantial percentage of Chinese males. The analysis of microsatellite variation in Y chromosomes with the L1 insertion indicates that, despite having a distribution essentially restricted to China, it is likely to be an old event originating in the Palaeolithic.
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RESULTS |
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Identification of an L1 insertion within the Y chromosome alphoid array
Y alphoid DNA has a simple tandemly repeating structure with a high degree of homology between units (25). Consequently, restriction enzymes are expected to cut either within each unit, or not at all within the entire array. Cleavage patterns have been determined experimentally using pulsed-field gel electrophoresis (PFGE) (26,27) and, in most individuals, fulfil these expectations. However, in a small number of individuals [initially m38 (26)], an additional site for many enzymes has been found within the array. The mapping of these sites in one individual (m255) (Fig. 1a) revealed that 12 of 13 lie within a single cluster with a size below the limit of resolution of PFGE. We therefore set out to establish the molecular basis of this variation.
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A cosmid library was constructed from m255 and screened with the pY
1 probe using conditions that detect typical and diverged Y alphoid DNA, but not alphoid DNA from other chromosomes. We expected that clones spanning the variant region would contain typical Y alphoid units linked to sequences with a different restriction pattern, perhaps consisting of non-alphoid DNA. One cosmid (53C), containing both typical Y alphoid DNA fragments and atypically sized fragments, was isolated and characterized further.
Hybridization of EcoRI digests of cosmid 53C with pY1 revealed the presence of a band containing only non-alphoid DNA (data not shown). This non-alphoid fragment was subcloned and sequenced. The 334 bp fragment (Fig. 1b) was highly homologous to the L1 family of repeats, showing that, in this cosmid clone, alphoid DNA was linked to an L1 element. Experiments described below show that the clone was representative of genomic DNA and was not an in vitro cloning artefact. We therefore conclude that the alphoid array of m255 contains an L1 insertion, designated LY1.
Characterization of the L1 element
L1 elements differ in sequence, and a classification thought to reflect their evolutionary history has been proposed (28,29). The subcloned region of 334 bp had high homology to specific members of the Ta subset of L1 elements. The presence of an MboI site at the beginning of the sequence attached to the SuperCos multicloning site indicated that it was derived from the edge of the 53C clone. As the sequenced L1 was highly homologous (333/334 bp) to position 3097–3430 of the typical Ta subset retrotransposon L1.2 (GenBank accession no. M80343), cosmid 53C was predicted to carry ~3 kb of L1 sequence, including its 3' end with the poly(A) tail probably attached to alphoid sequences. To test this prediction, we designed PCR primers based on the known Ta subset of L1 sequences (30) and the Y alphoid consensus (25) to allow amplification and subcloning of the likely 3' insertion site of the L1 element. Excluding the primers, poly(A) tail and alphoid DNA, the PCR subclones produced 72 bp of sequence with complete homology to position 5952–6023 of the retrotransposon L1.2. Nucleotide variants characteristic of the small number of L1 sequences that currently undergo active transposition are found at the 3' end. LY1 shows a perfect match to most members of the Ta subset, followed by a poly(A) tail of ~40 nucleotides. The 3' flanking sequence is Y alphoid DNA, but the exact insertion site cannot be deduced as we lack the duplicated target site just before the 5' end of LY1 which has not been cloned. However, the next recognizable alphoid sequence after the poly(A) tract is composed of GAAAAGAAAGG, a polypurine tract forming a likely insertion site for retroposons as previously suggested (31,32).
The cosmid clone ends within the L1 sequence and contains its 3' end with a poly(A) tail, showing that the element is at least 3 kb long, but does not reveal the full length of LY1. Attempts to amplify the 5' end of the element from the genomic DNA of m255 using primers designed from the L1 and Y alphoid sequences were unsuccessful. However, the map of the array (Fig. 1a) includes sites for BglI, PvuII, BstEII and SacI within the internal cluster, and the typical L1 Ta subset L1.2 sequence contains these sites only at positions 17, 656 + 798, 1627 and 1857, respectively, from the 5' end. It is therefore likely that additional 5' L1 sequences are present and that LY1 represents a full-length or nearly full-length member of the actively transposing Ta subset.
