RESUMEN
Malaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geographically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 3-4 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria.
Asunto(s)
Enfermedades Endémicas , Predisposición Genética a la Enfermedad , Glicoforinas/genética , Sistema del Grupo Sanguíneo MNSs/genética , Malaria Falciparum/genética , Selección Genética , África del Sur del Sahara , Sustitución de Aminoácidos , Animales , Secuencia de Bases , Eritrocitos/metabolismo , Eritrocitos/parasitología , Etnicidad/genética , Exones , Sitios Genéticos , Glicoforinas/química , Glicoforinas/clasificación , Humanos , Malaria Falciparum/sangre , Malaria Falciparum/epidemiología , Datos de Secuencia Molecular , Filogenia , Plasmodium falciparum , Polimorfismo de Nucleótido Simple , Estructura Terciaria de ProteínaRESUMEN
BACKGROUND: Perfusion functional magnetic resonance imaging (fMRI) was used to investigate the effect of genetic variation of the human serotonin transporter (5-HTT) gene (5-HTTLPR, SLC6A4) on resting brain function of healthy individuals. METHODS: Twenty-six healthy subjects, half homozygous for the 5-HTTLPR short allele (s/s group) and half homozygous for the long allele (l/l group), underwent perfusion functional and structural magnetic resonance imaging during a resting state. The two genotype groups had no psychiatric illness and were similar in age, gender, and personality scores. RESULTS: Compared with the l/l group, the s/s group showed significantly increased resting cerebral blood flow (CBF) in the amygdala and decreased CBF in the ventromedial prefrontal cortex. The effect of functional modulation in these regions by 5-HTTLPR genotype cannot be accounted for by variations in brain anatomy, personality, or self-reported mood. CONCLUSIONS: The 5-HTTLPR genotype alters resting brain function in emotion-related regions in healthy individuals, including the amygdala and ventromedial prefrontal cortex. Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.
Asunto(s)
Encéfalo/fisiopatología , Variación Genética/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Amígdala del Cerebelo/fisiopatología , Encéfalo/irrigación sanguínea , Mapeo Encefálico , Trastorno Depresivo/epidemiología , Trastorno Depresivo/genética , Trastorno Depresivo/fisiopatología , Lóbulo Frontal/fisiopatología , Predisposición Genética a la Enfermedad , Variación Genética/fisiología , Genotipo , Humanos , Imagen por Resonancia Magnética/estadística & datos numéricos , Polimorfismo Genético , Corteza Prefrontal/fisiopatología , Flujo Sanguíneo Regional/genética , Flujo Sanguíneo Regional/fisiología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/fisiologíaRESUMEN
BACKGROUND: Impairments in social behaviors are highly disabling symptoms of autism, schizophrenia, and other psychiatric disorders. Mouse model systems are useful for identifying the many genes and environmental factors likely to affect complex behaviors, such as sociability (the tendency to seek social interaction). To progress toward developing such a model system, we tested the hypothesis that C57BL/6J inbred mice show higher levels of sociability than BALB/cJ inbred mice. METHODS: Mice tested for sociability were 4- and 9-week-old, male and female C57BL/6J and BALB/cJ mice. On 2 consecutive days, the sociability of each test mouse toward an unfamiliar 4-week-old DBA/2J stimulus mouse was assessed with a social choice paradigm conducted in a three-chambered apparatus. Measures of sociability included the time that the test mouse spent near versus far from the stimulus mouse, the time spent directly sniffing the stimulus mouse, and the time spent in contact between test and stimulus mice in a free interaction. RESULTS: C57BL/6J mice showed higher levels of sociability than BALB/cJ mice overall in each of these measures. CONCLUSIONS: We propose that C57BL/6J and BALB/cJ mice will be a useful mouse model system for future genetic and neurobiological studies of sociability.