Increasing obsidian diversity during the Chalcolithic Period at Yeghegis-1 Rockshelter (Armenia) reveals shifts in land use and social networks.

The newly excavated rockshelter of Yeghegis-1 in Armenia reflects an occupation of five centuries, as attested by radiocarbon dates from ∼ 4100 to 4000 cal BCE in the lowest layer to ∼ 3600-3500 cal BCE at the top. It is a partially collapsed cave in which pastoralists, we hypothesize, wintered with their herds. The stone tool assemblage is predominantly obsidian (92.1%), despite the shelter being > 60 km on foot from the nearest sources. We use obsidian sourcing to investigate two purported trends in the Southern Caucasus during the Chalcolithic Period: (1) occupation of more varied high-altitude environments and (2) more expansive social networks. Our data show both trends were dynamic phenomena. There was a greater balance in use of the nearest pasturelands over time, perhaps linked to risk management and/or resource sustainability. During later occupations, artifacts from distant sources reveal more extensive connections. This increase in connectivity likely played a central role in the shifts in societal complexity that gave rise to widely shared material culture throughout the Armenian Highlands around the start of the Early Bronze Age. In such a model, greater social connectivity becomes a key mechanism for, rather than a product of, the spread of cultural and/or technological innovations.

Genotypes of the UCP1 gene polymorphisms and cardiometabolic diseases: A multifactorial study of association with disease probability.

Cardiometabolic diseases (CMDs) are complex disorders with a heterogenous phenotype, which are caused by multiple factors including genetic factors. Single nucleotide polymorphisms (SNPs) rs45539933 (p.Ala64Thr), rs10011540 (c.-112A>C), rs3811791 (c.-1766A>G), and rs1800592 (c.-3826A>G) in the UCP1 gene have been analyzed for association with CMDs in many studies providing controversial results. However, previous studies only considered individual UCP1 SNPs and did not evaluate them in an integrated manner, which is a more powerful approach to uncover genetic component of complex diseases. This study aimed to investigate associations between UCP1 genotype combinations and CMDs or CMD risk factors in the context of non-genetic factors. We performed multiple logistic regression analysis and proposed new methodology of testing different combinations of SNP genotypes. We found that probability of CMDs increased in presence of the three-SNP combination of genotypes with minor alleles of c.-3826A>G and p.Ala64Thr and wild allele of c.-112A>C, with increasing age, body mass index (BMI), body fat percentage (BF%) and may differ between sexes and between countries. The combination of genotypes with c.-3826A>G minor allele and wild homozygotes of c.-112A>C and p.Ala64Thr was associated with increased probability of diabetes. While combination of genotypes with minor alleles of all three SNPs reduced the CMD probability. The present results suggest that age, BMI, sex, and UCP1 three-SNP combinations of genotypes significantly contribute to CMD probability. Varying of c.-112A>C alleles in the genotype combination with minor alleles of c.-3826A>G and p.Ala64Thr markedly changes CMD probability.

Prevalence of uncoupling protein one genetic polymorphisms and their relationship with cardiovascular and metabolic health.

Contribution of UCP1 single nucleotide polymorphisms (SNPs) to susceptibility for cardiometabolic pathologies (CMP) and their involvement in specific risk factors for these conditions varies across populations. We tested whether UCP1 SNPs A-3826G, A-1766G, Ala64Thr and A-112C are associated with common CMP and their risk factors across Armenia, Greece, Poland, Russia and United Kingdom. This case-control study included genotyping of these SNPs, from 2,283 Caucasians. Results were extended via systematic review and meta-analysis. In Armenia, GA genotype and A allele of Ala64Thr displayed ~2-fold higher risk for CMP compared to GG genotype and G allele, respectively (p<0.05). In Greece, A allele of Ala64Thr decreased risk of CMP by 39%. Healthy individuals with A-3826G GG genotype and carriers of mutant allele of A-112C and Ala64Thr had higher body mass index compared to those carrying other alleles. In healthy Polish, higher waist-to-hip ratio (WHR) was observed in heterozygotes A-3826G compared to AA homozygotes. Heterozygosity of A-112C and Ala64Thr SNPs was related to lower WHR in CMP individuals compared to wild type homozygotes (p<0.05). Meta-analysis showed no statistically significant odds-ratios across our SNPs (p>0.05). Concluding, the studied SNPs could be associated with the most common CMP and their risk factors in some populations.

HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity.

