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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)...
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