Genetic similarities within and between human populations

The proportion of human genetic variation due to differences between populations is modest, and individuals from different populations can be genetically more similar than individuals from the same population. Yet sufficient genetic data can permit accurate classification of individuals into populations. Both findings can be obtained from the same data set, using the same number of polymorphic loci. This article explains why. Our analysis focuses on the frequency, omega, with which a pair of random individuals from two different populations is genetically more similar than a pair of individuals randomly selected from any single population. We compare omega to the error rates of several classification methods, using data sets that vary in number of loci, average allele frequency, populations sampled, and polymorphism ascertainment strategy. We demonstrate that classification methods achieve higher discriminatory power than omega because of their use of aggregate properties of populations. The number of loci analyzed is the most critical variable: with 100 polymorphisms, accurate classification is possible, but omega remains sizable, even when using populations as distinct as sub-Saharan Africans and Europeans. Phenotypes controlled by a dozen or fewer loci can therefore be expected to show substantial overlap between human populations. This provides empirical justification for caution when using population labels in biomedical settings, with broad implications for personalized medicine, pharmacogenetics, and the meaning of race.     

Evidence for alternate splicing within the mRNA transcript encoding the DNA damage response kinase ATR

The ITGB4BP gene encodes for a highly conserved protein, named p27BBP (also known as eIF6), originally identified in mammals as a cytoplasmic interactor of beta4 integrin. In vitro and in vivo studies demonstrated that p27BBP is essential for cell viability and has a primary function in the biogenesis of the 60S ribosomal subunit. Here we report the genomic organization of the human ITGB4BP gene and show that its gene product is expressed with features of a housekeeping element in vitro, but is regulated in a cell specific fashion in vivo. The human gene spans 10 kb and comprises seven exons and six introns. The 5' flanking region shows a TATA-less promoter, canonical CpG islands, and binding sites for serum responsive elements. In cultured cells, p27BBP mRNA and protein are constitutively expressed and stable. A gradual loss of p27BBP mRNA can be observed only after prolonged serum starvation, and heat shock treatment. In contrast, p27BBP mRNA and protein levels in vivo are variable among different organs. More strikingly, immunohistochemical analysis shows that the p27BBP protein is present in a cell specific fashion, even within the same tissue. Taken together, these data show that ITGB4BP gene expression is highly regulated in vivo, possibly by the combination of tissue specific factors and protein synthesis pathways.     

Non-traditional Alu evolution and primate genomic diversity

Alu elements belonging to the previously identified "young" subfamilies are thought to have inserted in the human genome after the divergence of humans from non-human primates and therefore should not be present in non-human primate genomes. Polymerase chain reaction (PCR) based screening of over 500 Alu insertion loci resulted in the recovery of a few "young" Alu elements that also resided at orthologous positions in non-human primate genomes. Sequence analysis demonstrated these "young" Alu insertions represented gene conversion events of pre-existing ancient Alu elements or independent parallel insertions of older Alu elements in the same genomic region. The level of gene conversion between Alu elements suggests that it may have a significant influence on the single nucleotide diversity within the genome. All the instances of multiple independent Alu insertions within the same small genomic regions were recovered from the owl monkey genome, indicating a higher Alu amplification rate in owl monkeys relative to many other primates. This study suggests that the majority of Alu insertions in primate genomes are the products of unique evolutionary events.     

The USH1C 216G→A mutation and the 9-repeat VNTR(t,t) allele are in complete linkage disequilibrium in the Acadian population

Recently, mutations in USH1C were shown to be associated with Usher syndrome type IC, and a mutation (216G-->A) in exon 3 was identified in an Acadian family. In addition, a 45-bp variable number of tandem repeat (VNTR) polymorphism was found in intron 5 of USH1C. Polymerase chain reaction amplification of the VNTR region and restriction enzyme analysis of exon 3 of USH1C showed that, of 44 Acadian patients, 43 were homozygous for both the 216G-->A mutation and nine repeats of the VNTR, with a "t" nucleotide replacing a "g" nucleotide at the 8th position of both the eighth and ninth copies of the repeat, viz., 9VNTR(t,t). The remaining Acadian patient was reported to be a compound heterozygote for 216G-->A/9VNTR(t,t) and 238-239insC, a USH1C mutation that has been found in other populations. These data demonstrate that the 9VNTR(t,t) allele is in complete linkage disequilibrium with the 216G-->A mutation in the Acadian population. Among 82 Acadian controls, one was heterozygous for 216G-->A/9VNTR(t,t). The 238-239insC mutation was not found in Acadian controls. Analysis of 340 non-Acadian normal samples showed the presence of a 9-repeat VNTR allele in one Hispanic sample. This individual had neither the 216G-->A mutation nor the Acadian VNTR(t,t) structure. These results suggest that the 216G-->A mutation and the 9VNTR(t,t) allele are restricted to the Acadians and are in complete linkage disequilibrium.     

Distribution of the HIV resistance CCR5-Delta32 allele among Egyptians and Syrians

A mutant allele of the beta-chemokine receptor gene CCR5 bearing a 32-basepair (bp) deletion that prevents cell invasion by the primary transmitting strain of HIV-1 has recently been characterized. Individuals homozygous for the mutation are resistant to infection, even after repeated high-risk exposure, but this resistance appears not absolute, as isolated cases of HIV-positive deletion homozygotes are emerging. The consequence of the heterozygous state is not clear, but it may delay the progression to AIDS in infected individuals. In order to evaluate the frequency distribution of CCR5-Delta32 polymorphism among Egyptians, a total of 200 individuals (154 from Ismailia and 46 from Sinai) were tested. Only two heterozygous individuals from Ismailia carried the CCR5-Delta32 allele (0.6%), and no homozygous (Delta32/Delta32) individuals were detected among the tested samples. The presence of the CCR5-Delta32 allele among Egyptians may be attributed to the admixture with people of European descent. Thus we conclude that the protective deletion CCR5-Delta32 is largely absent in the Egyptian population.     

Different evolutionary fates of recently integrated human and chimpanzee LINE-1 retrotransposons

The long interspersed element-1 (LINE-1 or L1) is a highly successful retrotransposon in mammals. L1 elements have continued to actively propagate subsequent to the human–chimpanzee divergence,  6 million years ago, resulting in species-specific inserts. Here, we report a detailed characterization of chimpanzee-specific L1 subfamily diversity and a comparison with their human-specific counterparts. Our results indicate that L1 elements have experienced different evolutionary fates in humans and chimpanzees within the past  6 million years. Although the species-specific L1 copy numbers are on the same order in both species (1200–2000 copies), the number of retrotransposition-competent elements appears to be much higher in the human genome than in the chimpanzee genome. Also, while human L1 subfamilies belong to the same lineage, we identified two lineages of recently integrated L1 subfamilies in the chimpanzee genome. The two lineages seem to have coexisted for several million years, but only one shows evidence of expansion within the past three million years. These differential evolutionary paths may be the result of random variation, or the product of competition between L1 subfamily lineages. Our results suggest that the coexistence of several L1 subfamily lineages within a species may be resolved in a very short evolutionary period of time, perhaps in just a few million years. Therefore, the chimpanzee genome constitutes an excellent model in which to analyze the evolutionary dynamics of L1 retrotransposons.