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).

Origin and diffusion of human Y chromosome haplogroup J1-M267.

Human Y chromosome haplogroup J1-M267 is a common male lineage in West Asia. One high-frequency region-encompassing the Arabian Peninsula, southern Mesopotamia, and the southern Levant-resides ~ 2000 km away from the other one found in the Caucasus. The region between them, although has a lower frequency, nevertheless demonstrates high genetic diversity. Studies associate this haplogroup with the spread of farming from the Fertile Crescent to Europe, the spread of mobile pastoralism in the desert regions of the Arabian Peninsula, the history of the Jews, and the spread of Islam. Here, we study past human male demography in West Asia with 172 high-coverage whole Y chromosome sequences and 889 genotyped samples of haplogroup J1-M267. We show that this haplogroup evolved ~ 20,000 years ago somewhere in northwestern Iran, the Caucasus, the Armenian Highland, and northern Mesopotamia. The major branch-J1a1a1-P58-evolved during the early Holocene ~ 9500 years ago somewhere in the Arabian Peninsula, the Levant, and southern Mesopotamia. Haplogroup J1-M267 expanded during the Chalcolithic, the Bronze Age, and the Iron Age. Most probably, the spread of Afro-Asiatic languages, the spread of mobile pastoralism in the arid zones, or both of these events together explain the distribution of haplogroup J1-M267 we see today in the southern regions of West Asia.

Insights into matrilineal genetic structure, differentiation and ancestry of Armenians based on complete mitogenome data.

Distinctive peculiarities of Armenians such as their millennia-long genetic isolation and strong national identity attract a keen interest while studying the demographic history of the West Asia. Here, to examine their fine-scale matrilineal genetic structure, ancestry and relationships with neighboring populations, we analyzed 536 complete mitogenomes (141 of which are novel) from 8 geographically different Armenian populations, covering the whole stretch of historical Armenia. The observed patterns highlight a remarkable degree of matrilineal genetic heterogeneity and weak population structuring of Armenians. Moreover, our phylogeographic analysis reveals common ancestries for some mtDNA lineages shared by West Asians, Transcaucasians, Europeans, Central Asians and Armenians. About third of the mtDNA subhaplogroups found in Armenian gene pool might be considered as Armenian-specific, as these are virtually absent elsewhere in Europe, West Asia and Transcaucasia. Coalescence ages of most of these lineages do not exceed 3.1 kya and coincide well with the population size growth started around 1.8-2.8 kya detectable only in the Bayesian Skyline Plots based on the Armenian-specific mtDNA haplotypes.

The genetic history of admixture across inner Eurasia.

The indigenous populations of inner Eurasia-a huge geographic region covering the central Eurasian steppe and the northern Eurasian taiga and tundra-harbour tremendous diversity in their genes, cultures and languages. In this study, we report novel genome-wide data for 763 individuals from Armenia, Georgia, Kazakhstan, Moldova, Mongolia, Russia, Tajikistan, Ukraine and Uzbekistan. We furthermore report additional damage-reduced genome-wide data of two previously published individuals from the Eneolithic Botai culture in Kazakhstan (~5,400 BP). We find that present-day inner Eurasian populations are structured into three distinct admixture clines stretching between various western and eastern Eurasian ancestries, mirroring geography. The Botai and more recent ancient genomes from Siberia show a decrease in contributions from so-called 'ancient North Eurasian' ancestry over time, which is detectable only in the northern-most 'forest-tundra' cline. The intermediate 'steppe-forest' cline descends from the Late Bronze Age steppe ancestries, while the 'southern steppe' cline further to the south shows a strong West/South Asian influence. Ancient genomes suggest a northward spread of the southern steppe cline in Central Asia during the first millennium BC. Finally, the genetic structure of Caucasus populations highlights a role of the Caucasus Mountains as a barrier to gene flow and suggests a post-Neolithic gene flow into North Caucasus populations from the steppe.

Ancient pathogen DNA in human teeth and petrous bones.

