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Objective: To map geographic clusters of rare disorders and congenital anomalies reported in South America. Methods: Qualitative systematic review conducted in Medline/PubMed, Lilacs, and Scielo electronic databases to identify studies meeting eligibility criteria. The strategy resulted in 1 672 unique articles, from which 164 were selected for full reading by a pair of reviewers. Results: Fifty-five articles reported at least one cluster of genetic disorders or congenital anomalies in South American territory. From these papers, 122 clusters were identified, of which half (61) were related to autosomal recessive disorders. Sixty-five (53.3%) of the clusters were located in Brazil. Conclusions: The results of the review reinforce that rare diseases and congenital anomalies can occur in a non-random way in space, which is discussed in the perspective of the complex history of formation, social organization, and genetic structure of the South American population. Mapping clusters in population medical genetics can be an important public health tool, given that such places concentrate cases of rare diseases that frequently require multiprofessional, specialized care. Therefore, these results can support important agendas in public health related to rare diseases and congenital anomalies, such as health promotion and surveillance.
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[ABSTRACT]. Objective. To map geographic clusters of rare disorders and congenital anomalies reported in South America. Methods. Qualitative systematic review conducted in Medline/PubMed, Lilacs, and Scielo electronic data- bases to identify studies meeting eligibility criteria. The strategy resulted in 1 672 unique articles, from which 164 were selected for full reading by a pair of reviewers. Results. Fifty-five articles reported at least one cluster of genetic disorders or congenital anomalies in South American territory. From these papers, 122 clusters were identified, of which half (61) were related to autoso- mal recessive disorders. Sixty-five (53.3%) of the clusters were located in Brazil. Conclusions. The results of the review reinforce that rare diseases and congenital anomalies can occur in a non-random way in space, which is discussed in the perspective of the complex history of formation, social organization, and genetic structure of the South American population. Mapping clusters in population medical genetics can be an important public health tool, given that such places concentrate cases of rare diseases that frequently require multiprofessional, specialized care. Therefore, these results can support important agendas in public health related to rare diseases and congenital anomalies, such as health promotion and surveillance.
[RESUMEN]. Objetivo. Trazar los conglomerados geográficos de los trastornos y las malformaciones congénitas poco frecuentes notificados en América del Sur. Métodos. Se realizó una revisión sistemática cualitativa en las bases de datos electrónicas Medline/PubMed, Lilacs y Scielo para encontrar los estudios que cumplieran con los criterios de selección. Se encontraron 1672 artículos originales, de los que se seleccionaron 164 para su lectura completa por un par de revisores. Resultados. En 55 artículos se informó de al menos un conglomerado de trastornos genéticos o malforma- ciones congénitas en América del Sur. A partir de estos artículos, se encontraron 122 conglomerados, de los cuales la mitad (61) se asociaron con trastornos autosómicos recesivos. Sesenta y cinco (53,3%) de los conglomerados se ubicaron en Brasil. Conclusiones. Los resultados de la revisión confirman que las enfermedades raras y las malformaciones congénitas pueden presentarse de una forma no aleatoria en el espacio, lo que se comenta desde la per- spectiva de la complejidad histórica del proceso de formación, organización social y estructura genética de la población de América del Sur. Definir geográficamente los conglomerados en la genética médica pobla- cional puede ser una importante herramienta de salud pública, ya que en esos lugares se concentran casos de enfermedades raras que suelen requerir una atención especializada y multidisciplinaria. Por lo tanto, estos resultados pueden servir de apoyo a importantes programas de salud pública relacionados con las enferme- dades raras y las malformaciones congénitas como, por ejemplo, la promoción de la salud y la vigilancia.
[RESUMO]. Objetivo. Mapear agrupamentos geográficos de doenças raras e anomalias congênitas relatados na América do Sul. Métodos. Revisão sistemática qualitativa realizada nas bases de dados eletrônicos Medline/PubMed, Lilacs e Scielo para identificar estudos que atendessem aos critérios de elegibilidade. A estratégia resultou em 1.672 artigos únicos, dos quais 164 foram selecionados para leitura completa por uma dupla de revisores. Resultados. Cinquenta e cinco artigos relataram pelo menos um agrupamento de distúrbios genéticos ou anomalias congênitas no território sul-americano. A partir desses artigos, foram identificados 122 agrupamen- tos, dos quais metade (61) estava relacionada a doenças autossômicas recessivas. Sessenta e cinco (53,3%) dos agrupamentos estavam localizados no Brasil. Conclusões. Os resultados da revisão reforçam a observação de que doenças raras e anomalias congênitas podem ocorrer de forma não aleatória no espaço, o que é discutido na perspectiva da complexa história de formação, organização social e estrutura genética da população sul-americana. O mapeamento de agrupa- mentos em genética médica populacional pode ser uma importante ferramenta de saúde pública, visto que esses locais concentram casos de doenças raras que frequentemente requerem atendimento multiprofissional especializado. Portanto, esses resultados podem apoiar importantes agendas de saúde pública relacionadas a doenças raras e anomalias congênitas, como a vigilância e a promoção da saúde.
