Genetic Chaos

Thursday, August 19, 2004

A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus

A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) – TaqI “A”, “B”, and “D” sites – and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P<0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI “B” and “A”, was highly significant with D’ values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI “B” site in all populations, with D’ values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an “Out of Africa” model for recent human evolution.

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In our genes

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Global survey of haplotype frequencies and linkage disequilibrium at the RET locus

We have constructed haplotypes based on normal variation at six polymorphic sites–five single nucleotide polymorphisms (SNPs) and one short tandem repeat polymorphism (STRP)–at the RET locus for samples of normal individuals from 32 populations distributed across the major continental regions of the world. The haplotyped system spans 41.6 kilobases and encompasses most of the coding region of the gene. All of the markers are polymorphic in all regions of the world and in most individual populations. Expected heterozygosities for the six-site haplotypes range from 82 to 94% for all populations studied except for two Amerindian groups from the Amazon basin at 61 and 76%. Individual populations had from four to eight haplotypes with frequencies exceeding 5%. In general, African, southwest Asian and European groups have the highest numbers of total and of commonly occurring haplotypes; the lowest numbers are observed in Amerindian populations. Overall linkage disequilibrium (LD) for the five SNP sites was very significant (P < or = 0.001) for all the non-African populations, but significant at that level for only one of the seven African populations. In general, the permutation-based xi coefficient that quantifies overall LD tends to increase the farther the population is from Africa, but variability of this measure of LD is often large within geographic regions. Pairwise LD measures among the SNPs also show considerable variation among populations. Association of STRP alleles with the SNP-defined background haplotypes is generally higher outside of Africa than in Africa, but is highly variable.

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Thursday, August 05, 2004

The Context of Human Genetic Evolution

The debate on modern human origins has often focused on the relationship between genes and fossils. Although more and more genetic evidence has been accumulating in favor of a recent African origin for modern humans, it has been assumed by many that the fossil evidence remains ambiguous. On the contrary, it has been clear for some time that the fossil evidence does not support the multiregional model: Fossils and archeology indicate a pattern of multiple dispersals from and beyond Africa, against which the genetic data can be compared. The continuing value of paleobiology is in complementing genetic information by revealing the context of human evolution: locating the dispersals and extinctions of populations in time and space, correlating these events with the environmental forces that shaped them, and providing an increasingly detailed understanding of the morphology and technology of early humans.

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Modern human origins: progress and prospects

The question of the mode of origin of modern humans (Homo sapiens) has dominated palaeoanthropological debate over the last decade. This review discusses the main models proposed to explain modern human origins, and examines relevant fossil evidence from Eurasia, Africa and Australasia. Archaeological and genetic data are also discussed, as well as problems with the concept of ‘modernity’ itself. It is concluded that a recent African origin can be supported for H. sapiens, morphologically, behaviourally and genetically, but that more evidence will be needed, both from Africa and elsewhere, before an absolute African origin for our species and its behavioural characteristics can be established and explained.

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Wednesday, August 04, 2004

Patterns of Ancestral Human Diversity: An Analysis of Alu-Insertion and Restriction-Site Polymorphisms

We have analyzed 35 widely distributed, polymorphic Alu loci in 715 individuals from 31 world populations. The average frequency of Alu insertions (the derived state) is lowest in Africa (.42) but is higher and similar in India (.55), Europe (.56), and Asia (.57). A comparison with 30 restriction-site polymorphisms (RSPs) for which the ancestral state has been determined shows that the frequency of derived RSP alleles is also lower in Africa (.35) than it is in Asia (.45) and in Europe (.46). Neighbor-joining networks based on Alu insertions or RSPs are rooted in Africa and show African populations as separate from other populations, with high statistical support. Correlations between genetic distances based on Alu and nuclear RSPs, short tandem-repeat polymorphisms, and mtDNA, in the same individuals, are high and significant. For the 35 loci, Alu gene diversity and the diversity attributable to population subdivision is highest in Africa but is lower and similar in Europe and Asia. The distribution of ancestral alleles is consistent with an origin of early modern human populations in sub-Saharan Africa, the isolation and preservation of ancestral alleles within Africa, and an expansion out of Africa into Eurasia. This expansion is characterized by increasing frequencies of Alu inserts and by derived RSP alleles with reduced genetic diversity in non-African populations.

