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

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

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

Diversity and genealogy estimates.

<p>The diversity in disease and non-disease genes measured as the A) average intron SNP density, B) the average intron SNP density divided by intron divergence, C) and the mean minor allele frequency (MAF). Error bars represent the 95% confidence intervals.</p

The large-scale distribution of somatic mutations in cancer genomes

Recently, the genome sequences from sev- eral cancers have been published, along with the genome from a noncancer tissue from the same individual, allowing the identification of new somatic mutations in the cancer. We show that there is significant variation in the den- sity of mutations at the 1-Mb scale within three cancer genomes and that the density of mutations is correlated between them. We also demonstrate that the density of mutations is correlated to that in the germline, as mea- sured by the divergence between humans and chimpanzees and humans and macaques. We show that the density of mutations is correlated to the guanine and cytosine (GC) conent, replication time, distance to telomere and cen- tromere, gene density, and nucleosome occupancy in the cancer genomes. However, overall, all factors explain less than 40% of the variance in mutation density and each factor explains very little of the variance. We find that genes associated with cancer occupy regions of the genome with significantly lower mutation rates than the average. Finally, we show that the density of mutations varies at a 10-Mb and a chromosomal scale, but that the variation at these scales is weak

Sinusoidal modelling for ecoacoustics

International audienceBiodiversity assessment is a central and urgent task, necessary to monitoring the changes to ecological systems and under- standing the factors which drive these changes. Technological advances are providing new approaches to monitoring, which are particularly useful in remote regions. Situated within the framework of the emerging field of ecoacoustics, there is grow- ing interest in the possibility of extracting ecological informa- tion from digital recordings of the acoustic environment. Rather than focusing on identification of individual species, an increas- ing number of automated indices attempt to summarise acoustic activity at the community level, in order to provide a proxy for biodiversity. Originally designed for speech processing, sinu- soidal modelling has previously been used as a bioacoustic tool, for example to detect particular bird species. In this paper, we demonstrate the use of sinusoidal modelling as a proxy for bird abundance. Using data from acoustic surveys made during the breeding season in UK woodland, the number of extracted sinusoidal tracks is shown to correlate with estimates of bird abundance made by expert ornithologists listening to the recordings. We also report ongoing work exploring a new approach to investigate the composition of calls in spectro-temporal space that constitutes a promising new method for Ecoaoustic biodiversity assessment

Data from: Polymorphism in the neurofibromin gene, Nf1, is associated with antagonistic selection on wing size and development time in Drosophila melanogaster

In many invertebrates, body size shows genetically based clines, with size increasing in colder climates. Large body size is typically associated with prolonged development times. We consider variation in the CNS-specific gene neurofibromin 1 (Nf1) and its association with body size and development time. We identified two major Nf1 haplotypes in natural populations, Nf1-insertion-A and Nf1-deletion-G. These haplotypes are characterized by a 45-base insertion/deletion (INDEL) in Nf1 intron 2 and an A/G synonymous substitution (locus L17277). Linkage disequilibrium (LD) between the INDEL and adjacent sites is high but appears to be restricted within the Nf1 gene interval. In Australia, the frequency of the Nf1-insertion-A haplotype increases with latitude where wing size is larger, independent of the chromosomal inversion In(3R)Payne. Unexpectedly, the Nf1-insertion-A haplotype is negatively associated with wing size. We found that the Nf1-insertion-A haplotype is enriched in females with shorter development time. This suggests that the Nf1 haplotype cline may be driven by selection for development time rather than size; females from southern (higher latitude) D. melanogaster populations maintain a rapid development time despite being relatively larger, and the higher incidence of Nf1-insertion-A in southern Australia may contribute to this pattern whereas the effects of the Nf1 haplotypes on size may be countered by other loci with antagonistic effects on size and development time. Our results point to the potential complexity involved in identifying selection on genetic variants exhibiting pleiotropic effects when studies are based on spatial patterns or association studies