Dataset Information

Testing the role of predicted gene knockouts in human anthropometric trait variation.

ABSTRACT: Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established in recessive Mendelian diseases, we have not yet explored how such gene knockouts (KOs) could influence complex human phenotypes. Here, we developed a statistical framework to test the association between gene KOs and quantitative human traits. Our method is flexible, publicly available, and compatible with common genotype format files (e.g. PLINK and vcf). We characterized gene KOs in 4498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100×), 1976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7×), and >100 000 participants from the Genetic Investigation of ANthropometric Traits (GIANT) Consortium genotyped on an exome array. We tested associations between gene KOs and three anthropometric traits: body mass index (BMI), height and BMI-adjusted waist-to-hip ratio (WHR). Despite our large sample size and multiple datasets available, we could not detect robust associations between specific gene KOs and quantitative anthropometric traits. Our results highlight several limitations and challenges for future gene KO studies in humans, in particular when there is no prior knowledge on the phenotypes that might be affected by the tested gene KOs. They also suggest that gene KOs identified with current DNA sequencing methodologies probably do not strongly influence normal variation in BMI, height, and WHR in the general human population.

SUBMITTER: Lessard S

PROVIDER: S-EPMC5062577 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Testing the role of predicted gene knockouts in human anthropometric trait variation.

Lessard Samuel S Manning Alisa K AK Low-Kam Cécile C Auer Paul L PL Giri Ayush A Graff Mariaelisa M Schurmann Claudia C Yaghootkar Hanieh H Luan Jian'an J Esko Tonu T Karaderi Tugce T Bottinger Erwin P EP Lu Yingchang Y Carlson Chris C Caulfield Mark M Dubé Marie-Pierre MP Jackson Rebecca D RD Kooperberg Charles C McKnight Barbara B Mongrain Ian I Peters Ulrike U Reiner Alex P AP Rhainds David D Sotoodehnia Nona N Hirschhorn Joel N JN Scott Robert A RA Munroe Patricia B PB Frayling Timothy M TM Loos Ruth J F RJ North Kari E KE Edwards Todd L TL Tardif Jean-Claude JC Lindgren Cecilia M CM Lettre Guillaume G

Human molecular genetics 20160221 10

Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established in recessive Mendelian diseases, we have not yet explored how such gene knockouts (KOs) could influence complex human phenotypes. Here, we developed a statistical framework to test the association between gene KOs and quantitative human traits. Our method is flexible, publicly available, and compatible with common genotype format files (e.g. PLINK and vcf). We characterized ge ...[more]

PMID: 26908616

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Project description:The trimeric thrombospondin homologs, TSP1 and TSP2, are both components of bone tissue and contribute in redundant and distinct ways to skeletal physiology. TSP1-null mice display increased femoral cross-sectional area and thickness due to periosteal expansion, as well as diminished matrix quality and impaired osteoclast function. TSP2-null mice display increased femoral cross-sectional thickness and reduced marrow area due to increased endosteal osteoblast activity, with very little periosteal expansion. Osteoblast lineage cells are reduced in TSP2-null mice, but not in TSP1-null. The functional effects of combined TSP1 and TSP2 deficiency remain to be elucidated. Here, we examined the spectrum of detergent soluble proteins in diaphyseal cortical bone of growing (6-week old) male and female mice deficient in both thrombospondins (double knockout (DKO)). Of 3429 detected proteins, 195 were differentially abundant in both male and female DKO bones. Physiologically relevant annotation terms identified by Ingenuity Pathway Analysis included "ECM degradation" and "Quantity of Monocytes." Manual inspection revealed that a number of proteins with shared expression among osteoclasts and osteocytes were reduced in DKO bones. To associate changes in protein content with phenotype, we examined 12-week old male and female DKO and WT mice. DKO mice were smaller than WT and in male DKO, femoral cross section area was reduced. Some of the male DKO femora also had a flattened, less circular cross-section. Male DKO bones were less stiff in bending and they displayed reduced ultimate load. Displacements at yield load and at max load were both elevated in male DKO. However, the ratios of post-yield to pre-yield displacements significantly diminished in DKO suggesting proportionally reduced post-yield behavior. Male DKO mice also exhibited reductions in trabecular bone mass, which were surprisingly associated with equivalent osteoblast numbers and accordingly increased osteoblast surface. Marrow-derived colony forming unit-fibroblastic was reduced in male and female DKO mice. Together our data suggest that when both TSP1 and TSP2 are absent, a unique, sex-specific bone phenotype not predicted by the single knockouts, is manifested.

Project description:BackgroundDistributed robustness is thought to influence the buffering of random phenotypic variation through the scale-free topology of gene regulatory, metabolic, and protein-protein interaction networks. If this hypothesis is true, then the phenotypic response to the perturbation of particular nodes in such a network should be proportional to the number of links those nodes make with neighboring nodes. This suggests a probability distribution approximating an inverse power-law of random phenotypic variation. Zero phenotypic variation, however, is impossible, because random molecular and cellular processes are essential to normal development. Consequently, a more realistic distribution should have a y-intercept close to zero in the lower tail, a mode greater than zero, and a long (fat) upper tail. The double Pareto-lognormal (DPLN) distribution is an ideal candidate distribution. It consists of a mixture of a lognormal body and upper and lower power-law tails.Objective and methodsIf our assumptions are true, the DPLN distribution should provide a better fit to random phenotypic variation in a large series of single-gene knockout lines than other skewed or symmetrical distributions. We fit a large published data set of single-gene knockout lines in Saccharomyces cerevisiae to seven different probability distributions: DPLN, right Pareto-lognormal (RPLN), left Pareto-lognormal (LPLN), normal, lognormal, exponential, and Pareto. The best model was judged by the Akaike Information Criterion (AIC).ResultsPhenotypic variation among gene knockouts in S. cerevisiae fits a double Pareto-lognormal (DPLN) distribution better than any of the alternative distributions, including the right Pareto-lognormal and lognormal distributions.Conclusions and significanceA DPLN distribution is consistent with the hypothesis that developmental stability is mediated, in part, by distributed robustness, the resilience of gene regulatory, metabolic, and protein-protein interaction networks. Alternatively, multiplicative cell growth, and the mixing of lognormal distributions having different variances, may generate a DPLN distribution.

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Dataset Information

Testing the role of predicted gene knockouts in human anthropometric trait variation.

Publications

Testing the role of predicted gene knockouts in human anthropometric trait variation.

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