scholarly journals A Test of Neutrality Based on Interlocus Associations

Genetics ◽  
1997 ◽  
Vol 146 (3) ◽  
pp. 1197-1206 ◽  
Author(s):  
John K Kelly

The evolutionary processes governing variability within genomic regions of low recombination have been the focus of many studies. Here, I investigate the statistical properties of a measure of intrlocus genetic associations under the assumption that mutations are selectively neutral and sites are completely linked. This measure, denoted ZnS, is based on the squared correlation of allelic identity at pairs of polymorphic sites. Upper bounds for ZnS are determined by simulations. Various deviations from the neutral model, including several different forms of natural selection, will inflate the value of ZnS relative to its neutral theory expectations. Larger than expected values of ZnS are observed in genetic samples from the yellow-ac-scute and Adh regions of Drosophila melanogaster.

1987 ◽  
Vol 49 (1) ◽  
pp. 31-41 ◽  
Author(s):  
Elizabeth Montgomery ◽  
Brian Charlesworth ◽  
Charles H. Langley

SummaryThe numbers of members of three families of copia-like elements were counted on twenty X, 2nd and 3rd chromosomes collected from a natural population of Drosophila melanogaster. Theoretical predictions were computed for two models of copy number stabilization: (1) element frequencies are regulated by a simple genetic process such as copy number dependent transposition or excision, independent of chromosomal location; (2) elements are eliminated by natural selection against mutational effects of their insertion into the chromosome. Since insertions into the X can be expected to suffer more selection than autosomal insertions, due to expression of mutant phenotypes in the hemizygous state, hypothesis 2, called the disproportional model, predicts that the proportion of elements on the X will be smaller than the proportion of the genome contributed by the X, while hypothesis 1, called the equiproportional model, predicts that this proportionality will be unaffected. Two of the elements, 297 and roo, showed no evidence for deficiency of X-linked elements, but the data for a third element, 412, were consistent with the prediction based on the selective model.These results indicate that simple selection against mutational effects of insertions of transposable elements is not generally adequate to account for their distribution within populations. We argue that a mechanism such as recombination between elements at different chromosomal sites, leading to rearrangements with highly deleterious, dominant effects could play a role in stabilizing copy number. This process would lead to a higher abundance of elements in genomic regions with restricted crossing over. We present some data indicating such an effect, and discuss possible interpretations.


1996 ◽  
Vol 68 (2) ◽  
pp. 101-108 ◽  
Author(s):  
Marta L. Wayne ◽  
Martin Kreitman

SummaryIn Drosophila melanogaster and closely related species, polymorphism has been shown to be reduced at loci located in regions of low recombination on the X chromosome and on the fourth chromosome, which does not normally recombine. Thispositive correlation between nucleotide polymorphism level and recombination rate is not predicted by standard neutral theory and therefore must result from natural selection and genetic hitchhiking along the chromosomes. We report here the near-complete absence of variation at concertina (cta), a locus located in the β-heterochromatic base ofchromosome 2L, a region of strongly reduced recombination. A 1.2 kilobase region containing coding regions and introns was sequenced from each of nine lines of D. melanogaster and nine lines of D. simulans representingworldwide collections. Variation is significantly reduced in cta in both species compared with other available loci on the same chromosome. Two analyses of background selection demonstrate that the reduction in variation at cta, considered in combination with other loci on chromosome 2L or alone, is consistent with the background selection model.


Genetics ◽  
1995 ◽  
Vol 139 (2) ◽  
pp. 849-859 ◽  
Author(s):  
T F Mackay ◽  
R F Lyman ◽  
W G Hill

Abstract A highly inbred strain of Drosophila melanogaster was subdivided into 20 replicate sublines that were maintained independently with 10 pairs of randomly sampled parents per generation for 180 generations. The variance between lines in abdominal and sternopleural bristle number increased little after 100 generations, in contrast to the neutral expectation of a linear increase; and the covariances of line means between different generations declined with increasing number of generations apart, in contrast to the neutral expectation of constant covariance. Thus, under a neutral model, the estimates of mutational variance were lower than for previous estimates from the first 100 generations of subline divergence. An autoregressive model was fitted to the variance of line means that indicated strong natural selection. There is no single unequivocal explanation for the results. Possible and nonexclusive alternatives include stabilizing selection on bristle number and deleterious effects on fitness of bristle mutations. The inferred strengths of selection on both traits are too high for stabilizing selection alone, and the between-line variance did not continue to increase sufficiently for pleiotropy alone to account for the observations. A third potential explanation that does not invoke selection is duplicate epistasis between mutations affecting bristle number.


