Instituto Multidisciplinario de Biología Celular

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. Deep whole-genome sequencing of 300 individuals from 142 diverse populations provides insights into key population genetic parameters, shows that all modern human ancestry outside of Africa including in Australasians is consistent with descending from a single founding population, and suggests a higher rate of accumulation of mutations in non-Africans compared to Africans since divergence. Three international collaborations reporting in this issue of Nature describe 787 high-quality genomes from individuals from geographically diverse populations. David Reich and colleagues analysed whole-genome sequences of 300 individuals from 142 populations. Their findings include an accelerated estimated rate of accumulation of mutations in non-Africans compared to Africans since divergence, and that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans but from the same source as that of other non-Africans. Eske Willerlsev and colleagues obtained whole-genome data for 83 Aboriginal Australians and 25 Papuans from the New Guinea Highlands. They estimate that Aboriginal Australians and Papuans diverged from Eurasian populations 51,000–72,000 years ago, following a single out-of-Africa dispersal. Luca Pagani et al. report on a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations. Their analyses support the model by which all non-African populations derive most of their genetic ancestry from a single recent migration out of Africa, although a Papuan contribution suggests a trace of an earlier human expansion.

Native Americans derive from a small number of Asian founders who likely arrived to the Americas via Beringia. However, additional details about the initial 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.

A phylogenetic analysis of sex-chromosomal zinc-finger genes (Zfx and Zfv) indicates that the genes have not evolved completely independently since their initial separation. The sequence similarities suggest gene conversion in the last exon between the duplicated Y-chromosomal genes Zfv-1 and Zfy-2 in the mouse. There are also indications of conversion (or recombination) between the X-and Y-chromosomal genes in the crab-eating fox and in the mouse. The method for estimating synonymous and nonsynonymous substitutions is modified by incorporating the substitutions in the twofold-degenerate sites in a novel way. The estimates of synonymous substitutions support the generation-time hypothesis in that the obtained rates are higher in mice (by a factor of 4.7) than in humans and higher in the Y-chromosomal genes (by a factor of 1.9) than in the X-chromosomal genes.

The large and diverse population of Latin America is potentially a powerful resource for elucidating the genetic basis of complex traits through admixture mapping. However, no genome-wide characterization of admixture across Latin America has yet been attempted. Here, we report an analysis of admixture in thirteen Mestizo populations (i.e. in regions of mainly European and Native settlement) from seven countries in Latin America based on data for 678 autosomal and 29 X-chromosome microsatellites. We found extensive variation in Native American and European ancestry (and generally low levels of African ancestry) among populations and individuals, and evidence that admixture across Latin America has often involved predominantly European men and both Native and African women. An admixture analysis allowing for Native American population subdivision revealed a differentiation of the Native American ancestry amongst Mestizos. This observation is consistent with the genetic structure of pre-Columbian populations and with admixture having involved Natives from the area where the Mestizo examined are located. Our findings agree with available information on the demographic history of Latin America and have a number of implications for the design of association studies in population from the region.

This study was undertaken to establish the prevalence rates at birth of the skeletal dysplasias that can be recognised in the perinatal period. Using the data base of the Latin-American Collaborative Study of Congenital Malformations (ECLAMC), for the years 1978 to 1983, on 349 470 births (live and stillbirths), a crude prevalence rate of 2.3/10 000 was observed. However, several indications of under-registration suggest that the real value is about twice that observed. The most frequent types of skeletal dysplasia were achondroplasia, with a prevalence rate between 0.5 and 1.5/10 000 births, the thanatophoric dysplasia/achondrogenesis group (0.2 and 0.5/10 000 births), and osteogenesis imperfecta (0.4/10 000 births). The mutation rate for autosomal dominant achondroplasia was estimated at between 1.72 and 5.57 X 10(-5) per gamete per generation.

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.

