Significance: Through the Peruvian Genome Project we generate and analyze the genomes of 280 individuals where the majority have >90% Native American ancestry and explore questions at the interface of evolutionary genetics, history, anthropology, and medicine. This is the most extensive sampling of high-coverage Native American and mestizo whole genomes to date. We estimate an initial peopling of Peru was rapid and began by 12,000 y ago. In addition, the mestizo populations exhibit admixture between Native American groups prior to their Spanish admixture and was likely influenced by the Inca Empire and Spanish conquest. Our results address important Native American population history questions and establish a dataset beneficial to address the underrepresentation of Native American ancestry in sequencing studies.

The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed a genome-wide analysis using 6,267 individuals from 25 populations to infer how different African groups contributed to North-, South-American, and Caribbean populations, in the context of geographic and geopolitical factors, and compared genetic data with demographic history records of the Transatlantic Slave Trade. We observed that West-Central Africa and Western Africa-associated ancestry clusters are more prevalent in northern latitudes of the Americas, whereas the South/East Africa-associated ancestry cluster is more prevalent in southern latitudes of the Americas. This pattern results from geographic and geopolitical factors leading to population differentiation. However, there is a substantial decrease in the between-population differentiation of the African gene pool within the Americas, when compared with the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This between-population homogenization in the Americas is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the United States and Southeast-Brazil, with respect to historical-demography expectations. We also inferred that in most of the Americas, intercontinental admixture intensification occurred between 1750 and 1850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural, and political debate regarding ancestry, admixture, and the mestizaje process in the Americas.

Early detection and diagnosis of tuberculosis remain major global priorities for tuberculosis control. Few studies have used a qualitative approach to investigate the social determinants contributing to diagnostic delay and none have compared data collected from individual, community, and health-system levels. We aimed to characterize the social determinants that contribute to diagnostic delay among persons diagnosed with tuberculosis living in resource-constrained settings. Data were collected in public health facilities with high tuberculosis incidence in 19 districts of Lima, Peru. Semi-structured interviews with persons diagnosed with tuberculosis (n = 105) and their family members (n = 63) explored health-seeking behaviours, community perceptions of tuberculosis and socio-demographic circumstances. Focus groups (n = 6) were conducted with health personnel (n = 35) working in the National Tuberculosis Program. All interview data were transcribed and analysed using a grounded theory approach. The median delay between symptom onset and the public health facility visit that led to the first positive diagnostic sample was 57 days (interquartile range 28–126). The great majority of persons diagnosed with tuberculosis distrusted the public health system and sought care at public health facilities only after exhausting other options. It was universally agreed that persons diagnosed with tuberculosis faced discrimination by public and health personnel. Self-medication with medicines bought at local pharmacies was reported as the most common initial health-seeking behaviour due to the speed and low-cost of treatment in pharmacies. Most persons diagnosed with tuberculosis initially perceived their illness as a simple virus. Diagnostic delay was common and prolonged. When individuals reached a threshold of symptom severity, they addressed their health with the least time-consuming, most economically feasible, and well-known healthcare option available to them. In high-burden settings, more human and material resources are required to promote tuberculosis case-finding initiatives, reduce tuberculosis associated stigma and address the social determinants underlying diagnostic delay.

The metabolic conversion of dietary omega-3 and omega-6 18 carbon (18C) to long chain (>20 carbon) polyunsaturated fatty acids (LC-PUFAs) is vital for human life. The rate-limiting steps of this process are catalyzed by fatty acid desaturase (FADS) 1 and 2. Therefore, understanding the evolutionary history of the FADS genes is essential to our understanding of hominin evolution. The FADS genes have two haplogroups, ancestral and derived, with the derived haplogroup being associated with more efficient LC-PUFA biosynthesis than the ancestral haplogroup. In addition, there is a complex global distribution of these haplogroups that is suggestive of Neanderthal introgression. We confirm that Native American ancestry is nearly fixed for the ancestral haplogroup, and replicate a positive selection signal in Native Americans. This positive selection potentially continued after the founding of the Americas, although simulations suggest that the timing is dependent on the allele frequency of the ancestral Beringian population. We also find that the Neanderthal FADS haplotype is more closely related to the derived haplogroup and the Denisovan clusters closer to the ancestral haplogroup. Furthermore, the derived haplogroup has a time to the most recent common ancestor of 688,474 years before present. These results support an ancient polymorphism, as opposed to Neanderthal introgression, forming in the FADS region during the Pleistocene with possibly differential selection pressures on both haplogroups. The near fixation of the ancestral haplogroup in Native American ancestry calls for future studies to explore the potential health risk of associated low LC-PUFA levels in these populations.

