Disentangling Signatures of Selection Before and After European Colonization in Latin Americans

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas

Identifying signals of positive selection in Peruvian populations

Poster presented at the Human Evolution, held between 30th Octuber and 1st November in 2019, in Cambridge (UK).Since our origin in Africa, humans have colonise d very diverse environments and confronted distinctive selective pressures that have left traceable signatures across the human genome. Perú is an extremely diverse country, hosting three main ecologically differentiated regions or ecozones: the desert Pacific coast, the Andean highlands and the Amazonian jungle. Our goal is to elucidate novel insights into the adaptive allelic variants and phenotypes that favoured adaptation to the different environments of the three Peruvian ecozones. To do so, we count on a geographically extensive dataset that includes 155 samples from 23 Peruvian populations genotyped with Illumina Infinium® Multi-Ethnic Global Array (MEGA; 1,779,819 SNPs). Global ancestry analyses, including principal component and admixture analyses, were performed to infer population structure and individual ancestry fractions. Broadly, the Native American ancestry component predominantes in all Peruvian populations but especially in the highland ones. On the contrary, only a small fraction of European ancestry component is present mostly in the Amazonian and coastal populations, where some African ancestry component can be appreciated. Signals of positive selection according to the hard sweep model were investigated using tests based on population differentiation (Fixation index [Fst] and Population Branch Statistic [PBS]) and on linkage disequilibrium (integrated Haplotype Score [iHS] and cross-population Extended Haplotype Homozygosity [XP-EHH]). As for signals of polygenic selection, we computed SUMSTAT to check whether particular pathways and gene sets show stronger selection signals than randomly generated gene sets. Preliminary results of tests comparing highland to lowland populations (including the coast and jungle ecozones) confirm previously described candidate genes for adaptation to hypoxia, such as NOS2, BRINP3, EPAS1, FADS2, TGFA and ULBP1. Similarly, several pathways (REACTOME, KEGG) and GO terms associated to cardiovascular health were confirmed to be involved in high-altitude adaptation. Currently, we are investigating the selection signals specific to the Amazonian jungle and desert Pacific coast ecozone.Peer reviewe

Successful enrichment and recovery of whole mitochondrial genomes from ancient human dental calculus

OBJECTIVES: Archaeological dental calculus is a rich source of host-associated biomolecules. Importantly, however, dental calculus is more accurately described as a calcified microbial biofilm than a host tissue. As such, concerns regarding destructive analysis of human remains may not apply as strongly to dental calculus, opening the possibility of obtaining human health and ancestry information from dental calculus in cases where destructive analysis of conventional skeletal remains is not permitted. Here we investigate the preservation of human mitochondrial DNA (mtDNA) in archaeological dental calculus and its potential for full mitochondrial genome (mitogenome) reconstruction in maternal lineage ancestry analysis. MATERIALS AND METHODS: Extracted DNA from six individuals at the 700-year-old Norris Farms #36 cemetery in Illinois was enriched for mtDNA using in-solution capture techniques, followed by Illumina high-throughput sequencing. RESULTS: Full mitogenomes (7-34×) were successfully reconstructed from dental calculus for all six individuals, including three individuals who had previously tested negative for DNA preservation in bone using conventional PCR techniques. Mitochondrial haplogroup assignments were consistent with previously published findings, and additional comparative analysis of paired dental calculus and dentine from two individuals yielded equivalent haplotype results. All dental calculus samples exhibited damage patterns consistent with ancient DNA, and mitochondrial sequences were estimated to be 92-100% endogenous. DNA polymerase choice was found to impact error rates in downstream sequence analysis, but these effects can be mitigated by greater sequencing depth. DISCUSSION: Dental calculus is a viable alternative source of human DNA that can be used to reconstruct full mitogenomes from archaeological remains

Uncovering Signals of Positive Selection in Peruvian Populations from Three Ecological Regions.

