DNA polymorphism in population genetics

In the review, the literature evidence on DNA polymorphism obtained in the last 10-15 years using various molecular-genetic methods is summarized. All main types of DNA variation are considered but attention is focused on those extensively used in population genetics. The areas of using DNA markers are outlined and the limitations of their potential in analyzing genetic processes in populations are discussed. Particular emphasis is placed on the relationship between the earlier developed biochemical genetics based on protein polymorphism analysis and modern molecular population genetics based on DNA polymorphism. The possible role of selection in maintaining DNA variation is considered.     

Evolutionary anthropology and genes: Investigating the genetics of human evolution from excavated skeletal remains

The development of molecular tools for the extraction, analysis and interpretation of DNA from the remains of ancient organisms (paleogenetics) has revolutionised a range of disciplines as diverse as the fields of human evolution, bioarchaeology, epidemiology, microbiology, taxonomy and population genetics. The paper draws attention to some of the challenges associated with the extraction and interpretation of ancient DNA from archaeological material, and then reviews the influence of paleogenetics on the field of human evolution. It discusses the main contributions of molecular studies to reconstructing the evolutionary and phylogenetic relationships between extinct hominins (human ancestors) and anatomically modern humans. It also explores the evidence for evolutionary changes in the genetic structure of anatomically modern humans in recent millennia. This breadth of research has led to discoveries that would never have been possible using traditional approaches to human evolution.     

Iberia: population genetics, anthropology, and linguistics.

Basques, Portuguese, Spaniards, and Algerians have been studied for HLA and mitochondrial DNA markers, and the data analysis suggests that pre-Neolithic gene flow into Iberia came from ancient white North Africans (Hamites). The Basque language has also been used to translate the Iberian-Tartesian language and also Etruscan and Minoan Linear A. Physical anthropometry of Iberian Mesolithic and Neolithic skeletons does not support the demic replacement in Iberia of preexisting Mesolithic people by Neolithic people bearing new farming technologies from Europe and the Middle East. Also, the presence of cardial impressed pottery in western Mediterranean Europe and across the Maghreb (North Africa) coasts at the beginning of the Neolithic provides good evidence of pre-Neolithic circum-Mediterranean contacts by sea. In addition, pre-dynastic Egyptian El-Badari culture (4,500 years ago) is similar to southern Iberian Neolithic settlements with regard to pottery and animal domestication. Taking the genetic, linguistic, anthropological, and archeological evidence together with the documented Saharan area desiccation starting about 10,000 years ago, we believe that it is possible that a genetic and cultural pre-Neolithic flow coming from southern Mediterranean coasts existed toward northern Mediterranean areas, including at least Iberia and some Mediterranean islands. This model would substitute for the demic diffusion model put forward to explain Neolithic innovations in Western Europe.     

DNA length polymorphism located 5'' to the human myelin basic protein gene.

A region of DNA 5' to the human myelin basic protein (MBP) gene, located on the long arm of chromosome 18, is a site of restriction-fragment-length polymorphism (RFLP) showing 37% heterozygosity in 40 subjects studied. Southern transfer analysis using a 0.9-kb genomic fragment encompassing the first exon of the human MBP gene reveals this polymorphism with at least nine restriction enzymes, indicating that insertion, deletion, or both is the basis for the DNA length variation. Double restriction-enzyme digest analysis suggests that this polymorphism is within the region 0.5-2.0 kb upstream of the coding region of the first exon of the human MBP gene. Eleven different allelic RFLPs were identified, differing in size by as many as 450 bp. The distribution of insertion/deletion-size variants from this region is bimodal, with most restriction fragments varying in size over a 0.1-kb range. Pedigree analysis of polymorphism at this site in one three-generation family shows Mendelian assortment of parental haplotypes. The form and frequency of polymorphism generated by this site is similar to that reported for human DNA regions comprised of homologous short tandem repeats.     

Simple method for analyzing the pattern of DNA polymorphism and its application to SNP data of human

In order to analyze the pattern of DNA polymorphism in detail, we have developed a simple method using a new statistic theta(i) which estimates 4Nmu from the number of segregating sites whose allelic nucleotide frequency is i/n among n DNA sequences, where N is the effective population size and mu is the mutation rate per generation per nucleotide site. Under the assumption that mutations are selectively neutral and a population size is constant, the expectation of theta(i) is equal to that of theta, which estimates 4Nmu from the number of segregating sites, so that the distribution of theta(i) is flat. Therefore, the departure of the distribution of theta(i) from the horizontal line, which represents the value of theta, reflects change in population size and natural selection. Results of the coalescent simulation show that the distributions of theta(i) in the populations which experienced expansion and reduction are U-shaped and upside-down U-shaped, respectively. And the distributions of theta(i) in some populations that experienced bottleneck are W-shaped. Furthermore, we have applied this method to the SNP data in the International HapMap Project. Results of data analyses show that the distributions of theta(i) in the CEU (European), CHB and JPT (Asian) populations are different from that in the YRI population (African). From these results of data analyses in nuclear DNA and the pattern of polymorphism in human mitochondrial DNA already known, we infer that the CEU, CHB and JPT populations experienced the bottleneck.     

Structure and polymorphism of human telomere-associated DNA

We have analyzed the DNA sequences associated with four different human telomeres. Two are members of distinct repeated sequence families which are located mainly but not exclusively at telomeres. Two are unique in the genome, one deriving from the long arm telomere of chromosome 7 and the other from the pseudoautosomal telomere. One telomere-associated repeated sequence has a polymorphic distribution among the chromosome ends, being present at a different combination of ends in different individuals. These data thus identify a new source of human genetic variation and indicate that the canonical features of the organization of telomere-associated DNA are widely conserved in evolution.     

