Connie J. Mulligan

Beringian Standstill and Spread of Native American Founders

Native Americans derive from a small number of Asian founders who likely arrived to the Americas via Beringia. However, additional details about the intial colonization of the Americas remain unclear. To investigate the pioneering phase in the Americas we analyzed a total of 623 complete mtDNAs from the Americas and Asia, including 20 new complete mtDNAs from the Americas and seven from Asia. This sequence data was used to direct high-resolution genotyping from 20 American and 26 Asian populations. Here we describe more genetic diversity within the founder population than was previously reported. The newly resolved phylogenetic structure suggests that ancestors of Native Americans paused when they reached Beringia, during which time New World founder lineages differentiated from their Asian sister-clades. This pause in movement was followed by a swift migration southward that distributed the founder types all the way to South America. The data also suggest more recent bi-directional gene flow between Siberia and the North American Arctic.

Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight.

Early life experiences, including those in utero, have been linked to increased risk for adult-onset chronic disease. The underlying assumption is that there is a critical period of developmental plasticity in utero when selection of the fetal phenotype that is best adapted to the intrauterine environment occurs. The current study is the first to test the idea that extreme maternal psychosocial stressors, as observed in the Democratic Republic of Congo, may modify locus-specific epigenetic marks in the newborn resulting in altered health outcomes. Here we show a significant correlation between culturally relevant measures of maternal prenatal stress, newborn birth weight and newborn methylation in the promoter of the glucocorticoid receptor NR3C1. Increased methylation may constrain plasticity in subsequent gene expression and restrict the range of stress adaptation responses possible in affected individuals, thus increasing their risk for adult-onset diseases.

A Three-Stage Colonization Model for the Peopling of the Americas

Background We evaluate the process by which the Americas were originally colonized and propose a three-stage model that integrates current genetic, archaeological, geological, and paleoecological data. Specifically, we analyze mitochondrial and nuclear genetic data by using complementary coalescent models of demographic history and incorporating non-genetic data to enhance the anthropological relevance of the analysis. Methodology/Findings Bayesian skyline plots, which provide dynamic representations of population size changes over time, indicate that Amerinds went through two stages of growth ≈40,000 and ≈15,000 years ago separated by a long period of population stability. Isolation-with-migration coalescent analyses, which utilize data from sister populations to estimate a divergence date and founder population sizes, suggest an Amerind population expansion starting ≈15,000 years ago. Conclusions/Significance These results support a model for the peopling of the New World in which Amerind ancestors diverged from the Asian gene pool prior to 40,000 years ago and experienced a gradual population expansion as they moved into Beringia. After a long period of little change in population size in greater Beringia, Amerinds rapidly expanded into the Americas ≈15,000 years ago either through an interior ice-free corridor or along the coast. This rapid colonization of the New World was achieved by a founder group with an effective population size of ≈1,000–5,400 individuals. Our model presents a detailed scenario for the timing and scale of the initial migration to the Americas, substantially refines the estimate of New World founders, and provides a unified theory for testing with future datasets and analytic methods.

Bayesian phylogenetic analysis of Semitic languages identifies an Early Bronze Age origin of Semitic in the Near East

The evolution of languages provides a unique opportunity to study human population history. The origin of Semitic and the nature of dispersals by Semitic-speaking populations are of great importance to our understanding of the ancient history of the Middle East and Horn of Africa. Semitic populations are associated with the oldest written languages and urban civilizations in the region, which gave rise to some of the worlds first major religious and literary traditions. In this study, we employ Bayesian computational phylogenetic techniques recently developed in evolutionary biology to analyse Semitic lexical data by modelling language evolution and explicitly testing alternative hypotheses of Semitic history. We implement a relaxed linguistic clock to date language divergences and use epigraphic evidence for the sampling dates of extinct Semitic languages to calibrate the rate of language evolution. Our statistical tests of alternative Semitic histories support an initial divergence of Akkadian from ancestral Semitic over competing hypotheses (e.g. an African origin of Semitic). We estimate an Early Bronze Age origin for Semitic approximately 5750 years ago in the Levant, and further propose that contemporary Ethiosemitic languages of Africa reflect a single introduction of early Ethiosemitic from southern Arabia approximately 2800 years ago.

Updated Three-Stage Model for the Peopling of the Americas

Background We re-assess support for our three stage model for the peopling of the Americas in light of a recent report that identified nine non-Native American mitochondrial genome sequences that should not have been included in our initial analysis. Removal of these sequences results in the elimination of an early (i.e. ∼40,000 years ago) expansion signal we had proposed for the proto-Amerind population. Methodology/Findings Bayesian skyline plot analysis of a new dataset of Native American mitochondrial coding genomes confirms the absence of an early expansion signal for the proto-Amerind population and allows us to reduce the variation around our estimate of the New World founder population size. In addition, genetic variants that define New World founder haplogroups are used to estimate the amount of time required between divergence of proto-Amerinds from the Asian gene pool and expansion into the New World. Conclusions/Significance The period of population isolation required for the generation of New World mitochondrial founder haplogroup-defining genetic variants makes the existence of three stages of colonization a logical conclusion. Thus, our three stage model remains an important and useful working hypothesis for researchers interested in the peopling of the Americas and the processes of colonization.

