Genetics of VEGF Serum Variation in Human Isolated Populations of Cilento: Importance of VEGF Polymorphisms

Vascular Endothelial Growth Factor (VEGF) is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs) influencing VEGF serum levels in one population (Campora), two already reported in the literature (rs3025039, rs25648) and one new signal (rs3025020). A fourth SNP (rs41282644) was found to affect VEGF serum levels in another population (Cardile). All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile). Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels

A comparative perspective on the evolution of tamarin and marmoset social systems

Tamarins and marmosets (callitrichids) present an unusual opportunity for study of the determinants of primate social systems, because both the mating and infant care patterns of callitrichids are variable, even within individual populations. In this paper, I briefly describe three characteristics of callitrichid social systems that distinguish them from most other primates: extensive male parental care, helping by nonreproductive individuals, and variable mating patterns. I then discuss the evolution of these characteristics and of the frequent twinning exhibited by callitrichids. I suggest that an ancestor of modern callitrichids gave birth to a single offspring at a time, mated monogamously, and had significant paternal care. The idea that males of this ancestral form must have provided paternal care, even though only single infants were born, derives from a comparison of litter/mother weight ratios in modern primate species. Twinning perhaps then evolved because of a combination of dwarfing in the callitrichid lineage, leading to higher litter/mother weight ratios, and a high infant mortality rate, and because the extensive paternal care already present facilitated the raising of twins. I propose that the helping behavior of older offspring may have coevolved with twinning, because helpers would have increased the chances of survival of twins, and the presence of twins would have increased the benefits of helping. Finally, the high costs of raising twins and the variability of group compositions, especially the fact that some groups would not have had older offspring to serve as helpers, may have selected for facultative polyandry in saddle-back tamarins ( Saguinus fuscicollis ) and perhaps in other callitrichid species. Both helping and cooperative polyandry have been extensively studied in bird species, and I apply some of the conclusions of these studies to the discussion of the evolution of callitrichid social systems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44556/1/10764_2005_Article_BF02193696.pd

A new F-box protein 7 gene mutation causing typical Parkinson's disease

BackgroundRecessive mutations in the F-box protein 7 gene (FBXO7; PARK15) have been identified as a cause of the parkinsonian-pyramidal syndrome. Here, we report clinical and genetic findings in a Turkish family with novel FBXO7 mutations

Genetic Variants Modulating CRIPTO Serum Levels Identified by Genome-Wide Association Study in Cilento Isolates

<div><p><i>Cripto</i>, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-β, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. <i>Cripto</i> is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the <i>CRIPTO</i> gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides <i>CRIPTO</i>, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5’UTR of <i>CRIPTO</i> gene which is able to strongly modulate <i>CRIPTO</i> expression through an AP-1-mediate transcriptional regulation.</p></div

Consanguinity around the world: what do the genomic data of the HGDP-CEPH diversity panel tell us?

Inbreeding coefficients and consanguineous mating types are usually inferred from population surveys or pedigree studies. Here, we present a method to estimate them from dense genome-wide single-nucleotide polymorphism genotypes and apply it to 940 unrelated individuals from the Human Genome Diversity Panel (HGDP-CEPH). Inbreeding is observed in almost all populations of the panel, and the highest inbreeding levels and frequencies of inbred individuals are found in populations of the Middle East, Central South Asia and the Americas. In these regions, first cousin (1C) marriages are the most frequent, but we also observed marriages between double first cousins (2 × 1C) and between avuncular (AV) pairs. Interestingly, if 2 × 1C marriages are preferred to AV marriages in Central South Asia and the Middle East, the contrary is found in the Americas. There are thus some regional trends but there are also some important differences between populations within a region. Individual results can be found on the CEPH website at ftp://ftp.cephb.fr/hgdp_hbd/

Manhattan plot of genome-wide association results in discovery analysis.

<p>Truncated Manhattan Plot showing -log₁₀(p-values) for all SNPs of the CRIPTO discovery GWAS ordered by their chromosomal position. The dashed horizontal line represents the threshold for genome-wide significance (p-value<5*10^-8). SNPs associated at the genome-wide significance level are all located on chromosome 3 (lowest p-value = 1.03*10^–159).</p

Functional analysis of the associated genes.

<p>The network was algorithmically constructed by Ingenuity Pathway Analysis (IPA) software on the basis of the functional and biological connectivity of genes. The network highlights the interconnections of 3 loci (marked in grey) identified from serum CRIPTO levels GWAS with a p-value = 1*10^–6. <i>CRIPTO</i> gene is reported as <i>TDGF1</i>. Lines between genes represent known interactions and the nodes are displayed using various shapes that represent the functional class of the gene product (legend).</p

The rs112481213 variant alter the AP-1 binding site.

<p><b>(A)</b> Electrophoretic mobility shift assay (EMSA) for AP-1 binding in nuclear extracts (NEs) of PC-3 cell line. The binding activities of NEs (lanes 2–14) were analyzed by EMSA using biotin-labeled AP-1 probe (lanes 2–4), -222 T probe (lanes 5–9) and-222 A probe (lanes 10–14). Competition was performed with 50 and 200 fold molar excess of the cold probe (lanes 3–4, 6–7, 11–12). Cross competition was performed using the cold probe carrying the alternative allele (lane 8 and 13) and the cold scrambled probe (lane 9 and lane 14) at 200 fold molar excess. No binding was detectable for-222 T probe (lanes 5–9). The DNA-protein complex of-222 A probe (lane 10) can be eliminated by 50 or 200 fold molar excess of cold-222 A probe (lanes 11, 12) but not by 200 fold molar excess of cold-222 T probe and cold scrambled probe. <b>(B)</b> Specificity of AP-1 binding activity. Supershift assay was carried out for-222 A probe using specific antibodies for the AP-1 components c-Jun (lane 3), JunB (lane 4), JunD (lane 5), Fra-1 (lane 6) and Fra-2 (lane 8). A supershifted DNA-protein-antibody complex (indicated by the arrow) is observed (lanes 3, 5, 6, 8). Lane 7 shows that the specific complexes were eliminated by addition of 200 fold molar excess of cold-222 A probe. No supershifted complex was observed adding HA-probe antibody used as negative control (lane 9). The results are representative of three independent determinations.</p