RESUMEN
BACKGROUND: The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced. RESULTS: We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first ß-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation. CONCLUSIONS: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.
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Evolución Molecular , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad , Hombre de Neandertal , Humanos , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Animales , Hombre de Neandertal/genética , Selección Genética/genética , Hominidae/genética , Haplotipos/genética , Densidad Ósea/genética , Genoma Humano/genéticaRESUMEN
The genetic variation of the European population at a macro-geographic scale follows genetic gradients which reflect main migration events. However, less is known about factors affecting mating patterns at a micro-geographic scale. In this study we have analyzed 726,718 autosomal single nucleotide variants in 435 individuals from the catalan Pyrenees covering around 200 km of a vast and abrupt region in the north of the Iberian Peninsula, for which we have information about the geographic origin of all grand-parents and parents. At a macro-geographic scale, our analyses recapitulate the genetic gradient observed in Spain. However, we also identified the presence of micro-population substructure among the sampled individuals. Such micro-population substructure does not correlate with geographic barriers such as the expected by the orography of the considered region, but by the bishoprics present in the covered geographic area. These results support that, on top of main human migrations, long ongoing socio-cultural factors have also shaped the genetic diversity observed at rural populations.
RESUMEN
The 1000 Genomes Project (1000G) is one of the most popular whole genome sequencing datasets used in different genomics fields and has boosting our knowledge in medical and population genomics, among other fields. Recent studies have reported the presence of ghost mutation signals in the 1000G. Furthermore, studies have shown that these mutations can influence the outcomes of follow-up studies based on the genetic variation of 1000G, such as single nucleotide variants (SNV) imputation. While the overall effect of these ghost mutations can be considered negligible for common genetic variants in many populations, the potential bias remains unclear when studying low frequency genetic variants in the population. In this study, we analyze the effect of the sequencing center in predicted loss of function (LoF) alleles, the number of singletons, and the patterns of archaic introgression in the 1000G. Our results support previous studies showing that the sequencing center is associated with LoF and singletons independent of the population that is considered. Furthermore, we observed that patterns of archaic introgression were distorted for some populations depending on the sequencing center. When analyzing the frequency of SNPs showing extreme patterns of genotype differentiation among centers for CEU, YRI, CHB, and JPT, we observed that the magnitude of the sequencing batch effect was stronger at MAF < 0.2 and showed different profiles between CHB and the other populations. All these results suggest that data from 1000G must be interpreted with caution when considering statistics using variants at low frequency.
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Técnicas de Cultivo Celular por Lotes/métodos , Genética de Población , Genoma Humano , Genómica/normas , Polimorfismo de Nucleótido Simple , Programas Informáticos , Secuenciación Completa del Genoma/normas , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Población Rural , EspañaRESUMEN
The area of the Spanish Pyrenees is particularly interesting for studying the demographic dynamics of European rural areas given its orography, the main traditional rural condition of its population and the reported higher patterns of consanguinity of the region. Previous genetic studies suggest a gradient of genetic continuity of the area in the West to East axis. However, it has been shown that micro-population substructure can be detected when considering high-quality NGS data and using spatial explicit methods. In this work, we have analyzed the genome of 30 individuals sequenced at 40× from five different valleys in the Spanish Eastern Pyrenees (SEP) separated by less than 140 km along a west to east axis. Using haplotype-based methods and spatial analyses, we have been able to detect micro-population substructure within SEP not seen in previous studies. Linkage disequilibrium and autozygosity analyses suggest that the SEP populations show diverse demographic histories. In agreement with these results, demographic modeling by means of ABC-DL identify heterogeneity in their effective population sizes despite of their close geographic proximity, and suggests that the population substructure within SEP could have appeared around 2500 years ago. Overall, these results suggest that each rural population of the Pyrenees could represent a unique entity.
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Pool de Genes , Aislamiento Reproductivo , Población Rural , Haplotipos , Humanos , Desequilibrio de Ligamiento , Polimorfismo Genético , España , Secuenciación Completa del Genoma/estadística & datos numéricosRESUMEN
Attention-deficit/hyperactivity disorder (ADHD) is an impairing neurodevelopmental condition highly prevalent in current populations. Several hypotheses have been proposed to explain this paradox, mainly in the context of the Paleolithic versus Neolithic cultural shift but especially within the framework of the mismatch theory. This theory elaborates on how a particular trait once favoured in an ancient environment might become maladaptive upon environmental changes. However, given the lack of genomic data available for ADHD, these theories have not been empirically tested. We took advantage of the largest GWAS meta-analysis available for this disorder consisting of over 20,000 individuals diagnosed with ADHD and 35,000 controls, to assess the evolution of ADHD-associated alleles in European populations using archaic, ancient and modern human samples. We also included Approximate Bayesian computation coupled with deep learning analyses and singleton density scores to detect human adaptation. Our analyses indicate that ADHD-associated alleles are enriched in loss of function intolerant genes, supporting the role of selective pressures in this early-onset phenotype. Furthermore, we observed that the frequency of variants associated with ADHD has steadily decreased since Paleolithic times, particularly in Paleolithic European populations compared to samples from the Neolithic Fertile Crescent. We demonstrate this trend cannot be explained by African admixture nor Neanderthal introgression, since introgressed Neanderthal alleles are enriched in ADHD risk variants. All analyses performed support the presence of long-standing selective pressures acting against ADHD-associated alleles until recent times. Overall, our results are compatible with the mismatch theory for ADHD but suggest a much older time frame for the evolution of ADHD-associated alleles compared to previous hypotheses.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Genoma Humano , Genómica/métodos , Hombre de Neandertal/genética , Alelos , Animales , Trastorno por Déficit de Atención con Hiperactividad/historia , Trastorno por Déficit de Atención con Hiperactividad/patología , Teorema de Bayes , Bases de Datos Genéticas , Aprendizaje Profundo , Evolución Molecular , Historia Antigua , HumanosRESUMEN
Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a promising therapeutic tool for many diseases, including aged tissues and organs at high risk of failure. However, the intrinsic self-renewal and pluripotency of ES and iPS cells make them tumorigenic, and hence, the risk of tumor development hinders their clinical application. Here, we present a novel approach to limit their tumorigenicity and increase their safety through increased copy number of tumor suppressors. iPS containing an extra copy of the p53 or Ink4a/ARF locus show normal pluripotency, as determined by in vitro and in vivo differentiation assays. Yet, while retaining full pluripotency, they also possess an improved engagement of the p53 pathway during teratocarcinoma formation, which leads to a reduced tumorigenic potential in various in vitro and in vivo assays. Furthermore, they show an improved response to anticancer drugs, which could aid in their elimination in case tumors arise with no adverse effects on cell function or aging. Our system provides a model for studying tumor suppressor pathways during reprogramming, differentiation, and cell therapy applications. This offers an improved understanding of the pathways involved in tumor growth from engrafted pluripotent stem cells, which could facilitate the use of ES and iPS cells in regenerative medicine.