On the allelic spectrum of human disease.

Human disease genes show enormous variation in their allelic spectra; that is, in the number and population frequency of the disease-predisposing alleles at the loci. For some genes, there are a few predominant disease alleles. For others, there is a wide range of disease alleles, each relatively rare. The allelic spectrum is important: disease genes with only a few deleterious alleles can be more readily identified and are more amenable to clinical testing. Here, we weave together strands from the human mutation and population genetics literature to provide a framework for understanding and predicting the allelic spectra of disease genes. The theory does a reasonable job for diseases where the genetic etiology is well understood. It also has bearing on the Common Disease/Common Variants (CD/CV) hypothesis, predicting that at loci where the total frequency of disease alleles is not too small, disease loci will have relatively simple spectra.

Linkage disequilibrium in the human genome.

With the availability of a dense genome-wide map of single nucleotide polymorphisms (SNPs), a central issue in human genetics is whether it is now possible to use linkage disequilibrium (LD) to map genes that cause disease. LD refers to correlations among neighbouring alleles, reflecting 'haplotypes' descended from single, ancestral chromosomes. The size of LD blocks has been the subject of considerable debate. Computer simulations and empirical data have suggested that LD extends only a few kilobases (kb) around common SNPs, whereas other data have suggested that it can extend much further, in some cases greater than 100 kb. It has been difficult to obtain a systematic picture of LD because past studies have been based on only a few (1-3) loci and different populations. Here, we report a large-scale experiment using a uniform protocol to examine 19 randomly selected genomic regions. LD in a United States population of north-European descent typically extends 60 kb from common alleles, implying that LD mapping is likely to be practical in this population. By contrast, LD in a Nigerian population extends markedly less far. The results illuminate human history, suggesting that LD in northern Europeans is shaped by a marked demographic event about 27,000-53,000 years ago.

Detecting association in a case-control study while correcting for population stratification.

Case-control studies are subject to the problem of population stratification, which can occur in ethnically mixed populations and can lead to significant associations being detected at loci that have nothing to do with disease. Here, we describe a way to measure and correct for stratification by genotyping a moderate number of unlinked genetic markers in the same set of cases and controls in which a candidate association was found. The average of association statistics across the markers directly measures stratification. By dividing the candidate association statistic by this average, a P-value can be obtained that corrects for stratification.

Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse.

Single-nucleotide polymorphisms (SNPs) have been the focus of much attention in human genetics because they are extremely abundant and well-suited for automated large-scale genotyping. Human SNPs, however, are less informative than other types of genetic markers (such as simple-sequence length polymorphisms or microsatellites) and thus more loci are required for mapping traits. SNPs offer similar advantages for experimental genetic organisms such as the mouse, but they entail no loss of informativeness because bi-allelic markers are fully informative in analysing crosses between inbred strains. Here we report a large-scale analysis of SNPs in the mouse genome. We characterized the rate of nucleotide polymorphism in eight mouse strains and identified a collection of 2,848 SNPs located in 1,755 sequence-tagged sites (STSs) using high-density oligonucleotide arrays. Three-quarters of these SNPs have been mapped on the mouse genome, providing a first-generation SNP map of the mouse. We have also developed a multiplex genotyping procedure by which a genome scan can be performed with only six genotyping reactions per animal.

Age estimates of two common mutations causing factor XI deficiency: recent genetic drift is not necessary for elevated disease incidence among Ashkenazi Jews.

The type II and type III mutations at the FXI locus, which cause coagulation factor XI deficiency, have high frequencies in Jewish populations. The type III mutation is largely restricted to Ashkenazi Jews, but the type II mutation is observed at high frequency in both Ashkenazi and Iraqi Jews, suggesting the possibility that the mutation appeared before the separation of these communities. Here we report estimates of the ages of the type II and type III mutations, based on the observed distribution of allelic variants at a flanking microsatellite marker (D4S171). The results are consistent with a recent origin for the type III mutation but suggest that the type II mutation appeared >120 generations ago. This finding demonstrates that the high frequency of the type II mutation among Jews is independent of the demographic upheavals among Ashkenazi Jews in the 16th and 17th centuries.

The use of microsatellite variation to infer population structure and demographic history in a natural model system.

To assess the reliability of genetic markers it is important to compare inferences that are based on them to a priori expectations. In this article we present an analysis of microsatellite variation within and among populations of island foxes (Urocyon littoralis) on California's Channel Islands. We first show that microsatellite variation at a moderate number of loci (19) can provide an essentially perfect description of the boundaries between populations and an accurate representation of their historical relationships. We also show that the pattern of variation across unlinked microsatellite loci can be used to test whether population size has been constant or increasing. Application of these approaches to the island fox system indicates that microsatellite variation may carry considerably more information about population history than is currently being used.

Genetic evidence for a recent origin by hybridization of red wolves.

Genetic data suggest that red wolves (Canis rufus) resulted from a hybridization between coyotes (C. latrans) and grey wolves (C. lupus). The data of the hybridization, however, is uncertain. According to one hypothesis, the two species came into contact as coyotes increased their geographical range in conjunction with the advance of European settlers and as grey wolves were extirpated from the American south. Alternatively, the red wolves could have originated tens of thousands of years ago as a result of climate and habitat changes that disturbed the ecology of the two parent species. To obtain an upper limit on the date of hybridization that would help to distinguish the two scenarios, we compared microsatellite allele length distributions from red wolves, coyotes and grey wolves. Subject to the assumptions of our analysis, we conclude that the red wolves originated as a result of hybridizations that occurred during the past 12,800 years, and probably during the past 2500 years.

Genetic evidence for a Paleolithic human population expansion in Africa.

Human populations have undergone dramatic expansions in size, but other than the growth associated with agriculture, the dates and magnitudes of those expansions have never been resolved. Here, we introduce two new statistical tests for population expansion, which use variation at a number of unlinked genetic markers to study the demographic histories of natural populations. By analyzing genetic variation in various aboriginal populations from throughout the world, we show highly significant evidence for a major human population expansion in Africa, but no evidence of expansion outside of Africa. The inferred African expansion is estimated to have occurred between 49,000 and 640,000 years ago, certainly before the Neolithic expansions, and probably before the splitting of African and non-African populations. In showing a significant difference between African and non-African populations, our analysis supports the unique role of Africa in human evolutionary history, as has been suggested by most other genetic work. In addition, the missing signal in non-African populations may be the result of a population bottleneck associated with the emergence of these populations from Africa, as postulated in the "Out of Africa" model of modern human origins.

Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.

The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.