How much of the variation in the mutation rate along the human genome can be explained?

It has been claimed recently that it may be possible to predict the rate of de novo mutation of each site in the human genome with a high degree of accuracy [Michaelson et al. (2012), Cell 151: 143121442]. We show that this claim is unwarranted. By considering the correlation between the rate of de novo mutation and the predictions from the model of Michaelson et al., we show there could be substantial unexplained variance in the mutation rate. We investigate whether the model of Michaelson et al. captures variation at the single nucleotide level that is not due to simple context. We show that the model captures a substantial fraction of this variation at CpG dinucleotides but fails to explain much of the variation at non-CpG sites

Sounding out ecoacoustic metrics: avian species richness is predicted by acoustic indices in temperate but not tropical habitats

Affordable, autonomous recording devices facilitate large scale acoustic monitoring and Rapid Acoustic Survey is emerging as a cost-effective approach to ecological monitoring; the success of the approach rests on the de- velopment of computational methods by which biodiversity metrics can be automatically derived from remotely collected audio data. Dozens of indices have been proposed to date, but systematic validation against classical, in situ diversity measures are lacking. This study conducted the most comprehensive comparative evaluation to date of the relationship between avian species diversity and a suite of acoustic indices. Acoustic surveys were carried out across habitat gradients in temperate and tropical biomes. Baseline avian species richness and subjective multi-taxa biophonic density estimates were established through aural counting by expert ornithol- ogists. 26 acoustic indices were calculated and compared to observed variations in species diversity. Five acoustic diversity indices (Bioacoustic Index, Acoustic Diversity Index, Acoustic Evenness Index, Acoustic Entropy, and the Normalised Difference Sound Index) were assessed as well as three simple acoustic descriptors (Root-mean-square, Spectral centroid and Zero-crossing rate). Highly significant correlations, of up to 65%, between acoustic indices and avian species richness were observed across temperate habitats, supporting the use of automated acoustic indices in biodiversity monitoring where a single vocal taxon dominates. Significant, weaker correlations were observed in neotropical habitats which host multiple non-avian vocalizing species. Multivariate classification analyses demonstrated that each habitat has a very distinct soundscape and that AIs track observed differences in habitat-dependent community composition. Multivariate analyses of the relative predictive power of AIs show that compound indices are more powerful predictors of avian species richness than any single index and simple descriptors are significant contributors to avian diversity prediction in multi-taxa tropical environments. Our results support the use of community level acoustic indices as a proxy for species richness and point to the potential for tracking subtler habitat-dependent changes in community composition. Recommendations for the design of compound indices for multi-taxa community composition appraisal are put forward, with consideration for the requirements of next generation, low power remote monitoring networks

The role of mutation rate variation and genetic diversity in the architecture of human disease

Background We have investigated the role that the mutation rate and the structure of genetic variation at a locus play in determining whether a gene is involved in disease. We predict that the mutation rate and its genetic diversity should be higher in genes associated with disease, unless all genes that could cause disease have already been identified. Results Consistent with our predictions we find that genes associated with Mendelian and complex disease are substantially longer than non-disease genes. However, we find that both Mendelian and complex disease genes are found in regions of the genome with relatively low mutation rates, as inferred from intron divergence between humans and chimpanzees, and they are predicted to have similar rates of non-synonymous mutation as other genes. Finally, we find that disease genes are in regions of significantly elevated genetic diversity, even when variation in the rate of mutation is controlled for. The effect is small nevertheless. Conclusions Our results suggest that gene length contributes to whether a gene is associated with disease. However, the mutation rate and the genetic architecture of the locus appear to play only a minor role in determining whether a gene is associated with disease

Evidence that Localized Variation in Primate Sequence Divergence Arises from an Influence of Nucleosome Placement on DNA Repair

Understanding the origins of localized substitution rate heterogeneity has important implications for identifying functional genomic sequences. Outside of gene regions, the origins of rate heterogeneity remain unclear. Experimental studies establish that chromatin compaction affects rates of both DNA lesion formation and repair. A functional association between chromatin status and 5-methyl-cytosine also exists. These suggest that both the total rate and the type of substitution will be affected by chromatin status. Regular positioning of nucleosomes, the building block of chromatin, further predicts that substitution rate and type should vary spatially in an oscillating manner. We addressed chromatin's influence on substitution rate and type in primates. Matched numbers of sites were sampled from Dnase I hypersensitive (DHS) and closed chromatin control flank (Flank). Likelihood ratio tests revealed significant excesses of total and of transition substitutions in Flank compared with matched DHS for both intergenic and intronic samples. An additional excess of CpG transitions was evident for the intergenic, but not intronic, regions. Fluctuation in substitution rate along ∼1,800 primate promoters was measured using phylogenetic footprinting. Significant positive correlations were evident between the substitution rate and a nucleosome score from resting human T-cells, with up to ∼50% of the variance in substitution rate accounted for. Using signal processing techniques, a dominant oscillation at ∼200 bp was evident in both the substitution rate and the nucleosome score. Our results support a role for differential DNA repair rates between open and closed chromatin in the spatial distribution of rate heterogeneity

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

The Role of Mutation Rate Variation and Genetic Diversity in the Architecture of Human Disease

Abstract Background: We have investigated the role that the mutation rate and the structure of genetic variation at a locus play in determining whether a gene is involved in disease. We predict that the mutation rate and its genetic diversity should be higher in genes associated with disease, unless all genes that could cause disease have already been identified

CDS length.

<p>(A) Mean total CDS length, and (B) Mean average CDS length. Total CDS length is the sum of all constitutive and alternately spliced exons; average CDS length is the average CDS length of each transcript. Error bars represent the 95% confidence intervals.</p

Standardised regression coefficients from multiple regressions.

<p>Note that the replication time data is such that a negative slope indicates an increase in the variable through the cell cycle * p<0.05, ** p<0.01 and *** p<0.001.</p