World-wide distribution of the LY1 chromosomes
We tested 633 males from around the world by PFGE for the presence of an internal cluster of three or more restriction enzyme sites. Of these, 15 (~2.5%) contained these sites (Table 1; but see below) and are therefore likely to carry LY1. A PCR assay was established to detect the presence of LY1 directly, using one primer from within the L1 sequence, and the other from within the alphoid DNA. No product was obtained from female DNA, or from males lacking the cluster of restriction sites, but a product of ~140 bp was seen when either the cosmid 53C or males carrying the cluster of restriction sites were amplified (Fig. 2). Another Y locus, 92R7 (Fig. 2, 55 bp), was included in the same PCR reaction as a control for successful amplification. The LY1 PCR product (Fig. 2) appeared as a fuzzy band probably due to Taq polymerase slippage across the poly(A) tail during PCR. Indeed, the two distinct PCR clones sequenced (53Cj1 and 53Cj2) displayed a 10 bp difference in the length of the poly(A) tail (data not shown). A few individuals also displayed visible variation in size of the amplified LY1 band, but this has not been investigated further. Variation in the poly(A) tract from another retroposon insertion, YAP, has been observed previously (12). In a comparison of the PFGE and PCR assays, 15 males contained LY1 according to both assays and 497 lacked it. A single male showed the presence of LY1 according to the PCR assay but appeared to lack the internal cluster of restriction sites; on further analysis he was found to carry the cluster of sites precisely in the centre of the array so that the two fragments co-migrated on the pulsed-field gel. (The revised result has been incorporated into Table 1.) The PCR assay therefore provides a reliable and convenient way to score the presence or absence of LY1. Chromosomes carrying the L1 insertion are designated haplogroup 13.
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In a total of 2311 males, 33 carried LY1 (1.4%) (Table 1). LY1 was absent from the African, European, Pacific and American individuals tested, but was present in several Asian populations (Fig. 3). It was found at highest frequency in China, where it represented 23% of the Han tested. It was also found at 11 and 26%, respectively, in smaller samples of two Chinese minority populations, the Tujia and Miao from Hunan. It was present at much lower frequencies (1–2%) in the surrounding geographical areas: Mongolia to the north, Japan to the east, Indonesia to the south and India to the west, producing a symmetrical geographical pattern centred on China (Fig. 3).
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Diversity within the LY1 lineage
The geographical distribution seen in Figure 3 could arise if LY1 had inserted recently into a Chinese Y chromosome and the lineage had increased in frequency in the population, but had not spread very far. In order to investigate this scenario, we have analysed a set of seven Y microsatellites within the LY1 lineage. This provides a measure of the diversity within the lineage and allows us to compare the haplotypes of Chinese and non-Chinese LY1 chromosomes (Table 2). The resulting microsatellite haplotypes were used to construct a median-joining network (Fig. 4) (33). The network has several striking features. Most haplotypes are represented by only a single chromosome, and are usually separated by several steps, showing that they represent a diverse set of chromosomes. Chromosomes from each ethnic group within China or from each country are scattered within the network and do not cluster according to their origin.
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Two dating methods were used to estimate the time to the most recent common ancestor (TMRCA) of these chromosomes incorporating the mutation rate of 0.0021 per locus per generation measured for this set of Y microsatellites (34). With a method relying on the variance being proportional to time (35), and an effective population size for males of ~4500 (36), our observed average variance per locus was 0.74, which is equivalent to 367 generations. Using a generation time of 25 years, we obtain ~9200 years; with 95% confidence limits for the variance, the range is between ~7100 and ~11 700, whereas with 95% confidence limits for the mutation rate [0.0006–0.0049 per locus per generation (34) as well], the range is ~3300 to ~59 000 years. The second method used the average number of mutation steps per locus from a likely root (37) as applied previously (10). For LY1 chromosomes, it was difficult to establish the root (Fig. 4), so we used an unobserved haplotype carrying the average repeat number at each locus. We obtained ~0.58 mutations on average from the likely root, which gives 275 generations, equivalent to ~6900 years if the generation time is 25 years. Using the 95% confidence intervals for the mutation rate, we obtained ~2900 and ~24 000 years. Because of the uncertainties in these estimates, we refer to the age as ‘~10 000 years’.