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Hotspot de Doença , Doenças Raras , Anormalidades Congênitas , Revisão Sistemática , América do Sul , Hotspot de Doença , Doenças Raras , Anormalidades Congênitas , Revisão Sistemática , América do Sul , Hotspot de Doença , Doenças Raras , Anormalidades Congênitas , Revisão Sistemática , América do SulRESUMO
ABSTRACT Objective. To map geographic clusters of rare disorders and congenital anomalies reported in South America. Methods. Qualitative systematic review conducted in Medline/PubMed, Lilacs, and Scielo electronic databases to identify studies meeting eligibility criteria. The strategy resulted in 1 672 unique articles, from which 164 were selected for full reading by a pair of reviewers. Results. Fifty-five articles reported at least one cluster of genetic disorders or congenital anomalies in South American territory. From these papers, 122 clusters were identified, of which half (61) were related to autosomal recessive disorders. Sixty-five (53.3%) of the clusters were located in Brazil. Conclusions. The results of the review reinforce that rare diseases and congenital anomalies can occur in a non-random way in space, which is discussed in the perspective of the complex history of formation, social organization, and genetic structure of the South American population. Mapping clusters in population medical genetics can be an important public health tool, given that such places concentrate cases of rare diseases that frequently require multiprofessional, specialized care. Therefore, these results can support important agendas in public health related to rare diseases and congenital anomalies, such as health promotion and surveillance.
RESUMEN Objetivo. Trazar los conglomerados geográficos de los trastornos y las malformaciones congénitas poco frecuentes notificados en América del Sur. Métodos. Se realizó una revisión sistemática cualitativa en las bases de datos electrónicas Medline/PubMed, Lilacs y Scielo para encontrar los estudios que cumplieran con los criterios de selección. Se encontraron 1672 artículos originales, de los que se seleccionaron 164 para su lectura completa por un par de revisores. Resultados. En 55 artículos se informó de al menos un conglomerado de trastornos genéticos o malformaciones congénitas en América del Sur. A partir de estos artículos, se encontraron 122 conglomerados, de los cuales la mitad (61) se asociaron con trastornos autosómicos recesivos. Sesenta y cinco (53,3%) de los conglomerados se ubicaron en Brasil. Conclusiones. Los resultados de la revisión confirman que las enfermedades raras y las malformaciones congénitas pueden presentarse de una forma no aleatoria en el espacio, lo que se comenta desde la perspectiva de la complejidad histórica del proceso de formación, organización social y estructura genética de la población de América del Sur. Definir geográficamente los conglomerados en la genética médica poblacional puede ser una importante herramienta de salud pública, ya que en esos lugares se concentran casos de enfermedades raras que suelen requerir una atención especializada y multidisciplinaria. Por lo tanto, estos resultados pueden servir de apoyo a importantes programas de salud pública relacionados con las enfermedades raras y las malformaciones congénitas como, por ejemplo, la promoción de la salud y la vigilancia.
RESUMO Objetivo. Mapear agrupamentos geográficos de doenças raras e anomalias congênitas relatados na América do Sul. Métodos. Revisão sistemática qualitativa realizada nas bases de dados eletrônicos Medline/PubMed, Lilacs e Scielo para identificar estudos que atendessem aos critérios de elegibilidade. A estratégia resultou em 1.672 artigos únicos, dos quais 164 foram selecionados para leitura completa por uma dupla de revisores. Resultados. Cinquenta e cinco artigos relataram pelo menos um agrupamento de distúrbios genéticos ou anomalias congênitas no território sul-americano. A partir desses artigos, foram identificados 122 agrupamentos, dos quais metade (61) estava relacionada a doenças autossômicas recessivas. Sessenta e cinco (53,3%) dos agrupamentos estavam localizados no Brasil. Conclusões. Os resultados da revisão reforçam a observação de que doenças raras e anomalias congênitas podem ocorrer de forma não aleatória no espaço, o que é discutido na perspectiva da complexa história de formação, organização social e estrutura genética da população sul-americana. O mapeamento de agrupamentos em genética médica populacional pode ser uma importante ferramenta de saúde pública, visto que esses locais concentram casos de doenças raras que frequentemente requerem atendimento multiprofissional especializado. Portanto, esses resultados podem apoiar importantes agendas de saúde pública relacionadas a doenças raras e anomalias congênitas, como a vigilância e a promoção da saúde.