Western South America was one of the worldwide cradles of civilization. The well-known Inca Empire was the tip of the iceberg of an evolutionary process that started 11,000 to 14,000 years ago. Genetic data from 18 Peruvian populations reveal the following: 1) The between-population homogenization of the central southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes, and Amazonia accompanied cultural and socioeconomic interactions revealed by archeology. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower, and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia. 2) The genetic homogenization between the populations of the arid Andes is not only due to migrations during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the Wari Empire (600 to 1,000 years before present). 3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, a putative enhancer in HAND2-AS1 (heart and neural crest derivatives expressed 2 antisense RNA1, a noncoding gene related to cardiovascular function) and rs269868-C/Ser1067 in DUOX2 (dual oxidase 2, related to thyroid function and innate immunity) genes and, in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T and B lymphocytes in viral–host interaction. Significance Native Americans are neglected in human genetics studies, despite recent interest in the study of ancient DNA of their ancestors. Our findings on Andean and Amazonian populations exemplify how the current pattern of genetic diversity in human populations is influenced by the interaction of history and environment. In the present case, this pattern is influenced by 1) altitudinal and climatic differences among the northern, lower, and fertile Andes versus the southern, higher, and arid Andes and 2) the sharp differences between the Andean highlands and the Amazon lowlands, where natural selection and other evolutionary forces acted for millennia, shaping differences in the frequencies of genetic variants related to immune response, drug response, and cardiovascular and hematological functions.

M. tuberculosis (MTB) species-specific antigenic determinants of the human T cell response are important for immunodiagnosis and vaccination. As hypoxia is a stimulus in chronic tuberculosis infection, we analyzed transcriptional profiles of MTB subject to 168 hours of hypoxia to test the hypothesis that upregulation by hypoxia might result in gene products being recognized as antigens. We identified upregulation of two region of difference (RD) 11 (Rv2658C and Rv2659c), and one RD2 (Rv1986) absent from commonly used BCG strains. In MTB infected persons, the IL-2 ELISpot response to Rv1986 peptides was several times greater than the corresponding IFN-γ response to the reference immunodominant ESAT-6 or CFP-10 antigens. The IL-2 response was confined to two epitopic regions containing residues 61–80 and 161–180. The biggest population of IL-2 secreting T cells was single cytokine positive central memory T cells. The IL-2 response to live MTB bacilli lacking Rv1986 was significantly lower than the response to wild type or mutant complemented with Rv1986. In addition, the IL-2 response to Rv1986 was significantly lower in HIV-TB co-infected persons than in HIV uninfected persons, and significantly increased during antiretroviral therapy. These findings demonstrate that Rv1986 is an immunodominant target of memory T cells and is therefore of relevance when considering the partial efficacy of currently used BCG vaccines and provide evidence for a clinical trial comparing BCG strains. Mycobacterium tuberculosis (the cause of tuberculosis) can persist for many years in humans without causing disease but has the potential to reactivate. One of the conditions the bacterium must survive in these circumstances is hypoxia. In order to do so, the bacterium uses a characteristic set of genes that help alter its metabolism. It follows that the products of such genes may encode protein antigens that can be recognized by the immune response. We therefore analyzed gene response patterns of tuberculosis subject to prolonged hypoxia as a guide to the discovery of new antigens that might be useful as vaccines or diagnostic agents. Amongst the genes most strongly increased by low oxygen levels, one was identified (known as Rv1986) that is missing from most strains of the tuberculosis vaccine Mycobacterium bovis BCG. When we analyzed human immune responses to this protein in tuberculosis infected people our experiments showed it was particularly well recognized by cells that produce a chemical messenger (cytokine) called interleukin-2. Interleukin-2 is important for long-term immunological memory. The BCG vaccine is only partially effective and our experiments therefore suggest one of the reasons could be that an important immunological target is missing from many strains. Further evaluation of BCG strains in which Rv1986 is present or absent is therefore warranted in the hope that this might improve the efficacy of existing or new tuberculosis vaccines.