utation rate estimation for 15 autosomal STR loci in a large population from Mainland China

Mutation rate estimation for 15 autosomal STR loci in a large population from Mainland China
Zhuo Zhao , Hua Wang , Jie Zhang , Zhi-Peng Liu , Ming Liu , Yuan Zhang , Li Sun , Hui Zhang
doi: http://dx.doi.org/10.1101/015875

STR, short trandem repeats, is well known as a type of powerful genetic marker and widely used in studying human population genetics. Compared with the conventional genetic markers, the mutation rate of STR is higher. Additionally, the mutations of STR loci do not lead to genetic inconsistencies between the genotypes of parents and children; therefore, the analysis of STR mutation is more suited to assess the population mutation. In this study, we focused on 15 autosomal STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, FGA). DNA samples from a total of 42416 unrelated healthy individuals (19037 trios) from the population of Mainland China collected between Jan 2012 and May 2014 were successfully investigated. In our study, the allele frequencies, paternal mutation rates, maternal mutation rates and average mutation rates were detected in the 15 STR loci. Furthermore, we also investigated the relationship between paternal ages, maternal ages, pregnant time, area and average mutation rate. We found that paternal mutation rate is higher than maternal mutation rate and the paternal, maternal, and average mutation rates have a positive correlation with paternal ages, maternal ages and times respectively. Additionally, the average mutation rates of coastal areas are higher than that of inland areas. Overall, these results suggest that the 15 autosomal STR loci can provide highly informative polymorphic data for population genetic assessment in Mainland China, as well as confirm and extend the application of STR analysis in population genetics.

Recent evolution in Rattus norvegicus is shaped by declining effective population size

Recent evolution in Rattus norvegicus is shaped by declining effective population size
Eva E Deinum , Daniel L Halligan , Rob W Ness , Yao-Hua Zhang , Lin Cong , Jian-Xu Zhang , Peter D Keightley
doi: http://dx.doi.org/10.1101/015818

The brown rat, Rattus norvegicus, is both a notorious pest and a frequently used model in biomedical research. By analysing genome sequences of 12 wild-caught brown rats from their ancestral range in NE China, along with the sequence of a black rat, R. rattus, we investigate the selective and demographic forces shaping variation in the genome. We estimate that the recent effective population size (N_e) of this species = 1.24 x 10^5, based on silent site diversity. We compare patterns of diversity in these genomes with patterns in multiple genome sequences of the house mouse Mus musculus castaneus), which has a much larger N_e. This reveals an important role for variation in the strength of genetic drift in mammalian genome evolution. By a Pairwise Sequentially Markovian Coalescent (PSMC) analysis of demographic history, we infer that there has been a recent population size bottleneck in wild rats, which we date to approximately 20,000 years ago. Consistent with this, wild rat populations have experienced an increased flux of mildly deleterious mutations, which segregate at higher frequencies in protein-coding genes and conserved noncoding elements (CNEs). This leads to negative estimates of the rate of adaptive evolution (alpha) in proteins and CNEs, a result which we discuss in relation to the strongly positive estimates observed in wild house mice. As a consequence of the population bottleneck, wild rats also show a markedly slower decay of linkage disequilibrium with physical distance than wild house mice.

Speciation in Heliconius Butterflies: Minimal Contact Followed by Millions of Generations of Hybridisation

Speciation in Heliconius Butterflies: Minimal Contact Followed by Millions of Generations of Hybridisation
Simon Henry Martin , Anders Eriksson , Krzysztof M. Kozak , Andrea Manica , Chris D. Jiggins
doi: http://dx.doi.org/10.1101/015800

Documenting the full extent of gene flow during speciation poses a challenge, as species ranges change over time and current rates of hybridisation might not reflect historical trends. Theoretical work has emphasized the potential for speciation in the face of ongoing hybridisation, and the genetic mechanisms that might facilitate this process. However, elucidating how the rate of gene flow between species may have changed over time has proved difficult. Here we use Approximate Bayesian Computation (ABC) to fit a model of speciation between the Neotropical butterflies Heliconius melpomene and Heliconius cydno. These species are ecologically divergent, rarely hybridize and display female hybrid sterility. Nevertheless, previous genomic studies suggests pervasive gene flow between them, extending deep into their past, and potentially throughout the speciation process. By modelling the rates of gene flow during early and later stages of speciation, we find that these species have been hybridising for hundreds of thousands of years, but have not done so continuously since their initial divergence. Instead, it appears that gene flow was rare or absent for as long as a million years in the early stages of speciation. Therefore, by dissecting the timing of gene flow between these species, we are able to reject a scenario of purely sympatric speciation in the face of continuous gene flow. We suggest that the period of minimal contact early in speciation may have allowed for the accumulation of genomic changes that later enabled these species to remain distinct despite a dramatic increase in the rate of hybridisation.