Ancient DNA from Nubian and Somali wild ass provides insights into donkey ancestry and domestication

Genetic data from extant donkeys (Equus asinus) have revealed two distinct mitochondrial DNA haplogroups, suggestive of two separate domestication events in northeast Africa about 5000 years ago. Without distinct phylogeographic structure in domestic donkey haplogroups and with little information on the genetic makeup of the ancestral African wild ass, however, it has been difficult to identify wild ancestors and geographical origins for the domestic mitochondrial clades. Our analysis of ancient archaeological and historic museum samples provides the first genetic information on the historic Nubian wild ass (Equus africanus africanus), Somali wild ass (Equus africanus somaliensis) and ancient donkey. The results demonstrate that the Nubian wild ass was an ancestor of the first donkey haplogroup. In contrast, the Somali wild ass has considerable mitochondrial divergence from the Nubian wild ass and domestic donkeys. These findings resolve the long-standing issue of the role of the Nubian wild ass in the domestication of the donkey, but raise new questions regarding the second ancestor for the donkey. Our results illustrate the complexity of animal domestication, and have conservation implications for critically endangered Nubian and Somali wild ass.

Comment on "Population Size Does Not Influence Mitochondrial Genetic Diversity in Animals"

Bazin et al. (Reports, 28 April, 2006, p. 570) found no relationship between mitochondrial DNA (mtDNA) diversity and population size when comparing across large groups of animals. We show empirically that species with smaller populations, as represented by eutherian mammals, exhibit a positive correlation between mtDNA and allozyme variation, suggesting that mtDNA diversity may correlate with population size in these animals.

Regional Differences in the Distribution of the Sub-Saharan, West Eurasian, and South Asian mtDNA Lineages in Yemen

Despite its key location for population movements out of and back into Africa, Yemen has not yet been sampled on a regional level for an investigation of sub-Saharan, West Eurasian, and South Asian genetic contributions. In this study, we present mitochondrial DNA (mtDNA) data for regionally distinct Yemeni populations that reveal different distributions of mtDNA lineages. An extensive database of mtDNA sequences from North and East African, Middle Eastern and Indian populations was analyzed to provide a context for the regional Yemeni mtDNA datasets. The groups of western Yemen appear to be most closely related to Middle Eastern and North African populations, while the eastern Yemeni population from Hadramawt is most closely related to East Africa. Furthermore, haplotype matches with Africa are almost exclusively confined to West Eurasian R0a haplogroup in southwestern Yemen, although more sub-Saharan L-type matches appear in more northern Yemeni populations. In fact, Yemeni populations have the highest frequency of R0a haplotypes detected to date, thus Yemen or southern Arabia may be the site of the initial expansion of this haplogroup. Whereas two variants of the sub-Saharan haplogroup M1 were detected only in southwestern Yemen close to the Bab el-Mandeb Strait, different non-African M haplotypes were detected at low frequencies (approximately 2%) in western parts of the country and at a higher frequency (7.5%) in the Hadramawt. We conclude that the Yemeni gene pool is highly stratified both regionally and temporally and that it has received West Eurasian, Northeast African, and South Asian gene flow.

Genetic Ancestry, Social Classification, and Racial Inequalities in Blood Pressure in Southeastern Puerto Rico

Background The role of race in human genetics and biomedical research is among the most contested issues in science. Much debate centers on the relative importance of genetic versus sociocultural factors in explaining racial inequalities in health. However, few studies integrate genetic and sociocultural data to test competing explanations directly. Methodology/Principal Findings We draw on ethnographic, epidemiologic, and genetic data collected in southeastern Puerto Rico to isolate two distinct variables for which race is often used as a proxy: genetic ancestry versus social classification. We show that color, an aspect of social classification based on the culturally defined meaning of race in Puerto Rico, better predicts blood pressure than does a genetic-based estimate of continental ancestry. We also find that incorporating sociocultural variables reveals a new and significant association between a candidate gene polymorphism for hypertension (α2C adrenergic receptor deletion) and blood pressure. Conclusions/Significance This study addresses the recognized need to measure both genetic and sociocultural factors in research on racial inequalities in health. Our preliminary results provide the most direct evidence to date that previously reported associations between genetic ancestry and health may be attributable to sociocultural factors related to race and racism, rather than to functional genetic differences between racially defined groups. Our results also imply that including sociocultural variables in future research may improve our ability to detect significant allele-phenotype associations. Thus, measuring sociocultural factors related to race may both empower future genetic association studies and help to clarify the biological consequences of social inequalities.

Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo.

Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which prenatal stress affects postnatal functioning. This study addresses this gap by examining the effect of chronic stress and traumatic war-related stress on epigenetic changes in four key genes regulating the HPA axis in neonatal cord blood, placenta, and maternal blood: CRH, CRHBP, NR3C1, and FKBP5. Participants were 24 mother-newborn dyads in the conflict-ridden region of the eastern Democratic Republic of Congo. BW data were collected at delivery and maternal interviews were conducted to assess culturally relevant chronic and war-related stressors. Chronic stress and war trauma had widespread effects on HPA axis gene methylation, with significant effects observed at transcription factor binding (TFB) sites in all target genes tested. Some changes in methylation were unique to chronic or war stress, whereas others were observed across both stressor types. Moreover, stress exposures impacted maternal and fetal tissues differently, supporting theoretical models that stress impacts vary according to life phase. Methylation in several NR3C1 and CRH CpG sites, all located at TFB sites, was associated with BW. These findings suggest that prenatal stress exposure impacts development via epigenetic changes in HPA axis genes.