Genetic Chaos

Thursday, July 20, 2006

Evidence for an apartheid-like social structure in early Anglo-Saxon England

The role of migration in the Anglo-Saxon transition in England remains controversial. Archaeological and historical evidence is inconclusive, but current estimates of the contribution of migrants to the English population range from less than 10,000 to as many as 200,000. In contrast, recent studies based on Y-chromosome variation posit a considerably higher contribution to the modern English gene pool (50–100%). Historical evidence suggests that following the Anglo-Saxon transition, people of indigenous ethnicity were at an economic and legal disadvantage compared to those having Anglo-Saxon ethnicity. It is likely that such a disadvantage would lead to differential reproductive success. We examine the effect of differential reproductive success, coupled with limited intermarriage between distinct ethnic groups, on the spread of genetic variants. Computer simulations indicate that a social structure limiting intermarriage between indigenous Britons and an initially small Anglo-Saxon immigrant population provide a plausible explanation of the high degree of Continental male-line ancestry in England.

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Tuesday, July 11, 2006

The Delta ccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe

The chemokine receptor CCR5 is encoded by the CMKBR5 gene located on the p21.3 region of human chromosome 3, and constitutes the major co- receptor for the macrophage-tropic strains of HIV-1. A mutant allele of the CCR5 gene, Delta ccr5 , was shown to provide to homozygotes with a strong resistance against infection by HIV. The frequency of the Delta ccr5 allele was investigated in 18 European populations. A North to South gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%). Highly polymorphic microsatellites (IRI3.1, D3S4579 and IRI3.2, D3S4580 ) located respectively 11 kb upstream and 68 kb downstream of the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the Delta ccr5 variant. A strong linkage disequilibrium was found between Delta ccr5 and specific alleles of the IRI3.1 and IRI3.2 microsatellites: >95% of the Delta ccr5 chromosomes carried the IRI3.1-0 allele, while 88% carried the IRI3.2-0 allele. These alleles were found respectively in only 2 or 1.5% of the chromosomes carrying a wild-type CCR5 gene. From these data, it was inferred that most, if not all Delta ccr5 alleles originate from a single mutation event, and that this mutation event probably took place a few thousand years ago in Northeastern Europe. The high frequency of the Delta ccr5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with homo- or heterozygous carriers of the Delta ccr5 allele.

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Dating the Origin of the CCR5-D32 AIDS-Resistance Allele by the Coalescence of Haplotypes

The CCR5-D32 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-D32 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-D32 containing ancestral haplotype to be ~700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-D32 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.

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Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes

Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large well characterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

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The Use of Intraallelic Variability for Testing Neutrality and Estimating Population Growth Rate

To better understand the forces affecting individual alleles, we introduce a method for finding the joint distribution of the frequency of a neutral allele and the extent of variability at closely linked marker loci (the intraallelic variability). We model three types of intraallelic variability: (a) the number of nonrecombinants at a linked biallelic marker locus, (b) the length of a conserved haplotype, and (c) the number of mutations at a linked marker locus. If the population growth rate is known, the joint distribution provides the basis for a test of neutrality by testing whether the observed level of intraallelic variability is consistent with the observed allele frequency. If the population growth rate is unknown but neutrality can be assumed, the joint distribution provides the likelihood of the growth rate and leads to a maximum-likelihood estimate. We apply the method to data from published data sets for four loci in humans. We conclude that the Delta32 allele at CCR5 and a disease-associated allele at MLH1 arose recently and have been subject to strong selection. Alleles at PAH appear to be neutral and we estimate the recent growth rate of the European population to be ~0.027 per generation with a support interval of (0.017–0.037). Four of the relatively common alleles at CFTR also appear to be neutral but DeltaF508 appears to be significantly advantageous to heterozygous carriers.

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The geographic spread of the CCR5 Delta32 HIV-resistance allele

The Delta32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Delta32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Delta32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Delta32 allele, we implemented a spatially explicit model of the spread of Delta32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Delta32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Delta32 allele is consistent with previous reports of a strong selective advantage (>10%) for Delta32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Delta32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Delta32 allele and establish a general methodology for studying the geographic distribution of selected alleles.

