Human chip molecular similarities

Human chip molecular similarities - 4 No.39 Population...

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Unformatted text preview: 4 No.39 Population Genetics and Molecular Evolution (1.985) (Olua, T. and Add, K., ed.), pp. 41—64, Japan Sa'. Soc. me, Tokyo/Springer Verlag, Berlin Human Evolution at the Molecular Level MASATOSHI NEI Center for Demographic and Population Genetics, University of Texas at Houston, Houston, Texas 77225, U.S.A. For the past 15 years, my colleagues and I have been studying human evolution at the molecular level by using statistical methods we developed (1—5). Using electrophoretic data, we first showed that the net gene differences between the three major races of man, Caucasoid, Ne- groid, and Mongoloid, are much smaller than the differences between individuals of the same races, but this small amount of gene diiTerences corresponds to a divergence time of 50,000 to 100,000 years. Later, we extended our analysis to various human populations to study their evolutionary relationships in relation to geographical distribution. Re- cently, we have been studying the interracial variation of mitochondrial DNA (mtDNA) in man and the genetic relationships of man and apes. In these studies, we are using data on both restriction-site polymorphism and sequence variation of mtDNA. In this paper, I shall present the results of our recent studies which have been conducted in collabora- tion with Arun Roychoudhury, Clay Stephens, and Naruya Saitou. Specifically, I shall discuss three problems: i) evolutionary divergence of the three major races of man, ii) genetic relationships of various 41 42 M. NE! human populations, and iii) phylogenetic relationship of man and apes. EVOLUTIONARY DIVERGENCE OF THREE MAJOR RACES OF MAN In the process of human racial evolution, gene migration seems to have occurred frequently among neighboring populations. Indeed, the genetic distances between neighboring populations are generally very small, as shown by Nei and Roychoudhury (3). However, European Caucasoids, Central African Negroids, and Far-Eastern Mongoloids seem to have been isolated for a long time. Coon (6) argued that this isolation was caused mainly by two barriers, i.e., the Sahara Desert in Africa and the Movius line in Eurasia (high mountains in the west and south of Tibet). It is, therefore, interesting to know how long these three major races have been separated. This problem can be studied by using Nei’s (7) genetic distance based on protein loci since this distance is expected to be proportional to evolutionary time. The evolutionary time can also be estimated from data on restriction site polymorphism in mtDNA' (8—11). ' 1. Electrophoretic Data The genetic distances (the number of codon substitutions per locus that are detectable by the biochemical technique used) between Cauca- soid, Negroid, and Mongoloid for protein and blood group loci are given in Table I. Here, Caucasoid, Negroid, and Mongoloid are re- presented by northem Europeans (mainly English), central Africans, and far-eastern Asians (Japanese, Chinese, Koreans), respectively. The protein data in Table I indicate that Caucasoid and Mongoloid are more closely related to each other than to Negroid, so that the evolu- TABLE I Genetic Distances and Efiective Divergence Times between the Three Major Races of Man (3) Comparison Proteins Blood groups Total Efiective divergence (62 loci) (23 loci) (85 loci) time (years) Caucasoid/Negroid 0.030 0.038 0.032 113,000i34,000 Caucasoid/Mongoloid 0.011 0.043 0.019 41 ,000j; 15,000 Negroid/Mongoloid 0.031 0.096 0.047 116,000:i;34,000 HUMAN EVOLUTION 43 A B Negroid Caucasoid Mongoloid Negroid Caucasoid Mongoloid Fig. l. Evolutionary schemes of Caucasoid, Negroid, and Mongoloid as suggested by genetic distance estimates for protein (A) and blood group (B) loci. tionary relationship among the three major races becomes as given in Fig. 1A. The genetic distances computed from blood group data do not give the same genetic relationship (Fig. 1B), but the relationship is similar to that given by Cavalli-Sforza and Bodmer (12). If this relation- ship is correct, it suggests that there was a considerable amount of gene migration between Caucasoid and Negroid in the past. However, the relationship between blood group phenotype and nucleotide se- quence in the gene is not clear, so that protein data seem to be more reliable. If we accept the genetic relationship obtained from protein data, we can estimate the times of divergence of these races using Nei’s (13) method. (Actually, we estimate “effective divergence times,” since our genetic distances might have been affected by migration (2)). The results obtained suggest that Negroid and the Caucasoid-Mongoloid group diverged about 110,000 years ago, whereas Caucasoid and Mon- goloid diverged about 40,000 years ago (3). These estimates are in agree- ment with our earlier results obtained from a smaller number of loci (2). Around 1974, when we first published our estimates of divergence time, most anthropologists believed that modern man (Homo sapiens) evolved only about 25,000 years ago, after the disappearance of Nean- derthals (14). They did not pay much attention to our estimates. In the last decade, however, a number of authors have reported fossils of modern men which are as old as 120,000 years (15, IQ. Therefore, our estimates are no longer incompatible with the fossil records, even if Neanderthals are not genuine Homo sapiens. 