Nucleotide variability and linkage disequilibrium patterns in the porcine MUC4 gene

Abstract We studied the effect of multilocus balancing selection on neutral nucleotide variability at linked sites by simulating a model where diallelic polymorphisms are maintained at an arbitrary number of selected loci by means of symmetric overdominance. Different combinations of alleles define different genetic backgrounds that subdivide the population and strongly affect variability. Several multilocus fitness regimes with different degrees of epistasis and gametic disequilibrium are allowed. Analytical results based on a multilocus extension of the structured coalescent predict that the expected linked neutral diversity increases exponentially with the number of selected loci and can become extremely large. Our simulation results show that although variability increases with the number of genetic backgrounds that are maintained in the population, it is reduced by random fluctuations in the frequencies of those backgrounds and does not reach high levels even in very large populations. We also show that previous results on balancing selection in single-locus systems do not extend to the multilocus scenario in a straightforward way. Different patterns of linkage disequilibrium and of the frequency spectrum of neutral mutations are expected under different degrees of epistasis. Interestingly, the power to detect balancing selection using deviations from a neutral distribution of allele frequencies seems to be diminished under the fitness regime that leads to the largest increase of variability over the neutral case. This and other results are discussed in the light of data from the Mhc.

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Nucleotide Variability atG6pdand the Signature of Malarial Selection in Humans

Genetics ◽

10.1093/genetics/162.4.1849 ◽

2002 ◽

Vol 162 (4) ◽

pp. 1849-1861 ◽

Cited By ~ 3

Author(s):

Matthew A Saunders ◽

Michael F Hammer ◽

Michael W Nachman

Keyword(s):

Linkage Disequilibrium ◽

X Chromosome ◽

G6pd Deficiency ◽

Human Populations ◽

Nucleotide Variability ◽

Signature Of Selection ◽

History Of ◽

Glucose 6 Phosphate Dehydrogenase ◽

The Impact

AbstractGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans. Deficiency alleles for this X-linked disorder are geographically correlated with historical patterns of malaria, and the most common deficiency allele in Africa (G6PD A-) has been shown to confer some resistance to malaria in both hemizygous males and heterozygous females. We studied DNA sequence variation in 5.1 kb of G6pd from 47 individuals representing a worldwide sample to examine the impact of selection on patterns of human nucleotide diversity and to infer the evolutionary history of the G6PD A-allele. We also sequenced 3.7 kb of a neighboring locus, L1cam, from the same set of individuals to study the effect of selection on patterns of linkage disequilibrium. Despite strong clinical evidence for malarial selection maintaining G6PD deficiency alleles in human populations, the overall level of nucleotide heterozygosity at G6pd is typical of other genes on the X chromosome. However, the signature of selection is evident in the absence of genetic variation among A-alleles from different parts of Africa and in the unusually high levels of linkage disequilibrium over a considerable distance of the X chromosome. In spite of a long-term association between Plasmodium falciparum and the ancestors of modern humans, patterns of nucleotide variability and linkage disequilibrium suggest that the A-allele arose in Africa only within the last 10,000 years and spread due to selection.

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Contrasting Evolutionary Histories of Two Introns of the Duchenne Muscular Dystrophy Gene, Dmd, in Humans

Genetics ◽

10.1093/genetics/155.4.1855 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1855-1864 ◽

Cited By ~ 9

Author(s):

Michael W Nachman ◽

Susan L Crowell

Keyword(s):

Linkage Disequilibrium ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Nucleotide Diversity ◽

High Rate ◽

Significant Linkage Disequilibrium ◽

Nucleotide Variability ◽

Interspecific Divergence ◽

Significant Linkage ◽

Common Chimpanzee

Abstract The Duchenne muscular dystrophy (Dmd) locus lies in a region of the X chromosome that experiences a high rate of recombination and is thus expected to be relatively unaffected by the effects of selection on nearby genes. To provide a picture of nucleotide variability at a high-recombination locus in humans, we sequenced 5.4 kb from two introns of Dmd in a worldwide sample of 41 alleles from Africa, Asia, Europe, and the Americas. These same regions were also sequenced in one common chimpanzee and one orangutan. Dramatically different patterns of genetic variation were observed at these two introns, which are separated by >500 kb of DNA. Nucleotide diversity at intron 44 (π = 0.141%) was more than four times higher than nucleotide diversity at intron 7 (π = 0.034%) despite similar levels of divergence for these two regions. Intron 7 exhibited significant linkage disequilibrium extending over 10 kb and also showed a significant excess of rare polymorphisms. In contrast, intron 44 exhibited little linkage disequilibrium and no skew in the frequency distribution of segregating sites. Intron 7 was much more variable in Africa than in other continents, while intron 44 displayed similar levels of variability in different geographic regions. Comparison of intraspecific polymorphism to interspecific divergence using the HKA test revealed a significant reduction in variability at intron 7 relative to intron 44, and this effect was most pronounced in the non-African samples. These results are best explained by positive directional selection acting at or near intron 7 and demonstrate that even genes in regions of high recombination may be influenced by selection at linked sites.

