RESUMO
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.
Assuntos
Pré-Eclâmpsia , Altitude , Fatores de Coagulação Sanguínea , Proteínas Sanguíneas/genética , Estudos de Casos e Controles , Fator VII/genética , Fator X/genética , Feminino , Humanos , Peru/epidemiologia , Placenta , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/genética , GravidezRESUMO
The genetic trait of lactase persistence (LP) evolved as an adaptation to milking pastoralism in the Old World and is a well-known example of positive natural selection in humans. However, the specific mechanisms conferring this selective advantage are unknown. To understand the relationship between milk drinking, LP, growth, reproduction, and survival, communities of the Coquimbo Region in Chile, with recent adoption of milking agropastoralism, were used as a model population. DNA samples and data on stature, reproduction, and diet were collected from 451 participants. Lactose tolerance tests were done on 41 of them. The European -13,910*T (rs4988235) was the only LP causative variant found, showing strong association (99.6%) with LP phenotype. Models of associations of inferred LP status and milk consumption, with fertility, mortality, height, and weight were adjusted with measures of ancestry and relatedness to control for population structure. Although we found no statistically significant effect of LP on fertility, a significant effect (P = 0.002) was observed of LP on body mass index (BMI) in males and of BMI on fertility (P = 0.003). These results fail to support a causal relationship between LP and fertility yet suggest the idea of a nutritional advantage of LP. Furthermore, the proportion of European ancestry around the genetic region of -13,910*T is significantly higher (P = 0.008) than the proportion of European ancestry genome-wide, providing evidence of recent positive selection since European-Amerindian admixture. This signature was absent in nonpastoralist Latin American populations, supporting the hypothesis of specific adaptation to milking agropastoralism in the Coquimbo communities.
Assuntos
Agricultura , Etnicidade/genética , Evolução Molecular , Lactase/genética , Animais , Índice de Massa Corporal , Chile , Feminino , Fertilidade , Frequência do Gene , Estudos de Associação Genética , Cabras , Haplótipos , Humanos , Intolerância à Lactose/genética , Masculino , Leite , Fenômenos Fisiológicos da Nutrição , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
Assuntos
Migração Humana , Indígenas Norte-Americanos/genética , Indígenas Sul-Americanos/genética , Haplótipos , Humanos , México , Nariz/anatomia & histologia , América do SulRESUMO
A pesar de su reciente incorporación en la investigación médica, la biología evolutiva ha contribuido significativamente en el entendimiento del origen, desarrollo y mantenimiento de muchas enfermedades importantes para el ser humano. Investigaciones en enfermedades infecciosas, sobretodo en la resistencia contra antibióticos son claros ejemplos de esto. Así mismo, ha cambiando la forma en que vemos y entendemos a nuestro cuerpo, y su vulnerabilidad a ciertos tipos de enfermedades. Otras áreas como el cáncer, enfermedades mentales y envejecimiento han empezado a beneficiarse de la perspectiva evolutiva. Más específicamente, la filogenética como una disciplina de la biología evolutiva, ha mostrado ser una herramienta eficiente para descubrir los orígenes de enfermedades y determinar que cepas poseen mayor probabilidad de propagación. Debido a esto, este artículo tiene como objetivo brindar una idea básica de qué son y cómo interpretar los denominados árboles filogenéticos. Los médicos que puedan entender estos métodos, sin duda, podrán estar mejor preparados para comprender la creciente literatura médica que aborda este tipo de aproximación metodológica que se deriva de la biología evolutiva.
Despite its recent incorporation into medical research, evolutionary biology has contributed significantly in the understanding of the origin, development and maintenance of many important human diseases. Research on infectious diseases, such as antibiotic resistance is a clear example of this. It has also changed the way we see and understand our bodies, as well as their vulnerability to certain types of illnesses. Other areas of research such as cancer therapeutics, mental disorders and aging have begun to benefit from adopting an evolutionary perspective. More precisely, phylogenetics, as a discipline of evolutionary biology, has proved itself an efficient tool for discovering the origins of many diseases and thus determine which strains have higher likelihood of spreading. This article aims to provide a basic understanding of what phylogenetic trees are and how to interpret them. Physicians who can understand these methods will undoubtedly be better prepared to comprehend the growing literature that addresses this type of approach derived from evolutionary biology.