Effects of the shape of distribution of mutant effect in nearly neutral mutation models

1996 ◽  
Vol 75 (1) ◽  
pp. 33-48 ◽  
Author(s):  
Hidenori Tachida
Keyword(s):  
Neutral Mutation ◽  
Mutant Effect

scholarly journals A study on a nearly neutral mutation model in finite populations.

Genetics ◽  
1991 ◽  
Vol 128 (1) ◽  
pp. 183-192
Author(s):  
H Tachida
Keyword(s):  
Standard Deviation ◽  
Equilibrium State ◽  
Mutation Rate ◽  
Selection Coefficient ◽  
Average Heterozygosity ◽  
Finite Populations ◽  
Mutation Model ◽  
Neutral Mutation ◽  
Mutant Effect ◽  
The Relationship

Abstract As a nearly neutral mutation model, the house-of-cards model is studied in finite populations using computer simulations. The distribution of the mutant effect is assumed to be normal. The behavior is mainly determined by the product of the population size, N, and the standard deviation, sigma, of the distribution of the mutant effect. If 4N sigma is large compared to one, a few advantageous mutants are quickly fixed in early generations. Then most mutation becomes deleterious and very slow increase of the average selection coefficient follows. It takes very long for the population to reach the equilibrium state. Substitutions of alleles occur very infrequently in the later stage. If 4N sigma is the order of one or less, the behavior is qualitatively similar to that of the strict neutral case. Gradual increase of the average selection coefficient occurs and in generations of several times the inverse of the mutation rate the population almost reaches the equilibrium state. Both advantageous and neutral (including slightly deleterious) mutations are fixed. Except in the early stage, an increase of the standard deviation of the distribution of the mutant effect decreases the average heterozygosity. The substitution rate is reduced as 4N sigma is increased. Three tests of neutrality, one using the relationship between the average and the variance of heterozygosity, another using the relationship between the average heterozygosity and the average number of substitutions and Watterson's homozygosity test are applied to the consequences of the present model. It is found that deviation from the neutral expectation becomes apparent only when 4N sigma is more than two. Also a simple approximation for the model is developed which works well when the mutation rate is very small.

scholarly journals GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma/paraganglioma

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Yeqing Dong ◽  
Yongsheng Huang ◽  
Chengyan Fan ◽  
Liang Wang ◽  
Ran Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Chromaffin Cells ◽  
Disease Free Survival ◽  
Suppressor Gene ◽  
Adrenal Chromaffin Cell ◽  
Putative Tumor Suppressor Gene ◽  
Mutant Effect ◽  
Hereditary Tumors

AbstractPheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27, suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.

Neutral mutation hypothesis test

Nature ◽  
1991 ◽  
Vol 354 (6349) ◽  
pp. 116-116 ◽  
Author(s):  
JOHN H. MCDONALD ◽  
MARTIN KREITMAN
Keyword(s):  
Hypothesis Test ◽  
Neutral Mutation

scholarly journals On branching process with rare neutral mutation

Bernoulli ◽  
2018 ◽  
Vol 24 (2) ◽  
pp. 1576-1612
Author(s):  
Airam Blancas ◽  
Víctor Rivero
Keyword(s):  
Branching Process ◽  
Neutral Mutation

GENE NUMBERS AND GENIC VARIABILITY IN CIONA INTESTINALIS AND BRANCHIOSTOMA LANCEOLATUM

1978 ◽  
Vol 20 (1) ◽  
pp. 61-70 ◽  
Author(s):  
J. Schmidtke ◽  
B. Kunz ◽  
W. Engel
Keyword(s):  
Ciona Intestinalis ◽  
Homologous Proteins ◽  
Allozymic Variation ◽  
Neutral Mutation ◽  
Number Of Genes ◽  
Branchiostoma Lanceolatum ◽  
Identical Gene

The number of genes coding for various enzymes have been determined in Ciona intestinalis (Tunicata) in comparison with Branchiostoma lanceolatum (Cephalochordata) using electrophoretic methods. Both species, generally, have identical gene numbers for homologous proteins. This finding does not support the hypothesis that Branchiostoma represents an anciently polyploid step relative to Ciona. High levels of allozymic variation were observed in the two species. The data are discussed in view of the neutral mutation hypothesis.

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