Search

Implications for evolution of modern humans and for the source of myotonic dystrophy mutations can be found in results of a global haplotype analysis of the myotonic dystrophy locus. Haplotypes made up of the (CTG) sub n repeat and of several flanking markers and the myotonic dystrophy (DM) locus have been studied in normal persons from 25 populations, made up of 5 African, 3 European, 2 Middle Eastern, 3 Pacific/Australo-Melanesian, 6 Amerindian and 6 East Asian groups. Haplotype diversity and linkage disequilibrium patterns indicate a recent African-origin modern human evolution. An original mutation event seems to have led up to DM-causing alleles and to have been in a population ancestral to non-Africans before modern humans migrated from Africa.

Haplotypes consisting of alleles at a short tandem repeat polymorphism (STRP) and an Alu deletion polymorphism at the CD4 locus on chromosome 12 were analyzed in more than 1600 individuals sampled from 42 geographically dispersed populations (13 African, 2 Middle Eastern, 7, European, 9 Asian, 3 Pacific, and 8 Amerindian). Sub-Saharan African populations had more haplotypes and exhibited more variability in frequencies of haplotypes than the Northeast African or non-African populations. The Alu deletion was nearly always associated with a single STRP allele in non-African and Northeast African populations but was associated with a wide range of STRP alleles in the sub-Saharan African populations. Tbis global pattern of haplotype variation and linkage disequilibrium suggests a common and recent African origin for all non-African human populations., Several models for the origin of Homo sapiens sapiens have been proposed. The 'multiregional origin' model suggests that there was no single origin for all modern humans (1, 2). After [...]

The construction of human evolutionary trees incorporating polymorphic microsatellite details enables the understanding of evolutionary relations. This approach is applicable only to human populations and not among ape species possibly due to allele length variation constraints. The microsatellite diversity, unlike other nuclear markers, is highest in Africa, thus reinforcing the possible African origin for humans.

Data on normal genetic variation are analyzed from a population perspective using results on multiple individual DNA-based polymorphisms, many clustered in haplotypes, studied in multiple populations representing all major geographic regions of the world. These data support a hypothesis for human dispersal around the world and refine the understanding of population structures and genetic relationships.

Over the past few years our lab has assembled a collection of cell lines on over 30 populations including at least three populations from each of the major geographic regions of the world. To date we have a complete set of allele frequency data on 14 haplotyped loci (46 sites total, two to six sites per locus) and 9 single-site loci on 30 distinct populations with an average sample size n@50. This complete dataset of 23 independent loci on 30 distinct populations has now been analyzed for genetic distances, etc. The Fst values for the 55 individual sites across the 30 populations range from 0.04 to 0.41, with a mean of 0.16. The smallest value occurred at one site at the D4S 10 locus but the haplotypes for D4S 10 had an Fst =0.17. The largest value occurred for a single SNP in the ADH gene cluster. PCA analyses give four main clusters of populations corresponding to Africa, Europe and Southwest Asia, East Asia, and the Americas. In tree analyses, the Africa-Europe pair is separated by a long branch from the East Asia-Americas pair. Three populations do not fall clearly in any of these clusters: Nasioi Melanesians, Micronesians, and Yakut Siberians. The overall pattern is consistent with an out-of-Africa model; indeed, some of the haplotypes included-CD4, DRD2, DM, PAH-have been used on subsets of these populations to argue strongly for that model. The additional data at those and the other haplotyped loci continue to be consistent with the existence of a significant founder effect associated with the expansion out of Africa and accumulating drift and loss of variation from West to East across Eurasia and then from North to South in the Americas. Supported by NIH grants GM57672, AA09379, and NSF grant BCS-9912028.

As part of an ongoing study to examine the patterns of linkage disequilibrium at multiple regions of the genome, we have collected data on over 2000 individuals from 38 populations distributed across all major regions of the globe. Data ate available on all populations for more than 20 haplotyped loci involving three to seven single nucleotide polymorphisms (SNPs); about half also contain a short tandem repeat polymorphism (STRP). In addition, several independent SNPs are available for the same populations. Genetic distance analyses give an extremely robust framework for the global population relationships. When compared to geography-based 'migrational' distances between populations, there is a clear correlation between genetic similarity and geographic proximity. However, compared to these 'migrational' distances, the genetic data show greater variation among populations in the same geographic region and less variation between geographic regions. The patterns of gene frequency variation and linkage disequilibrium both provide strong support for an out of Africa model with both increasing genetic distance and increasing linkage disequilibrium as populations are further from Africa, with some notable exceptions. For example, the Druze from Israel cluster genetically with other European populations but tend to show more linkage disequilibrium. An African-American sample shows genetic distances clustering with other African populations but displaced toward Europeans; the average level of linkage disequilibrium, however, is the same or less than that seen for most sub-Saharan African populations and considerably less than that seen for European populations. Supported by GM57672, MH62495, and NSF BCS-9912028.

ALFRED (http://alfred.med.yale.edu) is designed to be a resource to the genetic anthropology and population genetics communities by providing a central curated resource for allele frequency data for DNA-based polymorphisms typed on defined population samples. It is hoped that it will help the research community fill in the missing cells in the largely empty population-polymorphism matrix. Most of the effort during the past year was put towards increasing the quantity and quality of data in ALFRED. Currently, frequency tables (one population typed for one site) involve 672 polymorphisms and 228 populations and have increased from 3561 (September, 2001) to 6301 (September, 2002). The staff are now systematically extracting gene frequency data from recent issues of major human genetics and physical anthropology journals. Curatorial software tools to ensure data accuracy and consistency were developed and we are in the final stages of migration of the existing ALFRED data from a Microsoft Access database to a more robust and powerful Oracle database. An improved Web-based search and retrieval system is being developed. As part of that effort a Document Type Definition (DTD) has been developed for importing and exporting ALFRED data in XML format. We are now beginning to accept data directly from researchers. While XML data or a spreadsheet are preferable, we can also accept data in most any electronic form if the descriptive information is submitted in parallel. (Ongoing support of ALFRED is provided by NSF grant BCS-0096588)

We are converting ALFRED (http:// alfred.med.yale.edu/alfred/) into a curated publicly accessible database expanding the contents to include published allele frequency data on defined population samples and unpublished data from other researchers who are willing to submit them. To encourage user input to the design and enhanced functionality of the database we have placed links on each page of the Web interface to the administrator's email address. This email address also serves to accumulate suggestions from the community about what criteria should be used to evaluate data for entry into the database since allele frequency data based on very small or ill-defined samples have limited anthropologic utility. Data that do not meet the quality standards agreed to by the community should not be entered into the database or should have a clear 'warning' associated with the entry. As of September, 2001, ALFRED contains over 3500 allele frequency tables (one polymorphism in one population); this number should increase rapidly in the next few months. Currently ALFRED has tools for accessing the raw allele frequency data and the data can be displayed graphically either as frequencies or as heterozygosities and numerically in different tabular representations. To the degree possible ALFRED will either contain or have links to specific protocols used to type the polymorphisms as well as links to other relevant databases. (Ongoing support of ALFRED is provided by NSF grant BCS-0096588.).