Parkinsonism genes: culprits and clues

Parkinson's disease (PD) is characterized by a unique clinical constellation that includes: slowness, rigidity, gait difficulty, and tremor at rest. Pathological studies have linked this presentation to the loss of midbrain dopamine neurons (Gelb et al. 1999) although other neuronal populations are also targeted in PD. Epidemiological data implicate both genetic and environmental factors in the etiology of the disease. The identification of a series of genes that underlie relatively rare, familial forms of Parkinsonism (a clinical term that encompasses 'sporadic' PD, familial Parkinson's-like forms, as well as other related syndromes) has brought excitement to the field. Three of the mutated familial Parkinsonism (FP) genes: Parkin, DJ-1, and PINK1, typically present with apparent autosomal recessive inheritance and are implicated in mitochondria and oxidative stress-related survival pathways. Two other FP genes: alpha-Synuclein (alphaSyn) and LRRK2, present in an autosomal dominant pattern and are associated with prominent intracellular protein inclusions. A series of recent publications suggest novel pathways that may link the FP genes.     

Novel Loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis

Association testing of multiple correlated phenotypes offers better power than univariate analysis of single traits. We analyzed 6,600 individuals from two population-based cohorts with both genome-wide SNP data and serum metabolomic profiles. From the observed correlation structure of 130 metabolites measured by nuclear magnetic resonance, we identified 11 metabolic networks and performed a multivariate genome-wide association analysis. We identified 34 genomic loci at genome-wide significance, of which 7 are novel. In comparison to univariate tests, multivariate association analysis identified nearly twice as many significant associations in total. Multi-tissue gene expression studies identified variants in our top loci, SERPINA1 and AQP9, as eQTLs and showed that SERPINA1 and AQP9 expression in human blood was associated with metabolites from their corresponding metabolic networks. Finally, liver expression of AQP9 was associated with atherosclerotic lesion area in mice, and in human arterial tissue both SERPINA1 and AQP9 were shown to be upregulated (6.3-fold and 4.6-fold, respectively) in atherosclerotic plaques. Our study illustrates the power of multi-phenotype GWAS and highlights candidate genes for atherosclerosis.     

Novel intron length polymorphic (ILP) markers from starch biosynthesis genes reveal genetic relationships in Indian wheat varieties and related species

Molecular Biology Reports - Introns experience lesser selection pressure, thus are liable for higher polymorphism. Intron Length Polymorphic (ILP) markers designed from exon-flanking introns...     

Natural selection and evolution of streptococcal virulence genes involved in tissue-specific adaptations

The molecular mechanisms underlying niche adaptation in bacteria are not fully understood. Primary infection by the pathogen group A streptococcus (GAS) takes place at either the throat or the skin of its human host, and GAS strains differ in tissue site preference. Many skin-tropic strains bind host plasminogen via the plasminogen-binding group A streptococcal M protein (PAM) present on the cell surface; inactivation of genes encoding either PAM or streptokinase (a plasminogen activator) leads to loss of virulence at the skin. Unlike PAM, which is present in only a subset of GAS strains, the gene encoding streptokinase (ska) is present in all GAS isolates. In this study, the evolution of the virulence genes known to be involved in skin infection was examined. Most genetic diversity within ska genes was localized to a region encoding the plasminogen-docking domain (beta-domain). The gene encoding PAM displayed strong linkage disequilibrium (P < 0.01) with a distinct phylogenetic cluster of the ska beta-domain-encoding region. Yet, ska alleles of distant taxa showed a history of intragenic recombination, and high intrinsic levels of recombination were found among GAS strains having different tissue tropisms. The data suggest that tissue-specific adaptations arise from epistatic coselection of bacterial virulence genes. Additional analysis of ska genes showed that approximately 4% of the codons underwent strong diversifying selection. Horizontal acquisition of one ska lineage from a commensal Streptococcus donor species was also evident. Together, the data suggest that new phenotypes can be acquired through interspecies recombination between orthologous genes, while constrained functions can be preserved; in this way, orthologous genes may provide a rich and ready source for new phenotypes and thereby play a facilitating role in the emergence of new niche adaptations in bacteria.     