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Thursday, July 06, 2006

Mitochondrial DNA diversity among five tribal populations of southern India

DNA samples from 160 unrelated individuals belonging to five Dravidian tribal populations of southern India were analysed for ten mitochondrial DNA (mtDNA) restriction site polymorphisms (RSPs) and one insertion/deletion polymorphism. There is extensive sharing of mtDNA haplotypes among all the tribal populations studied, indicating that there was a small female founding population in India. The 9-bp deletion analysed was observed only in the Kadar population with a low frequency. The Asian-specific haplogroup M is found at a higher frequency in all the populations, thus supporting the hypothesis that this haplogroup arose in India and was carried to Africa from India. Haplogroup U is also found in all the populations and it is consistent with the theory that Dravidian-speaking populations were more widespread in India and that the Aryan-speakers pushed them to their present habitat.

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Genetic structure and affinities among tribal populations of southern India: a study of 24 autosomal DNA markers

We describe the genetic structure and affinities of five Dravidian-speaking tribal populations inhabiting the Nilgiri hills of Tamil Nadu, in south India, using 24 autosomal DNA markers. Our goals were: (i). to examine what evolutionary forces have most significantly impacted south Indian tribal genetic variation, and (ii). to test whether the phenotypic similarities of some south Indian tribal groups to Africans represent a signature of close relationship to Africans or are due to convergence. All loci were polymorphic and average heterozygosities were substantial (range: 0.347-0.423). Genetic differentiation was high (Gst= 6.7%) and genetic distances were not significantly correlated with geographic distances. Genetic drift therefore probably played a significant role in shaping the patterns of genetic variation observed in southern Indian tribal populations. Otherwise, analyses of population relationships showed that Indian populations are closely related to one another, regardless of phenotypic characteristics, and do not show particular affinities to Africans. We conclude that the phenotypic similarities of some Indian groups to Africans do not reflect a close relationship between these groups, but are better explained by convergence.

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Phylogeny of Mitochondrial DNA Macrohaplogroup N in India, Based on Complete Sequencing: Implications for the Peopling of South Asia

To resolve the phylogeny of the autochthonous mitochondrial DNA (mtDNA) haplogroups of India and determine the relationship between the Indian and western Eurasian mtDNA pools more precisely, a diverse subset of 75 macrohaplogroup N lineages was chosen for complete sequencing from a collection of 1800 control-region sequences sampled across India. We identified five new autochthonous haplogroups (R7, R8, R30, R31, and N5) and fully characterized the autochthonous haplogroups (R5, R6, N1d, U2a, U2b, and U2c) that were previously described only by first hypervariable segment (HVS-I) sequencing and coding-region restriction-fragment–length polymorphism analysis. Our findings demonstrate that the Indian mtDNA pool, even when restricted to macrohaplogroup N, harbors at least as many deepest-branching lineages as the western Eurasian mtDNA pool. Moreover, the distribution of the earliest branches within haplogroups M, N, and R across Eurasia and Oceania provides additional evidence for a three-founder-mtDNA scenario and a single migration route out of Africa.

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In situ origin of deep rooting lineages of mitochondrial Macrohaplogroup M in India


Macrohaplogroups ‘M’ and ‘N’ have evolved almost in parallel from a founder haplogroup L3. Macrohaplogroup N in India has already been defined in previous studies and recently the macrohaplogroup M among the Indian populations has been characterized. In this study, we attempted to reconstruct and re-evaluate the phylogeny of Macrohaplogroup M, which harbors more than 60% of the Indian mtDNA lineage, and to shed light on the origin of its deep rooting haplogroups.


Using 11 whole mtDNA and 2231 partial coding sequence of Indian M lineage selected from 8670 HVS1 sequences across India, we have reconstructed the tree including Andamanese-specific lineage M31 and calculated the time depth of all the nodes. We defined one novel haplogroup M41, and revised the classification of haplogroups M3, M18, and M31.


Our result indicates that the Indian mtDNA pool consists of several deep rooting lineages of macrohaplogroup ‘M’ suggesting in-situ origin of these haplogroups in South Asia, most likely in the India. These deep rooting lineages are not language specific and spread over all the language groups in India. Moreover, our reanalysis of the Andamanese-specific lineage M31 suggests population specific two clear-cut subclades (M31a1 and M31a2). Onge and Jarwa share M31a1 branch while M31a2 clade is present in only Greate Andamanese individuals. Overall our study supported the one wave, rapid dispersal theory of modern humans along the Asian coast.

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