Peru hosts extremely diverse ecosystems which can be broadly classified into the following three major ecoregions: the Pacific desert coast, the Andean highlands, and the Amazon rainforest. Since its initial peopling approximately 12,000 years ago, the populations inhabiting such ecoregions might have differentially adapted to their contrasting environmental pressures. Previous studies have described several candidate genes underlying adaptation to hypobaric hypoxia among Andean highlanders. However, the adaptive genetic diversity of coastal and rainforest populations has been less studied. Here, we gathered genome-wide single-nucleotide polymorphism-array data from 286 Peruvians living across the three ecoregions and analyzed signals of recent positive selection through population differentiation and haplotype-based selection scans. Among highland populations, we identify candidate genes related to cardiovascular function (TLL1, DUSP27, TBX5, PLXNA4, SGCD), to the Hypoxia-Inducible Factor pathway (TGFA, APIP), to skin pigmentation (MITF), as well as to glucose (GLIS3) and glycogen metabolism (PPP1R3C, GANC). In contrast, most signatures of adaptation in coastal and rainforest populations comprise candidate genes related to the immune system (including SIGLEC8, TRIM21, CD44, and ICAM1 in the coast; CBLB and PRDM1 in the rainforest; and BRD2, HLA-DOA, HLA-DPA1 regions in both), possibly as a result of strong pathogen-driven selection. This study identifies candidate genes related to human adaptation to the diverse environments of South America

Uncovering signals of positive selection in peruvian populations from three ecological regions

Peru hosts extremely diverse ecosystems which can be broadly classified into the following three major ecoregions: the Pacific desert coast, the Andean highlands, and the Amazon rainforest. Since its initial peopling approximately 12,000 years ago, the populations inhabiting such ecoregions might have differentially adapted to their contrasting environmental pressures. Previous studies have described several candidate genes underlying adaptation to hypobaric hypoxia among Andean highlanders. However, the adaptive genetic diversity of coastal and rainforest populations has been less studied. Here, we gathered genome-wide single-nucleotide polymorphism-array data from 286 Peruvians living across the three ecoregions and analyzed signals of recent positive selection through population differentiation and haplotype-based selection scans. Among highland populations, we identify candidate genes related to cardiovascular function (TLL1, DUSP27, TBX5, PLXNA4, SGCD), to the Hypoxia-Inducible Factor pathway (TGFA, APIP), to skin pigmentation (MITF), as well as to glucose (GLIS3) and glycogen metabolism (PPP1R3C, GANC). In contrast, most signatures of adaptation in coastal and rainforest populations comprise candidate genes related to the immune system (including SIGLEC8, TRIM21, CD44, and ICAM1 in the coast; CBLB and PRDM1 in the rainforest; and BRD2, HLA-DOA, HLA-DPA1 regions in both), possibly as a result of strong pathogen-driven selection. This study identifies candidate genes related to human adaptation to the diverse environments of South America.This work was supported by the Ministerio de Ciencia e Innovación and the Agencia Estatal de Investigación (AEI) (PID2019-110933GB-I00/AEI/10.13039/501100011033 to E.B.); the Unidad de Excelencia María de Maeztu funded by the Ministerio de Ciencia e Innovación and the Agencia Estatal de Investigación (DOI: 10.13039/501100011033; ref: CEX2018-000792-M to E.B. and R.C.-C.); the National Science Foundation (NSF) SBE (Postdoctoral Research Fellowship Award No. 1711982 to M.A.N.-C.), NSF-BCS (BCS-0242958 to A.C.S.) and NSF-Research Experience for Undergraduates (BCS-0242958 to A.C.S.); the Mexican National Council for Science and Technology (CONACYT) (FONCICYT/50/2016 to A.M.-E.); and the International Center for Genetic Engineering and Biotechnology (ICGEB, Italy) (CRP/MEX15-04_EC to A.M.-E.). The PEGEN-BC study was supported by the National Cancer Institute at the National Institutes of Health (R01CA204797 to L.F.) and the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru

Deciphering signals of positive selection in Peruvian populations from three ecoregions

