Eugene E. Harris

Human populations show reduced DNA sequence variation at the Factor IX locus

Levels and patterns of human DNA sequence variation vary widely among loci. However, some of this variation may be due to the different populations used in different studies. So far, few studies of diverse human populations have compared different genetic loci for the same samples of populations and individuals. Here, we present new polymorphism data from intron 4 of the Factor IX gene (FIX) sequenced in diverse Old World populations. An explicit comparison is made with another X-linked gene, PDHA1, for which the sampling of individuals was very similar. Despite having a similar amount of divergence from chimpanzees, as do other nuclear genes, FIX has comparatively much less DNA sequence variation among humans. Nucleotide diversity at FIX is the lowest among the existing non-Y chromosome nuclear gene datasets and is less than 10% of the diversity found at PDHA1. Estimates of effective population size based on FIX are 8,558, about half of the value obtained for PDHA1, and the time to the most recent common ancestry among human FIX gene copies (282,000 years) is one of the most recent estimates reported for human genes. Analyses presented here suggest a history for the FIX region that includes recent positive directional selection, or background, selection. The general conclusion emerging is that very large variations can exist between the histories of similar genomic regions, even when sampling differences are minimized.

Nonadaptive processes in primate and human evolution.

Evolutionary biology has tended to focus on adaptive evolution by positive selection as the primum mobile of evolutionary trajectories in species while underestimating the importance of nonadaptive evolutionary processes. In this review, I describe evidence that suggests that primate and human evolution has been strongly influenced by nonadaptive processes, particularly random genetic drift and mutation. This is evidenced by three fundamental effects: a relative relaxation of selective constraints (i.e., purifying selection), a relative increase in the fixation of slightly deleterious mutations, and a general reduction in the efficacy of positive selection. These effects are observed in protein-coding, regulatory regions, and in gene expression data, as well as in an augmentation of fixation of large-scale mutations, including duplicated genes, mobile genetic elements, and nuclear mitochondrial DNA. The evidence suggests a general population-level explanation such as a reduction in effective population size (N(e)). This would have tipped the balance between the evolutionary forces of natural selection and random genetic drift toward genetic drift for variants having small selective effects. After describing these proximate effects, I describe the potential consequences of these effects for primate and human evolution. For example, an increase in the fixation of slightly deleterious mutations could potentially have led to an increase in the fixation rate of compensatory mutations that act to suppress the effects of slightly deleterious substitutions. The potential consequences of compensatory evolution for the evolution of novel gene functions and in potentially confounding the detection of positively selected genes are explored. The consequences of the passive accumulation of large-scale genomic mutations by genetic drift are unclear, though evidence suggests that new gene copies as well as insertions of transposable elements into genes can potentially lead to adaptive phenotypes. Finally, because a decrease in selective constraint at the genetic level is expected to have effects at the morphological level, I review studies that compare rates of morphological change in various mammalian and island populations where N(e) is reduced. Furthermore, I discuss evidence that suggests that craniofacial morphology in the Homo lineage has shifted from an evolutionary rate constrained by purifying selection toward a neutral evolutionary rate.

Cytochrome B Sequences Show Subdivision between Populations of the Brown Howler Monkey (Alouatta guariba) from Rio de Janeiro and Santa Catarina, Brazil

The brown howler monkey (Alouatta guariba) is a mediumsized and fully arboreal monkey that inhabits the Atlantic Forest of South America. Its geographic distribution extends from southern Bahia through the coastal Brazilian states south to the province of Misiones in northernmost Argentina (Kinzey, 1982; Di Bitetti et al., 1994; Rylands et al., 1988, 1996). Traditionally, two subspecies have been recognized, A. guariba guariba in the north and A. guariba clamitans in the south, although their exact distributions remain unclear. Kinzey (1982) reported that the transition from one subspecies to the other occurs in Espírito Santo and Minas Gerais, in regions flanking the Rio Doce, while Rylands et al. (1988) found evidence suggesting that A. guariba clamitans extends as far north as the Rio Jequitinhonha in northern Minas Gerais, and that A. guariba guariba may be restricted to southern Bahia (see Rylands et al., 1996).

Human Demography in the Pleistocene: Do Mitochondrial and Nuclear Genes Tell the Same Story?