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Genetic perspectives on human origins and differentiation

This is a review of genetic evidence about the ancient demography of the ancestors of our species and about the genesis of worldwide human diversity. The issue of whether or not a population size bottleneck occurred among our ancestors is under debate among geneticists as well as among anthropologists. The bottleneck, if it occurred, would confirm the Garden of Eden (GOE) model of the origin of modern humans. The competing model, multiregional evolution (MRE), posits that the number of human ancestors has been large, occupying much of the temperate Old World for the last two million years. While several classes of genetic marker seem to contain a strong signal of demographic recovery from a small number of ancestors, other nuclear loci show no such signal. The pattern at these loci is compatible with the existence of widespread balancing selection in humans. The study of human diversity at (putatively) neutral genetic marker loci has been hampered since the beginning by ascertainment bias since they were discovered in Europeans. The high levels of polymorphism at microsatellite loci means that they are free of this bias. Microsatellites exhibit a clear almost linear diversity gradient away from Africa, so that New World populations are approximately 15% less diverse than African populations. This pattern is not compatible with a model of a single large population expansion and colonization of most of the Earth by our ancestors but suggests, instead, gradual loss of diversity in successive colonization bottlenecks as our species grew and spread.

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Patterns of Human Diversity, within and among Continents, Inferred from Biallelic DNA Polymorphisms

Previous studies have reported that about 85% of human diversity at Short Tandem Repeat (STR) and Restriction Fragment Length Polymorphism (RFLP) autosomal loci is due to differences between individuals of the same population, whereas differences among continental groups account for only 10% of the overall genetic variance. These findings conflict with popular notions of distinct and relatively homogeneous human races, and may also call into question the apparent usefulness of ethnic classification in, for example, medical diagnostics. Here, we present new data on 21 Alu insertions in 32 populations. We analyze these data along with three other large, globally dispersed data sets consisting of apparently neutral biallelic nuclear markers, as well as with a beta-globin data set possibly subject to selection. We confirm the previous results for the autosomal data, and find a higher diversity among continents for Y-chromosome loci. We also extend the analyses to address two questions: (1) whether differences between continental groups, although small, are nevertheless large enough to confidently assign individuals to their continent on the basis of their genotypes; (2) whether the observed genotypes naturally cluster into continental or population groups when the sample source location is ignored. Using a range of statistical methods, we show that classification errors are at best around 30% for autosomal biallelic polymorphisms and 27% for the Y chromosome. Two data sets suggest the existence of three and four major groups of genotypes worldwide, respectively, and the two groupings are inconsistent. These results suggest that, at random biallelic loci, there is little evidence, if any, of a clear subdivision of humans into biologically defined groups.

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Categorization of humans in biomedical research: genes, race and disease

A debate has arisen regarding the validity of racial/ethnic categories for biomedical and genetic research. Some claim ‘no biological basis for race’ while others advocate a ‘race-neutral’ approach, using genetic clustering rather than self-identified ethnicity for human genetic categorization. We provide an epidemiologic perspective on the issue of human categorization in biomedical and genetic research that strongly supports the continued use of self-identified race and ethnicity.

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Short Tandem-Repeat Polymorphism/Alu Haplotype Variation at the PLAT Locus: Implications for Modern Human Origins

Two dinucleotide short tandem-repeat polymorphisms (STRPs) and a polymorphic Alu element spanning a 22-kb region of the PLAT locus on chromosome 8p12-q11.2 were typed in 1,287–1,420 individuals originating from 30 geographically diverse human populations, as well as in 29 great apes. These data were analyzed as haplotypes consisting of each of the dinucleotide repeats and the flanking Alu insertion/deletion polymorphism. The global pattern of STRP/Alu haplotype variation and linkage disequilibrium (LD) is informative for the reconstruction of human evolutionary history. Sub-Saharan African populations have high levels of haplotype diversity within and between populations, relative to non-Africans, and have highly divergent patterns of LD. Non-African populations have both a subset of the haplotype diversity present in Africa and a distinct pattern of LD. The pattern of haplotype variation and LD observed at the PLAT locus suggests a recent common ancestry of non-African populations, from a small population originating in eastern Africa. These data indicate that, throughout much of modern human history, sub-Saharan Africa has maintained both a large effective population size and a high level of population substructure. Additionally, Papua New Guinean and Micronesian populations have rare haplotypes observed otherwise only in African populations, suggesting ancient gene flow from Africa into Papua New Guinea, as well as gene flow between Melanesian and Micronesian populations.