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Human Leukocyte Antigen (HLA)-G participates in several biological processes, including reproduction, vascular remodeling, immune tolerance, and hypoxia response. HLA-G is a potential candidate gene for high altitude adaptation since its expression is modulated in both micro and macro environment under hypoxia and constant cellular stress. Besides the promoter region, the HLA-G 3'untranslated region (UTR) influences HLA-G expression patterns through several post-transcriptional mechanisms. Currently, the 3'UTR genetic diversity in terms of altitude adaptation of Native American populations is still unexplored, particularly at high altitude ecoregions. Here, we evaluated 288 Native Americans from 9 communities located in the Andes [highland (HL); ≥2,500 m (range = 2,838-4,433 m)] and 8 populations located in lowland (LL) regions [<2,500 m (range = 80-431 m); Amazonian tropical forest, Brazilian central plateau, and Chaco] of South America. In total, nine polymorphic sites and ten haplotypes were observed. The most frequent haplotypes (UTR-1, UTR-2, and UTR-3) accounted for â¼ 77% of haplotypes found in LL, while in the HL, the same haplotypes reach â¼ 93%. Also, a remarkable high frequency of putative ancestral UTR-5 haplotype was observed in LL (21.5%), while in HL UTR-2 reaches up to 47%. Further, UTR-2 frequency positively correlates with altitude-related variables, while a negative correlation for UTR-5 was observed. From an evolutionary perspective, we observed a tendency towards balancing selection in HL and LL populations thus suggesting that haplotypes of ancient and more derived alleles may have been co-opted for relatively recent adaptations such as those experienced by modern humans in the highland and lowland of South America. We also discuss how long-term balancing selection can be a reservoir of genetic variants that can be positively selected. Finally, our study provides some pieces of evidence that HLA-G 3'UTR haplotypes may have contributed to high altitude adaptation in the Andes.
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Indígena Americano ou Nativo do Alasca , Antígenos HLA-G , Regiões 3' não Traduzidas/genética , Brasil , Frequência do Gene , Genótipo , Antígenos HLA-G/genética , Haplótipos , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
STAT2 plays a strategic role in defending viral infection through the signaling cascade involving the immune system initiated after type I interferon release. Many flaviviruses target the inactivation or degradation of STAT2 as a strategy to impair this host's line of defense. Primates are natural reservoirs for a range of disease-causing flaviviruses (e.g., Zika, Dengue, and Yellow Fever virus), while rodents appear less susceptible. We analyzed the STAT2 coding sequence of 28 Rodentia species and 49 Primates species. Original data from 19 Platyrrhini species were sequenced for the SH2 domain of STAT2 and included in the analysis. STAT2 has many sites whose variation can be explained by positive selection, measurement by two methods (PALM indicated 12, MEME 61). Both evolutionary tests significantly marked sites 127, 731, 739, 766, and 780. SH2 is under evolutionary constraint but presents episodic positive selection events within Rodentia: in one of them, a moderately radical change (serine > arginine) at position 638 is found in Peromyscus species, and can be implicated in the difference in susceptibility to flaviviruses within Rodentia. Some other positively selected sites are functional such as 5, 95, 203, 251, 782, and 829. Sites 251 and 287 regulate the signaling mediated by the JAK-STAT2 pathway, while 782 and 829 create a stable tertiary structure of STAT2, facilitating its connection with transcriptional co-activators. Only three positively selected sites, 5, 95, and 203, are recognized members who act on the interface between STAT2 and flaviviruses NS5 protein. We suggested that due to the higher evolutionary rate, rodents are, at this moment, taking some advantage in the battle against infections for some well-known Flaviviridae, in particular when compared to primates. Our results point to dynamics that fit with a molecular evolutionary scenario shaped by a thought-provoking virus-host arms race.
