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Auto Tag: de novo mutation

September 22, 2019  |  

Insights into platypus population structure and history from whole-genome sequencing.

The platypus is an egg-laying mammal which, alongside the echidna, occupies a unique place in the mammalian phylogenetic tree. Despite widespread interest in its unusual biology, little is known about its population structure or recent evolutionary history. To provide new insights into the dispersal and demographic history of this iconic species, we sequenced the genomes of 57 platypuses from across the whole species range in eastern mainland Australia and Tasmania. Using a highly improved reference genome, we called over 6.7?M SNPs, providing an informative genetic data set for population analyses. Our results show very strong population structure in the platypus, with our sampling locations corresponding to discrete groupings between which there is no evidence for recent gene flow. Genome-wide data allowed us to establish that 28 of the 57 sampled individuals had at least a third-degree relative among other samples from the same river, often taken at different times. Taking advantage of a sampled family quartet, we estimated the de novo mutation rate in the platypus at 7.0?×?10-9/bp/generation (95% CI 4.1?×?10-9-1.2?×?10-8/bp/generation). We estimated effective population sizes of ancestral populations and haplotype sharing between current groupings, and found evidence for bottlenecks and long-term population decline in multiple regions, and early divergence between populations in different regions. This study demonstrates the power of whole-genome sequencing for studying natural populations of an evolutionarily important species.

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September 22, 2019  |  

NextSV: a meta-caller for structural variants from low-coverage long-read sequencing data.

Structural variants (SVs) in human genomes are implicated in a variety of human diseases. Long-read sequencing delivers much longer read lengths than short-read sequencing and may greatly improve SV detection. However, due to the relatively high cost of long-read sequencing, it is unclear what coverage is needed and how to optimally use the aligners and SV callers.In this study, we developed NextSV, a meta-caller to perform SV calling from low coverage long-read sequencing data. NextSV integrates three aligners and three SV callers and generates two integrated call sets (sensitive/stringent) for different analysis purposes. We evaluated SV calling performance of NextSV under different PacBio coverages on two personal genomes, NA12878 and HX1. Our results showed that, compared with running any single SV caller, NextSV stringent call set had higher precision and balanced accuracy (F1 score) while NextSV sensitive call set had a higher recall. At 10X coverage, the recall of NextSV sensitive call set was 93.5 to 94.1% for deletions and 87.9 to 93.2% for insertions, indicating that ~10X coverage might be an optimal coverage to use in practice, considering the balance between the sequencing costs and the recall rates. We further evaluated the Mendelian errors on an Ashkenazi Jewish trio dataset.Our results provide useful guidelines for SV detection from low coverage whole-genome PacBio data and we expect that NextSV will facilitate the analysis of SVs on long-read sequencing data.

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September 22, 2019  |  

The mutation rate and the age of the sex chromosomes in Silene latifolia.

Many aspects of sex chromosome evolution are common to both plants and animals [1], but the process of Y chromosome degeneration, where genes on the Y become non-functional over time, may be much slower in plants due to purifying selection against deleterious mutations in the haploid gametophyte [2, 3]. Testing for differences in Y degeneration between the kingdoms has been hindered by the absence of accurate age estimates for plant sex chromosomes. Here, we used genome resequencing to estimate the spontaneous mutation rate and the age of the sex chromosomes in white campion (Silene latifolia). Screening of single nucleotide polymorphisms (SNPs) in parents and 10 F1 progeny identified 39 de novo mutations and yielded a rate of 7.31 × 10-9 (95% confidence interval: 5.20 × 10-9 – 8.00 × 10-9) mutations per site per haploid genome per generation. Applying this mutation rate to the synonymous divergence between homologous X- and Y-linked genes (gametologs) gave age estimates of 11.00 and 6.32 million years for the old and young strata, respectively. Based on SNP segregation patterns, we inferred which genes were Y-linked and found that at least 47% are already dysfunctional. Applying our new estimates for the age of the sex chromosomes indicates that the rate of Y degeneration in S. latifolia is nearly 2-fold slower when compared to animal sex chromosomes of a similar age. Our revised estimates support Y degeneration taking place more slowly in plants, a discrepancy that may be explained by differences in the life cycles of animals and plants. Copyright © 2018 Elsevier Ltd. All rights reserved.

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September 22, 2019  |  

Multisite de novo mutations in human offspring after paternal exposure to ionizing radiation.

A genome-wide evaluation of the effects of ionizing radiation on mutation induction in the mouse germline has identified multisite de novo mutations (MSDNs) as marker for previous exposure. Here we present the results of a small pilot study of whole genome sequencing in offspring of soldiers who served in radar units on weapon systems that were emitting high-frequency radiation. We found cases of exceptionally high MSDN rates as well as an increased mean in our cohort: While a MSDN mutation is detected in average in 1 out of 5 offspring of unexposed controls, we observed 12 MSDNs in altogether 18 offspring, including a family with 6 MSDNs in 3 offspring. Moreover, we found two translocations, also resulting from neighboring mutations. Our findings indicate that MSDNs might be suited in principle for the assessment of DNA damage from ionizing radiation also in humans. However, as exact person-related dose values in risk groups are usually not available, the interpretation of MSDNs in single families would benefit from larger molecular epidemiologic studies on this new biomarker.

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