Only a limited number of complete mitochondrial genome sequences belonging to Native American haplogroups were available until recently, which left America as the continent with the least amount of information about sequence variation of entire mitochondrial DNAs. In this study, a comprehensive overview of all available complete mitochondrial DNA (mtDNA) genomes of the four pan-American haplogroups A2, B2, C1, and D1 is provided by revising the information scattered throughout GenBank and the literature, and adding 14 novel mtDNA sequences. The phylogenies of haplogroups A2, B2, C1, and D1 reveal a large number of sub-haplogroups but suggest that the ancestral Beringian population(s) contributed only six (successful) founder haplotypes to these haplogroups. The derived clades are overall starlike with coalescence times ranging from 18,000 to 21,000 years (with one exception) using the conventional calibration. The average of about 19,000 years somewhat contrasts with the corresponding lower age of about 13,500 years that was recently proposed by employing a different calibration and estimation approach. Our estimate indicates a human entry and spread of the pan-American haplogroups into the Americas right after the peak of the Last Glacial Maximum and comfortably agrees with the undisputed ages of the earliest Paleoindians in South America. In addition, the phylogenetic approach also indicates that the pathogenic status proposed for various mtDNA mutations, which actually define branches of Native American haplogroups, was based on insufficient grounds.

It had been proposed that the colonization of the New World took place by three successive migrations from northeastern Asia. The first one gave rise to Amerindians (Paleo-Indians), the second and third ones to Nadene and Aleut-Eskimo, respectively. Variation in mtDNA has been used to infer the demographic structure of the Amerindian ancestors. The study of RFLP all along the mtDNA and the analysis of nucleotide substitutions in the D-loop region of the mitochondrial genome apparently indicate that most or all full-blooded Amerindians cluster in one of four different mitochondrial haplotypes that are considered to represent the founder maternal lineages of Paleo-Indians. We have studied the mtDNA diversity in 109 Amerindians belonging to 3 different tribes, and we have reanalyzed the published data on 482 individuals from 18 other tribes. Our study confirms the existence of four major Amerindian haplotypes. However, we also found evidence supporting the existence of several other potential founder haplotypes or haplotype subsets in addition to the four ancestral lineages reported. Confirmation of a relatively high number of founder haplotypes would indicate that early migration into America was not accompanied by a severe genetic bottleneck.

Weight loss triggers important metabolic responses to conserve energy, especially via the fall in leptin levels. Consequently, weight loss becomes increasingly difficult with weight regain commonly occurring in most dieters. Here we show that central growth hormone (GH) signaling also promotes neuroendocrine adaptations during food deprivation. GH activates agouti-related protein (AgRP) neurons and GH receptor (GHR) ablation in AgRP cells mitigates highly characteristic hypothalamic and metabolic adaptations induced by weight loss. Thus, the capacity of mice carrying an AgRP-specific GHR ablation to save energy during food deprivation is impaired, leading to increased fat loss. Additionally, administration of a clinically available GHR antagonist (pegvisomant) attenuates the fall of whole-body energy expenditure of food-deprived mice, similarly as seen by leptin treatment. Our findings indicate GH as a starvation signal that alerts the brain about energy deficiency, triggering key adaptive responses to conserve limited fuel stores.

There is great scientific and popular interest in understanding the genetic history of populations in the Americas. We wish to understand when different regions of the continent were inhabited, where settlers came from, and how current inhabitants relate genetically to earlier populations. Recent studies unraveled parts of the genetic history of the continent using genotyping arrays and uniparental markers. The 1000 Genomes Project provides a unique opportunity for improving our understanding of population genetic history by providing over a hundred sequenced low coverage genomes and exomes from Colombian (CLM), Mexican-American (MXL), and Puerto Rican (PUR) populations. Here, we explore the genomic contributions of African, European, and especially Native American ancestry to these populations. Estimated Native American ancestry is 48% in MXL, 25% in CLM, and 13% in PUR. Native American ancestry in PUR is most closely related to populations surrounding the Orinoco River basin, confirming the Southern American ancestry of the Taíno people of the Caribbean. We present new methods to estimate the allele frequencies in the Native American fraction of the populations, and model their distribution using a demographic model for three ancestral Native American populations. These ancestral populations likely split in close succession: the most likely scenario, based on a peopling of the Americas 16 thousand years ago (kya), supports that the MXL Ancestors split 12.2kya, with a subsequent split of the ancestors to CLM and PUR 11.7kya. The model also features effective populations of 62,000 in Mexico, 8,700 in Colombia, and 1,900 in Puerto Rico. Modeling Identity-by-descent (IBD) and ancestry tract length, we show that post-contact populations also differ markedly in their effective sizes and migration patterns, with Puerto Rico showing the smallest effective size and the earlier migration from Europe. Finally, we compare IBD and ancestry assignments to find evidence for relatedness among European founders to the three populations.

