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TRENDS in Genetics Vol.18 No.10 October 2002
http://tig.trends.com 0168-9525/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
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Strong balancing selection in the regulatory region of CCR5Leukocytes (white blood cells) possesstransmembrane proteins that act asreceptors for chemokines, molecules thatattract leukocytes. The AIDS virus (HIV-1)subverts one of these chemokine receptors,CCR5, to gain initial entry into the cell.Interestingly, individuals that havedecreased cell-surface expression of theprotein because of the variants of the CCR5 gene that they possess, are lesssusceptible to HIV infection. These variants,however, are found at low frequency andonly in some human populations. Morerecently, researchers have investigated theupstream (5′) regulatory region of CCR5,wherein several single nucleotidepolymorphisms (SNPs) with effects on AIDSprogression have been found. However,many of these SNPs are in strong linkagedisequilibrium with one another. Thus,assigning effects to individual nucleotidesites is at best very complicated.
Bamshad et al. [1] recently published alarge-scale sequencing project of theregulatory region that is from ~1.7 to ~2.8 kbupstream of the translational start sequenceof CCR5. They examined 176 chromosomesfrom a multiracial sample from the USA,224 chromosomes from the ‘Old World’(62 African, 54 Asian, 48 European, and60 South Indian), as well as chromosomesfrom chimpanzees and a gorilla. The humandata depart from expectations based uponon the neutral theory of molecular evolutionin several ways. First, surprisingly littledifferentiation is found among African,Asian and European populations at the5′ regulatory region. The Fst value (i.e. the proportion of variation that is
among populations for this region), is not statistically different from zero (i.e. no differentiation). This value issubstantially and significantly lower thanthat typically observed among humanpopulations and than that measured forrandom Alu sequences of the sameindividuals. Low differentiation is consistentwith, but not necessarily proof of, balancingselection (e.g. heterozygote advantage,frequency-dependent selection) operatingon the region.
Other tests support the hypothesis ofbalancing selection. The Asian, Europeanand South Indian populations each hadsignificantly positive values of Tajima’sD statistic for the regulatory region, signifyingthat a greater than expected number ofvariants are present at intermediate asopposed to low frequencies. The D statisticfor the African population was positive butnot significantly so. Positive D values couldarise from population subdivision (andunlikely to be based on the Fst values), butare more likely the result of some form ofbalancing selection. Because the Tajima testis known to have little statistical power, theauthors argue that the balancing selectionoperating is probably rather strong.
Under the neutral theory, ratios ofintraspecific polymorphism to interspecific divergence should be the sameacross all genes for a given sample ofindividuals. The authors used theHudson–Krietman–Aguade (HKA) test totest for significant deviations from equalpolymorphism to divergence ratios in the5′ region of CCR5 and a noncodingsequence of the CYP1A2 gene. The test
rejected the null hypothesis expected underneutrality and in the direction expected ifthe CCR5 sequence were under balancingselection. Although test by itself onlyindicates that the two genes havesignificantly different polymorphism todivergence ratios, there is no otherindication that the CYP1A2 sequencedeviates from neutrality. Furthermore, CCR5 also shows significant HKA scoreswhen tested against other genes.
Finally, the haplotype network of thehuman CCR5 data shows an extraordinarilydeep genealogical structure. A minimum-spanning haplotype network separates theCCR5 haplotypes into two clusters separatedby five SNPs. Consistent with balancingselection, heterozygotes for haplotypesfrom different clusters tend to have slowerprogression into AIDS after HIV infectionthan homozygotes. Obviously the deepgenealogical structure implies that theclusters have been under balancingselection long before the origin of HIV. In fact, the authors estimate the time ofdivergence to be around two million years.Perhaps like the genes of the MajorHistocompatibility Complex, which havealso been under persistent balancingselection, this regulatory region of CCR5 hasa more general role in disease resistance.
1 Bamshad, M. J. et al. (2002) A strong signatureof balancing selection in the 5′ cis-regulatoryregion of CCR5. Proc. Natl. Acad. Sci. U. S. A.99, 10539–10544
Norman Johnson
geographical signal. Two, for instance,consisted mainly of types only found innorth European ponies (Exmoor, Fjord,Icelandic and Scottish Highland). A thirdlineage included many Iberian (Andalusian)and North African (Barb) horses. Although asimilar geographical structure was notevident across all lineages, theseobservations, together with the extensivegenetic diversity, are consistent with ascenario of recruitment of wild mares fordomestication from geographicallydifferent areas. An obvious question, and a broadly important one, is then: was the practise of horse domesticationindependently developed by different
human societies in different places or wasthere a single origin of the required humanexpertise? This is an issue frequentlydiscussed by archaeologists, with at leastsome favouring a reading of thearchaeological record to suggest a diffusionof knowledge rather than independentlyderived ideas.
Several recent genetic studies haveaddressed the process of animaldomestication based on analysis of mtDNA.One obvious goal for further research in thisfield is to make the picture more completeby studying the paternal contribution todomestication, that is, to characterize theamount and structure of Y chromosome
diversity; for the domestic horse this will beof particular interest. Current breedingpractice implies using a limited number ofsuccessful stallions to cover a large numberof mares. If early human societies practicedbreeding in the same way, it suggests thatthe Y chromosome diversity of thedomestic horse should be much less thanthat of mtDNA.
1 Jansen, T. et al. (2002) Mitochondrial DNA andthe origins of the domestic horse. Proc. Natl.Acad. Sci. U. S. A. 99, 10905–10910
Hans Ellegren