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Antivirais , Evolução Molecular , Primatas/genética , Roedores/genética , Fator de Transcrição STAT2/genética , Animais , Fator de Transcrição STAT2/metabolismo , Transdução de SinaisRESUMO
Prolactin (PRL) is a pleiotropic neurohormone secreted by the mammalian pituitary gland into the blood, thus reaching many tissues and organs beyond the brain. PRL binds to its receptor, PRLR, eliciting a molecular signaling cascade. This system modulates essential mammalian behaviors and promotes notable modifications in the reproductive female tissues and organs. Here, we explore how the intracellular domain of PRLR (PRLR-ICD) modulates the expression of the PRLR gene. Despite differences in the reproductive strategies between eutherian and metatherian mammals, there is no clear distinction between PRLR-ICD functional motifs. However, we found selection signatures that showed differences between groups, with many conserved functional elements strongly maintained through purifying selection across the class Mammalia. We observed a few residues under relaxed selection, the levels of which were more pronounced in Eutheria and particularly striking in primates (Simiiformes), which could represent a pre-adaptive genetic element protected from purifying selection. Alternative, new motifs, such as YLDP (318-321) and others with residues Y283 and Y290, may already be functional. These motifs would have been co-opted in primates as part of a complex genetic repertoire related to some derived adaptive phenotypes, but these changes would have no impact on the primordial functions that characterize the mammals as a whole and that are related to the PRL-PRLR system.
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Prolactina , Receptores da Prolactina , Animais , Evolução Molecular , Feminino , Mamíferos/genética , Mamíferos/metabolismo , Hipófise/metabolismo , Prolactina/metabolismo , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismoRESUMO
We carried out an exhaustive review regarding human skin color variation and how much it may be related to vitamin D metabolism and other photosensitive molecules. We discuss evolutionary contexts that modulate this variability and hypotheses postulated to explain them; for example, a small amount of melanin in the skin facilitates vitamin D production, making it advantageous to have fair skin in an environment with little radiation incidence. In contrast, more melanin protects folate from degradation in an environment with a high incidence of radiation. Some Native American populations have a skin color at odds with what would be expected for the amount of radiation in the environment in which they live, a finding challenging the so-called "vitamin D-folate hypothesis." Since food is also a source of vitamin D, dietary habits should also be considered. Here we argue that a gene network approach provides tools to explain this phenomenon since it indicates potential alleles co-evolving in a compensatory way. We identified alleles of the vitamin D metabolism and pigmentation pathways segregated together, but in different proportions, in agriculturalists and hunter-gatherers. Finally, we highlight how an evolutionary approach can be useful to understand current topics of medical interest.
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Pigmentação da Pele , Vitamina D , Adaptação Fisiológica/genética , Evolução Biológica , Humanos , Pele , Pigmentação da Pele/genética , Indígena Americano ou Nativo do AlascaRESUMO
Platyrrhini (New World monkeys, NWm) are a group of primates characterized by behavioral and reproductive traits that are otherwise uncommon among primates, including social monogamy, direct paternal care, and twin births. As a consequence, the study of Platyrrhine primates is an invaluable tool for the discovery of the genetic repertoire underlying these taxon-specific traits. Recently, high conservation of vasopressin (AVP) sequence, in contrast with high variability of oxytocin (OXT), has been described in NWm. AVP and OXT functions are possible due to interaction with their receptors: AVPR1a, AVPR1b, AVPR2, and OXTR; and the variability in this system is associated with the traits mentioned above. Understanding the variability in the receptors is thus fundamental to understand the function and evolution of the system as a whole. Here we describe the variability of AVPR1b coding region in 20 NWm species, which is well-known to influence behavioral traits such as aggression, anxiety, and stress control in placental mammals. Our results indicate that 4% of AVPR1b sites may be under positive selection and a significant number of sites under relaxed selective constraint. Considering the known role of AVPR1b, we suggest that some of the changes described here for the Platyrrhini may be a part of the genetic repertoire connected with the complex network of neuroendocrine mechanisms of AVP-OXT system in the modulation of the HPA axis. Thus, these changes may have promoted the emergence of social behaviors such as direct paternal care in socially monogamous species that are also characterized by small body size and twin births.