2. Mitochondrial DNA Brown (17) studied the restriction-site patterns of mtDNAs of 21 44 M. mar individuals from the three major races. Nei (5) estimated the nucleotide differences per site for all pairs of these mtDNAs using the methods of Nei and Li (8) and Nei and Tajima (18). He then computed the number of net nucleotide differences between two races (d) using the following equation, d: dxy—(dx+dY)/29 where d" is the average number of nucleotide differences between genes of populations (or races) X and Y, and dz and dy are the average ' number of nucleotide difl‘erences between two randomly chosen genes in populations X and Y, respectively (8). The expectation of d is known to be equal to 2111, where 1 is the rate of nucleotide substitution per year and t is the number of years since divergence of the two races (8). Nei’s estimates of d are presented in Table II. It is seen that the pattern of racial divergence as revealed by the net nucleotide difl'erences is in agreement with that obtained from protein loci rather than with that obtained from blood group loci. Brown et al. (19) estimated the rate of nucleotide substitution (2) in mtDNA to be 10‘“ per site per year from their data on restriction-site maps for primates. However, a more reliable estimate is obtained from Brov'vn et al.’s (20) nucleotide sequence data, as will be discussed later. It becomes 2=7.15X10—9 per nucleotide site per year. If we use this TABLE 11 DNA Divergences (d) and Estimates of Effective Divergence Time (I) between the Three Major Races of Man d x 100 ’ 1 (years) All 21 individuals used ' Caucasoid/Negroid 005010.096 35,000 Caucasoid/Mongoloid 0.019 $0.110 13,000 Negroid/Mongoloid 0.045 i0.124 31,000 20 individuals used Caucasoid/Negroid 0.107 $0.105 75,000 Caucasoid/Mongoloid 0.019 $0.110 13,000 Negroid/Mongoloid 0.087 i0.135 61,000 d represents the number of net nucleotide substitutions per site. I was computed under the assumption that the substitution rate (11) is 7.15 X 10" per year. Eighteen restriction enzymes were used. (The data used are those of Brown (17)) HUMAN EVOLUTION . 45 rate, the divergence time between Negroid and Caucasoid or between Negroid and Mongoloid is estimated to be about 35,000 years, whereas the divergence time between Caucasoid and Mongoloid is about 13,000 years. Brown’s (17) study includes one American black who was sus- pected to have a white female in his or her maternal lineage. Even if we exclude this individual from our analysis, the estimate of the diver- gence time between Negroid and Caucasoid is 75,000 years. Note, how- ever, that the standard errors of these estimates are so large that these estimates are not really reliable. 1n the hope of obtaining more reliable estimates of the divergence times, we recently analyzed Cann’s (21) new restriction-site data. These data were obtained by comparing all restriction sites with Anderson et al.’s (22) DNA sequence so that they are more reliable than Brown’s. Furthermore, since Cann used mainly four-base enzymes (r=4 in Nei and Tajima’s (11) classification), her data are more informative. She studied 121 individuals from various human populations, but in our study we used 10 randomly chosen individuals from each of Caucasoid (English-origin Caucasians or northern Europeans), Negroid (Nigerians and American Blacks), and Mongoloid (Japanese, Koreans, and Chi- nese). Using data for 11 four-base enzymes (including five-base enzymes with r=4), we first estimated the number of nucleotide substitutions for all pairs of individuals. (We did not use the data for the two six-base enzymes because they were not very informative.) We then constructed a phylogenetic tree for the 30 individuals. The tree obtained is given in Fig. 2. Figure 2 shows that the individuals from difl‘erent races are intermingled, though there is some tendency for the individuals from the same race to cluster. A similar intermingling of individuals from different races was observed by Cann (21) and Cann et a1. (23). Cann (21) interpreted this pattern as being a result of gene migration. How- ever, the intermingling of individuals belonging to different races is expected to occur even without migration if the ancestral population was polymorphic and the time since divergence between the populations is relatively short (24, 25)., This is because many of the polymorphic genes in the current populations are expected to have diverged before population splitting (see Fig. 3). It should also be noted that the time of gene splitting is usually much earlier than the time of population 46 M. NE! —_r'—F4‘fi—I—r-_1——u——y_. 0.008 0.004 0 d 6 4 2 0 t Years (X105) Fig. 2. Phylogenetic tree of mtDNAs for 30 individuals sampled from the Caucasian (C), Negroid (N), and Mongoloid (M) populations. (Data from Cann (2]) were used) 95 T: 95 Ta 95 T1 psT 0 Fig. 3. Diagram showing that the time of gene splitting (Th T., or T.) is usually earlier than the time of population splitting (T) when polymorphism exists. splitting, and thus the former cannot be used for estimating the latter (25). Figure 2 shows that the oldest Mongoloid or Caucasoid gene diverged from one old Negroid gene about 300,000 years ago, but this HUMAN EVOLUTION 47 TABLE III Estimates of Interpopulational (dxr), Intrapopulational (dx or dy). and Net (d) Nucleotide Differences among the Three Major Races of Man Caucasoid Negroid Mongoloid Caucasoid 0.255 $0.039 0.008 $0.045 0.0059 $0.030 Negroid 0.379$0.049 0.487 $0.067 —0.0024$0.044 Mongoloid 0.308 $0.029 