Polymorphisms in the α4 Integrin of Neotropical Primates: Insights for Binding of Natural Ligands and HIV-1 gp120 to the Human α4β7

The α4 integrin subunit associates with β7 and β1 and plays important roles in immune function and cell trafficking. The gut-homing receptor α4β7 has been recently described as a new receptor for HIV. Here, we describe polymorphisms of ITGA4 gene in New World primates (NWP), and tested their impact on the binding to monoclonal antibodies, natural ligands (MAdCAM and VCAM), and several gp120 HIV-1 envelope proteins. Genomic DNA of NWP specimens comprising all genera of the group had their exons 5 and 6 (encoding the region of binding to the ligands studied) analyzed. The polymorphisms found were introduced into an ITGA4 cDNA clone encoding the human α4 subunit. Mutant α4 proteins were co-expressed with β7 and were tested for binding of mAbs, MAdCAM, VCAM and gp120 of HIV-1, which was compared to the wild-type (human) α4. Mutant α4 proteins harboring the K201E/I/N substitution had reduced binding of all ligands tested, including HIV-1 gp120 envelopes. The mAbs found with reduced biding included one from which a clinically-approved drug for the treatment of neurological disorders has been derived. α4 polymorphisms in other primate species may influence outcomes in the development and treatment of infectious and autoimmune diseases in humans and in non-human primates

The germline mutational landscape of BRCA1 and BRCA2 in Brazil

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.This work was supported in part by grants from Barretos Cancer Hospital (FINEP - CT-INFRA, 02/2010), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2013/24633-2 and 2103/23277-8), Fundação de Apoio à Pesquisa do Rio Grande do Norte (FAPERN), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Ministério da Saúde, the Breast Cancer Research Foundation (Avon grant #02-2013-044) and National Institute of Health/National Cancer Institute (grant #RC4 CA153828-01) for the Clinical Cancer Genomics Community Research Network. Support in part was provided by grants from Fundo de Incentivo a Pesquisa e Eventos (FIPE) from Hospital de Clínicas de Porto Alegre, by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, BioComputacional 3381/2013, Rede de Pesquisa em Genômica Populacional Humana), Secretaria da Saúde do Estado da Bahia (SESAB), Laboratório de Imunologia e Biologia Molecular (UFBA), INCT pra Controle do Câncer and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). RMR and PAP are recipients of CNPq Productivity Grants, and Bárbara Alemar received a grant from the same agencyinfo:eu-repo/semantics/publishedVersio

Chromosomes and spermatozoa of the great apes and man

The chromosome complement of four species phylogenetically related to man, the chimpanzee (Pan troglodytes), the pygmy chimpanzee (Pan paniscus), the gorilla (Gorilla gorilla), and the orangutan (Pongo pygmaeus) have been analysed with chromosome banding techniques and compared to the human chromosome comple¬ ment. This has shown remarkable homologies between species, and presumed mechanisms of chromosome evolution have been proposed. Chromosome heteromorphisms in the great apes have been compared to those found in human populations, and most of them affected the distribution or the amount of constitutive heterochromatin and/or brilliantly fluorescent material, a situation comparable to man where such variations have been established as chromosome polymorphisms. However, a balanced polymorphic structural rearrangement involving large segments of euchromatic material has been found in two populations of orangutan. This rearrangement consisted of two pericentric inversions, one inside the other, comprising an unusual kind of chromosome polymorphism in mammalian populations. Moreover, it showed that pericentric inversions, the most probable chromosome rearrangements in the phylogeny of the chromosomes of man and the great apes, might not necessarily be restricted by infertility barriers, but may spread successfully in the population. The patterns of late replication of the chromosomes of the great apes and man have been compared, using BUdr as a thymidine substitute in the cell cycle. This has shown remarkable similarities in the patterns of late replication between species, and, as in the human chromosomes, most regions of late replication in the chromosomes of the great apes corresponded to areas of positive G-banding. Q-, C- and G-banding as methods of demonstrating chromosome homologies between these species have been analysed in relation to the content of highly repeated satellite DNAs in man and homologous sequences in the great apes. This has shown that the banding patterns are not informative about these sequences, and that they must reflect a degree of chromosome organization due to DNA packaging rather than DNA composition. Finally, the phylogeny of the chromosomes of man and the great apes has been reconstructed in view of the findings presented in this work and of previous data in the literature. In this study, man and gorilla resembled each other more closely than to any of the other species studied, a finding that is contrary to the generally held view that man and the chimpanzee are the two most closely related species. Comparative studies of the spermatozoa of the great apes and man were undertaken and showed that man was not unique in producing pleiomorphic spermatozoa, since this feature was also present in the gorilla. Moreover, the morphology of human and gorilla spermatozoa resembled each other so closely that on morphological grounds it was impossible to distinguish the spermiogram of these two species. Fluorescent ("f") bodies were detected in the spermatozoa of the African apes, although the distribution of such bodies did not resemble that of human spermatozoa, where the Y chromosome is usually visible. An analysis of the haploid DNA content of the great apes and man w®3 undertaken by estimating the total dry mass of the sperm head in these species. Man showed the lowest DNA content, whilst the gorilla showed the highest; this latter latter species also showed a higher variability in the haploid DNA content than all other species, including man. Diploid spermatozoa were also detected in the gorilla, in proportions similar to those found in man. These findings on spermatozoa are indicative of a closer relationship between man and gorilla than between man and the other hominoid apes. Moreover, the heteromorphism of spermatozoa in both human and gorilla semen samples makes it unlikely that clothing induced hyperthermia is the cause of pleiomorphic spermatozoa in man

Gene tree for capuchin monkeys using Dataset 3

<p>Gene tree using the cytochrome b for capuchin monkey species using Dataset 3. For more information see Nascimento et al. Journal of Biogeography (under review).</p

Gene tree for capuchin monkeys using Dataset 2

<p>Gene tree using the cytochrome b for capuchin monkey species using Dataset 2. For more information see Nascimento et al. Journal of Biogeography (under review).</p

DNA sequence alignment for capuchin monkeys using Dataset 1

<p>DNA sequence alignment in nexus format for the cytochrome b using Dataset 1. For more information see Nascimento et al. Journal of Biogeography (under review).</p

DNA sequence alignment for capuchin monkeys using Dataset 2

<p>DNA sequence alignment in nexus format for the cytochrome b gene using Dataset 2</p

Gene tree for capuchin monkey using Dataset 1

<p>Gene tree using the cytochrome b for capuchin monkey species using Dataset 1. For more information see Nascimento et al. Journal of Biogeography (under review).</p

DNA sequence alignment for capuchin monkeys using Dataset 3

<p>DNA sequence alignment in nexus format for the cytochrome b using Dataset 3. For more information see Nascimento et al. Journal of Biogeography (under review).</p