The insertion of mobile elements into the genome represents a new class of genetic markers for the study of human evolution. Long interspersed elements (LINEs) have amplified to a copy number of about 100,000 over the last 100 million years of mammalian evolution and comprise ∼15% of the human genome. The majority of LINE-1 (L1) elements within the human genome are 5Ј truncated copies of a few active L1 elements that are capable of retrotransposition. Some of the young L1 elements have inserted into the human genome so recently that populations are polymorphic for the presence of an L1 element at a particular chromosomal location. L1 insertion polymorphisms offer several advantages over other types of polymorphisms for human evolution studies. First, they are typed by rapid, simple, polymerase chain reaction (PCR)-based assays. Second, they are stable polymorphisms that rarely undergo deletion. Third, the presence of an L1 element represents identity by descent, because the probability is negligible that two different young L1 repeats would integrate independently between the exact same two nucleotides. Fourth, the ancestral state of L1 insertion polymorphisms is known to be the absence of the L1 element, which can be used to root plots/trees of population relationships. Here we report the development of a PCR-based display for the direct identification of dimorphic L1 elements from the human genome. We have also developed PCR-based assays for the characterization of six polymorphic L1 elements within the human genome. PCR analysis of human/rodent hybrid cell line DNA samples showed that the polymorphic L1 elements were located on several different chromosomes. Phylogenetic analysis of nonhuman primate DNA samples showed that all of the recently integrated "young" L1 elements were restricted to the human genome and absent from the genomes of nonhuman primates. Analysis of a diverse array of human populations showed that the allele frequencies and level of heterozygosity for each of the L1 elements was variable. Polymorphic L1 elements represent a new source of identical-by-descent variation for the study of human evolution.

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 ␤-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.In various areas of applied genetics, it is customary to regard the human species as divided in distinct and objectively recognizable groups. Forensic scientists compare DNA profiles from the place of a crime with databases from the general population, usually grouped into broad racial categories (for instance, African-American, European-American, Asian, and Hispanic), to estimate the probability that an unrelated individual would have the identical DNA profile. The markers chosen for DNA profiling are considered to be essentially uniform across populations of the same category. Although the existence of problems with group definition has been acknowledged (e.g., Weir 2001), the fact that some individuals may not be easy to allocate to any such group is usually regarded as unimportant (National Research Council 1992;Lander and Budowle 1994;Morton 1994;Roeder 1994;Gill and Evett 1995). In clinical practice, a correlation of racial affiliation, as assessed from skin color, facial characteristics, hair texture, and so forth, with disease pathology and drug response is widely believed to exist. A PubMed search with the keywords "human races" (January 10, 2002) In contrast, population studies have suggested that genetic variation is essentially continuous through space amon...

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Depletion or dysfunction of CD4 + T lymphocytes profoundly perturbs host defenses and impairs immunogenicity of vaccines. Here, we show that plasmid DNA vaccination with a cassette encoding antigen (OVA) and a second cassette encoding full-length CD40 ligand (CD40L), a molecule expressed on activated CD4 + T lymphocytes and critical for T cell helper function, can elicit significant titers of antigen-specific immunoglobulins in serum and Tc1 CD8 + T cell responses in CD4-deficient mice. To investigate whether this approach leads to CD4 + T cell-independent vaccine protection against a prototypic AIDS-defining infection, Pneumocystis (PC) pneumonia, we used serum from mice vaccinated with PC-pulsed, CD40L-modifed DCs to immunoprecipitate PC antigens. Kexin, a PC antigen identified by this approach, was used in a similar DNA vaccine strategy with or without CD40L. CD4-deficient mice receiving DNA vaccines encoding Kexin and CD40L showed significantly higher anti-PC IgG titers as well as opsonic killing of PC compared with those vaccinated with Kexin alone. Moreover, CD4-depleted, Kexin-vaccinated mice showed a 3-log greater protection in a PC challenge model. Adoptive transfer of CD19 + cells or IgG to SCID mice conferred protection against PC challenge, indicating a role of humoral immunity in the protection. The results of these studies show promise for CD4-independent vaccination against HIV-related or other opportunistic pathogens.

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