0.416$0.044 ‘0.350$0.032 All values are multiplied by 100. The figures on the diagonal refer to dx (or dy), and those below the diagonal dxy. The figures above the diagonal represent the values of d=dxy— (dx+dy)/2. (The data used are those of Cann (21)) time of gene divergence is almost certainly earlier than the time of racial splitting, since many other Caucasoid and Mongoloid genes diverged from Negroid genes at later times (Fig. 2). Table III shows the estimates of d”, dx, dy, and d for each pair of races that were obtained from Cann’s data. It is noted that the number of intrapopulational nucleotide differences ((1,) for Negroid is twice that for Caucasoid. This is caused by the fact that a number of Negroid individuals, particularly DH2, have diverged extensively from other individuals. It is also noted that d is very small compared with dx and has a large standard error for all pairs of races. Thus, d is again unreliable for estimating evolutionary time. ' Actually, the unreliability of d for estimating evolutionary time for this case is expected from our recent theoretical study. Using the in- finite-site model of neutral mutations (26, 27), Takahata and Nei (25) studied the theoretical variance of d for various values of effective population size (N), mutation rate per nucleotide site (y), and divergence time (g). Some of their results are presented in Table IV. It is clear that when the time since divergence between two populations is rel- atively small, the standard error (s..) of d is expected to be larger than the expectation, even if a large number of genes are sampled. In the case of divergence of mtDNA between Negroid and Caucasoid, we may assume g=5,000 generations, N=2,500, and #:10‘7 per genera- tion to get a rough idea of sd. In this case, the expectation of d is E(d)= 0.001, and 5., becomes 0.00116 for sample size m=10. Therefore, the standard error is expected to be larger than E(d). It is noted that if we assume a larger value of N, sd becomes even larger. This large value of 48 ' M. NH TABLE IV Theoretical Standard Errors (3.1) of d=dxy —(dx+dy) ___—______—_———-—————————— Generations Standard error (so: X 100) N since 5(4) x 100 “=" divergence 2 lo 100 _____________________—__-—— 2,500 5,000 0.1 0.149 0.116 0.111 2,500 50,000 1.0 0.339 0.327 0.326 25,000 5,000 0.1 0.728 0.211 0.122 25,000 50,000 1.0 1.03 0.786 0.743 25,000 500,000 10.0 1.58 1.45 1.44 250,000 5,000 0.1 6.54 1.13 0.215 250,000 50,000 1.0 7.03 2.05 1.13 250,000 500,000 10.0 10.30 7.33 7.00 It is assumed that a gene consists of 1,000 nucleotide pairs and the rate of nucleotide sub- stitution (mutation rate) is 10'7 per nucleotide site per generation. E(d) is the expected value of d. (Adapted from Takahata and Nei (25)) N, efi'ective population size; m, n, sample sizes from populations X and Y. s., is mainly due to the stochastic errors of nucleotide substitution, and thus it is not reduced appreciably by increasing sample size. It is-unfortunate that mtDNA is not very useful for estimating the time of divergence of human races despite the fact that it can easily be studied experimentally. For DNA data to be useful for our purpose, we must use many independent genes (25). It is, therefore, hoped that in the future many different genes from nuclear DNA will be studied. Of course, if one is interested in the evolution of more distantly related organisms, such as those of man and apes, even a single genome of mtDNA is quite useful, as will be discussed later. It should be noted that, although it is difficult to obtain a reliable estimate of divergence time from mtDNA in the present case, some idea about the pattern of racial differentiation can be obtained from the evolutionary tree given in Fig. 2. This tree shows that one Negroid mtDNA is quite different from the other mtDNAs and all others diverged from this mtDNA about 500,000 years ago. It is also noted that many mtDNAs from Caucasoid and Mongoloid are derived from Negroid mtDNAs. Although we cannot regard this tree as the true tree, this observation suggests that Negroid diverged from the Caucasoid-Mon- goloid group earlier than Caucasoid and Mongoloid diverged. This interpretation agrees with the pattern of racial differentiation inferred HUMAN EVOLUTION 49 from protein data (Fig. 1A). It is also in agreement with the pattern observed by Nei (5) in his phylogenetic analysis of Brown’s (I 7) mtDNA data and that observed by Johnson et a1. (28) for their own mtDNA data. Cann et al. (23) presented a phylogenetic tree of 110 mtDNAs from various human populations, showing ‘that the oldest mtDNA exists in Australian Aborigines. However, Cann’s (21) more extensive and careful study has shown that the oldest mtDNA actually exists in the Negroid population rather than in the Australian Aborigines. Her later study of DNA sequences (R.N. Cann, personal communication) has confirmed this pattern of mtDNA differentiation. In this connec- tion, it is interesting to note that the oldest fossils of Homo sapiens were discovered in Africa (15, 16). The pattern of racial difl‘erentiation can also be inferred by using d", which has a smaller coeflicient of variation than d (see Table III). As defined earlier, d” is the average number of nucleotide differences between genes of populations X and Y, and is composed of two com- ponents, i.e., i) the average number of nuCIeotide difl'erences between two randomly chosen genes at the time of population splitting (do) and ii) the number of nucleotide substitutions