Recent ancient DNA (aDNA) studies of human pathogens have provided invaluable insights into their evolutionary history and prevalence in space and time. Most of these studies were based on DNA extracted from teeth or postcranial bones. In contrast, no pathogen DNA has been reported from the petrous bone which has become the most desired skeletal element in ancient DNA research due to its high endogenous DNA content. To compare the potential for pathogenic aDNA retrieval from teeth and petrous bones, we sampled these elements from five ancient skeletons, previously shown to be carrying Yersinia pestis. Based on shotgun sequencing data, four of these five plague victims showed clearly detectable levels of Y. pestis DNA in the teeth, whereas all the petrous bones failed to produce Y. pestis DNA above baseline levels. A broader comparative metagenomic analysis of teeth and petrous bones from 10 historical skeletons corroborated these results, showing a much higher microbial diversity in teeth than petrous bones, including pathogenic and oral microbial taxa. Our results imply that although petrous bones are highly valuable for ancient genomic analyses as an excellent source of endogenous DNA, the metagenomic potential of these dense skeletal elements is highly limited. This trade-off must be considered when designing the sampling strategy for an aDNA project.

The genetic variation in the R1a clade among the Ashkenazi Levites' Y chromosome.

Approximately 300,000 men around the globe self-identify as Ashkenazi Levites, of whom two thirds were previously shown to descend from a single male. The paucity of whole Y-chromosome sequences precluded conclusive identification of this ancestor's age, geographic origin and migration patterns. Here, we report the variation of 486 Y-chromosomes within the Ashkenazi and non-Ashkenazi Levite R1a clade, other Ashkenazi Jewish paternal lineages, as well as non-Levite Jewish and non-Jewish R1a samples. Cumulatively, the emerging profile is of a Middle Eastern ancestor, self-affiliating as Levite, and carrying the highly resolved R1a-Y2619 lineage, which was likely a minor haplogroup among the Hebrews. A star-like phylogeny, coalescing similarly to other Ashkenazi paternal lineages, ~1,743 ybp, suggests it to be one of the Ashkenazi paternal founders; to have expanded as part of the overall Ashkenazi demographic expansion, without special relation to the Levite affiliation; and to have subsequently spread to non-Ashkenazi Levites.

The mRNA expression levels of uncoupling proteins 1 and 2 in mononuclear cells from patients with metabolic disorders: obesity and type 2 diabetes mellitus.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders whose major hallmark is insulin resistance. Impaired mitochondrial activity, such as reduced ratio of energy production to respiration, has been implicated in the development of insulin resistance. Uncoupling proteins (UCPs) are proton carriers, expressed in the mitochondrial inner membrane, that uncouple oxygen consumption by the respiratory chain from ATP synthesis. AIM: The aim of the study was to determine transcriptional levels of UCP1 and UCP2 in peripheral blood mononuclear cells (PBMCs) from patients with metabolic disorders: T2DM, obesity and from healthy individuals. MATERIAL/METHODS: The mRNA levels of UCP1, UCP2 were determined by Real-Time PCR method using Applied Biosystems assays. RESULTS: The UCP1 mRNA expression level was not detectable in the majority of studied samples, while very low expression was found in PBMCs from 3 obese persons. UCP2 mRNA expression level was detectable in all samples. The median mRNA expression of UCP2 was lower in all patients with metabolic disorders as compared to the controls (0.20+0.14 vs. 0.010+0.009, p=0.05). When compared separately, the differences of medians UCP2 mRNA expression level between the obese individuals and the controls as well as between the T2DM patients and the controls did not reach statistical significance. CONCLUSIONS: Decreased UCP2 gene expression in mononuclear cells from obese and diabetic patients might contribute to the immunological abnormalities in these metabolic disorders and suggests its role as a candidate gene in future studies of obesity and diabetes.

Eight Millennia of Matrilineal Genetic Continuity in the South Caucasus.

The South Caucasus, situated between the Black and Caspian Seas, geographically links Europe with the Near East and has served as a crossroad for human migrations for many millennia [1-7]. Despite a vast archaeological record showing distinct cultural turnovers, the demographic events that shaped the human populations of this region is not known [8, 9]. To shed light on the maternal genetic history of the region, we analyzed the complete mitochondrial genomes of 52 ancient skeletons from present-day Armenia and Artsakh spanning 7,800 years and combined this dataset with 206 mitochondrial genomes of modern Armenians. We also included previously published data of seven neighboring populations (n = 482). Coalescence-based analyses suggest that the population size in this region rapidly increased after the Last Glacial Maximum ca. 18 kya. We find that the lowest genetic distance in this dataset is between modern Armenians and the ancient individuals, as also reflected in both network analyses and discriminant analysis of principal components. We used approximate Bayesian computation to test five different demographic scenarios explaining the formation of the modern Armenian gene pool. Despite well documented cultural shifts in the South Caucasus across this time period, our results strongly favor a genetic continuity model in the maternal gene pool. This has implications for interpreting prehistoric migration dynamics and cultural shifts in this part of the world.

