Worldwide genetic variation at the 3'-UTR region of the LDLR gene: possible influence of natural selection.

The low density lipoprotein receptor gene (LDLR) contains many Alu insertions, and is especially Alu-rich at its 3'-untranslated region (3'-UTR). Previous studies suggested that the LDLR 3'-UTR could regulate gene expression by the stabilization of its mRNA. Given the faster Alu evolutionary rate, and wondering about its consequences in a possibly regulatory locus, we have studied approximately 800 bp of 222 chromosomes from individuals of African, Asian, Caucasian and Amerind ancestry, to better understand the evolution of the worldwide genetic diversity at this locus. Twenty-one polymorphic sites, distributed in 15 haplotypes, were found. High genetic diversity was observed, concentrated in one Alu insertion (Alu U), which also shows a fast evolutionary rate. Genetic diversity is similar in all populations except Amerinds, suggesting a bottleneck during the peopling of the American continent. Three haplotype clusters (A, B, C) are distinguished, cluster A being the most recently formed (approximately 500,000 years ago). No clear geographic structure emerges from the haplotype network, the global F(st) (0.079) being lower than the average for the human genome. When ancestral population growth is taken into account, neutrality statistics are higher than expected, possibly suggesting the action of balancing selection worldwide.

Identity by descent and DNA sequence variation of human SINE and LINE elements.

To test the hypothesis that Alu and L1 elements are genetic characters that are essentially homoplasy-free, we sequenced a total of five human L1 elements and eleven recently integrated Alu elements from 160 chromosomes (80 individuals representing four diverse human populations). Analysis of worldwide samples at L1 loci revealed 292 segregating sites and a nucleotide diversity of 0.0050. For Ya5 Alu loci, there were 129 segregating sites and nucleotide diversity was estimated at 0.0045. The Alu and L1 sequence diversity varied element to element. No completely or partially deleted Alu or L1 alleles were identified during the analysis. These data suggest that mobile element insertions are identical by descent characters for the study of human population genetics.

Alu insertions versus blood group plus protein genetic variability in four Amerindian populations.

BACKGROUND: Do the population relationships obtained using DNA or blood group plus protein markers remain the same or do they reveal different patterns, indicating that the factors which influence genetic variation at these two levels of analysis are diverse? Can these markers shed light on the biological classification of the Aché, a Paraguayan tribe which only recently established more permanent contacts with non-Indians? SUBJECTS AND METHODS: To consider these questions we typed 193 individuals from four Amerindian tribes in relation to 12 Alu polymorphisms (five of them never studied in these populations), while 22 blood group plus protein systems were studied among the Aché. These data were then integrated with those previously available (blood groups plus proteins) for the three other populations. DNA extraction and amplification, as well as the other laboratory procedures, were performed using standard methods currently in use in our laboratory. The genetic relationships were obtained using the D(A) distance, and the trees were constructed by the neighbour-joining method, both developed by M. Nei and collaborators. Reliability of the trees was tested by bootstrap replications. Other population variability values were also determined using Nei's methods. RESULTS: Alu polymorphism was observed in all populations and for most of the loci; in the seven systems from which we could compare our results with those of other Amerindian groups agreement was satisfactory. Unusual findings on the blood group plus protein systems of the Aché were a very low (5%) HP*1 frequency and the presence of the C(W) phenotype in the Rh blood group. The intertribal patterns of relationship and other aspects of their variation were remarkably congruent in the two sets (Alu; blood group plus protein) of systems. CONCLUSIONS: The answer to the first question posed above is affirmative. However, the problem of whether the Aché derived from a Gê group that preceded the Guarani colonization of Paraguay, or are just a differentiated Guarani group, could not be answered with the genetic information available; the second hypothesis seems more likely at present, but the point to be emphasized is the striking genetic distinctiveness of the Aché as compared to other Amerindians.

Estimating African American admixture proportions by use of population-specific alleles.

We analyzed the European genetic contribution to 10 populations of African descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45% between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8% (Jamaica) to 22.5% (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3%-2.7%). We also estimated the male and female European contribution to African Americans, on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater than the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resource for mapping traits with different prevalence in two parental populations.

Estimating African American admixture proportions by use of population-specific alleles

We analyzed the European genetic contribution to 10 populations of Africans descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45 percent between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8 percent (Jamaica) to 22.5 percent (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3 percent -2.7 percent). We also estimated the male and female European contribution to African Americans. on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater that the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resources for mapping traits with different prevalence in two parental populations (AU)