after population splitting (d). If we assume that do is the same for all of the three major races, dxy,s give a rough idea of the pattern of population splitting. (In Eq. (1), d0 is estimated by (dx+dy)/2.) In Table III, the d" value between Caucasoid and Mongoloid is considerably smaller than the values between Caucasoid and Negroid and between Negroid and Mongoloid. Therefore, the pattern of population splitting is roughly similar to that of Fig. 1A. 3. Skin-color Difl'erentiation between Caucasoid and Negroid One classical study which is relevant to the times of divergence between the three major races of man is that of skin-color difference between Caucasoid and Negroid. Studying the distribution of skin pigment intensity in Caucasoid/Negroid admixed populations, Stern (29, 30) estimated that the skin-color differences between Caucasoid and Negroid are controlled by 4—6 loci at which different alleles are fixed in the two populations. If Stern’s estimate is correct, how many years would have been necessary for the skin-color difference to be 50 M. NE! established after the two populations were separated? A crude answer to this question can be obtained if we assume that dark skin color is more advantageous than light skin color in the tropical region, whereas in the northern temperate region light skin color is more advantageous. A simple way of estimating the time of skin-color divergence is to use a deterministic model of gene frequency change. For simplicity, let us assume that there are five loci involved in the skin-color difference, the genotypes for Negroid and Caucasoid being AluAlnAgnAzn . . . AWABN and AloAchchgc . . . AaoAsc, respectively. We also assume that that the original ancestral population had black skin, living in tropical Africa, and later a group of individuals moved to a northern temperate region and accumulated light skin-color alleles. (At the pre- sent time, we do not know which population was ancestral in terms of skin pigmentation, Negroid or Caucasoid (or even Mongoloid), but it does not matter for our computation.) We further assume that the fitness difference between whites and blacks in the northern temperate region is 0.1 and that the allelic etfect (selection coefficient) at a locus is s=0.1/(2X5)=0.01. That is, the fitnesses of AmAm, AmAw, and AwAw are 1, 1+s, 1+2r, respectively. One might argue that s is larger than 0.01, but the fitness difference between whites and blacks does not seem to be much larger than 0.1 either in northern temperate regions or in tropical Africa. Suppose that the original population had the A0 allele at a locus with a frequency of po=0.001 and that if the allele frequency reaches p,=0.999, the allele is regarded to have been fixed. Then the time required for the frequency of allele A0 to change from 120 to p; is t: Llog. —————p‘(1 _p°) s Po(1 ‘P:) In primitive human populations, one generation probably corresponds to 25 years. If this is the case, the required time will be 34,525 years. - This time, however, would be minimal because in natural popula- tions, which are always finite, even advantageous mutations would not be fixed in the population with probability 1 (31-33). When the effective population size is of the order of 5,000—10,000, the probability of fixa- tion of rare alleles is quite small. Once the Ac allele is lost from the = 1,381 generations. HUMAN EVOLUTION 51 TABLE V Expected Evolutionary Times (T) Required for the Skin-color Difl‘erentiation between Whites and Blacks under Various Assumptions of Effective Population Size (N), Selection Coefiicient (s), Mutation Rate (v), and Initial Gene Frequency (pg) T (years) Case N s v po=0 po=0.001 po=0.01 1 5,000 0.005 5 x 10—1 525,000 504,000 234,000 2 2,500 0.01 10" 2,402,500 2,288,000 943,500 3 2,500 0.01 10" 262,500 252,000 117,000 4 1,250 0.02 5 x 10" 131,250 126,000 58,500 See text for the details. population, the population can no longer develop light skin-color unless new mutations are introduced. New mutations are also required when the original population happens to have no Ac alleles at the time of population splitting. Thus, a more realistic model would be a stochastic one in which gene frequency is subject to mutation, selection, and genetic drift. We consider a population of efl‘ective size N and assume that the initial frequency (p0) of AG at the time of population splitting is low (0, 0.001 or 0.01), but because of recurrent mutation from A; to A0, the popula- tion eventually develops light skin-color. Let v be the rate of mutation from AN to Ac (advantageous allele) and s be the selective advantage of Ac over AN as before. The expected time to fixation of the A0 allele in the population can then be studied by using Li and Nei’s (34) theory. This expected time to fixation depends on the values of N, s, v, and po in a complicated way. However, as is clear from Table V, it is quite long unless population size is extremely small. Here, we have assumed VSSX 10—“ per locus per generation, because we are dealing only with those mutations that would affect the intensity of skin-color pigmentation. Even if v=5x10‘“, s=0.02, and po=0.001, the expected time is 126,000 years. We note that the effective population size for mitochondrial genes is unlikely to be smaller than 1,250, though it is only about a quarter of that for nuclear genes (8). This is because the average number of nucleotide differences between two randomly chosen sequences within populations (dx) is quite large (Table III). Note that