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DISCUSSION |
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L1 elements may comprise as much as 17% of the human genome (38). Although most of the inserted copies are truncated and very old (39) some are known to be active in retrotransposition, but only a few polymorphic L1 retroposons have been described previously (30,40). Their use as polymorphic markers has not been extensively exploited. In addition, the centromeric position and Y-chromosomal location provide unique features of interest for LY1.
A centromeric L1 element
A considerable body of evidence supports the hypothesis that alphoid DNA is the normal human centromeric DNA sequence. However, entirely different DNA sequences can form neocentromeres (41), demonstrating that centromere function is not determined directly by the DNA sequence. It has been suggested that the last segment of DNA to replicate forms the centromere, and thus that the function of the satellite DNA is to delay replication (42). Retroposon insertions into a satellite array can potentially disrupt the normal pattern of replication. Retroposon locations within alphoid arrays have therefore been investigated extensively and all previously known elements have been found within diverged alphoid subsets or close to the ends of arrays (32,40). Our results now show that an L1 insertion within a major homogeneous alphoid array is compatible with normal centromere function. Perhaps only a short region of uninterrupted satellite is needed. However, the most likely evolutionary fate of such an element is loss during the normal satellite expansion/contraction processes, and their transience may explain why they have not been detected previously.
Dating the LY1 lineage
We assume that: (i) the insertion occurred only once, in agreement with all the available typing of the haplogroup 13 chromosomes with additional biallelic markers; and (ii) the ancestral state was the absence of the L1 element, so that the initial LY1-containing chromosome carried a single allele at each microsatellite locus. The microsatellites would subsequently have accumulated backward and forward slippage mutations. One potential complication is that the L1 and surrounding alphoid DNA may be deleted during normal satellite DNA evolution. If a change in alphoid array size occurs in 1 in 20 meioses, and changes generally involve only one or two units (43), the one unit of ~150 carrying the L1 may be deleted in ~1 in 3000 meioses, an insignificant frequency.
We used two distinct dating methods for the TMRCA of the chromosomes carrying the LY1 insertion; the insertion itself will have occurred earlier than this. The two methods have given consistent results for dating three different Y lineages: haplogroup 16, defined by the Tat C allele (10), haplogroup 24, defined by the M4 G allele (44), and haplogroup 22, defined by the SRY-2627 T allele (45). The most controversial parameter used is the mutation rate, which was calculated from meioses in deep-rooting pedigrees (34), using the same set of microsatellite loci. There may be problems related to the heterogeneity of rates among loci and alleles (46), and, for mtDNA, the mutation rates measured in pedigrees give more recent estimates than those measured indirectly through phylogenetic analysis (47). Thus the calculations may give consistent results but underestimate the true TMRCA.
Although our absolute dating for haplogroup 13 may be dubious, the insertion lineage is probably older than the other Y lineages analysed in this way (10,44,45). The comparison between distinct Y lineages, their microsatellite networks, dating and geographical distribution can still be informative for elucidating the history of haplogroup 13 chromosomes in China and the surrounding areas.
Chinese population history
LY1 was found in 23% of our Chinese Han sample. If the sample is representative of the entire Han population, this lineage will be found in ~6% of the world’s Y chromosomes. Its microsatellite diversity suggests that the lineage arose ~10 000 years ago, in the Palaeolithic period. This high diversity, and correspondingly ancient age, linked to a limited geographical range, contrast with the patterns found in other Y lineages. Haplogroup 22 (45) has a restricted distribution within Europe and a low microsatellite diversity. Haplogroup 16 chromosomes (10) have a wide distribution spanning most of northern Asia and Europe, but still a lower microsatellite diversity than LY1 chromosomes.