Genetics ◽  
2003 ◽  
Vol 165 (4) ◽  
pp. 1843-1851 ◽  
Author(s):  
John Parsch

AbstractIntron sizes show an asymmetrical distribution in a number of organisms, with a large number of “short” introns clustered around a minimal intron length and a much broader distribution of longer introns. In Drosophila melanogaster, the short intron class is centered around 61 bp. The narrow length distribution suggests that natural selection may play a role in maintaining intron size. A comparison of 15 orthologous introns among species of the D. melanogaster subgroup indicates that, in general, short introns are not under greater DNA sequence or length constraints than long introns. There is a bias toward deletions in all introns (deletion/insertion ratio is 1.66), and the vast majority of indels are of short length (<10 bp). Indels occurring on the internal branches of the phylogenetic tree are significantly longer than those occurring on the terminal branches. These results are consistent with a compensatory model of intron length evolution in which slightly deleterious short deletions are frequently fixed within species by genetic drift, and relatively rare larger insertions that restore intron length are fixed by positive selection. A comparison of paralogous introns shared among duplicated genes suggests that length constraints differ between introns within the same gene. The janusA, janusB, and ocnus genes share two short introns derived from a common ancestor. The first of these introns shows significantly fewer indels than the second intron, although the two introns show a comparable number of substitutions. This indicates that intron-specific selective constraints have been maintained following gene duplication, which preceded the divergence of the D. melanogaster species subgroup.


Genetics ◽  
1974 ◽  
Vol 77 (3) ◽  
pp. 569-589
Author(s):  
Martin L Tracey ◽  
Francisco J Ayala

ABSTRACT Recent studies of genetically controlled enzyme variation lead to an estimation that at least 30 to 60% of the structural genes are polymorphic in natural populations of many vertebrate and invertebrate species. Some authors have argued that a substantial proportion of these polymorphisms cannot be maintained by natural selection because this would result in an unbearable genetic load. If many polymorphisms are maintained by heterotic natural selection, individuals with much greater than average proportion of homozygous loci should have very low fitness. We have measured in Drosophila melanogaster the fitness of flies homozygous for a complete chromosome relative to normal wild flies. A total of 37 chromosomes from a natural population have been tested using 92 experimental populations. The mean fitness of homozygous flies is 0.12 for second chromosomes, and 0.13 for third chromosomes. These estimates are compatible with the hypothesis that many (more than one thousand) loci are maintained by heterotic selection in natural populations of D. melanogaster.


Genetics ◽  
1996 ◽  
Vol 144 (2) ◽  
pp. 689-703 ◽  
Author(s):  
Michael J Ford ◽  
Charles F Aquadro

Abstract We present the results of a restriction site survey of variation at five loci in Drosophila athabasca, complimenting a previous study of the period locus. There is considerably greater differentiation between the three semispecies of D. athabasca at the period locus and two other X-linked genes (neon-transient-A and E74A) than at three autosomal genes (Xdh, Adh and RC98). Using a modification of the HKA test, which uses fixed differences between the semispecies and a test based on differences in Fst among loci, we show that the greater differentiation of the X-linked loci compared with the autosomal loci is inconsistent with a neutral model of molecular evolution. We explore several evolutionary scenarios by computer simulation, including differential migration of X and autosomal genes, very low levels of migration among the semispecies, selective sweeps, and background selection, and conclude that X-linked selective sweeps in at least two of the semispecies are the best explanation for the data. This evidence that natural selection acted on the X-chromosome suggests that another X-linked trait, mating song differences among the semispecies, may have been the target of selection.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadav Brandes ◽  
Nathan Linial ◽  
Michal Linial

AbstractThe characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-wide association studies (GWAS). However, the results of such studies rarely provide biological insight or functional interpretation. In this study, we conducted a comprehensive analysis of cancer predisposition in the UK Biobank cohort using a new gene-based method for detecting protein-coding genes that are functionally interpretable. Specifically, we conducted proteome-wide association studies (PWAS) to identify genetic associations mediated by alterations to protein function. With PWAS, we identified 110 significant gene-cancer associations in 70 unique genomic regions across nine cancer types and pan-cancer. In 48 of the 110 PWAS associations (44%), estimated gene damage is associated with reduced rather than elevated cancer risk, suggesting a protective effect. Together with standard GWAS, we implicated 145 unique genomic loci with cancer risk. While most of these genomic regions are supported by external evidence, our results also highlight many novel loci. Based on the capacity of PWAS to detect non-additive genetic effects, we found that 46% of the PWAS-significant cancer regions exhibited exclusive recessive inheritance. These results highlight the importance of recessive genetic effects, without relying on familial studies. Finally, we show that many of the detected genes exert substantial cancer risk in the studied cohort determined by a quantitative functional description, suggesting their relevance for diagnosis and genetic consulting.


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