Trabajo presentado en el Second IBE PhD Symposium, celebrado online el 4 y 5 de febrero de 2021.Perú hosts three extremely diverse ecoregions: The Pacific coast desert, the Andean highlands, and the Amazonian rainforest. Multiple analyses have already identified potential candidate genes for human adaptation to hypobaric hypoxia in highlands, but selection in the Peruvian coast and rainforest remains unexplored. Genome-wide SNP data (Illumina Infinium® MEGA) from 198 individuals distributed across Perú were used to identify signals of recent positive selection in each ecoregion. Specifically, we computed population differentiation (PBS) and haplotype-based selection scans (iHS and XP-EHH). Across the top 50 candidate regions identified per scan, we explored for strong selective sweeps, as well as for signatures of polygenic selection using gene-set and SNP-trait enrichment approaches. Among the top 10 genomic signatures of recent positive selection found in highlands, we replicate some previously known candidates (TBX5, TGFA). We also identify novel signals related to cardiac function, glucose metabolism and epidermal growth factors. In the coast, we identify genes related to the immune system and to vitamin D synthesis. In the rainforest, we detect genes linked to respiratory functions, immune system, heart development and gametogenesis. Furthermore, we identify multiple common candidate regions among ecoregions, including genes involved in lipid metabolism (CPT2 and LRP8) and the immune system (DUOX2, DUOXA1 and DUOX1). Gene-set and trait-associated SNP overrepresentation analyses also yield common terms linked to xenobiotic metabolism and insulin. In addition, highland and coastal populations are also enriched in cardiac muscle contraction and lipid metabolism categories, whereas several immune function terms are enriched in the coast and in the rainforest. In summary, we find genes that provide adaptations specific to the local ecological conditions in the three ecoregions. However, we also detect shared adaptations among ecoregions that point to the recent common adaptive history of Peruvian populations.Peer reviewe

The genomic landscape of the Peruvian Andes

Poster presented at the 88th Annual Meeting of the American Association of Physical Anthropologists (2019), held on March 27-30th, 2019 in Cleveland, Ohio.The Peruvian Andes was home to multiple major civilization centers of the pre-contact Americas, and contemporary peoples in this region retain a large reservoir of Native American genomic diversity. Although large genomic studies have been conducted in Peru, most data is limited to urban areas or comes from a small number of rural populations. Other studies with more comprehensive sampling are limited to uniparental markers or small subsets of autosomal variants. Here we expand upon these efforts by examining genetic diversity among a large sample of Indigenous or traditional lifestyle communities located in each of the three Peruvian ecozones: the desert Pacific Coast, the Highlands and the Jungle Lowlands. We also include data for two coastal Afro-Peruvian communities

Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes.

Preeclampsia is a multi-organ complication of pregnancy characterized by sudden hypertension and proteinuria that is among the leading causes of preterm delivery and maternal morbidity and mortality worldwide. The heterogeneity of preeclampsia poses a challenge for understanding its etiology and molecular basis. Intriguingly, risk for the condition increases in high-altitude regions such as the Peruvian Andes. To investigate the genetic basis of preeclampsia in a population living at high altitude, we characterized genome-wide variation in a cohort of preeclamptic and healthy Andean families (n = 883) from Puno, Peru, a city located above 3,800 meters of altitude. Our study collected genomic DNA and medical records from case-control trios and duos in local hospital settings. We generated genotype data for 439,314 SNPs, determined global ancestry patterns, and mapped associations between genetic variants and preeclampsia phenotypes. A transmission disequilibrium test (TDT) revealed variants near genes of biological importance for placental and blood vessel function. The top candidate region was found on chromosome 13 of the fetal genome and contains clotting factor genes PROZ, F7, and F10. These findings provide supporting evidence that common genetic variants within coagulation genes play an important role in preeclampsia. A selection scan revealed a potential adaptive signal around the ADAM12 locus on chromosome 10, implicated in pregnancy disorders. Our discovery of an association in a functional pathway relevant to pregnancy physiology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations

Differential DNA methylation of vocal and facial anatomy genes in modern humans

Altres ajuts: Obra Social "La Caixa" i CERCA Programme/Generalitat de CatalunyaChanges in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie human-specific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that likely emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes associated with face and vocal tract anatomy went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-associated genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract