Emily Beck and Fengxiao Bu Present Their Research Thursday, 6/26/14

Abstract for Emily Beck 

Cyto-nuclear co-intogression in the sister species Drosophila yakuba and D. santomea

 

Introgression, also called introgressive hybridization, is the effective exchange of genetic information between species through natural hybridization, and can occur when reproductive isolation is incomplete. Previous genetic analysis of the hybrid zone formed by Drosophila yakuba and its sister species D. santomea showed that the mitochondrial genome of the former species had introgressed into the latter and completely replaced its native form. Since mitochondrial proteins work intimately with nuclear-encoded proteins in the oxidative phosphorylation (Oxphos) pathway, we hypothesized that some nuclear genes in Oxphos co-introgressed along with the mitochondrial genome allowing for preservation of function. We analyzed nucleotide variation in the 12 nuclear genes that form cytochrome c oxidase (COX), an Oxphos enzyme complex composed of both nuclear- and mitochondrial-encoded proteins, in 33 Drosophila lines. Using maximum likelihood methods, we detected significant introgression from D. yakuba to D. santomea in only the three nuclear genes composing subunit V of this complex. The detection of introgression in the three proteins that work together in same subunit, interact with one another, and directly with the mitochondrial-encoded core strongly supports coordinated cyto-nuclear co-introgression to allow for optimal COX activity. We aim to investigate the nuclear genes of all the other subunits of Oxphos (88 genes total) for evidence of co-introgression.

Abstract for Fengxiao Bu

CFH-mutation related atypical hemolytic uremic syndrome may be modulated by Coagulation factor X

F. Bu1,2, N. Borsa2, W. Tollefson3, M. Schnieders3, H. Azaiez2, K. Wang4, C. Thomas2,5, C. Nester2,5, R. Smith1,2,5

1) Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, IA; 2) Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA; 3) Department of Biochemistry, University of Iowa, Iowa City, IA, USA; 4) Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA; 5) Rare Renal Disease Clinic, Departments of Pediatrics and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA,

Background: Atypical hemolytic uremic syndrome (aHUS) is a complement-related rare renal disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. Mutations in CFH account for approximately 22% of aHUS cases. In familial cases, CFH-mutation penetrance ranges from 12.5% to 100% suggesting the involvement of other genetic factors/modifiers in the etiology of this disorder.

Methods: Five families carrying the same disease mutation – c.3644G>A, p.Arg1215Gln – in CFH were included in this study. Using targeted genomic enrichment and massively parallel sequencing, all coding exons of genes in complement and coagulation cascades were screened for coding variants. Data were analyzed using a customized local Galaxy pipeline. After filtering for quality and frequency, novel and rare variants were annotated based on computational algorithms and reported studies. For selected variants the predicted functional impact was confirmed in vitro.

Results: A known factor X deficiency variant (F10 c.424G>A, p.Glu142Lys) was identified in a three-generation pedigree. No carriers of both the F10 p.Glu142Lys variant and the CFH p.Arg1215Gln variant developed aHUS, although two persons carrying only the CFH p.Arg1215Gln variant developed disease in early childhood. Protein modeling shows that wild-type Glu142 hydrogen bonds with Cys129, while mutated Lys142 hydrogen bonds with Ser146, a shift that destabilizes an important intra-light-chain interaction between a two-stranded beta-sheet and a small alpha-helical secondary structure element. Consistent with this prediction, recombinant mutant factor X secretion was altered in HEK293 cells and its activity was reduced by 30%.

Conclusion: We have identified a variant in F10, p.Glu142Lys, that may modify CFH-related aHUS perhaps protecting CFH-mutation carriers from developing the phenotype.This finding may explain some instances of incomplete penetrance and offer new therapeutic targets to treat this life-threating disease.

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Posted on June 24, 2014, in Student Seminar. Bookmark the permalink. Leave a comment.

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