Traditionally, research on modern human origins has centered on questions of the time and geographical place of origin, with less attention given to the complex population dynamics of our evolutionary history. Recently, however, a focus has emerged within molecular anthropology that concentrates on the demographic aspects of the origin of modern humans.1-3 A popular hypothesis proposes that modern human populations passed through a bottleneck (or episodic reduction in size) in the late Middle or early Late Pleistocene, at which time there existed perhaps only several thousand breeding individuals, and that this was followed by a rapid, large expansion.1,2,4 Supporting evidence comes largely from the pattern of DNA sequence variation observed in mitochondrial genes. However, because the mitochondrial genome is only a very small fraction of the entire genome, its evolutionary history is not necessarily concordant with the history of the bulk of the genome, the nuclear genome. An important distinction can be made between evolutionary forces that affect just one locus and those forces that act on all the genes of a population. Population-level phenomena such as bottlenecks, expansions, population subdivisions, and speciation events are expected to produce similar patterns of genetic variation across many loci. In contrast, natural selection usually affects a small region of tight linkage, such as a single genetic locus. Therefore, hypotheses about population histories should be tested across many loci.5-8

Molecular evolution of a malaria resistance gene (DARC) in primates

Genes involved in host–pathogen interactions are often strongly affected by positive natural selection. The Duffy antigen, coded by the Duffy antigen receptor for chemokines (DARC) gene, serves as a receptor for Plasmodium vivax in humans and for Plasmodium knowlesi in some nonhuman primates. In the majority of sub-Saharan Africans, a nucleic acid variant in GATA-1 of the gene promoter is responsible for the nonexpression of the Duffy antigen on red blood cells and consequently resistance to invasion by P. vivax. The Duffy antigen also acts as a receptor for chemokines and is expressed in red blood cells and many other tissues of the body. Because of this dual role, we sequenced a ~3,000-bp region encompassing the entire DARC gene as well as part of its 5′ and 3′ flanking regions in a phylogenetic sample of primates and used statistical methods to evaluate the nature of selection pressures acting on the gene during its evolution. We analyzed both coding and regulatory regions of the DARC gene. The regulatory analysis showed accelerated rates of substitution at several sites near known motifs. Our tests of positive selection in the coding region using maximum likelihood by branch sites and maximum likelihood by codon sites did not yield statistically significant evidence for the action of positive selection. However, the maximum likelihood test in which the gene was subdivided into different structural regions showed that the known binding region for P. vivax/P. knowlesi is under very different selective pressures than the remainder of the gene. In fact, most of the gene appears to be under strong purifying selection, but this is not evident in the binding region. We suggest that the binding region is under the influence of two opposing selective pressures, positive selection possibly exerted by the parasite and purifying selection exerted by chemokines.