Comparison of Bombyx mori and Helicoverpa armigera cytoplasmic actin genes provides clues to the evolution of actin genes in insects

The cytoplasmic actin genes BmA3 and BmA4 of Bombyx mori were found clustered in a single genomic clone in the same orientation. As a similar clustering of the two cytoplasmic actin genes Ha3a and Ha3b also occurs in another lepidopteran, Helicoverpa armigera, we analyzed the sequence of the pair of genes from each species. Due to the high conservation of cytoplasmic actins, the coding sequence of the four genes was easily aligned, allowing the detection of similarities in noncoding exon and intron sequences as well as in flanking sequences. All four genes exhibited a conserved intron inserted in codon 117, an original position not encountered in other species. It can thus be postulated that all of these genes derived from a common ancestral gene carrying this intron after a single event of insertion. The comparison of the four genes revealed that the genes of B. mori and H. armigera are related in two different ways: the coding sequence and the intron that interrupts it are more similar between paralogous genes within each species than between orthologous genes of the two species. In contrast, the other (noncoding) regions exhibited the greatest similarity between a gene of one species and a gene of the other species, defining two pairs of orthologous genes, BmA3 and HaA3a on one hand and BmA4 and HaA3b on the other. However, in each species, the very high similarities of the coding sequence and of the single intron that interrupts it strongly suggest that gene conversion events have homogenized this part of the sequence. As the divergence of the B. mori genes was higher than that of the H. armigera genes, we postulated that the gene conversion occurred earlier in the B. mori lineage. This leads us to hypothesize that gene conversion could also be responsible for the original transfer of the common intron to the second gene copy before the divergence of the B. mori and H. armigera lineages.     

Seasonal variation in expression pattern of genes in irrigated and water stressed transcriptomes of Zea mays Z59

Journal of Plant Biochemistry and Biotechnology - Drought is the major limiting factor for maize cultivation in India. Though many drought tolerant genotypes have been developed, there is very poor...     

Amphioxus and ascidian Dmbx homeobox genes give clues to the vertebrate origins of midbrain development

The ancestral chordate neural tube had a tripartite structure, comprising anterior, midbrain-hindbrain boundary (MHB) and posterior regions. The most anterior region encompasses both forebrain and midbrain in vertebrates. It is not clear when or how the distinction between these two functionally and developmentally distinct regions arose in evolution. Recently, we reported a mouse PRD-class homeobox gene, Dmbx1, expressed in the presumptive midbrain at early developmental stages, and the hindbrain at later stages, with exclusion from the MHB. This gene provides a route to investigate the evolution of midbrain development. We report the cloning, genomic structure, phylogeny and embryonic expression of Dmbx genes from amphioxus and from Ciona, representing the two most closely related lineages to the vertebrates. Our analyses show that Dmbx genes form a distinct, ancient, homeobox gene family, with highly conserved sequence and genomic organisation, albeit more divergent in Ciona. In amphioxus, no Dmbx expression is observed in the neural tube, supporting previous arguments that the MHB equivalent region has been secondarily modified in evolution. In Ciona, the CiDmbx gene is detected in neural cells caudal to Pax2/5/8-positive cells (MHB homologue), in the Hox-positive region, but, interestingly, not in any cells rostral to them. These results suggest that a midbrain homologue is missing in Ciona, and argue that midbrain development is a novelty that evolved specifically on the vertebrate lineage. We discuss the evolution of midbrain development in relation to the ancestry of the tripartite neural ground plan and the origin of the MHB organiser.     

Expressed sequence tags from phytophthora sojae reveal genes specific to development and infection

Six unique expressed sequence tag (EST) libraries were generated from four developmental stages of Phytophthora sojae P6497. RNA was extracted from mycelia, swimming zoospores, germinating cysts, and soybean (Glycine max (L.) Merr.) cv. Harosoy tissues heavily infected with P. sojae. Three libraries were created from mycelia growing on defined medium, complex medium, and nutrient-limited medium. The 26,943 high-quality sequences obtained clustered into 7,863 unigenes composed of 2,845 contigs and 5,018 singletons. The total number of P. sojae unigenes matching sequences in the genome assembly was 7,412 (94%). Of these unigenes, 7,088 (90%) matched gene models predicted from the P. sojae sequence assembly, but only 2,047 (26%) matched P. ramorum gene models. Analysis of EST frequency from different growth conditions and morphological stages revealed genes that were specific to or highly represented in particular growth conditions and life stages. Additionally, our results indicate that, during infection, the pathogen derives most of its carbon and energy via glycolysis of sugars in the plant. Sequences identified with putative roles in pathogenesis included avirulence homologs possessing the RxLR motif, elicitins, and hydrolytic enzymes. This large collection of P. sojae ESTs will serve as a valuable public genomic resource.     

Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns

Congenital Diaphragmatic Hernia (CDH) is defined by the presence of an orifice in the diaphragm, more often left and posterolateral that permits the herniation of abdominal contents into the thorax. The lungs are hypoplastic and have abnormal vessels that cause respiratory insufficiency and persistent pulmonary hypertension with high mortality. About one third of cases have cardiovascular malformations and lesser proportions have skeletal, neural, genitourinary, gastrointestinal or other defects. CDH can be a component of Pallister-Killian, Fryns, Ghersoni-Baruch, WAGR, Denys-Drash, Brachman-De Lange, Donnai-Barrow or Wolf-Hirschhorn syndromes. Some chromosomal anomalies involve CDH as well. The incidence is < 5 in 10,000 live-births. The etiology is unknown although clinical, genetic and experimental evidence points to disturbances in the retinoid-signaling pathway during organogenesis. Antenatal diagnosis is often made and this allows prenatal management (open correction of the hernia in the past and reversible fetoscopic tracheal obstruction nowadays) that may be indicated in cases with severe lung hypoplasia and grim prognosis. Treatment after birth requires all the refinements of critical care including extracorporeal membrane oxygenation prior to surgical correction. The best hospital series report 80% survival but it remains around 50% in population-based studies. Chronic respiratory tract disease, neurodevelopmental problems, neurosensorial hearing loss and gastroesophageal reflux are common problems in survivors. Much more research on several aspects of this severe condition is warranted.     

Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns

ABSTRACT: BACKGROUND: Inherited malabsorption of cobalamin (Cbl) causes hematological and neurological abnormalities that can be fatal. Three genes have been implicated in Cbl malabsorption; yet, only about 10% of ~400-500 reported cases have been molecularly studied to date. Recessive mutations in CUBN or AMN cause Imerslund-Grasbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD). IGS and IFD differ in that IGS usually presents with proteinuria, which is not observed in IFD. The genetic heterogeneity and numerous differential diagnoses make clinical assessment difficult. METHODS: We present a large genetic screening study of 154 families or patients with suspected hereditary Cbl malabsorption. Patients and their families have been accrued over a period spanning >12 years. Systematic genetic testing of the three genes CUBN, AMN, and GIF was accomplished using a combination of single strand conformation polymorphism and DNA and RNA sequencing. In addition, six genes that were contenders for a role in inherited Cbl malabsorption were studied in a subset of these patients. RESULTS: Our results revealed population-specific mutations, mutational hotspots, and functionally distinct regions in the three causal genes. We identified mutations in 126/154 unrelated cases (82%). Fifty-three of 126 cases (42%) were mutated in CUBN, 45/126 (36%) were mutated in AMN, and 28/126 (22%) had mutations in GIF. We found 26 undescribed mutations in CUBN, 19 in AMN, and 7 in GIF for a total of 52 novel defects described herein. We excluded six other candidate genes as culprits and concluded that additional genes might be involved. CONCLUSIONS: Cbl malabsorption is found worldwide and genetically complex. However, our results indicate that population-specific founder mutations are quite common. Consequently, targeted genetic testing has become feasible if ethnic ancestry is considered. These results will facilitate clinical and molecular genetic testing of Cbl malabsorption. Early diagnosis improves the lifelong care required by these patients and prevents potential neurological long-term complications. This study provides the first comprehensive overview of the genetics that underlies the inherited Cbl malabsorption phenotype.     

Cloning and sequence analysis reveal structural variation among related zein genes in maize

We have isolated a gene encoding one of the 19,000 dalton zein proteins from a maize genomic library constructed in Charon 4A. This gene occurs on a 7.7 kb Eco RI fragment, and based on Southern hybridization analysis, represents one of several homologous sequences present in the maize genome. The nucleotide sequence of the gene predicts a protein composed of 235 amino acids, including a signal peptide of 21 amino acids. There are no intervening sequences in the gene. By comparing the nucleotide sequence of this gene with that of a homologous cDNA clone, we have identified a basis for microheterogeneity within the gene family. The 5′ nucleotide sequences of the genomic and cDNA clones are identical, but they differ in the center of the protein, where repeated amino acid sequences occur. A nucleotide sequence encoding a conserved peptide of 20 amino acids is repeated nine times in the center of both of these clones.