Role of UCP1 Gene Variants in Interethnic Differences in the Development of Cardio-Metabolic Diseases.

Cardio-metabolic diseases (CMDs) comprise a cluster of risk factors that contribute to chronic pathological conditions with adverse consequences for cardiovascular function and metabolic processes. A wide range of CMD prevalence rates among different ethnic groups has been documented. In view of accumulated evidence, there is a trend toward increasing CMD prevalence rates in Eastern Europe and Western Asia. Numerous studies have revealed an association between uncoupling protein 1 (UCP1) gene variants and CMDs. UCP1 activity is essential for brown adipose tissue (BAT)-mediated thermogenesis. Experimental animal studies and epidemiological studies in humans highlight the significance of BAT-mediated thermogenesis in protecting against obesity and maintaining a lean phenotype. We hypothesize that the genetic variation in UCP1 gene expression observed among different ethnic groups could contribute to the ethnic-specific predisposition to CMD development. Constructing such prevalence maps of UCP1 gene variants could contribute significantly into identifying high-risk ethnic groups predisposed to the development of CMDs, and further shaping public health policies by the improvement of existing preventive and management strategies.

The Simons Genome Diversity Project: 300 genomes from 142 diverse populations.

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.

East Eurasian ancestry in the middle of Europe: genetic footprints of Steppe nomads in the genomes of Belarusian Lipka Tatars.

Medieval era encounters of nomadic groups of the Eurasian Steppe and largely sedentary East Europeans had a variety of demographic and cultural consequences. Amongst these outcomes was the emergence of the Lipka Tatars-a Slavic-speaking Sunni-Muslim minority residing in modern Belarus, Lithuania and Poland, whose ancestors arrived in these territories via several migration waves, mainly from the Golden Horde. Our results show that Belarusian Lipka Tatars share a substantial part of their gene pool with Europeans as indicated by their Y-chromosomal, mitochondrial and autosomal DNA variation. Nevertheless, Belarusian Lipkas still retain a strong genetic signal of their nomadic ancestry, witnessed by the presence of common Y-chromosomal and mitochondrial DNA variants as well as autosomal segments identical by descent between Lipkas and East Eurasians from temperate and northern regions. Hence, we document Lipka Tatars as a unique example of former Medieval migrants into Central Europe, who became sedentary, changed language to Slavic, yet preserved their faith and retained, both uni- and bi-parentally, a clear genetic echo of a complex population interplay throughout the Eurasian Steppe Belt, extending from Central Europe to northern China.

Genetic Structure of the Armenian Population.

Located at the crossroads of Europe and the Middle East, the Armenian Highland served as a transition corridor for major waves of prehistoric and historic migrations. The genetic history of Armenians as an indigenous population of the region attracts keen scientific interest to resolve the puzzle of ancient Middle Eastern populations' expansion and the spread of Indo-European languages. Here, we review the current state of studies on the genetic structure of both modern and ancient inhabitants of the Armenian Highland and outline further steps to be fulfilled in this regard.

Coevolution of genes and languages and high levels of population structure among the highland populations of Daghestan.

As a result of the combination of great linguistic and cultural diversity, the highland populations of Daghestan present an excellent opportunity to test the hypothesis of language-gene coevolution at a fine geographic scale. However, previous genetic studies generally have been restricted to uniparental markers and have not included many of the key populations of the region. To improve our understanding of the genetic structure of Daghestani populations and to investigate possible correlations between genetic and linguistic variation, we analyzed ~550,000 autosomal single nucleotide polymorphisms, phylogenetically informative Y chromosome markers and mtDNA haplotypes in 21 ethnic Daghestani groups. We found high levels of population structure in Daghestan consistent with the hypothesis of long-term isolation among populations of the highland Caucasus. Highland Daghestani populations exhibit extremely high levels of between-population diversity for all genetic systems tested, leading to some of the highest FST values observed for any region of the world. In addition, we find a significant positive correlation between gene and language diversity, suggesting that these two aspects of human diversity have coevolved as a result of historical patterns of social interaction among highland farmers at the community level. Finally, our data are consistent with the hypothesis that most Daghestanian-speaking groups descend from a common ancestral population (~6000-6500 years ago) that spread to the Caucasus by demic diffusion followed by population fragmentation and low levels of gene flow.