Origins of modern humans still look recent

Hey and Harris take exception to some of the points that I raised about their recent work in my review of new findings in human origins research [1xHuman evolution: origins of modern humans still look recent. Disotell, T. Curr Biol. 1999; 9: R647–R650Abstract | Full Text | Full Text PDF | PubMed | Scopus (15)See all References[1]. Their first point regards the debate between the “recent replacement” model and the “multiregional model”. I defined the “recent replacement” model as one in which “a single population, most likely of African origin, expanded and replaced archaic populations throughout the world, beginning around 200,000 years ago.” The model in general is supported by numerous researchers (reviewed in [1xHuman evolution: origins of modern humans still look recent. Disotell, T. Curr Biol. 1999; 9: R647–R650Abstract | Full Text | Full Text PDF | PubMed | Scopus (15)See all References, 3xThe evolution of modern humans: a comparison of the African and non-African evidence. Brauer, G. : 123–154See all References, 9xSex-specific contributions to genome variation. Disotell, T.R. Curr Biol. 1999; 9: R29–R31Abstract | Full Text | Full Text PDF | PubMed | Scopus (13)See all References]), and this statement in particular does not imply that this population consisted of anatomically modern humans. It might very well have been, and probably was, an African archaic population, given that no anatomically modern fossils approach this date. Furthermore, although some of the oldest anatomically modern fossil humans are known from the Israeli sites of Skhul and Jebel Qafzeh, this area at the time could be considered an extension of Africa on the basis of the numerous “Ethiopian” mammal species present [2xThe Human Career: Human Biological and Cultural Origins. Klein, R.G. See all References[2]. Although this population might have been “out of Africa” by our contemporary standards, these people surely had close affinities with slightly older south, east, and north African populations. I cannot argue with their contention that population subdivision probably existed within Africa before populations left in a new wave of migrations most probably between 50,000 and 100,000 years ago, after the initial dispersals out of Africa more than a million years ago. My main point was that populations living in Asia and Europe at that time were replaced by these new immigrants as the vast majority of genetic systems studied to date suggest (reviewed in [1xHuman evolution: origins of modern humans still look recent. Disotell, T. Curr Biol. 1999; 9: R647–R650Abstract | Full Text | Full Text PDF | PubMed | Scopus (15)See all References, 3xThe evolution of modern humans: a comparison of the African and non-African evidence. Brauer, G. : 123–154See all References, 9xSex-specific contributions to genome variation. Disotell, T.R. Curr Biol. 1999; 9: R29–R31Abstract | Full Text | Full Text PDF | PubMed | Scopus (13)See all References]), which stands in opposition to the multiregional model that posits in situ evolution in these regions from indigenous archaic populations. I did make an error by implying that they only sequenced eight African individuals in their study of the PDHA1 locus [7xX chromosome evidence for ancient human histories. Harris, E.E. and Hey, J. Proc Natl Acad Sci USA. 1999; 96: 3320–3324Crossref | PubMed | Scopus (174)See all References[7], when in fact they found eight haplotypes out of the sixteen African individuals actually sequenced. Given the enormous diversity found within Africa for almost all of the genetic systems examined to date (which is supported by Harris and Hey’s study), I would still contend, as Seielstadt et al. [10xA view of modern human origins from Y chromosome microsatellite variation. Seielstad, M., Bekele, E., Ibrahim, M., Tour, A., and Traor, M. Genome Res. 1999; 9: 558–567PubMedSee all References[10] do, that additional sampling is merited to verify that alleles shared between Africans and non-Africans have not been missed. A good example of this problem has recently been reported by Kivisild et al. [11xDeep common ancestry of Indian and western Eurasian mtDNA lineages. Kivisild, T., Bamshad, M.J., Kaldma, K., Metspalu, M., Metspalu, E., Reidla, M., Laos, S., Parik, J., Watkins, W.S., Dixon, M.E. et al. Curr Biol. 1999; 9: 1331–1334Abstract | Full Text PDF | PubMedSee all References[11] in which the mitochondrial haplogroup U, which was considered to be western Eurasian-specific and had never been reported in India or further east, turns out to be the second most common haplogroup in the subcontinent after they typed 550 Indian mtDNA (mitochondrial DNA) samples. Hey and Harris and I also disagree over the significance of potential unequal rates of evolution in the PDHA1 locus among primates. I presented a phylogenetic analysis in which I suggested that unequal rates were present and were evidence of potential selection, which would call into question rate and dating estimates. I performed this analysis because, as Harding [12xMore on the X files. Harding, R.M. Proc Natl Acad Sci USA. 1999; 96: 2582–2584Crossref | PubMed | Scopus (8)See all References[12] did in a commentary on their work, I questioned a comparison to β globin as a test of the presence of selection. Given the known function of PDHA1, I along with Harding [12xMore on the X files. Harding, R.M. Proc Natl Acad Sci USA. 1999; 96: 2582–2584Crossref | PubMed | Scopus (8)See all References[12] and Brown et al. [13xTransfection screening for primary defects in the pyruvate dehydrogenase E1a subunit gene. Brown, R.M., Otero, L.J., and Brown, G.K. Human Mol Genet. 1997; 6: 1361–1367Crossref | PubMed | Scopus (19)See all References[13] suspect that selection might be acting on this locus. I also suspect that additional sampling of more chimpanzees will lead to review of numerous other substitutions, perhaps resulting in the reinterpretation of several of the within-human differences. My surprise was not that differences were found between the chimpanzees but that so few were found given that chimpanzees are several-fold more genetically diverse than humans [1xHuman evolution: origins of modern humans still look recent. Disotell, T. Curr Biol. 1999; 9: R647–R650Abstract | Full Text | Full Text PDF | PubMed | Scopus (15)See all References, 8xEvolution of a HOXB6 intergenic region within the great apes and humans. Deinard, A. and Kidd, K. J Hum Evol. 1999; 36: 687–703Crossref | PubMed | Scopus (47)See all References].Relative-rate tests [14xEvidence for higher rates of nucleotide substitution in rodents than in man. Wu, C.I. and Li, W.H. Proc Natl Acad Sci USA. 1985; 82: 1741–1745Crossref | PubMedSee all References[14] do not find statistically significant deviations from equivalent amounts of change along the human and chimpanzee lineages since their common ancestry (Hey, personal communication). This is probably because of the lack of power of this test when so few substitutions are present. The point of this exercise was, however, to again call into question the estimated rates of change and therefore divergence dates estimated from a locus known to have significant physiological effects [12xMore on the X files. Harding, R.M. Proc Natl Acad Sci USA. 1999; 96: 2582–2584Crossref | PubMed | Scopus (8)See all References, 13xTransfection screening for primary defects in the pyruvate dehydrogenase E1a subunit gene. Brown, R.M., Otero, L.J., and Brown, G.K. Human Mol Genet. 1997; 6: 1361–1367Crossref | PubMed | Scopus (19)See all References].To be compatible with the coalescent date of approximately 200,000 years ago for the haploid mtDNA and Y chromosome, X-linked loci such as PDHA1 should yield estimates three times as great, in the range of 600,000 years ago, not the 1.86 million year date inferred by Harris and Hey [7xX chromosome evidence for ancient human histories. Harris, E.E. and Hey, J. Proc Natl Acad Sci USA. 1999; 96: 3320–3324Crossref | PubMed | Scopus (174)See all References[7]. Nachman et al. [15xDNA variability and recombination rates at X-linked loci in humans. Nachman, M.W., Bauer, V.L., Crowell, S.L., and Aquadro, C.F. Genetics. 1998; 150: 1133–1141PubMedSee all References[15], in a study comprising seven X-linked loci, including Hey’s earlier study of PDHA1 [16xMitochondrial and nuclear genes present conflicting portraits of human origins. Hey, J. Mol Biol Evol. 1997; 14: 166–172Crossref | PubMedSee all References[16], estimate mean and mode values of 743,000 and 655,000 years ago, respectively, for the human coalescent date, which is broadly compatible with the mtDNA and Y chromosome results [9xSex-specific contributions to genome variation. Disotell, T.R. Curr Biol. 1999; 9: R29–R31Abstract | Full Text | Full Text PDF | PubMed | Scopus (13)See all References[9]. Interestingly, both PDHA1 and dystrophin produce the two oldest estimates in the study of Nachman et al. [15xDNA variability and recombination rates at X-linked loci in humans. Nachman, M.W., Bauer, V.L., Crowell, S.L., and Aquadro, C.F. Genetics. 1998; 150: 1133–1141PubMedSee all References[15]. Given the numerous genetic studies supporting the “recent replacement” model, my intent in reviewing Harris and Hey’s results was to amplify Harding’s [12xMore on the X files. Harding, R.M. Proc Natl Acad Sci USA. 1999; 96: 2582–2584Crossref | PubMed | Scopus (8)See all References[12] view that “…against the expectations suggested by most other polymorphism data, it is clear that something odd has happened — and perhaps is happening — at the PDHA1 locus.”Department of Anthropology, New York University, New York, NY 10003, USA. E-mail: todd.disotell@nyu.edu

