Detection of the CCR5-Δ32 HIV resistance gene in Bronze Age skeletons

Abstract

A mutant allele of the chemokine receptor CCR5 gene (CCR5-D32), which confers resistance to HIV-1 infection, is believed to have originated from a single mutation event in historic times, and rapidly expanded in Caucasian populations, owing to an unknown selective advantage. Among other candidates, the plague bacillus Yersinia pestis was implicated as a potential source of strong selective pressure on European populations during medieval times. Here, we report amplifications of the CCR5-D32 DNA sequence from up to 2900-year-old skeletal remains from different burial sites in central Germany and southern Italy. Furthermore, the allele frequency of CCR5-D32 in victims of the 14th century plague pandemic in Lü beck/ northern Germany was not different from a historic control group. Our findings indicate that this mutation was prevalent already among prehistoric Europeans. The results also argue against the possibility of plague representing a major selective force that caused rapid increase in CCR5-D32 gene frequencies within these populations. Genes and Immunity (2005) The human chemokine receptor CCR5 serves, together with CD4, as the principal coreceptor for macrophagetropic (R5) human immunodeficiency virus type 1 (HIV-1) strains. 1 A large number of genetic variants in the coding or the promotor region of the CCR5 gene have been identified in different ethnic groups. 2,3 Several of these naturally occurring mutations result in alterations of the receptor's amino-acid sequence and affect the ability of CCR5 to act as a chemokine receptor or HIV coreceptor. 4,5 The finding that nonfunctional receptor alleles are relatively frequent among different human populations has led to the hypothesis that a selective advantage might be associated with the loss of CCR5 function.The CCR5-D32 mutant, which is characterized by a 32-bp deletion in the gene segment encoding the second extracellular loop of the receptor, provides an instructive example of how host genetic variation may contribute to HIV-related pathology. Individuals homozygous for CCR5-D32 are almost completely protected against HIV-1 infection due to the absence of functional receptors from the cell surface. 6-8 Population surveys revealed a north to south gradient of CCR5-D32 allele frequencies of 16 to 3% across Europe and its absence in individuals of nonCaucasian descent. 9-11 Determination of the intrahaplotypic variation of flanking microsatellite loci in strong linkage disequilibrium with CCR5-D32 allowed calculation of the approximate age of the CCR5-D32 containing ancestral haplotype. Two different studies that analyzed separate microsatellite markers concluded that the CCR5-D32 allele originated from a single mutation event that took place in historic times approximately 700 years (95% confidence interval (CI): 275-1800) 11 to 3500 years (CI 400-13 000) 10 ago in northeastern Europe. Both studies assumed a heterozygote advantage of the CCR5-D32 mutant. The European locale and timing of the bubonic plague of the 14th century coincide with the calculat...

Estimation of 2Nes From Temporal Allele Frequency Data

“…In the first application we use a data set consisting of time-series allele frequency data for the CCR5-D32 locus (see Figure 2; Hummel et al 2005). Briefly, Hummel et al (2005) determined the frequency of this mutation from ancient human remains and an extant representative population of northern Europeans: samples were collected at five time points dating back to 900 B.C.…”

“…However, in a few cases, time series of allele frequencies are available. Examples of such data are ancient DNA (aDNA) data in humans (Hummel et al 2005), viral population data (Shankarappa et al 1999), and data on experimentally evolved populations such as Drosophila (Buri 1956), bacterial (Woods et al 2006), or viral/phage populations (Wichman et al 1999(Wichman et al , 2005Holder and Bull 2001;Bollback and Huelsenbeck 2007). Time-series data contain much more information regarding selection than samples obtained at a single point in time, because the expected changes in allele frequencies through time are closely related to the strength of selection.…”

Multi-locus analysis of genomic time series data from experimental evolution

“…The many areas where this design has been applied include demographic inference (see [1] for a recent review), recombination rate estimation [2][3][4][5][6], and detection of natural selection [7][8][9][10][11][12][13]. Recently, there has been much interest in utilizing time series genetic data-e.g., from ancient DNA [14][15][16][17][18][19][20][21], experimental evolution of a population under controlled laboratory environments [22][23][24][25][26], or direct measurements in fast evolving populations [27]-to enhance our ability to probe into evolution. In particular, understanding the genetic basis of adaptation to changes in the environment can be significantly facilitated by such temporal data.…”

A Simple Method for Finding Explicit Analytic Transition Densities of Diffusion Processes with General Diploid Selection

“…For example, such data arise from experimental evolution of model organisms in the laboratory (e.g., bacteria, see Lenski 2011), from viral/ phage populations (Shankarappa et al 1999;Wichman et al 1999), or from ancient DNA (Hummel et al 2005); see also Bollback et al (2008) and references therein. In particular, the recent sequencing of Neanderthal and Denisova (Reich et al 2010) genomes should provide new opportunities for studying the evolution of allele frequencies over time, possibly under the influence of natural selection.…”