Evolutionary Anthropology 81 Issues Human Demography in the Pleistocene: Do Mitochondrial and Nuclear Genes Tell the Same Story? raditionally, research on mod- genomic region of interest is selec- stable. The expected pattern under ern human origins has centered tively neutral, the amount and pattern selective neutrality and constant popu- Ton questions of the time and of nucleotide variation is expected to lation size10,17 is represented by the geographical place of origin, with less be proportional to the population size,9 hatched bars in Figure 2. The left- attention given to the complex popula- and to track changes in the population shifted distribution of mtDNA poly- tion dynamics of our evolutionary his- over time.10-12 Another simplifying as- morphism is consistent with an ini- tory. Recently, however, a focus has sumption that is often valid for the tially small population that recently emerged within molecular anthropol- nuclear genome (and less so for the has undergone a dramatic increase in ogy that concentrates on the demo- mitochondrial genome) is that muta- size. But, on the other hand, the pat- graphic aspects of the origin of mod- tions are rare at any one base position. tern could have been the result of a 1-3 ern humans. A popular hypothesis For example, a common assumption history dominated by natural selec- proposes that modern human popula- that greatly facilitates the develop- tion on the mitochondria. tions passed through a bottleneck (or ment of mathematical theory is the If the demographic story told on the episodic reduction in size) in the late infinite-sites model whereby muta- basis of the mtDNA variation is accu- Middle or early Late Pleistocene, at tions are assumed to have occurred rate and represents the actual history which time there existed perhaps only only once per polymorphic site.13 of modern humans, then we expect a several thousand breeding individu- One way in which nucleotide varia- similar pattern of variation across most als, and that this was followed by a tion can be described is by the fre- other loci. Because the mitochondrial rapid, large expansion.1,2,4 Supporting quency distribution of polymorphic genome lacks recombination, its con- evidence comes largely from the pat- sites within a genomic region. For stituent genes are all linked in their tern of DNA sequence variation ob- example, when a nucleotide site is inheritance. Evidence from this ge- served in mitochondrial genes. How- polymorphic, usually just two differ- nome’s 37 constituent genes and two ever, because the mitochondrial ent bases are found at that site. If we short noncoding regions cannot be genome is only a very small fraction of count the occurrences of the least fre- taken as independent evidence. There- the entire genome, its evolutionary quent base, this will give us the fre- fore, patterns of genetic variation must history is not necessarily concordant quency class for this particular site. be compared across multiple unlinked with the history of the bulk of the Mutations present in a single se- genes from the nuclear genome. In genome, the nuclear genome. quence (for example, at positions 2, 3, units of base pairs, the nuclear ge- An important distinction can be made between evolutionary forces that and 13 in Fig. 1) represent low-fre- nome is about two hundred-thousand affect just one locus and those forces quency mutations and all appear in times the size of the mitochondrial that act on all the genes of a popula- frequency class one. Likewise, muta- genome and harbors 50,000 to 100,000 tion. Population-level phenomena such tions appearing in half the sequences genes. As such, it is a largely untapped as bottlenecks, expansions, popula- (positions 5, 10, 12, and 15 in Fig. 1) resource of information about our ge- tion subdivisions, and speciation represent intermediate frequency mu- netic and populational history. events are expected to produce similar tations and appear in the highest fre- In comparing the variation at differ- patterns of genetic variation across quency class, or half the number of ent genes, the fundamental differ- many loci. In contrast, natural selec- sequences. ences among mitochondrial genes, au- tion usually affects a small region of The frequency distribution of poly- tosomal genes, and genes on other tight linkage, such as a single genetic morphic sites in the mtDNA control chromosomes should be kept in mind. locus. Therefore, hypotheses about regions I and II14 is shown in Figure 2. First, unlike diploid genes, mitochon- population histories should be tested It indicates an abundance of low fre- drial genes are not maintained on two across many loci.5-8 quency polymorphisms and only a distinct chromosomes, and though small fraction of polymorphisms at they are numerous in any one cell, the HOW CAN DNA SEQUENCE intermediate frequency. This left- processes of replication and turnover lead to their being passed on in an VARIATION REVEAL shifted