Early divergent strains of Yersinia pestis in Eurasia 5,000 years ago.

The bacteria Yersinia pestis is the etiological agent of plague and has caused human pandemics with millions of deaths in historic times. How and when it originated remains contentious. Here, we report the oldest direct evidence of Yersinia pestis identified by ancient DNA in human teeth from Asia and Europe dating from 2,800 to 5,000 years ago. By sequencing the genomes, we find that these ancient plague strains are basal to all known Yersinia pestis. We find the origins of the Yersinia pestis lineage to be at least two times older than previous estimates. We also identify a temporal sequence of genetic changes that lead to increased virulence and the emergence of the bubonic plague. Our results show that plague infection was endemic in the human populations of Eurasia at least 3,000 years before any historical recordings of pandemics.

Global diversity, population stratification, and selection of human copy-number variation.

In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide-variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.

The genetic legacy of the expansion of Turkic-speaking nomads across Eurasia.

The Turkic peoples represent a diverse collection of ethnic groups defined by the Turkic languages. These groups have dispersed across a vast area, including Siberia, Northwest China, Central Asia, East Europe, the Caucasus, Anatolia, the Middle East, and Afghanistan. The origin and early dispersal history of the Turkic peoples is disputed, with candidates for their ancient homeland ranging from the Transcaspian steppe to Manchuria in Northeast Asia. Previous genetic studies have not identified a clear-cut unifying genetic signal for the Turkic peoples, which lends support for language replacement rather than demic diffusion as the model for the Turkic language's expansion. We addressed the genetic origin of 373 individuals from 22 Turkic-speaking populations, representing their current geographic range, by analyzing genome-wide high-density genotype data. In agreement with the elite dominance model of language expansion most of the Turkic peoples studied genetically resemble their geographic neighbors. However, western Turkic peoples sampled across West Eurasia shared an excess of long chromosomal tracts that are identical by descent (IBD) with populations from present-day South Siberia and Mongolia (SSM), an area where historians center a series of early Turkic and non-Turkic steppe polities. While SSM matching IBD tracts (> 1cM) are also observed in non-Turkic populations, Turkic peoples demonstrate a higher percentage of such tracts (p-values ≤ 0.01) compared to their non-Turkic neighbors. Finally, we used the ALDER method and inferred admixture dates (~9th-17th centuries) that overlap with the Turkic migrations of the 5th-16th centuries. Thus, our results indicate historical admixture among Turkic peoples, and the recent shared ancestry with modern populations in SSM supports one of the hypothesized homelands for their nomadic Turkic and related Mongolic ancestors.

Deep phylogenetic analysis of haplogroup G1 provides estimates of SNP and STR mutation rates on the human Y-chromosome and reveals migrations of Iranic speakers.

Y-chromosomal haplogroup G1 is a minor component of the overall gene pool of South-West and Central Asia but reaches up to 80% frequency in some populations scattered within this area. We have genotyped the G1-defining marker M285 in 27 Eurasian populations (n= 5,346), analyzed 367 M285-positive samples using 17 Y-STRs, and sequenced ~11 Mb of the Y-chromosome in 20 of these samples to an average coverage of 67X. This allowed detailed phylogenetic reconstruction. We identified five branches, all with high geographical specificity: G1-L1323 in Kazakhs, the closely related G1-GG1 in Mongols, G1-GG265 in Armenians and its distant brother clade G1-GG162 in Bashkirs, and G1-GG362 in West Indians. The haplotype diversity, which decreased from West Iran to Central Asia, allows us to hypothesize that this rare haplogroup could have been carried by the expansion of Iranic speakers northwards to the Eurasian steppe and via founder effects became a predominant genetic component of some populations, including the Argyn tribe of the Kazakhs. The remarkable agreement between genetic and genealogical trees of Argyns allowed us to calibrate the molecular clock using a historical date (1405 AD) of the most recent common genealogical ancestor. The mutation rate for Y-chromosomal sequence data obtained was 0.78×10-9 per bp per year, falling within the range of published rates. The mutation rate for Y-chromosomal STRs was 0.0022 per locus per generation, very close to the so-called genealogical rate. The "clan-based" approach to estimating the mutation rate provides a third, middle way between direct farther-to-son comparisons and using archeologically known migrations, whose dates are subject to revision and of uncertain relationship to genetic events.