Erratum: Human Demography in the Pleistocene: Do Mitochondrial and Nuclear Genes Tell the Same Story? Evol. Anthropol. 8: 81–86.

Eugene E. Harris and Jody Hey (1999). Human Demography in the Pleistocene: Do Mitochondrial and Nuclear Genes Tell the Same Story? Evol. Anthropol. 8: 81–86.

Demic and cultural diffusion in prehistoric Europe in the age of ancient genomes

Ancient genomes can help us detect prehistoric migrations, population contractions, and admixture among populations. Knowing the dynamics of demography is invaluable for understanding culture change in prehistory, particularly the roles played by demic and cultural diffusion in transformations of material cultures. Prehistoric Europe is a region where ancient genome analyses can help illuminate the interplay between demography and culture change. In Europe, there is more archeological evidence, in terms of detailed studies, radiometric dates, and explanatory hypotheses that can be evaluated, than in any other region of the world. Here I show some important ways that ancient genomes have given us insights into population movements in European prehistory. I also propose that studies might be increasingly focused on specific questions of culture change, for example in evaluating the makers of “transitional” industries as well as the origins of the Gravettian and spread of the Magdalenian. I also discuss genomic evidence supporting the large role that demic expansion has played in the Neolithization of Europe and the formation of the European population during the Bronze Age.