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The influence of recombination on human genetic diversity.

Spencer CC, Deloukas P, Hunt S, Mullikin J, Myers S, Silverman B, Donnelly P, Bentley D, McVean G - PLoS Genet. (2006)

Bottom Line: In humans, the rate of recombination, as measured on the megabase scale, is positively associated with the level of genetic variation, as measured at the genic scale.Broad-scale association between recombination and diversity is explained through covariance of both factors with base composition.To our knowledge, these results are the first evidence of a direct and local influence of recombination hotspots on genetic variation and the fate of individual mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Statistics, University of Oxford, Oxford, United Kingdom.

ABSTRACT
In humans, the rate of recombination, as measured on the megabase scale, is positively associated with the level of genetic variation, as measured at the genic scale. Despite considerable debate, it is not clear whether these factors are causally linked or, if they are, whether this is driven by the repeated action of adaptive evolution or molecular processes such as double-strand break formation and mismatch repair. We introduce three innovations to the analysis of recombination and diversity: fine-scale genetic maps estimated from genotype experiments that identify recombination hotspots at the kilobase scale, analysis of an entire human chromosome, and the use of wavelet techniques to identify correlations acting at different scales. We show that recombination influences genetic diversity only at the level of recombination hotspots. Hotspots are also associated with local increases in GC content and the relative frequency of GC-increasing mutations but have no effect on substitution rates. Broad-scale association between recombination and diversity is explained through covariance of both factors with base composition. To our knowledge, these results are the first evidence of a direct and local influence of recombination hotspots on genetic variation and the fate of individual mutations. However, that hotspots have no influence on substitution rates suggests that they are too ephemeral on an evolutionary time scale to have a strong influence on broader scale patterns of base composition and long-term molecular evolution.

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Related in: MedlinePlus

Marginal Significance (−log10 p-value as Determined by t-Test) of the Wavelet Coefficients from Four Annotations as Predictors of the Coefficients of the Decomposition of Ascertainment Panel DiversityRed boxes highlight significant positive linear relationships and blue negative. The intensity of the colour is proportional to the degree of significance.(A) Smoothed coefficients.(B) Detail coefficients.Also shown is the adjusted r2, which can be interpreted as the proportion of the variance in the signal explained by the linear model.
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pgen-0020148-g003: Marginal Significance (−log10 p-value as Determined by t-Test) of the Wavelet Coefficients from Four Annotations as Predictors of the Coefficients of the Decomposition of Ascertainment Panel DiversityRed boxes highlight significant positive linear relationships and blue negative. The intensity of the colour is proportional to the degree of significance.(A) Smoothed coefficients.(B) Detail coefficients.Also shown is the adjusted r2, which can be interpreted as the proportion of the variance in the signal explained by the linear model.

Mentions: First, to compare our results with previous analyses, we performed linear model analysis of the smoothed coefficients including physical position as a covariate. This is equivalent to assessing correlations between statistics averaged over different window sizes. Figure 3A shows the results of the linear model analysis of diversity on the short and long arms. Divergence is a significant positive predictor over scales up to 1 Mb, while proximity to the centromere has a suppressing effect and GC content has a weak, but consistent, effect over and above divergence at fine scales. The effects of recombination and gene content are surprisingly different between the short and long arms. On the short arm, neither factor shows a significant correlation. On the long arm, exons show a strong negative correlation up to scales of 32 kb, while recombination shows a strong positive effect over scales up to 256 kb. Gene density on the short arm is less than half that on the long arm (and there are fewer observations at a given scale); hence, the lack of association with exons is probably due to power. It is not clear why recombination shows such a marked difference.


The influence of recombination on human genetic diversity.

Spencer CC, Deloukas P, Hunt S, Mullikin J, Myers S, Silverman B, Donnelly P, Bentley D, McVean G - PLoS Genet. (2006)

Marginal Significance (−log10 p-value as Determined by t-Test) of the Wavelet Coefficients from Four Annotations as Predictors of the Coefficients of the Decomposition of Ascertainment Panel DiversityRed boxes highlight significant positive linear relationships and blue negative. The intensity of the colour is proportional to the degree of significance.(A) Smoothed coefficients.(B) Detail coefficients.Also shown is the adjusted r2, which can be interpreted as the proportion of the variance in the signal explained by the linear model.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1575889&req=5

pgen-0020148-g003: Marginal Significance (−log10 p-value as Determined by t-Test) of the Wavelet Coefficients from Four Annotations as Predictors of the Coefficients of the Decomposition of Ascertainment Panel DiversityRed boxes highlight significant positive linear relationships and blue negative. The intensity of the colour is proportional to the degree of significance.(A) Smoothed coefficients.(B) Detail coefficients.Also shown is the adjusted r2, which can be interpreted as the proportion of the variance in the signal explained by the linear model.
Mentions: First, to compare our results with previous analyses, we performed linear model analysis of the smoothed coefficients including physical position as a covariate. This is equivalent to assessing correlations between statistics averaged over different window sizes. Figure 3A shows the results of the linear model analysis of diversity on the short and long arms. Divergence is a significant positive predictor over scales up to 1 Mb, while proximity to the centromere has a suppressing effect and GC content has a weak, but consistent, effect over and above divergence at fine scales. The effects of recombination and gene content are surprisingly different between the short and long arms. On the short arm, neither factor shows a significant correlation. On the long arm, exons show a strong negative correlation up to scales of 32 kb, while recombination shows a strong positive effect over scales up to 256 kb. Gene density on the short arm is less than half that on the long arm (and there are fewer observations at a given scale); hence, the lack of association with exons is probably due to power. It is not clear why recombination shows such a marked difference.

Bottom Line: In humans, the rate of recombination, as measured on the megabase scale, is positively associated with the level of genetic variation, as measured at the genic scale.Broad-scale association between recombination and diversity is explained through covariance of both factors with base composition.To our knowledge, these results are the first evidence of a direct and local influence of recombination hotspots on genetic variation and the fate of individual mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Statistics, University of Oxford, Oxford, United Kingdom.

ABSTRACT
In humans, the rate of recombination, as measured on the megabase scale, is positively associated with the level of genetic variation, as measured at the genic scale. Despite considerable debate, it is not clear whether these factors are causally linked or, if they are, whether this is driven by the repeated action of adaptive evolution or molecular processes such as double-strand break formation and mismatch repair. We introduce three innovations to the analysis of recombination and diversity: fine-scale genetic maps estimated from genotype experiments that identify recombination hotspots at the kilobase scale, analysis of an entire human chromosome, and the use of wavelet techniques to identify correlations acting at different scales. We show that recombination influences genetic diversity only at the level of recombination hotspots. Hotspots are also associated with local increases in GC content and the relative frequency of GC-increasing mutations but have no effect on substitution rates. Broad-scale association between recombination and diversity is explained through covariance of both factors with base composition. To our knowledge, these results are the first evidence of a direct and local influence of recombination hotspots on genetic variation and the fate of individual mutations. However, that hotspots have no influence on substitution rates suggests that they are too ephemeral on an evolutionary time scale to have a strong influence on broader scale patterns of base composition and long-term molecular evolution.

Show MeSH
Related in: MedlinePlus