Publications by authors named "Rakesh Chettier"

13 Publications

  • Page 1 of 1

Whole exome sequencing identifies hemizygous deletions in the UGT2B28 and USP17L2 genes in a three‑generation family with endometriosis.

Mol Med Rep 2019 Mar 3;19(3):1716-1720. Epub 2019 Jan 3.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, University of Crete, Heraklion 710 03, Crete, Greece.

Endometriosis is an enigmatic condition with an unknown etiology and a poorly understood pathogenesis. It is considered to appear from the interplay of many genetic and environmental factors, affecting up to 10% of women and represents a major cause of pain and infertility. The familial association of endometriosis, as demonstrated through monozygotic twin and family studies suggests a genetic contribution to the disease, with further case‑control and genome‑wide association studies (GWAS) detecting various endometriosis risk factors. In a recent study, we described a unique, three‑generation family of Cretan origin (Greece) with 7 females with surgically confirmed endometriosis (grandmother, 3 daughters and 3 granddaughters). All the affected members of this family displayed a variety of clinical manifestations and complications. In the present study, to further analyze the genetic variants conferring the risk of developing endometriosis, whole exome sequencing (WES) was performed, using the AmpliSeq technology on the Ion Proton platform. An initial analysis of 64 variants that were detected across the 14 genes previously confirmed to be associated with endometriosis, did not identify any deleterious exonic variants in these genes. However, further analysis revealed 2 hemizygous deletions in the grandmother that segregate in several of her affected offspring. The first deletion was found in the UGT2B28 locus, spanning 7 informative sequence variants across at least 14 kb. The second deletion, located in USP17L2, spans 3 informative variants across at least 2 kb. On the whole, the findings of the presents study implicate 2 additional genes in the pathogenesis of endometriosis, apart from those already identified by GWAS.
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http://dx.doi.org/10.3892/mmr.2019.9818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390005PMC
March 2019

Co-existence of endometriosis with 13 non-gynecological co-morbidities: Mutation analysis by whole exome sequencing.

Mol Med Rep 2018 Dec 1;18(6):5053-5057. Epub 2018 Oct 1.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion 71003, Greece.

Endometriosis is an enigmatic condition with an unknown etiology and poorly understood pathogenesis and women with endometriosis represent a high-risk population group for a large category of chronic conditions. The study focused on a 67-year-old woman who presented with a 40-year history of familial endometriosis associated with various non-gynecological co-morbidities, thus representing a unique case from a cohort of 1,000 patients with endometriosis. Her family history included infertile members suffering from endometriosis. Thirteen non-gynecological co-morbidities were documented throughout the years, including five autoimmune diseases (i.e., systemic lupus erythematosus, ankylosing spondylitis, multiple sclerosis, bronchial asthma and Crohn's disease), urinary bladder diverticulum, osteoporosis, multinodular goiter, cardiovascular diseases, gastroesophageal reflux disease, malignant tumor of urinary bladder, Barrett's esophagus and bilateral cataract. In order to understand the potential role of gene mutations in the development of all those co-morbidities, whole exome sequencing was performed and the presence of various disease-associated, potentially causal missense variants, were observed. These findings are in accordance with the previously suggested common underlying etiologic pathway for some, but not all, autoimmune disorders. This unusual case provides novel insights demonstrating that endometriosis can coexist with various chronic autoimmune diseases and other conditions, including non-gynecological malignancies, which possibly share a common genetic cause, a fact that should be taken into consideration seriously by clinicians.
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http://dx.doi.org/10.3892/mmr.2018.9521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236265PMC
December 2018

Cardiomyopathy and Preeclampsia.

Circulation 2018 11;138(21):2359-2366

Taueret Laboratories LLC, Salt Lake City, UT (R.C., A.B., K.W.).

Background: Preeclampsia is associated with diastolic dysfunction, peripartum cardiomyopathy, and both pre-existing and subsequent maternal cardiovascular disease. Gene mutations causing idiopathic cardiomyopathy were recently implicated in peripartum cardiomyopathy. We sought to determine whether cardiomyopathy gene mutations are also a contributory factor in preeclampsia.

Methods: Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of preeclampsia completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with cardiomyopathy. Missense variants were deemed damaging missense if so classified by any of 7 standard function prediction algorithms. Variants were defined as loss-of-function if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from 2 control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33 000 subjects in the Exome Aggregation Consortium. Preeclampsia was not excluded in control groups.

Results: Of 181 subjects with confirmed preeclampsia, 96% were white. Seventy-two percent had ≥1 preterm preeclampsia delivery <37 weeks. Among preeclampsia subjects, whole exome sequencing demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 cardiomyopathy genes considered. The prevalence of these loss-of-function variants was significantly higher in preeclampsia subjects (5.5%) compared with the local control (2.5%) population ( P=0.014). Sixty-eight percent of women with preeclampsia carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum cardiomyopathy, most mutations (55%) were found in the TTN gene. Seventy-three percent of preeclampsia subjects had TTN mutations in the preeclampsia cohort versus 48% in local controls ( P=1.36E-11).

Discussion: Women who develop preeclampsia are more likely to carry protein-altering mutations in genes associated with cardiomyopathy, particularly in TTN. Mutations promoting cardiomyopathy are prevalent in preeclampsia, idiopathic cardiomyopathy, and peripartum cardiomyopathy, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.031527DOI Listing
November 2018

Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis.

PLoS One 2015 12;10(2):e0117708. Epub 2015 Feb 12.

Affiliated Genetics, Inc., Salt Lake City, Utah, 84109, United States of America; Juneau Biosciences, LLC., Salt Lake City, Utah, 84109, United States of America.

Adolescent idiopathic scoliosis (AIS) is a clinically significant disorder with high heritability that affects 2-4% of the population. Genome-wide association studies have identified LBX1 as a strong susceptibility locus for AIS in Asian and Caucasian populations. Here we further dissect the genetic association with AIS in a Caucasian population. To identify genetic markers associated with AIS we employed a genome-wide association study (GWAS) design comparing 620 female Caucasian patients who developed idiopathic scoliosis during adolescence with 1,287 ethnically matched females who had normal spinal curves by skeletal maturity. The genomic region around LBX1 was imputed and haplotypes investigated for genetic signals under different inheritance models. The strongest signal was identified upstream of LBX1 (rs11190878, P(trend) = 4.18 × 10(-9), OR = 0.63[0.54-0.74]). None of the remaining SNPs pass the genome-wide significance threshold. We found rs11190870, downstream of LBX1 and previously associated with AIS in Asian populations, to be in modest linkage disequilibrium (LD) with rs11190878 (r(2) = 0.40, D' = 0.81). Haplotype analysis shows that rs11190870 and rs11190878 track a single risk factor that resides on the ancestral haplotype and is shared across ethnic groups. We identify six haplotypes at the LBX1 locus including two strongly associated haplotypes; a recessive risk haplotype (TTA, Control(freq) = 0.52, P = 1.25 × 10(-9), OR = 1.56), and a co-dominant protective haplotype (CCG, Control(freq) = 0.28, P = 2.75 × 10(-7), OR = 0.65). Together the association signals from LBX1 explain 1.4% of phenotypic variance. Our results identify two clinically relevant haplotypes in the LBX1-region with opposite effects on AIS risk. The study demonstrates the utility of haplotypes over un-phased SNPs for individualized risk assessment by more strongly delineating individuals at risk for AIS without compromising the effect size.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117708PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326419PMC
November 2015

Endometriosis is associated with rare copy number variants.

PLoS One 2014 1;9(8):e103968. Epub 2014 Aug 1.

Juneau Biosciences, LLC, Salt Lake City, Utah, United States of America.

Endometriosis is a complex gynecological condition that affects 6-10% of women in their reproductive years and is defined by the presence of endometrial glands and stroma outside the uterus. Twin, family, and genome-wide association (GWA) studies have confirmed a genetic role, yet only a small part of the genetic risk can be explained by SNP variation. Copy number variants (CNVs) account for a greater portion of human genetic variation than SNPs and include more recent mutations of large effect. CNVs, likely to be prominent in conditions with decreased reproductive fitness, have not previously been examined as a genetic contributor to endometriosis. Here we employ a high-density genotyping microarray in a genome-wide survey of CNVs in a case-control population that includes 2,126 surgically confirmed endometriosis cases and 17,974 population controls of European ancestry. We apply stringent quality filters to reduce the false positive rate common to many CNV-detection algorithms from 77.7% to 7.3% without noticeable reduction in the true positive rate. We detected no differences in the CNV landscape between cases and controls on the global level which showed an average of 1.92 CNVs per individual with an average size of 142.3 kb. On the local level we identify 22 CNV-regions at the nominal significance threshold (P<0.05), which is greater than the 8.15 CNV-regions expected based on permutation analysis (P<0.001). Three CNV's passed a genome-wide P-value threshold of 9.3 × 10(-4); a deletion at SGCZ on 8p22 (P = 7.3 × 10(-4), OR = 8.5, Cl = 2.3-31.7), a deletion in MALRD1 on 10p12.31 (P = 5.6 × 10(-4), OR = 14.1, Cl = 2.7-90.9), and a deletion at 11q14.1 (P = 5.7 × 10(-4), OR = 33.8, Cl = 3.3-1651). Two SNPs within the 22 CNVRs show significant genotypic association with endometriosis after adjusting for multiple testing; rs758316 in DPP6 on 7q36.2 (P = 0.0045) and rs4837864 in ASTN2 on 9q33.1 (P = 0.0002). Together, the CNV-loci are detected in 6.9% of affected women compared to 2.1% in the general population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103968PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118997PMC
November 2015

Genome-wide association study link novel loci to endometriosis.

PLoS One 2013 5;8(3):e58257. Epub 2013 Mar 5.

Juneau Biosciences, LLC, Salt Lake City, Utah, USA.

Endometriosis is a common gynecological condition with complex etiology defined by the presence of endometrial glands and stroma outside the womb. Endometriosis is a common cause of both cyclic and chronic pelvic pain, reduced fertility, and reduced quality-of-life. Diagnosis and treatment of endometriosis is, on average, delayed by 7-10 years from the onset of symptoms. Absence of a timely and non-invasive diagnostic tool is presently the greatest barrier to the identification and treatment of endometriosis. Twin and family studies have documented an increased relative risk in families. To identify genetic factors that contribute to endometriosis we conducted a two-stage genome-wide association study (GWAS) of a European cohort including 2,019 surgically confirmed endometriosis cases and 14,471 controls. Three of the SNPs we identify associated at P<5×10(-8) in our combined analysis belong to two loci: LINC00339-WNT4 on 1p36.12 (rs2235529; P = 8.65×10(-9), OR = 1.29, CI = 1.18-1.40) and RND3-RBM43 on 2q23.3 (rs1519761; P = 4.70×10(-8), OR = 1.20, Cl = 1.13-1.29, and rs6757804; P = 4.05×10(-8), OR = 1.20, Cl = 1.13-1.29). Using an adjusted Bonferoni significance threshold of 4.51×10(-7) we identify two additional loci in our meta-analysis that associate with endometriosis:, RNF144B-ID4 on 6p22.3 (rs6907340; P = 2.19×10(-7), OR = 1.20, Cl = 1.12-1.28), and HNRNPA3P1-LOC100130539 on 10q11.21 (rs10508881; P = 4.08×10(-7), OR = 1.19, Cl = 1.11-1.27). Consistent with previously suggested associations to WNT4 our study implicate a 150 kb region around WNT4 that also include LINC00339 and CDC42. A univariate analysis of documented infertility, age at menarche, and family history did not show allelic association with these SNP markers. Clinical data from patients in our study reveal an average delay in diagnosis of 8.4 years and confirm a strong correlation between endometriosis severity and infertility (n = 1182, P<0.001, OR = 2.18). This GWAS of endometriosis was conducted with high diagnostic certainty in cases, and with stringent handling of population substructure. Our findings broaden the understanding of the genetic factors that play a role in endometriosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058257PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589333PMC
December 2013

Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis.

Spine (Phila Pa 1976) 2010 Dec;35(25):E1455-64

Axial Biotech, Inc, Salt Lake City, UT 84109, USA.

Study Design: Validation of a prognostic DNA marker panel.

Objective: The goals of this study were to develop and test the negative predictive value of a prognostic DNA test for adolescent idiopathic scoliosis (AIS) and to establish clinically meaningful endpoints for the test.

Summary Of Background Data: Clinical features do not adequately predict which children diagnosed with minimal or mild AIS will have the progressive form of the disease; genetic markers associated with curve progression might offer clinically useful prognostic insights.

Methods: Logistic regression was used to develop an algorithm to predict spinal curve progression incorporating genotypes for 53 single nucleotide polymorphisms and the patient's presenting spinal curve (Cobb angle). Three cohorts with known AIS outcomes were selected to reflect intended-use populations with various rates of AIS progression: 277 low-risk females representing a screening cohort, 257 females representing higher risk patients followed at referral centers, and 163 high risk males. DNA was extracted from saliva, and genotypes were determined using TaqMan assays. AIS Prognostic Test scores ranging from 1 to 200 were calculated.

Results: Low-risk scores (<41) had negative predictive values of 100%, 99%, and 97%, respectively, in the tested populations. In the risk model, we used cutoff scores of 50 and 180 to identify 75% of patients as low-risk (<1% risk of progressing to a surgical curve), 24% as intermediate-risk, and 1% as high-risk.

Conclusion: Prognostic testing for AIS has the potential to reduce psychological trauma, serial exposure to diagnostic radiation, unnecessary treatments, and direct and indirect costs-of-care related to scoliosis monitoring in low-risk patients. Further improvements in test performance are expected as the optimal markers for each locus are identified and the underlying biologic pathways are better understood. The validity of the test applies only to white AIS patients; versions of the test optimized for AIS patients of other races have yet to be developed.
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http://dx.doi.org/10.1097/BRS.0b013e3181ed2de1DOI Listing
December 2010

Polygenic inheritance of adolescent idiopathic scoliosis: a study of extended families in Utah.

Am J Med Genet A 2010 May;152A(5):1178-88

Axial Biotech, Inc., Salt Lake City, Utah 84109, USA.

A heritability study of 69 extended Utah families with a history of adolescent idiopathic scoliosis (AIS) indicates that AIS is a polygenic, multifactorial condition. Each family reported a history of AIS within four generations; a total of 247 individuals were confirmed via X-rays and medical records to have AIS. Coefficient of kinship was more than 25 standard deviations higher for these 69 families than for the general population. Excluding all probands and assuming autosomal dominant inheritance, 1,260 individuals over the age of 16 were determined to be at risk for AIS because they have a parent with AIS. Assuming 50% of these individuals carry the allele, estimated penetrance in at-risk males is approximately 9%, and estimated penetrance in at-risk females is approximately 29%. Recurrence risk in relatives decreases as the degree of relationship to the affected individual becomes more distant; however, the lowest recurrence risk calculated, for third-degree relatives, is still an average of 9%, well above the general population's risk. Onset of AIS appears to be inherited separate from curve pattern and severity. In a study of phenotypes in 36 of the families, the affected individuals were consistent in either curve severity or curve pattern, but not both. It is unclear whether severity or pattern is more heritable, but it is possible that the location of the curve on the spine is the most heritable trait of the phenotype. The study demonstrates the genetic complexity of AIS, including the low penetrance of its cumulative alleles and variable expression.
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http://dx.doi.org/10.1002/ajmg.a.33145DOI Listing
May 2010

Progesterone receptor genotype, family history, and spontaneous preterm birth.

Obstet Gynecol 2010 Apr;115(4):765-770

From the University of Utah Department of Obstetrics and Gynecology; and Taueret Laboratories, Salt Lake City, Utah.

Objective: To examine whether women with a personal or family history of preterm birth are more likely to have genetic variation in the human progesterone receptor (hPR).

Methods: Women with a singleton preterm birth at less than 37 weeks of gestation between 2002 and 2006 were identified from a prospectively collected clinical and biologic obstetric database (cases). Women in the control group were those with only term deliveries at or above 38 weeks of gestation. The Utah Population Database was queried for family history (first- or second-degree relative) of preterm birth. DNA was extracted from stored buffy coats and genotyped for six single nucleotide polymorphisms in the hPR.

Results: One hundred fifty-four patients (92 women in the preterm case group, 62 women in the term control group) were included. All were white or Hispanic. There were no statistical differences between white and Hispanic allele frequencies. Women in the preterm case group were more likely to carry the minor allele, G (minor allele frequency 0.29 compared with 0.18, P=.035) for rs471767, and were more likely to carry the GT haplotype across rs471767 and rs578029 compared with women in the term control group. Similar haplotype block variation was seen among women with preterm birth plus a family history of preterm birth.

Conclusion: Allele and haplotype frequencies in the hPR are significantly different among women with preterm birth and women with preterm birth plus a family history of preterm birth. This suggests the hPR gene may be a candidate for association with preterm birth or familial preterm birth.

Level Of Evidence: III.
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http://dx.doi.org/10.1097/AOG.0b013e3181d53b83DOI Listing
April 2010

A human protein interaction network shows conservation of aging processes between human and invertebrate species.

PLoS Genet 2009 Mar 13;5(3):e1000414. Epub 2009 Mar 13.

Prolexys Pharmaceuticals, Salt Lake City, UT, USA.

We have mapped a protein interaction network of human homologs of proteins that modify longevity in invertebrate species. This network is derived from a proteome-scale human protein interaction Core Network generated through unbiased high-throughput yeast two-hybrid searches. The longevity network is composed of 175 human homologs of proteins known to confer increased longevity through loss of function in yeast, nematode, or fly, and 2,163 additional human proteins that interact with these homologs. Overall, the network consists of 3,271 binary interactions among 2,338 unique proteins. A comparison of the average node degree of the human longevity homologs with random sets of proteins in the Core Network indicates that human homologs of longevity proteins are highly connected hubs with a mean node degree of 18.8 partners. Shortest path length analysis shows that proteins in this network are significantly more connected than would be expected by chance. To examine the relationship of this network to human aging phenotypes, we compared the genes encoding longevity network proteins to genes known to be changed transcriptionally during aging in human muscle. In the case of both the longevity protein homologs and their interactors, we observed enrichments for differentially expressed genes in the network. To determine whether homologs of human longevity interacting proteins can modulate life span in invertebrates, homologs of 18 human FRAP1 interacting proteins showing significant changes in human aging muscle were tested for effects on nematode life span using RNAi. Of 18 genes tested, 33% extended life span when knocked-down in Caenorhabditis elegans. These observations indicate that a broad class of longevity genes identified in invertebrate models of aging have relevance to human aging. They also indicate that the longevity protein interaction network presented here is enriched for novel conserved longevity proteins.
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http://dx.doi.org/10.1371/journal.pgen.1000414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657003PMC
March 2009

Interaction of an atypical Plasmodium falciparum ETRAMP with human apolipoproteins.

Malar J 2008 Oct 20;7:211. Epub 2008 Oct 20.

Department of Genome Sciences, University of Washington, Box 355065, Seattle, WA 98195, USA.

Background: In order to establish a successful infection in the human host, the malaria parasite Plasmodium falciparum must establish interactions with a variety of human proteins on the surface of different cell types, as well as with proteins inside the host cells. To better understand this aspect of malaria pathogenesis, a study was conducted with the goal of identifying interactions between proteins of the parasite and those of its human host.

Methods: A modified yeast two-hybrid methodology that preferentially selects protein fragments that can be expressed in yeast was used to conduct high-throughput screens with P. falciparum protein fragments against human liver and cerebellum libraries. The resulting dataset was analyzed to exclude interactions that are not likely to occur in the human host during infection.

Results: An initial set of 2,200 interactions was curated to remove proteins that are unlikely to play a role in pathogenesis based on their annotation or localization, and proteins that behave promiscuously in the two-hybrid assay, resulting in a final dataset of 456 interactions. A cluster that implicates binding between P. falciparum PFE1590w/ETRAMP5, a putative parasitophorous vacuole membrane protein, and human apolipoproteins ApoA, ApoB and ApoE was selected for further analysis. Different isoforms of ApoE, which are associated with different outcomes of malaria infection, were shown to display differential interactions with PFE1590w.

Conclusion: A dataset of interactions between proteins of P. falciparum and those of its human host was generated. The preferential interaction of the P. falciparum PFE1590w protein with the human ApoE epsilon3 and ApoE epsilon4 isoforms, but not the ApoE epsilon2 isoform, supports the hypothesis that ApoE genotype affects risk of malaria infection. The dataset contains other interactions of potential relevance to disease that may identify possible vaccine candidates and drug targets.
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http://dx.doi.org/10.1186/1475-2875-7-211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577112PMC
October 2008

Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

PLoS Genet 2007 May;3(5):e82

Prolexys Pharmaceuticals, Salt Lake City, Utah, United States of America.

Huntington's disease (HD) is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt) protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%-4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to co-immunoprecipitate with full-length Htt from mouse brain. These studies demonstrate that high-throughput screening for protein interactions combined with genetic validation in a model organism is a powerful approach for identifying novel candidate modifiers of polyglutamine toxicity.
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http://dx.doi.org/10.1371/journal.pgen.0030082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866352PMC
May 2007

A protein interaction network of the malaria parasite Plasmodium falciparum.

Nature 2005 Nov;438(7064):103-7

Howard Hughes Medical Institute, University of Washington, Box 357730, Seattle, Washington 98195, USA.

Plasmodium falciparum causes the most severe form of malaria and kills up to 2.7 million people annually. Despite the global importance of P. falciparum, the vast majority of its proteins have not been characterized experimentally. Here we identify P. falciparum protein-protein interactions using a high-throughput version of the yeast two-hybrid assay that circumvents the difficulties in expressing P. falciparum proteins in Saccharomyces cerevisiae. From more than 32,000 yeast two-hybrid screens with P. falciparum protein fragments, we identified 2,846 unique interactions, most of which include at least one previously uncharacterized protein. Informatic analyses of network connectivity, coexpression of the genes encoding interacting fragments, and enrichment of specific protein domains or Gene Ontology annotations were used to identify groups of interacting proteins, including one implicated in chromatin modification, transcription, messenger RNA stability and ubiquitination, and another implicated in the invasion of host cells. These data constitute the first extensive description of the protein interaction network for this important human pathogen.
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http://dx.doi.org/10.1038/nature04104DOI Listing
November 2005