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Testing Models of Selection and Demography inDrosophila simulans

Genetics ◽

10.1093/genetics/162.1.203 ◽

2002 ◽

Vol 162 (1) ◽

pp. 203-216 ◽

Cited By ~ 44

Author(s):

Jeffrey D Wall ◽

Peter Andolfatto ◽

Molly Przeworski

Keyword(s):

Linkage Disequilibrium ◽

North American ◽

Demographic History ◽

North American Population ◽

Recombination Rates ◽

Nucleotide Variability ◽

Chromosome Arm ◽

History Of ◽

Founder Event ◽

Parameter Values

AbstractWe analyze patterns of nucleotide variability at 15 X-linked loci and 14 autosomal loci from a North American population of Drosophila simulans. We show that there is significantly more linkage disequilibrium on the X chromosome than on chromosome arm 3R and much more linkage disequilibrium on both chromosomes than expected from estimates of recombination rates, mutation rates, and levels of diversity. To explore what types of evolutionary models might explain this observation, we examine a model of recurrent, nonoverlapping selective sweeps and a model of a recent drastic bottleneck (e.g., founder event) in the demographic history of North American populations of D. simulans. The simple sweep model is not consistent with the observed patterns of linkage disequilibrium nor with the observed frequencies of segregating mutations. Under a restricted range of parameter values, a simple bottleneck model is consistent with multiple facets of the data. While our results do not exclude some influence of selection on X vs. autosome variability levels, they suggest that demography alone may account for patterns of linkage disequilibrium and the frequency spectrum of segregating mutations in this population of D. simulans.

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Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene QPC with low radial BMD in adult women.

10.31234/osf.io/93fcq ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Linkage Disequilibrium ◽

Multiple Regression ◽

Genetic Variations ◽

Strong Linkage Disequilibrium ◽

Adult Women ◽

Nucleotide Polymorphisms ◽

Haplotype Estimation ◽

Factors Affecting ◽

Glutaminyl Cyclase ◽

Strong Linkage

Correlation between 13 genetic variations of the glutaminyl-peptide cyclotransferase gene andadjusted aBMD was tested among 384 adult women. Among 13 variations with strong linkage disequilibrium,R54W showed a prominent association (p ? 0.0003), which was more striking when examined among 309 eldersubjects (>50 years; p ? 0.0001). Contribution for postmenopausal bone loss was suggested.Introduction: Alterations in homeostatic regulation of estrogen through the hypothalamus-pituitary-gonadal axis(HPG axis) importantly affect the pathogenesis of osteoporosis. Osteoporosis-susceptibility genes have beenproposed in this hormonal axis, such as estrogen receptor genes and the gonadotropin-releasing hormone gene(GnRH). Here we report another example of genes: glutaminyl-peptide cyclotransferase gene (QPCT), an essentialmodifier of pituitary peptide hormones, including GnRH.Materials and Methods: Analyses of association of 13 single nucleotide polymorphisms (SNPs) at the QPCT locuswith adjusted areal BMD (adj-aBMD) were carried out among 384 adult women. Linkage disequilibrium (LD) wasanalyzed by haplotype estimation and calculation of D? and r2. Multiple regression analysis was applied forevaluating the combined effects of the variations.Results and Conclusions: LD analysis indicated strong linkage disequilibrium within the entire 30-kb region of theQPCT gene. Significant correlations were observed between the genotypes of the six SNPs and the radial adj-aBMD,among which R54W (nt ? 160C?T) presented the most prominent association (p ? 0.0003). Striking associationwas observed for these SNPs among the 309 subjects ?50 years of age (R54W, p ? 0.0001; ?1095T?C, p ?0.0002; ?1844C?T, p ? 0.0002). Multiple regression analyses indicated that multiple SNPs in the gene might actin combination to determine the radial adj-aBMD. These results indicate that genetic variations in QPCT are theimportant factors affecting the BMD of adult women that contribute to susceptibility for osteoporosis. The datashould provide new insight into the etiology of the disease and may suggest a new target to be considered duringtreatment.J Bone Miner

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