Anthropometry and numerical taxonomy in clinical genetics: An example of applied biological anthropology

Biological anthropologists can contribute a unique perspective as well as technical expertise to the diagnosis and classification of genetic disorders. Anthropometry has been used with increasing frequency to characterize syndromes and to establish ranges of variation within syndromes. The specific anthropometric-radiologic technique of metacarpophalangeal pattern profile analysis has proven useful in discriminating individuals with the Prader-Labhart-Willi (PLW) syndrome from unaffected persons. Analysis of these data also indicate a negative correlation between age and Z-score transformations of individual hand bone lengths. These findings sound a cautionary note to clinical investigators who would use the Z-score transformation to standardize for age and sex. Problems encountered in the classification of genetic syndromes afford many parallels with those faced by anthropologists in the classification of living and fossil populations. The reliance on “key” traits and the necessity of focusing on pedigree analysis results in a deemphasis of the total range of variation and typological thinking. Application of numerical taxonomic techniques to the classification of the heterogeneous connective tissue disease osteogenesis imperfecta (OI) illustrates the heuristic value of this technique and points out the need to consider phenotypic overlap when defining typologies. Clinical genetics affords just one example of an area in medicine where the unique training and generalist perspective of the biological anthropologist is in demand. The decline in the availability of positions in the traditional academic habitat for biological anthropologists makes it imperative that graduate students be aware of alternatives and that they obtain training in the practical skills which such alternatives will demand.     

TheGunnera symbiosis: DNA restriction fragment length polymorphism and protein comparisons ofNostoc symbionts

Cyanobacteria separated from symbiosis with several species of the angiospermGunnera were comparatively characterized and correlated with the locales and taxonomy of their host plants. All were identified as strains ofNostoc. Protein profiles and DNA restriction fragment length polymorphisms (from hybridizations with heterologousnifH andglnA probes) determined that three of the four cyanobacteria fromGunnera grown at one site in Sweden, each from a different host species, were very similar or identical. Plants of one species,G. manicata, grown in a second location at the site were infected with a different cyanobiont. Among five isolates from two species ofGunnera, collected in the same locale in New Zealand, three subgroups were documented. Isolates from three differentGunnera species grown in separate locations in the United States were each uniquely different. None of the cyanobacteria differed in the molecular weights of their glutamine synthetase and Fe-nitrogenase proteins. The diversity and accessibility of compatibleNostoc populations present in the soil micro-environment, not a critical selective factor required byGunnera, were concluded to be a major determinant in symbiont selection.     

HLA-DR polymorphism in a Senegalese Mandenka population: DNA oligotyping and population genetics of DRB1 specificities.

HLA class II loci are useful markers in human population genetics, because they are extremely variable and because new molecular techniques allow large-scale analysis of DNA allele frequencies. Direct DNA typing by hybridization with sequence-specific oligonucleotide probes (HLA oligotyping) after enzymatic in vitro PCR amplification detects HLA allelic polymorphisms for all class II loci. A detailed HLA-DR oligotyping analysis of 191 individuals from a geographically, culturally, and genetically well-defined western African population, the Mandenkalu, reveals a high degree of polymorphism, with at least 24 alleles and a heterozygosity level of .884 for the DRB1 locus. The allele DRB1*1304, defined by DNA sequencing of the DRB1 first-domain exon, is the most frequent allele (27.1%). It accounts for an unusually high DR13 frequency, which is nevertheless within the neutral frequency range. The next most frequent specificities are DR11, DR3, and DR8. Among DRB3-encoded alleles, DR52b (DRB3*02) represents as much as 80.7% of all DR52 haplotypes. A survey of HLA-DR specificities in populations from different continents shows a significant positive correlation between genetic and geographic differentiation patterns. A homozygosity test for selective neutrality of DR specificities is not significant for the Mandenka population but is rejected for 20 of 24 populations. Observed high heterozygosity levels in tested populations are compatible with an overdominant model with a small selective advantage for heterozygotes.     

Genetic polymorphism of human anodal tear protein

Electrophoresis of human tears on slab polyacrylamide gels showed five phenotypes among anodal tear proteins. These phenotypes are the expression of autosomal codominant alleles. Gene frequencies are as follows: for Caucasians, At ¹=0.99, At ³=0.01; for Negroes, At ¹=0.97, At ²=0.03; for Chinese, At ¹=0.98, and At ⁴ and At ⁵ are both approximately 0.008.This study was supported by a grant from the National Institutes of Dental Research (5-R01-DE-E-03658-10).     

Theory of lipid polymorphism: application to phosphatidylethanolamine and phosphatidylserine

We introduce a microscopic model of a lipid with a charged headgroup and flexible hydrophobic tails, a neutral solvent, and counter ions. Short-ranged interactions between hydrophilic and hydrophobic moieties are included as are the Coulomb interactions between charges. Further, we include a short-ranged interaction between charges and neutral solvent, which mimics the short-ranged, thermally averaged interaction between charges and water dipoles. We show that the model of the uncharged lipid displays the usual lyotropic phases as a function of the relative volume fraction of the headgroup. Choosing model parameters appropriate to dioleoylphosphatidylethanolamine in water, we obtain phase behavior that agrees well with experiment. Finally we choose a solvent concentration and temperature at which the uncharged lipid exhibits an inverted hexagonal phase and turn on the headgroup charge. The lipid system makes a transition from the inverted hexagonal to the lamellar phase, which is related to the increased waters of hydration correlated with the increased headgroup charge via the charge-solvent interaction. The polymorphism displayed upon variation of pH mimics that of the behavior of phosphatidylserine.