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Evolução Molecular , Platirrinos/genética , Receptores de Vasopressinas/genética , Comportamento Social , Animais , Variação Genética , Tamanho da Ninhada de Vivíparos/genética , Comportamento Paterno , Fenótipo , Comportamento Sexual AnimalRESUMO
OBJECTIVES: The major aim of this article was to estimate the demographic impact of European arrival and colonization over Native American populations from southern Brazil and Uruguay. We also compared the mitochondrial DNA (mtDNA) genetic diversity, structure, and demography of Native American lineages present in current indigenous (Natives) and nonindigenous admixed (Admixed) populations to estimate the effective population size (Ne ) of contemporary and ancestral (pre-Columbian) Native American populations. METHODS: We retrieved published mtDNA sequences from Native (n = 396) and Admixed (n = 309) populations from southern Brazil, Uruguay, and surrounding areas. We conducted genetic diversity, structure, and demographic analyses. Finally, we used Approximate Bayesian Computation to estimate the Ne for current Native, Admixed, and pre-Columbian Native American populations. RESULTS: We found higher Native American mtDNA genetic diversity in admixed rather than in indigenous populations (131/309 vs 27/396 different haplotypes, respectively). Only Admixed populations maintained ancient signals of the Native American population expansion approximately 14 to 17 kya, which have decayed in Natives. Our Ne estimates suggest that Natives represent only 0.33% (0.18%-1.19%) of the Ne for ancestral pre-Columbian indigenous populations. CONCLUSIONS: Admixed populations represent an important genetic reservoir of Native American lineages, many of which are extinct in contemporary indigenous populations. In addition, the Native American lineages present in Admixed populations retain part of the past demographic history of Native Americans. The intensity of the reduction is congruent with historical accounts of strong indigenous depopulation during the colonization process.
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Colonialismo/história , DNA Mitocondrial/análise , Indígenas Sul-Americanos/genética , Densidade Demográfica , População Branca/genética , Teorema de Bayes , Brasil , História do Século XVI , História do Século XVII , Humanos , Modelos Biológicos , UruguaiRESUMO
Traits that undergo massive natural selection pressure, with multiple events of positive selection, are hard to find. Social behaviour, in social animals, is crucial for survival, and genetic networks involved in behaviour, such as those of serotonin (5-HT) and other neurotransmitters, must be the target of natural selection. Here, we used molecular analyses to search for signals of positive selection in the 5-HT system and found such signals in the M3-M4 intracellular domain of the 5-HT3A serotonin receptor subunit (HTR3A) in primates. We detected four amino acid sites with signs of putatively positive selection (398, 403, 432 and 416); the first three showed indications of being selected in New World monkeys (NWM, Platyrrhini), specifically in the Callitrichinae branch. Additionally, we searched for associations of these amino acid variants with social behavioural traits (i.e. sex-biased dispersal, dominance and social monogamy) using classical and Bayesian methods, and found statistically significant associations for unbiased sex dispersal (398L and 416S), unbiased sex dominance (416S) and social monogamy (416S), as well as significant positive correlation between female dispersal and 403G. Furthermore, we found putatively functional protein motifs determined by three selected sites, of which we highlight a ligand motif to GSK3 in the 416S variant, appearing only in Platyrrhini. 5-HT, 5-HT3A receptor and GSK3 are part of a network that participates in neurodevelopment and regulates behaviour, among other functions. We suggest that these genetic variations, together with those found in other neurotransmitter systems, must contribute to adaptive behaviours and consequently to fitness in NWMs.
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Comportamento Animal/fisiologia , Platirrinos/genética , Platirrinos/fisiologia , Seleção Genética , Serotonina/metabolismo , Animais , Evolução Molecular , Regulação da Expressão Gênica/fisiologia , Filogenia , Serotonina/genéticaRESUMO
OBJECTIVES: To determine genetic differences between agriculturalist and hunter-gatherer southern Native American populations for selected metabolism-related markers and to test whether Neel's thrifty genotype hypothesis (TGH) could explain the genetic patterns observed in these populations. MATERIALS AND METHODS: 375 Native South American individuals from 17 populations were genotyped using six markers (APOE rs429358 and rs7412; APOA2 rs5082; CD36 rs3211883; TCF7L2 rs11196205; and IGF2BP2 rs11705701). Additionally, APOE genotypes from 39 individuals were obtained from the literature. AMOVA, main effects, and gene-gene interaction tests were performed. RESULTS: We observed differences in allele distribution patterns between agriculturalists and hunter-gatherers for some markers. For instance, between-groups component of genetic variance (FCT ) for APOE rs429358 showed strong differences in allelic distributions between hunter-gatherers and agriculturalists (p = 0.00196). Gene-gene interaction analysis indicated that the APOE E4/CD36 TT and APOE E4/IGF2BP2 A carrier combinations occur at a higher frequency in hunter-gatherers, but this combination is not replicated in archaic (Neanderthal and Denisovan) and ancient (Anzick, Saqqaq, Ust-Ishim, Mal'ta) hunter-gatherer individuals. DISCUSSION: A complex scenario explains the observed frequencies of the tested markers in hunter-gatherers. Different factors, such as pleotropic alleles, rainforest selective pressures, and population dynamics, may be collectively shaping the observed genetic patterns. We conclude that although TGH seems a plausible hypothesis to explain part of the data, other factors may be important in our tested populations.