Most viewed on Haldane’s Sieve: February 2015

The most viewed posts on Haldane’s Sieve this month were:

Association mapping reveals the role of mutation-selection balance in the maintenance of genomic variation for gene expression.

Association mapping reveals the role of mutation-selection balance in the maintenance of genomic variation for gene expression.

Emily Josephs , Young Wha Lee , John R. Stinchcombe , Stephen I Wright
doi: http://dx.doi.org/10.1101/015743

The evolutionary forces that maintain genetic variation for quantitative traits within populations remain unknown. One hypothesis suggests that variation is maintained by a balance between new mutations and their removal by selection and drift. Theory predicts that this mutation-selection balance will result in an excess of low-frequency variants and a negative correlation between minor allele frequency and selection coefficients. Here, we test these predictions using the genetic loci associated with total expression variation (‘eQTLs’) and allele-specific expression variation (‘aseQTLs’) mapped within a single population of the plant Capsella grandiflora. In addition to finding eQTLs and aseQTLs for a large fraction of genes, we show that alleles at these loci are rarer than expected and exhibit a negative correlation between effect size and frequency. Overall, our results show that mutation-selection balance is the dominant contributor to genomic variation for expression within a single, outcrossing population.

Extensive de novo mutation rate variation between individuals and across the genome of Chlamydomonas reinhardtii

Extensive de novo mutation rate variation between individuals and across the genome of Chlamydomonas reinhardtii

Rob W Ness , Andrew D Morgan , Radhakrishnan B Vasanthakrishnan , Nick Colegrave , Peter D Keightley
doi: http://dx.doi.org/10.1101/015693

Describing the process of spontaneous mutation is fundamental for understanding the genetic basis of disease, the threat posed by declining population size in conservation biology, and in much evolutionary biology. However, directly studying spontaneous mutation is difficult because of the rarity of de novo mutations. Mutation accumulation (MA) experiments overcome this by allowing mutations to build up over many generations in the near absence of natural selection. In this study, we sequenced the genomes of 85 MA lines derived from six genetically diverse wild strains of the green alga Chlamydomonas reinhardtii. We identified 6,843 spontaneous mutations, more than any other study of spontaneous mutation. We observed seven-fold variation in the mutation rate among strains and that mutator genotypes arose, increasing the mutation rate dramatically in some replicates. We also found evidence for fine-scale heterogeneity in the mutation rate, driven largely by the sequence flanking mutated sites, and by clusters of multiple mutations at closely linked sites. There was little evidence, however, for mutation rate heterogeneity between chromosomes or over large genomic regions of 200Kbp. Using logistic regression, we generated a predictive model of the mutability of sites based on their genomic properties, including local GC content, gene expression level and local sequence context. Our model accurately predicted the average mutation rate and natural levels of genetic diversity of sites across the genome. Notably, trinucleotides vary 17-fold in rate between the most mutable and least mutable sites. Our results uncover a rich heterogeneity in the process of spontaneous mutation both among individuals and across the genome.

Phen-Gen: Combining Phenotype and Genotype to Analyze Rare Disorders

Phen-Gen: Combining Phenotype and Genotype to Analyze Rare Disorders

Asif Javed , Saloni Agrawal , Pauline Ng
doi: http://dx.doi.org/10.1101/015727

We introduce Phen-Gen, a method which combines patient’s disease symptoms and sequencing data with prior domain knowledge to identify the causative gene(s) for rare disorders. Simulations reveal that the causal variant is ranked first in 88% cases when it is coding; which is 52% advantage over a genotype-only approach and outperforms existing methods by 13-58%. If disease etiology is unknown, the causal variant is assigned top-rank in 71% of simulations.