MOTIVATION: After the outstanding breakthrough of AlphaFold in predicting protein 3D models, new questions appeared and remain unanswered. The ensemble nature of proteins, for example, challenges the structural prediction methods because the models should represent a set of conformers instead of single structures. The evolutionary and structural features captured by effective deep learning techniques may unveil the information to generate several diverse conformations from a single sequence. Here, we address the performance of AlphaFold2 predictions obtained through ColabFold under this ensemble paradigm. RESULTS: Using a curated collection of apo-holo pairs of conformers, we found that AlphaFold2 predicts the holo form of a protein in ∼70% of the cases, being unable to reproduce the observed conformational diversity with the same error for both conformers. More importantly, we found that AlphaFold2's performance worsens with the increasing conformational diversity of the studied protein. This impairment is related to the heterogeneity in the degree of conformational diversity found between different members of the homologous family of the protein under study. Finally, we found that main-chain flexibility associated with apo-holo pairs of conformers negatively correlates with the predicted local model quality score plDDT, indicating that plDDT values in a single 3D model could be used to infer local conformational changes linked to ligand binding transitions. AVAILABILITY AND IMPLEMENTATION: Data and code used in this manuscript are publicly available at https://gitlab.com/sbgunq/publications/af2confdiv-oct2021. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample.

The ghrelin receptor or growth hormone secretagogue receptor (GHSR) is a G-protein-coupled receptor that controls growth hormone and insulin secretion, food intake, and reward-seeking behaviors. Liver-expressed antimicrobial peptide 2 (LEAP2) was recently described as an endogenous antagonist of GHSR. Here, we present a study aimed at delineating the structural determinants required for LEAP2 activity toward GHSR. We demonstrate that the entire sequence of LEAP2 is not necessary for its actions. Indeed, the N-terminal part alone confers receptor binding and activity to LEAP2. We found that both LEAP2 and its N-terminal part behave as inverse agonists of GHSR and as competitive antagonists of ghrelin-induced inositol phosphate production and calcium mobilization. Accordingly, the N-terminal region of LEAP2 is able to inhibit ghrelin-induced food intake in mice. These data demonstrate an unexpected pharmacological activity for LEAP2 that is likely to have an important role in the control of ghrelin response under normal and pathological conditions.

This study departed from a preconceived definition of VACTERL, including more than one of these six anomalies in the same infant: V (vertebral anomalies), A (anal atresia), C (congenital heart disease), TE (tracheoesophageal fistula or esophageal atresia), R (reno-urinary anomalies), and L (radial limb defect). Under this definition, 524 infants were ascertained by ECLAMC from almost 3,000,000 births examined from 1967 through 1990. Observed association rates among VACTERL components as well as between VACTERL and other defects were compared against randomly expected values obtained from 10,084 multiply malformed infants (casuistic method) from the same birth sample. Conclusions were: 1) Cardiac defects are not a part of VACTERL. 2) Single umbilical artery, ambiguous genitalia, abdominal wall defects, diaphragmatic hernia, and anomalies that are secondary to VACTERL components (intestinal and respiratory anomalies, and oligohydramnios sequence defects) are frequent enough to be considered an "extension" of VACTERL, and cardiac defects should be included in this category. 3) Neural tube defects are negatively associated with VACTERL which could not be explained by selection bias or any other operational artifact. High embryonic lethality or mutually exclusive pathogenetic mechanisms could be suitable explanations. 4) Results were not clear enough to determine whether VACTERL should be defined by at least two or three component defects.