This may reflect the larger population in China and/or a lower geographical mobility. The origin of the lineage is likely to predate the Neolithic in China, and diversification in relatively small populations during the Palaeolithic may account for the lack of a star-like network. LY1 now provides a useful marker for further investigating genetic diversity and population relationships within China, and the migrations of Chinese elsewhere. Indeed, the presence of a few LY1 chromosomes found in bordering countries, whose microsatellite haplotypes were found scattered in the network (Fig. 4) indicate migrations from China.
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MATERIALS AND METHODS |
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DNA samples
DNA samples are listed in Table 1. Most were derived from previously described collections of the authors (5,10,26,43,48–50). Additional samples were collected by the authors in Pakistan (R.Q., S.Q.M. and collaborators), China (A.L.), Nepal (R.A.) and Greenland (P.d.K.), or were generously provided by John Clegg (Taiwan, Indonesia, Tahiti), Rebecca Oakey (Africa), Eduardo M. Tarazona-Santos and Davide Pettener (Quechua), and Mark Stoneking and Alan Redd (PNG and Indonesia).
Mapping of the m255 alphoid array
Most procedures were as described previously (27). Single digests were carried out with the enzymes shown in Figure 1a and SfiI, HpaI and ApaI; the last three enzymes produced only a single alphoid fragment, showing that only a single alphoid array was present. Double digests with AspI (an isoschizomer of Tth111I) were used to place some sites, but, since DNA stocks were limited, other sites were placed using the known maps from other arrays, or remained ambiguous as indicated.
Cosmid library construction and screening
Samples (2.5 µg) of genomic DNA from m255 were partially digested with dilutions of MboI for 30 min at 37°C. Suitably digested DNA was dephosphorylated and ligated to BamHI-cleaved SuperCos arms, packaged with GigaPack II (Stratagene, La Jolla, CA) and incubated with E.coli XL1 Blue MR host cells (Stratagene). Infected cells were spread by suction onto a nylon membrane (20 x 20 cm) and grown at 37°C on an LB plate with ampicillin until colonies were visible, after which a replica was made and allowed to grow 4 h longer at 37°C. The replica filter was then denatured and hybridized with 50 ng of 32P-labelled pYI (5) at moderate stringency (75°C) overnight, washed three times with 0.1x SSC, 1% SDS at 65°C for 10 min and autoradiographed.
Approximately 250 000 colonies (~2.5 genome equivalents) were screened and 145 Y alphoid positive colonies were isolated for further analysis. They were digested with EcoRI, which cuts once per unit, or double digested with EcoRI plus KpnI, SacI, PvuII or AvaII, which do not cut within the Y alphoid unit, but do cut within the variant region, and separated by agarose gel electrophoresis. Cosmids likely to contain non-alphoid DNA linked to typical alphoid repeats were transferred to a membrane and probed again with 32P-labelled pYI to allow the detection of bands containing alphoid and non-alphoid DNA.
Subcloning and sequencing
A single cosmid clone (53C) was selected for further analysis. A non-alphoid EcoRI fragment was purified by GeneClean (Bio 101, Vista, CA) and ligated into pTZ18R to generate subclones 53Ca5 and 53Ca7. The subclones were either sequenced manually using the T7 Sequenase kit (USB, Cleveland, OH), or the CycleSequencing kit (Amersham Pharmacia Biotech, Little Chalfont, UK). Reactions from the latter were run on an ALF DNA sequencer (Amersham Pharmacia Biotech). The sequence was deposited in GenBank under accession no. AF189307.
Subsequently, a specific PCR subcloning strategy was designed to allow the cloning of the 3' junction between the L1 element and the alphoid DNA of the cosmid 53C. The L1–alphoid junction was amplified using the primer L11, 5'-aca cat tag tgg gtg cag cgc acc-3', designed from the consensus 3' end sequence of L1 elements of the Ta subset (30), and a general alphoid primer YR, 5'-ttt gga gcc ctt tga ggc cta ttg-3', based on the consensus sequence of Y alphoid 171 bp subunits (25). Amplified bands were inserted into pUC18 using the SureClone kit (Amersham Pharmacia Biotech). Two PCR subclones called 53Cj1 and 53Cj2 were sequenced as described above. The sequence was deposited in GenBank under accession no. AF207859.
PCR detection of the L1 insertion
For typing of males for the presence or absence of LY1, we designed more specific primers which allow amplification of the L1–alphoid junction from genomic DNA. As a positive control for amplification, we amplified another Y-chromosomal locus named 92R7 (45) in the same tube. The primers specific for the L1–alphoid junction were: L1PR2, 5'-gca caa tgt gca cat gta ccc ta-3', and U2357, 5'-tga tgt gtg cat tca tct cat ata t-3', and the primers for amplification of the 55 bp 92R7 locus were 92R7a, 5'-tgc atg aac aca aaa gac gta-3', and 92R7b, 5'-gca ttg tta aat atg acc agc-3'. Each 12.5 µl PCR tube contained 200 µM dNTPs, 1.5 mM MgCl2, 1 µM primers L1PR2 and U2357, 0.1 µM control primers for the 92R7 locus, 5–50 ng of DNA template and 1 IU/tube of Ampli-Taq Gold DNA polymerase and 1x buffer (both from Perkin Elmer, Warrington, UK). The cycling conditions were: a first denaturation step at 94°C for 11 min, followed by 35 cycles with steps of 60°C for 30 s, 72°C for 45 s and 94°C for 20 s. After amplification, the samples were separated in an 18 cm native polyacrylamide gel in 1x TBE buffer for 1 h at 150 V and silver stained as described previously (51), or run on a 2% NuSieve, 1% agarose gel and stained with ethidium bromide.
Microsatellite analysis
Twenty-seven males bearing the L1 insertion were further analysed for the seven Y chromosome microsatellite loci DYS19, DYS389(D), DYS389(A+B), DYS390, DYS391, DYS392 and DYS393 by automated allele typing on an ALFexpress DNA sequencer (Amersham Pharmacia Biotech) or ABI 377 (Applied Biosystems, Foster City, CA) as previously described (15). Haplotypes consisting of the allelic state (repeat number) at each microsatellite locus were used for phylogeny reconstruction with the median network program Network1.1 (33). For dating analysis we used either the average repeat number differences between haplotypes and a likely root (37) as applied by Zerjal et al. (10), or the average variance for all microsatellite loci proportional to time (35).
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ACKNOWLEDGEMENTS |
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We thank Ed Southern for stimulating discussions and suggestions about the experiments, Hans Bandelt for helpful discussions, all DNA donors and John Clegg, Eduardo M. Tarazona-Santos, Davide Pettener, Rebecca Oakey, Mark Stoneking and Alan Redd for providing samples, and Gerard Roizes and Mark Jobling for comments on the text. F.R.S. was supported by the Leverhulme Trust, A.P. by the BBSRC, M.K. by the Deutsche Forschungsgemeinschaft, R.A. by a Wellcome Trust vacation grant and C.T.-S. by the C.R.C.
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FOOTNOTES |
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+ Present address: Departamento de Biologia Geral, ICB/UFMG, Caixa Postal 486, 31.270–910 Belo Horizonte, MG, Brazil
§ Present address: Max Planck Institute for Evolutionary Anthropology, Department of Evolutionary Genetics, Inselstrasse 22, D-04103 Leipzig, Germany
¶ Present address: Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
To whom correspondence should be addressed. Tel: +44 1865 275222; Fax: +44 1865 275259; Email: chris@bioch.ox.ac.uk
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REFERENCES |
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