distribution is typical of hu- man mitochondrial genes.15,16 This pat- effectively haploid fashion. Second, DEMOGRAPHIC HISTORY? tern, however, is not expected when whereas autosomal genes are transmit- Under the simplifying assumption sequences have evolved neutrally and ted by both parents, mitochondrial that DNA sequence variation in the when population sizes have remained genes are solely transmitted by the 82 Evolutionary Anthropology ISSUES discussing changes in the effective (chromosome 11)19; lipoprotein lipase 20,21 population size (Ne) of humans over (chromosome 8) ; several X-linked time. genes, including pyruvate dehydroge- The frequency distributions of poly- nase E1␣ subunit (PDHA1)15,18; dystro- morphic sites for each nuclear gene phin (Dmd)22; myelin proteolipid pro- can be compared with each other and tein (Plp); and glycerol kinase (Gk).23 with mitochondrial genes to test When compared with the frequency whether they are consistent with a distribution under a neutral model single population history. Hey15 ob- (the hatched bars in Fig. 2), these served that nuclear genes show an nuclear genes show even more muta- abundance of intermediate-frequency tions than expected at intermediate polymorphisms, in contrast to the over- frequencies. abundance of low-frequency polymor- HOW DO MITOCHONDRIAL AND Figure 1. Sample of sequences from a simu- lated population showing mutated bases that NUCLEAR GENE TREES DIFFER? differ in their frequency class. In units of base pairs, the The frequency distribution of poly- nuclear genome is about morphic sites bears a fairly simple mother. In contrast, X-linked genes relationship to the overall shape of the and Y-linked genes show different two hundred-thousand gene tree. For example, a star-shaped patterns. X chromosome genes are times the size of the gene tree (Fig. 4) in which the vast majority of coalescent events occur found as two copies in females but mitochondrial genome only one copy in males, but can be near or at the root is typical of a transmitted by either sex; Y chromo- and harbors 50,000 to population that has undergone rapid some genes are found as single copies population growth from an initially 100,000 genes. As such, 12 in males and are transmitted solely small population. The mutations that by them. The differences in number it is a largely untapped appear on this tree are not likely to and inheritance of these different resource of information have been inherited by more than a genes have significant effects on the single DNA copy in the sample and amount of variation they harbor. This about our genetic and will tend to be at low frequency. Such is solely because of the different populational history. a star-like tree is indicated by the number of gene copies existing in the pattern of mutations observed in population at any given moment. This mtDNA sequences, which show an point will be returned to later when abundance of low-frequency muta- tions. phisms found in the mtDNA, and com- In contrast, a tree with a more bal- pared several small nuclear gene data anced branching pattern and in which sets with the patterns found in the population size has been constant (Fig. mtDNA. The statistical tests were per- formed under a model of constant population size as well as a model of rapid population growth, as hypoth- esized by Rogers and Harpending.1 In all of the contrasts, the mitochondrial and nuclear genes were inconsistent with the same demographic histories. The frequency distribution for the X-linked PDHA1 region is shown in Figure 3.18 It shows an abundance of intermediate-frequency mutations and a paucity of low-frequency mutations. This pattern produces a distribution that is right-shifted, which is exactly the opposite of the distribution for Figure 2. The frequency distribution of polymor- mitochondrial genes. Interestingly, as Figure 3. The frequency distribution of polymor- phic sites for mtDNA control regions I and II. Hey15 noted, and as data that have phic sites for the PDHA X-linked gene. Black Black bars are the observed frequencies. emerged since then indicate, the major- bars are observed frequencies. Hatched bars Hatched bars are the expected frequencies ity of nuclear regions sequenced for are the expected frequencies under con- under constant population size and assuming human populations show a similar stant population size and assuming a neutral a neutral evolutionary model.10,17 The left- evolutionary model. The right-shifted distribu- shifted distribution of the mtDNA control re- right-shifted distribution, indicating an tion of the observed frequencies is typical of gion sequences is typical of mitochondrial abundance of intermediate-frequency all known large DNA sequence data sets for genes. mutations. These include ␤-globin nuclear loci. ISSUES Evolutionary Anthropology 83 could have operated on either the mi- of mtDNA showing that human tochondrial or nuclear genome, or mtDNA samples segregate high levels both.