To verify whether the decreasing neural tube defects birth prevalence rates in Chile are due to folic acid fortification or to pre-existing decreasing trends, we performed a population survey using a network of Estudio Colaborativo Latino Americano de Malformaciones Congenitas (ECLAMC, Latin American Collaborative Study of Congenital Malformations) maternity hospitals in Chile, between the years 1982 and 2002. Within each maternity hospital, birth prevalence rates of spina bifida and anencephaly were calculated from two pre-fortification periods (1982-1989 and 1990-2000), and from one fortified period (2001-2002). There was no historical trend for spina bifida birth prevalence rates before folic acid fortification, and there was a 51% (minimum 27%, maximum 66%) decrease in the birth prevalence rates of this anomaly in the fortified period. The relative risks of spina bifida were homogeneous among hospitals in the two period comparisons. There was no historical trend for the birth prevalence of anencephaly comparing the two pre-fortified periods, but the relative risks were heterogeneous among hospitals in this comparison. There was a 42% (minimum 10%, maximum 63%) decrease in the birth prevalence rate of anencephaly in the fortified period as compared with the immediately pre-fortified period, with homogeneous relative risks among hospitals. Within the methodological constraints of this study we conclude that the birth prevalence rates for both spina bifida and anencephaly decreased as a result of folic acid fortification, without interference of decreasing secular trends.

The rich fossil record of horses has made them a classic example of evolutionary processes. However, while the overall picture of equid evolution is well known, the details are surprisingly poorly understood, especially for the later Pliocene and Pleistocene, c. 3 million to 0.01 million years (Ma) ago, and nowhere more so than in the Americas. There is no consensus on the number of equid species or even the number of lineages that existed in these continents. Likewise, the origin of the endemic South American genus Hippidion is unresolved, as is the phylogenetic position of the "stilt-legged" horses of North America. Using ancient DNA sequences, we show that, in contrast to current models based on morphology and a recent genetic study, Hippidion was phylogenetically close to the caballine (true) horses, with origins considerably more recent than the currently accepted date of c. 10 Ma. Furthermore, we show that stilt-legged horses, commonly regarded as Old World migrants related to the hemionid asses of Asia, were in fact an endemic North American lineage. Finally, our data suggest that there were fewer horse species in late Pleistocene North America than have been named on morphological grounds. Both caballine and stilt-legged lineages may each have comprised a single, wide-ranging species.

We analyzed 40 pairs of breast normal/cancer tissues for the presence of mitochondrial (mt) genome instability and nuclear MSI in tumor cells. As mt, markers we used a (CA)n mt microsatellite (MS) starting at the 514-bp position of the D loop region and 4 informative MnlI sites located between the 16,108- and 16,420-bp positions of the D loop region. Nuclear microsatallite instability (MSI) was tested with 8 (CA)n MS, syntenic for the 13q chromosome arm. Moreover, we tested the spontaneous frequency of mtMSI and mt-MnlI mutations in 459 mother/descendant events. Mutations of mt-MnlI sites were found in 19 of 40 (47.5%) breast tumors, representing a 216-fold increase over the spontaneous rate in the female germline. Instability of the mtMS occurred in 17 of 40 (42.5%) breast cancers, which implies a 16-fold increase over the rate of spontaneous mutations. Nuclear MSI was found in 20 of 40 (50%) cases. In 15 of these cases the MSI was restricted to one locus, whereas in 5 instances the change of alleles was detected in 2 or 3 loci. Analysis of the correlation between mt and nuclear mutations showed no significant associations, suggesting that different systems are responsible for mt and nuclear genome instability in tumor cells. We propose that the two main mechanisms producing mtRFLP and mtMSI are damage by free radicals and error repair by the polymerase gamma, the first mechanism being a major cause of MnlI mutations and a secondary cause of mtMSI.