the expectation of dx for neutral mutations is 4Np, where y is the 52 M. NH mutation rate per nucleotide site per generation. This becomes 9x 10“ if N=l,250 and y=25X7.15X10‘“=1.8X 10-7. The present computa- ' tion therefore suggests that the divergence time between Caucasoid and Negroid is likely to be of the order of at least 100,000 years rather than the order of 25,000 years. GENETIC RELATIONSHIPS OF VARIOUS HUMAN POPULATIONS There seems to be no agreement concerning the classification of human races among anthropologists. Some anthropologists (e.g., Boyd (35)) prefer to classify human races into five major groups, adding Amerindian and Australoid (or Oceanian) to the three major races we have considered. We have therefore studied the genetic relationships of various human populations within each of these five groups by using Nei’s genetic distance (7). In this study, we have used gene fre- quency data for protein and blood group loci jointly because the data for protein loci were limited in some populations. The total number of loci used varied from 10 to 25, depending on the population group examined. In this paper, I shall not present all of the results because of space limitation. Rather, I present the genetic relationship of 18 representative populations of the world and then discuss the factors that caused genetic differentiation of populations. 1. Eighteen Representative Populations The 18 populations given in Table VI have been chosen mainly because they are of anthropological interest and the gene frequency data for them are available. All five racial groups are represented by them. The genetic distances in Table VI were obtained by using 14 protein loci and nine blood group loci. Figure 4 shows the dendrogram obtained from these distances by using the unweighted pair group method (UPGMA). It is clear that the Caucasoid and Mongoloid populations are again more closely related to each other than to the Negroid populations. However, Amerindians and Australoids, who are supposed to be closely related to Asian Mongoloids, make separate clusters. This is apparently due to the effect of inbreeding that has occurred in these small tribal populations. The relatively large distance 53 HUMAN EVOLUTION ndN m." N.N 0.: mg: md 5.2 w.» v.oN wd 9: fig 0.: m4: fia YNN v.2 Nan 9N“ wag 9w fi~N m6 N6 94. m6 wa— eé En m6 mg: v; fin Q: of oéN Nd od— ad ed. as. m6 Tm mé o._N .88qu E 38— you buomfieofi: omEo>n 2: 98 Ecomfiu 05 no 3.53 2F v6— .¢.m fim Won QS ad v.2 9: od— fioa 0.: 0.: wé N.m vi fiv v6 9v fin m.m fi.v m4” Nd 9m mé v4. fiv mé EN of fin in E— N.“ *4 ON oéN N.“ m6 v.0 fiVN nd nd N.nN md n.mN hm fiw m6 9m a.“ fie. N6 9v ad m.m n; N.N v.N QwN m6 9m o6 fie ad in fir m6 mi 9m fiN m.N N.m m6 vKN m6 #6 m6 9v v4. 95 m6 m6 ed 5.? 0.». fin n6 m6 m6 o6. Ev in fiw m6 N6 wd ed o.n 9m wé 9v N..v fiv QM N.m o.m 9N n.m 1m QN ad Em .v.m ho wd n4 rd 5.0 FA 98 N06 v.“ TN 5.— EN aafifiam 8: 35m 93 5:022 G: gamma Am: .382 a: 9.: OEEmm Am: 5:2: any—mm? AN: 3:2: .Nfim GS cave—.822 3: cave—SBA 8V >222 A8 085%.. AD 03:20 6V 56.: A3 5:55 E 5:“: A0 iii 6 n93 3 llll|||llll|l|ll|lllllll|lllllll|||ll 8: 9: G: 9: $5 G: AN: :3 85 A9 a: 5 6V 5 A3 5 2.83 05 Eat macaw—anon o>=55woao¢ M: .8.— .ooA 03050 N :0 woman 93 x 3 80:8 5 a 5 £9 0:250 and 336339302 ommao>< ~> mdmflw 54 M. NEI Lapp English Italian Iranian N.lndian Malay Chinese Japanese Polynesian Micronesian S.Amerind Eskimo Alaskan Indian Aust. Aborigine Papuan Nigerian Bantu Bushman —'———l——'—'——'___—‘ 4 3 2 'l 0 Genetic distance (DX'IO’) Fig. 4. Dendrogram for 18 representative races of man. Lapp Finn Basque German English Italian _____'__—_——-l—————. l 0.5 0 Genetic distance (DX 10’) Fig. 5. Dendrogram for six European populations. between Australian Aborigines and Papuans is also apparently caused by inbreeding. It is known that when population size is reduced dras- tically, genetic distance rapidly increases (36). It is noted that the genetic distance between English and Italian is very small compared with the distances between other populations. It is less than 1/10 of the distance between Chinese and Japanese, and 1/200 of that between Australian Aborigines and Papuans. Actually, all western European populations are genetically closely related, as HUMAN EVOLUTION 55 seen in Fig. 5. Note that even the Basques who speak a non-Indo- European language are closely related to the other European popula- tions. This is, of course, expected since there has been a substantial amount of gene migration in the recent history of Europe. In Europe, the only distantly related population is the Lapps, who are considered to have been isolated from other populations for a long time. 2. Factors Aflecting Gene Difl'erentiation Our study of the genetic relationships of various human popula- tions suggests that the most important factors affecting gene differen- tiation among populations are isolation and genetic drift. Figure 4 clearly shows that a pair of populations that have been isolated for a long time (e.g., Bushmen and Japanese) generally show a large genetic dis- tance. Thus, isolation is obviously the most important factor. The importance of genetic drift is indicated by the fact that a pair of tribal populations, such as Australian Aborigines and Papuans, generally have a large distance. This tendency was observed in many tribal pop- ulations in America, Africa, and Southeast Asia (3). Gene migration has the opposite effect of isolation. In the process of human evolution, migration apparently occurred