The Genom of Homo sapiens.pdf

82 BERTRANPETIT ET AL.diversity in humans means that the density of markers ina map may be restricted, and not all SNPs will be as abundantas required to pick up an LD signal with, for example,an infrequent variant with a small contribution to acomplex disease.As explained above, population size and its fluctuationsover time have a clear effect on LD, with low effectivepopulation sizes and bottlenecks contributing to it. Ifthe history of a population is sufficiently well known, thiscan be verified. For instance, Laan and Pääbo (1997) andKaessmann et al. (2002) found that the Saami and Evenki,reindeer herders of presumably constant size, showhigher levels of LD when compared to neighboring, expandingpopulations. This has two implications: (1) Asexplained in the next section, it is possible to attempt thereverse inference; that is, to infer (although in a rathervague and qualitative manner) population history fromLD and (2) population history matters in biomedical researchaimed at deciphering the genetic architecture ofcomplex disease making successful gene hunting morelikely in some populations. In particular, populations ofconstant size, such as the Saami and Evenki, may harborextensive LD that may allow the detection of the relevantgenetic associations in complex diseases. Moreover,these populations tend to be isolated, with lower geneticdiversity, which may also be reflected in a lesser allelicand genic heterogeneity in complex diseases, thus facilitatingthe discovery of such variants.Despite the hopes created by the isolated populationapproach, however, it is not clear what contribution itmay have to the understanding of genetic disease. Atworst, population history may be so complex and sopoorly known that LD in a population cannot be predictablea priori and should be determined empirically foreach population and genome region. The sources ofpaleodemographic data are scarce and are providedmainly by paleoanthropology, archaeology, and historicalsources, which necessarily implies large uncertainties.The example of the Icelandic population is quite revealing;from the first settlement by Vikings in the MiddleAges, the demographic history of the island is known inexceptionally excruciating detail, given the Icelandicnational passion for genealogy. However, the unknowndiversity in the settlers has precluded the use of LD as atool for association mapping in an efficient way, and themost valuable resource for biomedical research in Icelandremains the genealogical database.The genome-wide structure of LD in humans needs tobe tackled and understood if LD is to be used efficientlyas a gene discovery tool. However, the population samplingdensity required to obtain a description of the requiredlevel of detail is not clearly known. A cynical viewwould be that only the populations that can afford thecostly pharmaceutical diagnostics and treatments need tobe sampled; in an ideal world of universal health care, thelevel of detail that should be both relevant and nonredundantmay be just guessed if LD is to behave as genetic diversity.Then, there would be almost as much variationwithin as among continents, and all continents should besampled, with much more variation within Africa thanelsewhere. The old-fashioned vision of human diversityas made of monolithic Europeans, East Asians, andAfricans still prevails in genetics without a solid basis,and there is resistance to the realization that although itaccounts for a large fraction of the world population, itdoes not relate to the actual structure of LD and genomevariation.WORLDWIDE VARIATION OF LD INSPECIFIC GENE REGIONSThe usage of LD as a tool to unravel population historyand to reconstruct demographic aspects of human evolutionhas been pioneered by Kenn Kidd at Yale University,and his collaborators. The first global analysis of the LDvariation in human populations was undertaken in a regionof around 9.8 kb within the CD4 locus (Tishkoff etal. 1996). These first results based on 42 worldwide populationsshowed extremely reduced LD in sub-SaharanAfrican populations and significantly higher levels ofhaplotype diversity than in non-African populations. Thisfact has been explained by the larger effective populationsize maintained in sub-Saharan populations and the effectof a recent bottleneck in the expansion of modern humansout of Africa. The rationale of this conclusion is based onthe fact that LD decays through time due to recombination,and therefore large and old populations tend to presentreduced levels of LD, whereas not enough time haselapsed to reduce LD in small and recently formed populationsthat preserve the strong LD produced in a bottleneck.Thus, the global LD approach was consistent withthe hypothesis of the “out of Africa” origin of modern humans,already supported by a large body of genetic evidence.However, these results were derived from a singlelocus and may be the spurious result of other processessuch as differential selective pressures among humanpopulations or simple stochastic variation. Populationhistory, nonetheless, should affect all the genome withthe same average strength, and this signal should be detectedin other genome regions.Subsequent worldwide analyses in several other generegions did show a similar pattern of lower LD amongsub-Saharan African populations and a LD increase outsideAfrica. However, there were a number of deviationsfrom this overall theme. The extreme LD pattern shownby the CD4 locus (that is, low LD in Africa and muchhigher LD elsewhere) is also present in DRD2 (Kidd et al.1998), DM (Tischkoff et al. 1998), PLAT (Tishkoff et al.2000), and COMT (DeMille et al. 2002). Such LD geographicalstructure is moderate in PAH (Kidd et al. 2000)and PKLR-GBA region (Mateu et al. 2002); whereas LDin Africans is similar to that of non-Africans in CFTR(Mateu et al. 2001), and even higher in SLC6A4 (Gelernteret al. 1999). These different LD geographic structuresmay be explained by different recombination rates at eachlocus: Loci with higher recombination rates would haverecovered faster from the bottleneck, reaching again thelow African LD levels. Low-grained specific recombinationestimates are available (Kong et al. 2002), but theydo not seem to correlate with LD geographical patternsfor the specific genome regions, as shown in Table 1. Theincrease in LD caused by a bottleneck in the migration