A collaborative work was carried out by the Spanish and Portuguese ISFG Working Group (GEP-ISFG) to estimate Y-STR mutation rates. Seventeen Y chromosome STR loci (DYS19, DYS385, DYS389I and II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS460, DYS461, DYS635 [GATA C4], GATA H4, and GATA A10) were analyzed in a sample of 3,026 father/son pairs. Among 27,029 allele transfers, 54 mutations were observed, with an overall mutation rate across the 17 loci of 1.998 x 10(-3) (95% CI, 1.501 x 10(-3) to 2.606 x 10(-3)). With just one exception, all of the mutations were single-step, and they were observed only once per gametogenesis. Repeat gains were more frequent than losses, longer alleles were found to be more mutable, and the mutation rate seemed to increase with the father's age. Hum Mutat 26(6), 520-528, 2005. (c) 2005 Wiley-Liss, Inc.

The birth prevalence of specific types of congenital anomalies at low and high altitudes in South America were compared after adjustment for prenatal growth, ethnicity, and socioeconomic status. The material includes all 1,668,722 consecutive births occurring in 53 hospitals participating in the Latin-American Collaborative Study of Congenital Malformations (ECLAMC), having registered at least 100 malformed/control pairs between 1967 and 1995. The lowland subsample (below 2,000 m above the sea level) included 46,729 case-control pairs, ascertained in 1,539,432 births from 49 hospitals in 38 cities. The highlands (above 2,000 m) comprised 3,498 case-control pairs from 129,301 births, occurring in four hospitals from three cities. Unconditional logistic regression was used to estimate the relative risks for the exposure at high altitudes, adjusted by ethnicity (Amerindian yes/no), type of health service (public/private), and birth weight (below/equal and greater than 2, 500 g). The adjusted relative risks showed significantly (P < 0.01) higher values in the high than in the lowlands for four types of defects: cleft lip [relative risks (RR): 1.57; 95% confidence interval (CI): 1.27-1.94], microtia (RR: 3.21; 95% CI: 2.35-4.79), preauricular tag (RR: 2.09; 95% CI: 1.86-2.36), branchial arch anomaly complex (RR: 1.79; 95% CI: 1.23-2.61), constriction band complex (RR: 1.92; 95% CI: 1.11-3.31), and anal atresia (RR: 1.61; 95% CI: 1.01-2.57). Conversely, lower risks in the highlands were registered for two neural tube defects: anencephaly (RR: 0.33; 95% CI: 0.20-0.54), spina bifida (RR: 0.57; 95% CI: 0.37-0.78), as well as for hydrocephaly (RR: 0.41; 95% CI: 0.22-0.77) and pes equinovarus (RR: 0.70; 95% CI: 0.51-0.96). Even though some of these differences may be caused by undetected confounders, the coincidental finding of four types of craniofacial defects with higher, and two types of neural tube defect with lower frequencies in the highlands, suggest a real biological foundation.

The peptide hormone ghrelin acts in the central nervous system as a potent orexigenic signal. Not only is ghrelin recognized as playing an important role in feeding circuits traditionally thought of as affecting body weight homeostasis, but also an accumulating number of scientific studies have identified ghrelin as being a key regulator of reward-based, hedonic eating behaviors. In the current article, we review ghrelin's orexigenic actions, the evidence linking ghrelin to food reward behavior, potential mechanisms by which ghrelin mediates reward-based eating behavior, and those studies suggesting an obligatory role for ghrelin in the changed eating behaviors induced by stress. The peptide hormone ghrelin acts in the central nervous system as a potent orexigenic signal. Not only is ghrelin recognized as playing an important role in feeding circuits traditionally thought of as affecting body weight homeostasis, but also an accumulating number of scientific studies have identified ghrelin as being a key regulator of reward-based, hedonic eating behaviors. In the current article, we review ghrelin's orexigenic actions, the evidence linking ghrelin to food reward behavior, potential mechanisms by which ghrelin mediates reward-based eating behavior, and those studies suggesting an obligatory role for ghrelin in the changed eating behaviors induced by stress. Reward Aspects of Gastrointestinal Hormones Mediated by Brain G Protein–Coupled ReceptorsBiological PsychiatryVol. 72Issue 5PreviewIn association with food availability, specific endocrine cell populations within the gastrointestinal tract produce peptide hormones such as ghrelin or glucagon-like peptide-1 (GLP-1). The selective activation of their respective brain G protein-coupled receptors aims to adjust eating behavior, energy expenditure, and glucose metabolism. Full-Text PDF