quite often among neighboring populations. A good example is the Beja in Sudan. These tribesmen are nomads who have lived for thousands of years in the semi-desert areas of the Red Sea Coast and the hilly country behind. They belong to Negroid, but because of geographical proximity they seem to have had gene admixture with eastern Mediterranean Cauca- soids (37). This is reflected in the genetic distance matrix for the African and Mediterranean populations (3). Genetic distance data indicate that, although they are closely related to sub—Saharan Negroid populations, they are also genetically close to Italians and northern Caucasians. This clearly shows the importance of migration in making two pop- ulations genetically close. Gene migration makes it difficult to reconstruct a phylogenetic tree that reflects the evolutionary pathways of the populations con- cerned. In the reconstruction of phylogenetic trees, bifurcation of populations is generally assumed. In the presence of migration, however, this assumption is no longer satisfied, and thus the phylogenetic tree 56 M. NEI reconstructed does not necessarily reflect the true evolutionary scheme. It is, therefore, important to examine both the dendrogram and distance matrix when one wants to make any inference about evolution. In this connection, it should be noted that the dendrogram recon- structed is subject to errors caused by the stochastic changes of gene frequencies even if there is no disturbance due to migration (38). These errors are quite serious when the number of loci used is small. The only way to reduce these errors is to increase the number of loci. Ideally, any dendrogram should be based on at least 30 loci. In human populations, language can be a barrier to interracial hybridization. In practice, however, genetic distance is not clearly related to linguistic difl‘erence, except among very closely related pop- ulations (3). This is understandable because the language of a human population can rapidly change under certain circumstances. The rela- tionship between genetic distance and morphological difference is also generally weak. Figure 6 shows the dendrograms for 10 human pop- ulations. The Negritos and Aboriginal Malays in Southwest Asia, Papuans in New Guinea, and Pygmies and Bushmen in Africa have a number of common morphological features such as short stature, dark skin, and frizzled hairs. Because of these similarities, some anthropol- ogists believe that they have originated from the same common stock. Chinese Malay Filipino Aborig. Malay Malay Negrilo Phil. Negrito Aust. Aborigine Papuan Pygmy Bushman —-r——-———-—'r———'F_—‘ 8 6 4 2 0 Genetic distance (DXlOz) Fig. 6. Dendrogram for Negritos and their neighboring populations. Pygmies and Bush- men are included because they are phenotypically similar to Negritos. HUMAN EVOLUTION 57 Our genetic distance study, however, indicates that the African and Southeast Asian populations are genetically quite different, and they are generally more closely related to their neighboring populations. This indicates that the evolutionary change of morphological characters are quite different from those of average genes. Apparently morpho- logical characters are subject to stronger natural selection than average genes (1). PHYLOGENETIC RELATIONSHIP OF MAN AND APES In recent years, the phylogenetic relationship of man and apes has been studied intensively by using various molecular data. However, relatively little attention has been paid to the accuracy of the phylo- genetic tree reconstructed. In view of this circumstance, we have devel- oped a statistical method for computing the standard errors of branch- ing points of a tree reconstructed by UPGMA and have examined the reliability of the reconstructed trees of man and apes from four diflerent sets of data, i.e., amino acid sequences, nucleotide sequences, restric- tion-site polymorphisms, and electrophoretic data (39). Although amino acid sequencing was started more than 20 years ago, the sequence data for man and apes are still limited. The only data that could be used for our purpose were those for hemoglobins a and p, myoglobin, fibrinopeptides A and B, and two partial sequences (13 amino acids each) of the duplicate hemoglobin r chains for the human, chimpanzee, gorilla, and orangutan. The total number of amino acids 0.001 Human .\\\\\\\\\\\\\\\\ b C h i m p u n ze e -\\\\\\\\\\\\\\\\\\\\\\\\\\\\\‘ Gorilla .\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\Y Orangutan Fig. 7. Evolutionary tree for four hominoid species, which was reconstructed from amino acid sequence data. The number given for each branch represents the branch length or the number of amino acid substitutions per site. The hatched box represents 1 SE. on each side of the mean branching point. 