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Monday, August 02, 2004

Y Chromosome STR Haplotypes and the Genetic Structure of U.S. Populations of African, European, and Hispanic Ancestry

To investigate geographic structure within U.S. ethnic populations, we analyzed 1705 haplotypes on the basis of 9 short tandem repeat (STR) loci on the Y-chromosome from 9–11 groups each of African-Americans, European-Americans, and Hispanics. There were no significant differences in the distribution of Y-STR haplotypes among African-American groups, whereas European-American and Hispanic groups did exhibit significant geographic heterogeneity. However, the significant heterogeneity resulted from one sample; removal of that sample in each case eliminated the significant heterogeneity. Multidimensional scaling analysis of RST values indicated that African-American groups formed a distinct cluster, whereas there was some intermingling of European-American and Hispanic groups. MtDNA data exist for many of these same groups; estimates of the European-American genetic contribution to the African-American gene pool were 27.5%–33.6% for the Y-STR haplotypes and 9%–15.4% for the mtDNA types. The lack of significant geographic heterogeneity among Y-STR and mtDNA haplotypes in U.S ethnic groups means that forensic DNA databases do not need to be constructed for separate geographic regions of the U.S. Moreover, absence of significant geographic heterogeneity for these two loci means that regional variation in disease susceptibility within ethnic groups is more likely to reflect cultural/environmental factors, rather than any underlying genetic heterogeneity.

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Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping

Hispanic populations are a valuable resource that can and should facilitate the identification of complex trait genes by means of admixture mapping (AM). In this paper we focus on a particular Hispanic population living in the San Luis Valley (SLV) in Southern Colorado.We used a set of 22 Ancestry Informative Markers (AIMs) to describe the admixture process and dynamics in this population. AIMs are defined as genetic markers that exhibit allele frequency differences between parental populations >or=30%, and are more informative for studying admixed populations than random markers. The ancestral proportions of the SLV Hispanic population are estimated as 62.7 +/- 2.1% European, 34.1 +/- 1.9% Native American and 3.2 +/- 1.5% West African. We also estimated the ancestral proportions of individuals using these AIMs. Population structure was demonstrated by the excess association of unlinked markers, the correlation between estimates of admixture based on unlinked marker sets, and by a highly significant correlation between individual Native American ancestry and skin pigmentation (R2= 0.082, p < 0.001). We discuss the implications of these findings in disease gene mapping efforts.

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Diversity and heterogeneity in mitochondrial DNA of North American populations

Variation in the mitochondrial DNA (mtDNA) control region as detected by sequence-specific oligonucleotide (SSO) probes is described for 2282 individuals from African-American, European-American, and Hispanic subpopulations from five broadly defined regions of North America (Northeast, Southeast, Central, Northwest, Southwest). Population diversity estimates were uniformly high for all subpopulations and for each major ethnic group. Only the Pennsylvania Hispanic group was remarkable with respect to its mitochondrial DNA types, having both six low frequency population specific types (ranging from 1.2-8.6%) and three high frequency shared types (10-20% each). There was no statistically significant subpopulation heterogeneity present within any of the three major groups at either the subpopulation level or the regional level (p > 0.01). However, statistically significant heterogeneity was measured when comparing the three major groups to each other, with the variance component attributable to this large division accounting for 18.60% of the total variance (p < 0.001). Overall mtDNA is a satisfactory forensic typing locus within broadly defined African-American, European-American, and Hispanic groups from North America, based on the high diversity estimates and absence of heterogeneity, as characterized by SSO typing.

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