58 M. NH used was 496. We first estimated the number of amino acid substitu- tions per amino acid site using the Poisson correction method for all pairs of species. We then reconstructed a phylogenetic tree by using UPGMA. The tree obtained is presented in Fig. 7. The standard error of the branching points of this tree were obtained by Nei et al.’s (39) method. Figure 7 suggests that the human and chimpanzee are more closely related to each other than to gorilla, but the standard errors of the two branching points a and b are so large that the difference between them is not statistically significant. That is, we cannot decide which organism diverged first among the human, chimpanzee, and gorilla. By contrast, the difference between branching points b and c in Fig. 7 is significantly difl‘erent from 0. Therefore, the orangutan apparently diverged from the human line significantly earlier than the gorilla and chimpanzee did. 7 The second set of data'we used was Brown et al.’s (20) nucleotide sequences of mtDNAs (a segment of 896 nucleotides) from the human, chimpanzee, gorilla, orangutan, and gibbon. The numbers of nucleotide substitutions per site were estimated by Jukes and Cantor’s formula. The UPGMA tree obtained is given in Fig. 8. It is seen that the standard errors of branching points are much smaller than those of the tree in Fig. 7. Yet, the difference between the two branching points a and b is not statistically significant, whereas the difl'erence between the branch- ing points b and c is again significant. The third set of data used is that of restriction-site differences for 0309 0.047 Human Chimpanzee .\\\\\\\\\\ 0.0” c .\\\\\\\\\\\\\' Gorilla Orangutan .\\\\\\V\\\\\\\ Gibbon Fig. 8. Evolutionary tree for five hominoid species, which was reconstructed from nu- cleotide sequence data for a segment of mtDNA. The number given for each branch re- presents the branch length or the number of nucleotide substitutions per site. The hatched box represents 1 SE. on each side of the mean branching point. HUMAN wow-nor: 59 0.044 0,012 Chimpanzee O .\\\\\\\\\\\\\\\\‘ 0.0l6 b .\\\\\\\\\\\\\\\\‘ Gorilla 0.010 c .\\\\\\\\\\\\\\\\\\\\ 0'0“ I Human Orangutan A\\\\\\\\\\\\\\\\\\\‘ Gibbon Fig. 9. Evolutionary tree for five hominoid species, which was reconstructed from re- striction-site data for mtDNA. The number given for each branch represents the branch length (the number of nucleotide substitutions per site). The hatched box represents 1 5.13. on each side of the mean branching point. 0.10 c .\\\\\\\\\L\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\‘ .\“\\\k\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\u\\\\\\\ x\\\\\\\\\\\\\\\\\\\\\\\\\\ 0'07 Concolor Gibbon Fig. 10. Evolutionary tree for six hominoid species, which was reconstructed from elec- trophoretic data. The number given for each branch represents the branch length (genetic distance). The hatched box represents 1 SE. on each side of the mean branching point. mtDNA (40). In this case, the number of nucleotide differences for each pair of species was estimated by using Nei and Tajima’s (11) maximum likelihood method. The topology of the phylogenetic tree obtained from this set of data (Fig. 9) is difierent from that of Figs. 7 and 8 in that the chimpanzee is closer to gorilla than to the human. However, the standard errors of the branching points of this tree are much larger than those of the tree from nucleotide sequence data. Therefore, the branching order of the human, chimpanzee, and gorilla cannot be determined from this set of data. In the present case, even the difference between branching points b and c is not statistically significant. The final set of data used was Bruce and Ayala’s (41) isozyme gene frequencies. The genetic distances based on 20 loci were computed for 60 M. NE! all pairs of species by using Nei’s (7) method. In the present case, how— ever, the human had to be excluded because gene frequency data were not available for this species. Instead, two species of the chimpanzee and two species of the gibbon were included. The branching pattern of the chimpanzee, gorilla, orangutan, and gibbon is quite different from that of the previous trees, the orangutan now being closer to the chim- panzee than to the gorilla (Fig. 10). However, the standard errors of the branching points of this tree are so large that this tree is not very reliable. ' This low reliability of electrophoretic data is partly due to the small number of loci used. In a computer simulation, Nei et al. (38) have shown that when the number of loci used is less than 30, the topology of a reconstructed tree is subject to a large stochastic error. The ac- curacy of a reconstructed tree also depends on the detectability of protein differences by electrophoresis. The higher the detectability, the higher the reliability. It should be noted that in Bruce and Ayala’s experiment, this detectability was not particularly high. Previously, King and Wilson (42) had studied the genetic distance between the human and chimpanzee and obtained D=0.62, which is nearly two times higher than the estimate (0.39) obtained by Bruce and Ayala (41). Comparison of the four trees obtained from different sets of data suggests that the tree obtained from nucleotide sequence data is more reliable because this tree has the smallest standard errors of branching points. The topology of this tree is the same as that of the tree from amino acid sequence data, though the latter does not include the gib- bon. It should also be noted that this topology is in agreement with that of the trees reconstructed from both chromosomal studies (43) and DNA hybridization (44). The topology of the tree inferred from re- striction-site data for ribosomal DNA (45) also agrees with that of Fig. 8. Therefore, this topology seems to be the most reliable one. In a statistical analysis of the parsimony tree reconstructed by Ferris et al. (40), Templeton (46) concluded that the topology in Fig. 6 is significantly better than that in Fig. 8. However, his conclusion is not justified, since the parsimony method he used introduces many statistical biases when it is applied to restriction-site data (47). HUMAN EVOLUTION 61 TABLE VII Estimates of the Times of Divergence from the Human Lineage (Million Years) Divergence Sarich and Sibley and This node Wilson (1967) Ahlquist (1984) paperl Chimpanzee 5 6.3 6.6 Gorilla 5 8.0 7.8 Orangutan 8 13.0 13.0 Gibbon ' 10 18.2 15.0 Old World monkey 30 27.0 l The rate of nucleotide substitution used is 2=7.15 x10" per site per year. (Brown et al.'s (20) data were used) Divergence Times of Man and Apes If the topology given in Fig. 8 is correct, we can estimate the times of divergence among the human and ape species. For this purpose, however, we must first know the rate of nucleotide substitution (2). Brown et al. (19) estimated the rate to be about 10—3 per site per year, as mentioned earlier. However, their estimate is based on restriction- site data under the assumption that the estimates of the divergence times of man and apes based on the albumin block are correct. In practice, the estimates obtained from the albumin clock are subject to a rather large stochastic error (48). Therefore, it is desirable to estimate 1 from nucleotide sequence data and fossil records. According to An- drews (49) and Pilbeam (50), fossil apes Ramapithecus and Sivapithecus are considered to be ancestors of the present orangutan line. If this is the case, the orangutan line seems to have diverged from the human line about 13 million years ago (see Note added in proof in ref. 44). We can then estimate 2 from the estimate of the number of nucleotide substitutions in the orangutan line in Fig. 5. It becomes 1=0.093/(13 X 10°)=7.15x10" per nucleotide site per year. We can now estimate the times of divergence of various organisms from the human line using this value of Z and the branch lengths of the tree in Fig. 8. The results obtained are presented in Table VII, together with those obtained by Sarich and Wilson (51) and Sibley and Ahlquist (44). It is interesting to see that our estimates of divergence times are very close to Sibley and Ahlquist’s obtained from DNA hybridization data, except for the divergence time for the gibbon. This indicates that the relative branch lengths of the Sibley-Ahlquist tree are similar to 62 M. NE! those of ours. (Here, I have used Sibley and Ahlquist’s estimates based on the assumption that the divergence time for the orangutan is 13 million years.) By contrast, Sarich and Wilson’s estimates obtained from their albumin clock are somewhat difl‘erent from ours. They used the old world monkeys for calibrating time. At the present time, how- ever, it is premature to make any definite conclusion about the diver- gence times. The fossil records we have now are not sufficient for esti- mating a reliable evolutionary time. We also need more extensive molecular data. SUMMARY 1) The genetic relationship of the three major races of man, Caucasoid, Negroid, and Mongoloid, was studied by using gene fre- quency data for 62 protein loci and 23 blood group loci. Genetic dis- tance estimates obtained suggest that Caucasoid and Mongoloid are somewhat closer to each other than to Negroid and that Negroid and the Caucasoid-Mongoloid group diverged about 110,000:l: 34,000 years ago, whereas Caucasoid and Mongoloid diverged about 41,000: 15,000 years ago. This pattern of racial difi‘erentiation is supported by mtDNA data, but the latter data do not give reliable estimates of divergence time. ' 2) The genetic relationships of various populations in each group of Caucasoid, Negroid, and Mongoloid were also studied. All European populations are genetically close to one another except the Lapps, whereas many African, Oceanian, and Amerindian tribes show ex- tensive genetic differentiation. The major factor for this differentiation seems to be the bottleneck effect. There are indications that migration played an important role in forming the current genetic relationships of human populations. The extent of genetic differentiation among human populations is not always correlated with the degree of morphological differentiation. 3) The evolutionary relationship of the human, chimpanzee, gorilla, orangutan, and gibbon was studied by using data on amino acid substitutions in proteins, nucleotide sequences and restriction-site maps of mtDNA, and electrophoretic allele frequencies. The phylo- HUMAN EVOLUTION 63 genetic tree obtained from DNA sequence data seems to ’be most reli- able, and this tree indicates that the species that is closest to man is the chimpanzee, and the next closest species is the gorilla. Acknowledgments I thank Arun Roychoudhury, Clay Stephens, and Naruya Saitou for their help in data analysis, and Peter Smouse for his detailed com- ments on an earlier version of this manuscript. This study was supported by grants from the National Institutes of Health and the National Science Foundation. REFERENCES Nei, M. and Roychoudhury, A.K. (1972) Science 177, 434-436. Nei, M. and Roychoudhury, A.K. (1974) Am. J. Hum. Genet. 26, 421-443. Nei, M. and Roychoudhury, A.K. (1982) Evol. Biol. 14, 1-59. Nei, M. (1978) Japan. J. Hum. Genet. 23, 341—369. Nei, M. (1982) In Human Genetics, Part A: The Unfolding Genome (Bonné-Tamir, B. et al., eds.), pp. 167—181, Alan R. Liss, New York. Coon, CS. (1965) The Living Race: of Man, Knopf, New York. Nei, M. (1972) Am. Not. 106, 283-292. Nei, M. and Li, W.-1-1. (1979) Proc. Natl. Acad. Sci. U.S. 76, 5269—5273. Gotoh, 0., Hayashi, J.-I., Yonekawa, H., and Tagashira, Y. (1979) J. Mol. Evol. 14, 301-310. 10 Kaplan, N. and Langley, CH. (1979) J. Mol. 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